Platelet-type Bleeding Disorder 16

Mendelian MONDO:0008552 Pathograph 38 Show in embeddings browser Inherited bleeding disorder, platelet-type Inherited blood coagulation disorder Congenital macrothrombocytopenia

Platelet-type bleeding disorder 16 (BDPLT16, OMIM #187800) is an autosomal dominant congenital macrothrombocytopenia with platelet anisocytosis and a mild to moderate, sometimes absent, mucocutaneous bleeding tendency, caused by heterozygous activating variants in ITGA2B, the gene encoding the alphaIIb subunit of the platelet fibrinogen receptor integrin alphaIIbbeta3. The clinical literature also calls it the dominant or variant form of Glanzmann thrombasthenia, or Glanzmann thrombasthenia-like syndrome, but the mechanism runs in the opposite direction to classic Glanzmann thrombasthenia. In classic Glanzmann thrombasthenia biallelic loss-of-function variants remove or disable the integrin, platelet count and size are normal, and aggregation to every physiological agonist is absent. In BDPLT16 a single variant in the membrane-proximal part of alphaIIb, most often at Arg995 in the conserved GFFKR motif (Arg1026 in HGVS numbering), weakens the inner membrane clasp: the salt bridge between alphaIIb Arg995 and beta3 Asp723 that holds the receptor in its bent resting conformation. A fraction of the receptor pool then sits in the ligand-binding conformation without any inside-out signal, binding the activation-dependent antibody PAC-1 and fibrinogen on resting platelets that have not themselves been activated. Two consequences follow from that single lesion. In megakaryocytes, permanent integrin outside-in signalling disturbs cytoskeletal remodelling, and proplatelets form with fewer and larger tips, so fewer and larger platelets are released. In circulating platelets the constitutively engaged receptor is internalised, surface alphaIIbbeta3 falls to roughly half of normal, and agonist-induced aggregation is reduced rather than abolished. The resulting bleeding is milder than in classic thrombasthenia and reflects the reduced platelet count together with the impaired platelet function. Heterozygous activating variants in ITGB3 produce a clinically indistinguishable phenotype, and MONDO's definition of this term still names both genes, but OMIM curates the ITGB3 form separately as BDPLT24. This entry is therefore scoped to the ITGA2B form, and cites the shared mechanistic literature only where a source states its conclusion for activating alphaIIbbeta3 variants as a class.

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Inheritance

Autosomal dominant HP:0000006

Heterozygous ITGA2B variants segregating with macrothrombocytopenia across generations. The dominance follows from the mechanism: one activating allele is enough to put part of the integrin pool into a constitutively active conformation, and what that state then does to megakaryocyte cytoskeletal signalling does not require the second allele to be affected. Penetrance for the platelet phenotype is high within reported families, while bleeding severity varies and some carriers report no bleeding at all.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:29090484 SUPPORT Human Clinical

"Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H."

Two autosomal dominant macrothrombocytopenia families carrying the recurrent ITGA2B allele.

PMID:31119735 SUPPORT Human Clinical

"Sanger sequencing showed that the ITGA2B variant was present in heterozygous form in all affected family members and was absent in all unaffected family members."

Co-segregation of the heterozygous variant with the trait in a four-generation family, backed by linkage analysis.

◈

Mechanistic Hypotheses

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

constitutive_aiibb3_activation CANONICAL

A heterozygous variant at the membrane-proximal region of alphaIIb weakens the alphaIIb Arg995-beta3 Asp723 inner membrane clasp that keeps the integrin bent and inactive. Part of the receptor pool becomes partially and constitutively active and signals outside-in without ligand engagement, phosphorylating focal adhesion kinase and lowering RhoA activity. In megakaryocytes that disorganises cytoskeletal remodelling, and proplatelets form with fewer and larger tips, which is macrothrombocytopenia. In circulating platelets it drives internalisation of the receptor and arrests actin turnover, so surface alphaIIbbeta3 and agonist-induced aggregation both fall. CANONICAL because patient platelets, transfected cell lines, transduced murine megakaryocytes and patient-derived megakaryocytes agree on it; its limit is that constitutive activation is not demonstrable for every reported allele or in every patient.

Pathograph links

ITGA2B Membrane-Proximal Activating Variants -> Disruption of the alphaIIb-beta3 Inner Membrane Clasp DIRECT The substituted residues are the ones that form or position the alphaIIb Arg995-beta3 Asp723 salt bridge.

Disruption of the alphaIIb-beta3 Inner Membrane Clasp -> Constitutive Partial alphaIIbbeta3 Activation DIRECT Without the clasp, the receptor can reach its ligand-binding conformation with no inside-out signal.

Constitutive Partial alphaIIbbeta3 Activation -> Persistent alphaIIbbeta3 Outside-In Signalling DIRECT The active receptor signals into the cell as though ligand-engaged.

Constitutive Partial alphaIIbbeta3 Activation -> Receptor Internalisation and Reduced Surface alphaIIbbeta3 DIRECT A constitutively engaged receptor is taken off the surface.

Persistent alphaIIbbeta3 Outside-In Signalling -> Abnormal Proplatelet Formation by Megakaryocytes DIRECT The same cytoskeletal signal misdirects the terminal step of platelet production.

Persistent alphaIIbbeta3 Outside-In Signalling -> Arrested Platelet Cytoskeletal Remodelling DIRECT In the circulating platelet the persistent signal freezes actin turnover instead of remodelling it.

Abnormal Proplatelet Formation by Megakaryocytes -> Reduced Output of Enlarged Circulating Platelets DIRECT Fewer and larger proplatelet tips give fewer and larger platelets.

Abnormal Proplatelet Formation by Megakaryocytes -> Abnormal Platelet Alpha-Granules DIRECT Alpha-granule maturation is disturbed alongside proplatelet formation, so the platelets released carry abnormally large granules.

Receptor Internalisation and Reduced Surface alphaIIbbeta3 -> Impaired Agonist-Induced Platelet Aggregation DIRECT Fewer available fibrinogen receptors per platelet, so less interplatelet bridging on activation.

Receptor Internalisation and Reduced Surface alphaIIbbeta3 -> Decreased Platelet Surface Glycoprotein IIb-IIIa DIRECT The flow-cytometric finding that identifies these patients.

Arrested Platelet Cytoskeletal Remodelling -> Impaired Agonist-Induced Platelet Aggregation DIRECT A platelet that cannot remodel its cytoskeleton cannot spread and consolidate an aggregate.

Reduced Output of Enlarged Circulating Platelets -> Macrothrombocytopenia DIRECT Fewer and larger platelets, measured as a count and a volume.

Reduced Output of Enlarged Circulating Platelets -> Platelet Anisocytosis DIRECT Released platelets vary widely in size because the proplatelet tips they come from do.

Reduced Output of Enlarged Circulating Platelets -> Increased Mean Platelet Volume DIRECT The quantitative expression of the size shift.

Reduced Output of Enlarged Circulating Platelets -> Giant Platelets DIRECT The extreme tail of the size distribution, seen on the film.

Reduced Output of Enlarged Circulating Platelets -> Failure of Primary Hemostatic Plug Formation DIRECT Fewer platelets arrive at the site of injury, which is the quantitative half of this disorder's contribution to the shared endpoint.

Impaired Agonist-Induced Platelet Aggregation -> Impaired Platelet Aggregation DIRECT The aggregometry readout of this mechanism.

Impaired Agonist-Induced Platelet Aggregation -> Failure of Primary Hemostatic Plug Formation DIRECT The qualitative half of the contribution: the platelets that do arrive bridge each other poorly.

Failure of Primary Hemostatic Plug Formation -> Mucocutaneous Bleeding Diathesis DIRECT The clinical expression of the failed plug.

Mucocutaneous Bleeding Diathesis -> Bruising Susceptibility DIRECT The commonest manifestation, and often the only one.

Mucocutaneous Bleeding Diathesis -> Epistaxis DIRECT Mucosal bleeding, typically reported in childhood.

Mucocutaneous Bleeding Diathesis -> Gingival Bleeding DIRECT Mucosal bleeding, including bleeding on tooth brushing.

Mucocutaneous Bleeding Diathesis -> Menometrorrhagia DIRECT Heavy and irregular menstrual bleeding.

Mucocutaneous Bleeding Diathesis -> Post-Partum Hemorrhage DIRECT The most serious reported complication, and the one that has required transfusion and intensive care.

Mucocutaneous Bleeding Diathesis -> Prolonged Bleeding After Surgery DIRECT Post-tonsillectomy haemorrhage is the presentation in two reported families.

Mucocutaneous Bleeding Diathesis -> Prolonged Bleeding After Dental Extraction DIRECT A haemostatic challenge that reveals the disorder in some carriers and passes uneventfully in others.

Discussions and Knowledge Gaps

In ITGA2B-related macrothrombocytopenia, how much of the bleeding is due to the reduced platelet count and how much to the platelet function defect?

KNOWLEDGE GAP gap_which_arm_causes_the_bleeding

Attached to

pathophysiology#Failure of Primary Hemostatic Plug Formation phenotypes#Macrothrombocytopenia

The disorder breaks both the quantitative and the qualitative arm of primary haemostasis, and the two have never been separated in carriers of an ITGA2B variant. The question is not academic: it decides whether management should aim at the count, at platelet function, or only at local and antifibrinolytic measures, and it is the likeliest explanation for why bleeding severity tracks neither the platelet count nor the surface receptor level well. The one study that argues the question directly did so in patients carrying an ITGB3 allele and concluded that the cytoskeletal defect, not the count, is the effector of bleeding.

What explains macrothrombocytopenia in carriers whose receptor shows no constitutive activation?

KNOWLEDGE GAP gap_activation_negative_alleles

Attached to

pathophysiology#Constitutive Partial alphaIIbbeta3 Activation

Constitutive activation is the mechanism this entry curates, but it is not demonstrable for every allele or every patient: the transfected R995Q receptor was not locked into a high activation state, and in the largest series spontaneous PAC-1 binding appeared in a minority of patients and in healthy controls at a similar rate. Either the assays read the platelet pool too crudely, or some of these variants act on megakaryocyte cytoskeletal signalling without a detectable shift in receptor conformation, which is also what has been proposed for the non-activating ITGB3 variants described more recently.

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Pathophysiology

ITGA2B Membrane-Proximal Activating Variants

Heterozygous germline missense variants and small in-frame deletions in ITGA2B, clustered at the membrane-proximal part of alphaIIb: the cytoplasmic GFFKR motif (R995W, R995Q, G991C and F993del in legacy numbering) and, less often, the transmembrane domain, where p.Gly1007Val substitutes one of the glycines of the outer membrane clasp. R995W is the recurrent allele and has arisen at least twice independently, on Japanese and European haplotypes. The conformance target is the module's component-loss node read in its "dysfunctional" sense: the receptor is present and it is the wrong shape, which is also why a compound heterozygote carrying G991C opposite a nonsense allele sits at the severe, thrombasthenia-like end of the spectrum. The molecular function the lesion acts on is the receptor's own ligand binding: alphaIIbbeta3 binds fibrinogen, and the membrane-proximal region these variants sit in is what couples that binding to inside-out signalling rather than what performs it. The modifier is DYSREGULATED rather than INCREASED or GAIN_OF_FUNCTION because the evidence cuts both ways in the same patients. Fibrinogen binds resting platelets that have not been activated, which it should not; and binding induced by ADP or TRAP-6 is lower than normal, because less receptor is left on the surface. Neither half alone describes the function, and asserting only the first would also overstate the activation evidence, which is refuted for one allele and undetectable in most patients tested.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

ITGA2B hgnc:6138 ⇑ GAIN OF FUNCTION

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous germline activating variants in ITGA2B. The functional category is gain of function because the variant raises the activation state of the receptor rather than removing it, which is the mechanistic inverse of the biallelic loss-of-function variants that cause classic Glanzmann thrombasthenia in the same gene.

integrin alphaIIbbeta3 fibrinogen binding GO:0070051 ↕ DYSREGULATED

Downstream

Disruption of the alphaIIb-beta3 Inner Membrane Clasp The substituted residues are the ones that form or position the alphaIIb Arg995-beta3 Asp723 salt bridge.

Show evidence (6 references)

PMID:21454453 SUPPORT Human Clinical

"We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families."

The recurrent heterozygous ITGA2B allele that defines the molecular entity.

PMID:9834222 SUPPORT Human Clinical

"DNA sequencing showed a heterozygous mutation giving rise to amino acid substitution R995 to Q in the GFFKR sequence of the cytoplasmic domain of IIb"

The first natural variant found in the alphaIIb GFFKR motif, in the patient originally reported with giant platelets and a mild Glanzmann thrombasthenia-like syndrome.

PMID:24498605 SUPPORT Human Clinical

"two mutations in highly conserved Gly-Phe-Phe-Lys-Arg sequence in juxtamembrane region of αIIb"

Extends the allelic series in the same motif to G991C and F993del.

+ 3 more references

Disruption of the alphaIIb-beta3 Inner Membrane Clasp

In a resting platelet alphaIIbbeta3 is held bent and closed by two inter-subunit constraints, the transmembrane outer membrane clasp and the cytoplasmic inner membrane clasp, whose key contact is the salt bridge between alphaIIb Arg995 and beta3 Asp723. Physiological activation requires that clasp to open, so a variant that weakens it lowers the threshold for the conformational change rather than adding a new activity.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

integrin alphaIIb-beta3 complex GO:0070442

Downstream

Constitutive Partial alphaIIbbeta3 Activation Without the clasp, the receptor can reach its ligand-binding conformation with no inside-out signal.

Show evidence (2 references)

PMID:22102273 SUPPORT Other

"Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin in a bent resting state."

The structural role of the residue the recurrent ITGA2B variant replaces, stated in the review that defined this disease group.

PMID:41503871 SUPPORT Other

"The αIIbArg995/β3Asp723 salt bridge is a critical structure for maintaining the resting conformation of αIIbβ3."

A recent review restating the same constraint, and the frame in which both genes' membrane-proximal variants are read.

Constitutive Partial alphaIIbbeta3 Activation

Part of the surface receptor pool sits in a high-affinity state on resting platelets: PAC-1 and soluble fibrinogen bind without an agonist, and without P-selectin appearing, so the integrin is active while the platelet is not. In transfected cells the activation state conferred by alphaIIb R995W is higher than for the beta3 D723H salt-bridge variant and weaker than for the strongly activating beta3 N562 mutant, which is what "partial" means here. The activation is not uniform across alleles or patients, and the refuting evidence on this node is the reason it is not offered as a diagnostic test.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233 megakaryocyte CL:0000556

integrin activation GO:0033622 ↑ INCREASED

integrin alphaIIb-beta3 complex GO:0070442

Downstream

Persistent alphaIIbbeta3 Outside-In Signalling The active receptor signals into the cell as though ligand-engaged.

Receptor Internalisation and Reduced Surface alphaIIbbeta3 A constitutively engaged receptor is taken off the surface.

Show evidence (5 references)

PMID:21454453 SUPPORT Human Clinical

"There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression."

The observation in patient platelets: an active receptor on a platelet that has not degranulated.

PMID:21454453 SUPPORT In Vitro

"These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation."

The authors' conclusion from transfected-cell activation assays for the recurrent allele.

PMID:24498605 SUPPORT In Vitro

"All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells."

Constitutive activation demonstrated for two further ITGA2B GFFKR alleles.

+ 2 more references

Persistent alphaIIbbeta3 Outside-In Signalling

The constitutively active receptor signals continuously through the integrin-mediated pathway in megakaryocytes and platelets: focal adhesion kinase is spontaneously phosphorylated, and RhoA activity falls, which is the arm that couples the receptor to the cytoskeleton. In transfected non-haematopoietic cells the same signal produces membrane ruffling and abnormal cytoplasmic protrusions resembling the extensions a megakaryocyte makes when it forms proplatelets.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

megakaryocyte CL:0000556 platelet CL:0000233

integrin-mediated signaling pathway GO:0007229 ↑ INCREASED

Downstream

Abnormal Proplatelet Formation by Megakaryocytes The same cytoskeletal signal misdirects the terminal step of platelet production.

Arrested Platelet Cytoskeletal Remodelling In the circulating platelet the persistent signal freezes actin turnover instead of remodelling it.

Show evidence (2 references)

PMID:21454453 SUPPORT In Vitro

"αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions."

The morphological consequence of the signal, for the recurrent ITGA2B allele specifically.

PMID:25806962 SUPPORT INDIRECT In Vitro

"Moreover, we showed that formation of abnormal extensions occurred also in wild-type αIIbβ3 cells when activated by activating antibody."

Forcing a wild-type receptor into its active conformation reproduces the protrusions, which is what makes the active conformation rather than the particular variant the operative cause. Graded INDIRECT because the experiment uses beta3 variants and an antibody rather than an ITGA2B allele.

Abnormal Proplatelet Formation by Megakaryocytes

Megakaryocyte maturation itself is normal: ploidy and early differentiation are unaffected, and plasma thrombopoietin is not raised. What fails is the terminal step. Proplatelets extend with fewer branches and abnormally large tips, and transduced murine megakaryocytes additionally form asymmetric barbell proplatelets, so each megakaryocyte yields fewer and larger platelets. This is the quantitative arm of the disorder, which the primary_hemostatic_plug_failure module deliberately does not model, so no node here conforms to it.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

megakaryocyte CL:0000556

platelet formation GO:0030220 ↓ DECREASED actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Experimental models

alphaIIb-W995/beta3-transduced mouse fetal liver-derived megakaryocytes PRIMARY CELL CULTURE Transduced megakaryocytes form proplatelets with fewer and larger tips, which is the cellular defect this node asserts.

Patient-derived megakaryocyte cultures from ITGA2B R995W carriers PRIMARY CELL CULTURE Early maturation is normal and proplatelet formation is abnormal with enlarged tips, which localises the defect to the terminal step.

Downstream

Reduced Output of Enlarged Circulating Platelets Fewer and larger proplatelet tips give fewer and larger platelets.

Abnormal Platelet Alpha-Granules Alpha-granule maturation is disturbed alongside proplatelet formation, so the platelets released carry abnormally large granules.

Show evidence (3 references)

PMID:21454453 SUPPORT In Vitro

"The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation."

The defect measured in megakaryocytes expressing the recurrent ITGA2B allele itself.

PMID:29090484 SUPPORT Human Clinical

"Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips."

Confirms in megakaryocytes from patients, two of the three families carrying ITGA2B R995W, that the lesion is in the terminal step and not in maturation.

PMID:26452979 SUPPORT INDIRECT In Vitro

"del647-686β3-transduced murine megakaryocytes generated proplatelets with a reduced number of large tips and asymmetric barbell-proplatelets, suggesting that impaired cytoskeletal rearrangement is the cause of macrothrombocytopenia."

The same result for an activating ITGB3 allele, with the barbell abnormality that names the mechanism. INDIRECT because the allele is in the other subunit.

Receptor Internalisation and Reduced Surface alphaIIbbeta3

Surface alphaIIbbeta3 on patient platelets runs at roughly half of normal, which is the finding that first brought these patients to attention and is the reason they were read as having a mild form of thrombasthenia. The total platelet content of the receptor is much better preserved than the surface pool, and the missing fraction is internal: the constitutively engaged receptor is taken up and degraded rather than never made.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233

receptor internalization GO:0031623 ↑ INCREASED

cell surface GO:0009986

Downstream

Impaired Agonist-Induced Platelet Aggregation Fewer available fibrinogen receptors per platelet, so less interplatelet bridging on activation.

Decreased Platelet Surface Glycoprotein IIb-IIIa The flow-cytometric finding that identifies these patients.

Show evidence (5 references)

PMID:21454453 SUPPORT Human Clinical

"The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."

The quantitative reduction in patients carrying the recurrent ITGA2B allele.

PMID:1638023 SUPPORT Human Clinical

"The patient has a selective deficiency of the surface pool of GP IIb-IIIa complexes that is manifested clinically by a mild Glanzmann's thrombasthenia-like syndrome."

The original description of the first patient later shown to carry ITGA2B R995Q, and the observation that the deficiency is of the surface pool specifically.

PMID:1638023 SUPPORT Human Clinical

"Staining of ultrathin sections confirmed the presence of an internal pool of GP IIb-IIIa."

Where the receptor missing from the surface actually is, demonstrated morphologically before the mechanism was known.

+ 2 more references

Arrested Platelet Cytoskeletal Remodelling

Aggregation and spreading require actin to be turned over, not merely polymerised. Under permanent outside-in signalling actin turnover halts at the polymerisation stage, and the authors who showed this reproduced the patients' functional defect in normal platelets with jasplakinolide, a toxin that promotes nucleation and prevents depolymerisation. That pharmacological phenocopy is what makes the arrested cytoskeleton, rather than the reduced receptor number alone, the proximate cause of the platelet dysfunction.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233

actin filament polymerization GO:0030041 ↑ INCREASED actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Downstream

Impaired Agonist-Induced Platelet Aggregation A platelet that cannot remodel its cytoskeleton cannot spread and consolidate an aggregate.

Show evidence (2 references)

PMID:26452979 SUPPORT INDIRECT In Vitro

"The induction of actin polymerization by jasplakinolide, a natural toxin that promotes actin nucleation and prevents depolymerization of stress fibers, in control platelets produced an impairment of platelet function similar to that of patients with variant forms of dominant Glanzmann thrombasthenia."

The phenocopy experiment. Graded INDIRECT twice over: the patients studied carried an ITGB3 allele, and the argument runs from a chemical that arrests actin turnover to the mechanism in the disease.

PMID:26452979 SUPPORT INDIRECT In Vitro

"These data show that impaired cytoskeletal remodeling caused by a constitutively activated αIIbβ3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia."

The authors' summary of where the proximate lesion sits, for this disease group as a whole.

Reduced Output of Enlarged Circulating Platelets

The haematological result: a moderately reduced platelet count with a raised mean platelet volume and a wide platelet size distribution, often with giant forms on the film. Counts in reported families run from the twenties to the low normal range and the immature platelet fraction is raised, which is consistent with a production defect rather than with peripheral destruction. Plasma thrombopoietin is normal, and in one patient the count rose transiently after an influenza infection, both arguing against a profound global failure of thrombopoiesis.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233

Downstream

Macrothrombocytopenia Fewer and larger platelets, measured as a count and a volume.

Platelet Anisocytosis Released platelets vary widely in size because the proplatelet tips they come from do.

Increased Mean Platelet Volume The quantitative expression of the size shift.

Giant Platelets The extreme tail of the size distribution, seen on the film.

Failure of Primary Hemostatic Plug Formation Fewer platelets arrive at the site of injury, which is the quantitative half of this disorder's contribution to the shared endpoint.

Show evidence (2 references)

PMID:21454453 SUPPORT Human Clinical

"We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias."

The conclusion that puts this haematological picture, rather than thrombasthenia, at the centre of the disease.

PMID:24498605 SUPPORT Human Clinical

"These results suggest that gain-of-function mutations around membrane region of αIIbβ3 lead to abnormal platelet number and morphology with impaired surface αIIbβ3 expression."

Ties the three findings of this node and the node above, count, morphology and surface expression, to the same class of variant.

Impaired Agonist-Induced Platelet Aggregation

Aggregation and dense-granule ATP release in response to ADP, collagen, epinephrine and arachidonic acid are reduced, while ristocetin agglutination is preserved, so the lesion is in aggregation and not in adhesion. The reduction is partial, which is what separates this disorder from classic Glanzmann thrombasthenia at the bench: aggregation is diminished rather than absent, and the platelet function analyser closure times, although prolonged, never reach the values typical of thrombasthenia. Conformance is at the module's aggregation arm because the lesion is in alphaIIbbeta3 itself, with reduced surface receptor and reduced fibrinogen binding, rather than in an upstream arm reading out through aggregometry.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233

platelet aggregation GO:0070527 ↓ DECREASED

Downstream

Impaired Platelet Aggregation The aggregometry readout of this mechanism.

Failure of Primary Hemostatic Plug Formation The qualitative half of the contribution: the platelets that do arrive bridge each other poorly.

Show evidence (4 references)

PMID:33276370 SUPPORT Human Clinical

"Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound..."

The laboratory phenotype of the largest series, which includes five ITGA2B families.

PMID:29090484 SUPPORT Human Clinical

"Platelet aggregation tended to be reduced but not absent."

The partial character of the defect, in families carrying the recurrent ITGA2B allele.

PMID:33276370 SUPPORT Human Clinical

"Markedly increased closure times, such as those typically found in GT, have never been observed"

The same point measured on a different instrument, and the practical distinction from classic thrombasthenia.

+ 1 more reference

Failure of Primary Hemostatic Plug Formation

The rate-limiting step, reached here by two routes at once: too few platelets, and platelets that aggregate and spread poorly. Which route dominates is not settled, and it matters clinically, because bleeding severity in reported families tracks neither the platelet count nor the surface receptor level closely. The plug that forms is inadequate for small-vessel haemostasis under challenge, while spontaneous severe bleeding is unusual.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

platelet CL:0000233

Downstream

Mucocutaneous Bleeding Diathesis The clinical expression of the failed plug.

Show evidence (1 reference)

PMID:26452979 SUPPORT INDIRECT In Vitro

The authors argue that the functional defect rather than the count is the effector of bleeding in this disease group; graded INDIRECT because their patients carried an ITGB3 allele and no study has separated the two contributions in ITGA2B carriers.

Mucocutaneous Bleeding Diathesis

Mild to moderate and provoked rather than spontaneous. Easy bruising is the usual background finding; the events that bring families to attention are haemostatic challenges, most often tonsillectomy, dental extraction and delivery, and in several reported families the disorder was instead found incidentally on a routine platelet count. Bleeding scores in the largest series ranged from absent to high within the same disease, and one carrier of a severe bleeding score had a caesarean delivery complicated by postpartum haemorrhage requiring intensive care and transfusion.

Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton

Downstream

Bruising Susceptibility The commonest manifestation, and often the only one.

Epistaxis Mucosal bleeding, typically reported in childhood.

Gingival Bleeding Mucosal bleeding, including bleeding on tooth brushing.

Menometrorrhagia Heavy and irregular menstrual bleeding.

Post-Partum Hemorrhage The most serious reported complication, and the one that has required transfusion and intensive care.

Prolonged Bleeding After Surgery Post-tonsillectomy haemorrhage is the presentation in two reported families.

Prolonged Bleeding After Dental Extraction A haemostatic challenge that reveals the disorder in some carriers and passes uneventfully in others.

Show evidence (2 references)

PMID:29090484 SUPPORT Human Clinical

"For all affected patients, the bleeding syndrome and MTP was mild to moderate."

The severity statement for the families carrying the recurrent ITGA2B allele.

PMID:33276370 SUPPORT Human Clinical

"Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression"

The wider range seen across ten families, including patients with no bleeding at all.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 13

Macrothrombocytopenia VERY_FREQUENT HP:0040185

Show evidence (3 references)

PMID:29090484 SUPPORT Human Clinical

"Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H."

Macrothrombocytopenia as the presenting phenotype of two ITGA2B R995W families.

PMID:31119735 SUPPORT Human Clinical

"In contrast to our family (European ancestry), all previously reported families (Japanese ancestry) with HT due to the ITGA2B R1026W substitution exhibit macrothrombocytopenia (thrombocytopenia with large platelet size)"

States that every previously reported family with the recurrent allele had macrothrombocytopenia.

PMID:31119735 REFUTE Human Clinical

"Here we report a family with autosomal dominant (AD) thrombocytopenia with normal platelet size."

The exception, in a family carrying the same ITGA2B variant, which is why this phenotype is not curated as obligate.

Platelet Anisocytosis FREQUENT HP:0032438

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"The PB smears revealed PLT macrocytosis and anisocytosis in most of the patients analyzed"

The frequency of the finding across ten families, five of them with ITGA2B variants.

PMID:22102273 SUPPORT Other

"This was brought to light by the discovery of mutations at Arg995 in αIIb and Asp723 in β3 that lead to platelet anisotropy (increased size variation) and thrombocytopenia."

Ties the size variation specifically to the alphaIIb Arg995 variants this entry curates.

Increased Mean Platelet Volume VERY_FREQUENT HP:0011877

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"The MPV was increased (>11fL) in 28/32 patients tested (88%), with a median value of 13fL"

The proportion and the magnitude, from which the VERY_FREQUENT band is taken.

Giant Platelets OCCASIONAL HP:0001902

Show evidence (2 references)

PMID:1638023 SUPPORT Human Clinical

"Electron microscopy showed a wide diversity of platelet size including giant forms."

The morphological description in the index patient later shown to carry ITGA2B R995Q.

PMID:33276370 SUPPORT Human Clinical

"sometimes with a variable fraction of giant PLT"

The authors' own qualification, which is the basis for the OCCASIONAL band rather than a higher one.

Decreased Platelet Surface Glycoprotein IIb-IIIa VERY_FREQUENT Decreased platelet glycoprotein IIb-IIIa HP:0001975

Show evidence (2 references)

PMID:21454453 SUPPORT Human Clinical

"The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."

The measured range in the four families carrying the recurrent ITGA2B allele.

PMID:33276370 SUPPORT Human Clinical

"decreased expression of αIIbβ3 (around half of the normal)"

The same finding in the largest series, in the subgroup defined by variants at the alphaIIb Arg1026 residue.

Impaired Platelet Aggregation VERY_FREQUENT HP:0003540

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"impaired platelet aggregation/ATP release to physiological agonists"

The laboratory phenotype reported for the series as a whole.

PMID:1638023 SUPPORT Human Clinical

"The aggregation of washed platelets with ADP was improved but remained subnormal, as was aggregation with collagen and thrombin."

The agonist pattern in the index patient, including the partial correction on washing that distinguishes it from an absent response.

Abnormal Platelet Alpha-Granules Abnormal alpha granules HP:0012483

Show evidence (2 references)

PMID:29090484 SUPPORT Human Clinical

"Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α-granules with some giant forms showing signs of fusion."

The morphometric description in the families reporting this finding, two of the three carrying ITGA2B R995W.

PMID:29090484 SUPPORT Human Clinical

"It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/β3 D723 salt bridge."

The authors' own limit on how far the finding generalises, which is why no frequency is set here.

Bruising Susceptibility HP:0000978

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"The hemorrhagic symptoms consisted of easy bruising and menometrorrhagia, and she had no history of surgeries."

The index patient of family 5, one of the five ITGA2B families in this series.

PMID:24498605 SUPPORT Human Clinical

"Since her bleeding diathesis with easy epistaxis, bruising, and hemostatic difficulty after teeth extraction became worse at 9 years of age, she was referred to our hospital."

The clinical picture in the most severely affected reported case, a compound heterozygote for ITGA2B p.Gly991Cys and a nonsense allele.

Epistaxis HP:0000421

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"He reported bleeding after tonsillectomy at 7 years of age and epistaxis in childhood, as well as easy ecchymosis and gingival bleeding."

The index patient of family 4, who carries the ITGA2B p.Arg1026Gln variant.

PMID:33276370 SUPPORT Human Clinical

"He reported severe epistaxis as a child, but he had had multiple dental extractions without hemorrhage; there was no history of surgeries."

The index patient of family 3, carrying the recurrent ITGA2B allele, and an illustration of how selectively the bleeding presents.

Gingival Bleeding HP:0000225

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"as well as easy ecchymosis and gingival bleeding"

The index patient of family 4, carrying an ITGA2B variant at Arg1026.

PMID:33276370 SUPPORT Human Clinical

"she also reported bleeding after tooth brushing and easy bruising without trauma"

The mother in family 2, who carries the recurrent ITGA2B allele and had the highest bleeding score in that family.

Post-Partum Hemorrhage HP:0011891

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"cesarean delivery had been complicated by postpartum hemorrhage, demanding hospitalization in Intensive Care, and RBC and PLT transfusions"

The severe obstetric course in the mother of the family 2 index case, who carries the recurrent ITGA2B allele.

Prolonged Bleeding After Surgery HP:0004846

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"submitted to tonsillectomy complicated by hemorrhage and needing to be transfused with red blood cells"

The presentation of the first patient identified in the largest series, from an ITGA2B family.

PMID:33276370 SUPPORT Human Clinical

"He reported bleeding after tonsillectomy at 7 years of age and epistaxis in childhood"

The same presentation in a second, unrelated ITGA2B family.

Prolonged Bleeding After Dental Extraction HP:0006298

Show evidence (2 references)

PMID:24498605 SUPPORT Human Clinical

"hemostatic difficulty after teeth extraction became worse at 9 years of age"

The finding in a patient carrying ITGA2B p.Gly991Cys, noting that she is a compound heterozygote with a nonsense allele and sits at the severe end of the spectrum.

PMID:33276370 REFUTE Human Clinical

"he had had multiple dental extractions without hemorrhage"

A carrier of the recurrent ITGA2B allele for whom the same challenge passed uneventfully, which contradicts this being a consistent feature of the disease.

Genitourinary 1

Menometrorrhagia HP:0400008

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"The hemorrhagic symptoms consisted of easy bruising and menometrorrhagia, and she had no history of surgeries."

The index patient of family 5, diagnosed at 16 years of age.

🧬

Genetic Associations

ITGA2B

Gene: ITGA2B hgnc:6138 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia."

Names the gene-disease relationship and the disorder's alternative names in one sentence.

PMID:31119735 SUPPORT Human Clinical

"Homozygous or compound heterozygous loss of function mutations in ITGA2B result in Glanzmann thrombasthenia, a bleeding disorder characterized by normal platelet count but abnormal platelet function."

The contrast that makes zygosity and variant mechanism, not the gene, the thing that distinguishes the two diseases.

Variants (5)

ITGA2B p.Arg1026Trp Pathogenic

single nucleotide variant

The recurrent allele, legacy name R995W. Reported in four unrelated Japanese families in the first molecular series, in further Japanese, French and Portuguese families, and in one European-ancestry family in which it arose on a different haplotype. The substitution is a C to T transition at a CpG site.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"This family was subsequently found to have a heterozygous variant in ITGA2B (p.Arg1026Trp), in common with a case published in 2011"

The sentence introducing the variant in the first family of the series; the table of that paper gives it as NM_000419.4:c.3076C>T, p.(Arg1026Trp), classified pathogenic by legacy.

ITGA2B p.Arg1026Gln Pathogenic

single nucleotide variant

Legacy name R995Q, the first natural variant found in the alphaIIb GFFKR motif, in the patient described in 1992 with giant platelets and a mild thrombasthenia-like syndrome, and found again in one Portuguese family. The transfected receptor was not constitutively active in that first study, which is the main exception to the activation mechanism.

Show evidence (1 reference)

PMID:9834222 SUPPORT Human Clinical

"This is the first reported natural mutation in the highly conserved GFFKR sequence of the IIb cytoplasmic domain."

Establishes the allele as the first of its class to be described.

ITGA2B p.Gly991Cys Pathogenic

A GFFKR-motif substitution in legacy numbering, identified in a Japanese patient who also carried the nonsense allele p.Arg422* in trans and had the most severe reported phenotype, with surface alphaIIbbeta3 at 3 to 11 per cent of control.

Show evidence (1 reference)

PMID:24498605 SUPPORT Human Clinical

"One patient, who showed Glanzmann thrombasthenia-like marked reduction in surface αIIbβ3 expression (3-11% of normal control), was a compound heterozygote with ITGA2B p.Gly991Cys and a novel nonsense mutation, ITGA2B p.Arg422*."

The genotype and the degree of surface reduction that places this patient between the two diseases.

ITGA2B p.Phe993del Pathogenic

deletion

An in-frame single-residue deletion in the GFFKR motif in legacy numbering, heterozygous, in a Japanese family with macrothrombocytopenia and no bleeding history in the index case.

Show evidence (1 reference)

PMID:24498605 SUPPORT In Vitro

The functional demonstration for this allele, alongside the other two in the same study.

ITGA2B p.Gly1007Val Uncertain Significance

single nucleotide variant

A transmembrane-domain substitution reported as new in the largest series, at one of the glycines of the outer membrane clasp rather than in the cytoplasmic inner clasp, and classified there as a variant of uncertain significance.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"one of the novel variants found in our patients (αIIb: p.Gly1007Val) is a glycine substitution at αIIb p.Gly1007, interfering with inter-helical packing of the αIIb and β3 TMD"

States where the variant sits and the structural interaction it is proposed to disturb, which is the outer rather than the inner membrane clasp.

💊

Medical Actions

Desmopressin

Action: Pharmacotherapy NCIT:C15986

Agent: desmopressin CHEBI:4450

Platform: Peptide

Peri-procedural cover, and the option with the most direct support in an ITGA2B family: the first patient identified in the largest series had two caesarean sections and spinal surgery under desmopressin without bleeding, having previously haemorrhaged after a tonsillectomy performed without cover. It does nothing to the integrin. It raises plasma von Willebrand factor and factor VIII and shortens the bleeding time, so it improves the conditions in which a defective platelet works rather than correcting the platelet.

Mechanism Target:

BYPASSES Failure of Primary Hemostatic Plug Formation — Acts around the platelet lesion rather than on it, by improving the plasma contribution to primary haemostasis.

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"The patient subsequently underwent two caesarean sections and spinal surgery with desmopressin without bleeding, and she had no significant hemorrhagic symptoms in addition to easy bruising."

Three uneventful procedures under desmopressin in a patient from an ITGA2B family whose earlier unprotected tonsillectomy had bled. Observed in one patient, not a trial.

PMID:37611608 SUPPORT INDIRECT Other

"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."

Places desmopressin among the established options. Graded INDIRECT because the review addresses inherited platelet disorders as a class and no trial exists in this disorder.

Tranexamic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: tranexamic acid CHEBI:48669

Platform: Small molecule

Antifibrinolytic cover for procedures and for menorrhagia, which is the manifestation with the most cumulative morbidity here. It stabilises the clot that a reduced number of poorly aggregating platelets manages to build, and does not touch the underlying defect. No study of it exists in this disorder; the recommendation is inherited from the management of inherited platelet disorders generally.

Mechanism Target:

BYPASSES Mucocutaneous Bleeding Diathesis — Reduces bleeding without altering platelet number or function, by slowing dissolution of the clot that does form.

Show evidence (2 references)

PMID:37611608 SUPPORT INDIRECT Other

"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."

Class-level support. Graded INDIRECT for the same reason as desmopressin above.

PMID:37611608 SUPPORT INDIRECT Other

"Special attention is given to the treatment of menorrhagia and risk management during pregnancy in women with IPDs."

Identifies the two clinical situations that dominate management in this disorder, which is where antifibrinolytic cover is used.

Platelet Transfusion

Action: platelet transfusion Ontology label: Platelet Transfusion NCIT:C15366

Platform: Cell therapy

Reserved for serious bleeding and for major surgery. It supplies platelets with a normal integrin in normal number, so unlike the other options it corrects both arms of the defect for as long as the transfused platelets survive. In the largest series it was used for postpartum haemorrhage in a carrier of the recurrent ITGA2B variant, and prophylactically before surgery and delivery in other families. Repeated exposure carries an alloimmunisation risk, which in this disorder is not the anti-alphaIIbbeta3 isoimmunisation seen in Glanzmann thrombasthenia, since these patients express the receptor.

Mechanism Target:

RESTORES Failure of Primary Hemostatic Plug Formation — Replaces the deficient and dysfunctional platelet pool with a competent one for the life of the transfused platelets.

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"cesarean delivery had been complicated by postpartum hemorrhage, demanding hospitalization in Intensive Care, and RBC and PLT transfusions"

Platelet transfusion used for the most serious reported complication, in a carrier of the recurrent ITGA2B allele.

PMID:37611608 SUPPORT INDIRECT Other

"Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."

Class-level support for platelet concentrates. INDIRECT for the same reason as above.

🔬

Biochemical Markers

Platelet surface alphaIIbbeta3 expression by flow cytometry (DECREASED)

Context: Measured as CD41 (alphaIIb) or CD61 (beta3) binding on resting platelets and reported as a percentage of a normal control. In this disorder it sits at roughly 40 to 70 per cent of normal, which is the range that distinguishes it both from normal and from classic Glanzmann thrombasthenia, where the surface receptor is typically almost absent. The reduction correlates inversely with mean platelet volume across patients. The total platelet content of the receptor is far better preserved than the surface pool, because the missing fraction has been internalised.

Pathograph Readouts

Readout Of Receptor Internalisation and Reduced Surface alphaIIbbeta3 Negative Diagnostic

A partial reduction in surface alphaIIbbeta3 in a patient with macrothrombocytopenia is the finding that points at ITGA2B or ITGB3, and its degree is what separates this disorder from classic thrombasthenia.

Show evidence (1 reference)

PMID:21454453 SUPPORT Human Clinical

"The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."

The measured range in the families carrying the recurrent ITGA2B allele, expressed against a control as the assay reports it.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"Furthermore, GPIIb/IIIa and GPIIIa expression levels correlated inversely and moderately with the MPV values"

Links the biochemical readout to the platelet size phenotype within the same patients, which is what a single mechanism acting on both predicts.

Immature platelet fraction (INCREASED)

Context: The fraction of circulating platelets that are reticulated and recently released. It is raised in this disorder, with median values of 13 to 27 per cent across families in the largest series against a stated normal range of 1 to 7 per cent, and it correlates with mean platelet volume and platelet distribution width. A raised value with a low count is the pattern of a production disorder releasing large young platelets, not of accelerated peripheral destruction.

Pathograph Readouts

Readout Of Reduced Output of Enlarged Circulating Platelets Positive Diagnostic

Reports the abnormal platelet production arm of the disorder rather than its platelet function arm.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"The IPF correlated positively with the MPV and the PDW values"

The correlation that ties the young-platelet fraction to the size abnormality this node produces.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"increased IPF values (median of 14%)"

A representative median in the subgroup of families that includes the ITGA2B variants, against the 1 to 7 per cent normal range stated in the same paper's methods.

🔬

Diagnosis

Flow cytometry of platelet surface alphaIIbbeta3

The test that points at the gene. A partial reduction of CD41 or CD61 on resting platelets, to roughly half of a normal control, in a patient with macrothrombocytopenia, is the finding that distinguishes this disorder both from other inherited macrothrombocytopenias and from classic Glanzmann thrombasthenia. Spontaneous PAC-1 or bound-fibrinogen binding on resting platelets can be looked for in the same assay, but it is present in only a minority of patients and was seen at a similar rate in healthy controls in the largest series, so it confirms nothing when absent.

flow cytometry of platelet CD41 and CD61 NCIT:C16585

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes."

The combination of findings that defines the series, and so the pairing the test is looking for.

PMID:33276370 SUPPORT Human Clinical

"Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls."

Why the activation arm of the same assay is not a diagnostic criterion.

Light transmission aggregometry

Reduced but present aggregation and ATP release to ADP, collagen, epinephrine and arachidonic acid, with preserved ristocetin agglutination. The partial response is what distinguishes the trace from classic Glanzmann thrombasthenia, and closure times on a platelet function analyser are prolonged without reaching thrombasthenic values. No ontology term is bound here: NCIT codes platelet aggregometry only as data elements such as NCIT:C114210 Platelet Aggregometry Curve Type, which are not clinical procedures under NCIT:C25218 and so cannot fill this slot.

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"impaired platelet aggregation/ATP release to physiological agonists"

The aggregometry finding as the series reports it.

PMID:33276370 SUPPORT Human Clinical

"Markedly increased closure times, such as those typically found in GT, have never been observed"

The negative that keeps a thrombasthenic trace from being expected here.

Peripheral blood film and platelet indices

The cheapest step and often the one that raises the possibility at all: a low platelet count with a raised mean platelet volume and platelet distribution width, macrocytic and anisocytic platelets on the film, and sometimes giant forms. A raised immature platelet fraction alongside them argues for impaired production rather than peripheral destruction. Automated counters undercount very large platelets, so the count may read lower than it is. No ontology term is bound: NCIT:C79903 Blood Smear names the specimen rather than a clinical procedure and is not reachable from NCIT:C25218, so it fails the TreatmentActionTerm enum this slot uses.

Show evidence (1 reference)

PMID:33276370 SUPPORT Human Clinical

"The PB smears revealed PLT macrocytosis and anisocytosis in most of the patients analyzed"

The film findings across the series, which is what makes this the first test rather than a confirmatory one.

ITGA2B sequencing within a hereditary platelet disorder panel

Confirms the diagnosis. In practice ITGA2B and ITGB3 are sequenced inside a hereditary platelet or haematological disease panel rather than as single-gene tests, and the authors of the largest series argue that sequencing without platelet phenotyping is the wrong order to work in, because a heterozygous variant in either gene has to be interpreted against the platelet count, the platelet size and the surface receptor level before it means this disease rather than Glanzmann thrombasthenia carriership or nothing.

multi-gene panel sequencing of ITGA2B and ITGB3 NCIT:C198412

Show evidence (2 references)

PMID:33276370 SUPPORT Human Clinical

"Genetic analysis of ITGA2B and ITGB3 genes was performed by NGS in selected patients from families with novel variants, using a commercially available gene panel for hematologic diseases"

How the testing is actually done, on a panel rather than gene by gene.

PMID:33276370 SUPPORT Human Clinical

"Our study favors the idea that screening mutations by NGS alone (without performing phenotypic studies) may not be the best approach"

The authors' caution about sequencing without phenotyping, which is the interpretive point this entry records.

Distinction from acquired thrombocytopenia

Not a test but the decision the tests are for. Patients in the largest series had been followed for years with a diagnosis of chronic thrombocytopenia, and some had been treated as having autoimmune or gestational thrombocytopenia, which carries the cost of corticosteroids and platelet transfusions that cannot work. A family history is not always apparent, since relatives are often unaware of their own counts.

Show evidence (3 references)

PMID:33276370 SUPPORT Human Clinical

"some had been misdiagnosed (e.g. autoimmune thrombocytopenia, gestational thrombocytopenia), with therapeutic implications (e.g. corticosteroids and PLT transfusions)"

The misdiagnoses documented in this series and the treatment consequence of each.

PMID:33276370 SUPPORT Human Clinical

"even when a familial history is not obvious (as many patients are unaware of a family history of thrombocytopenia)"

Why an absent family history does not exclude an inherited disorder here.

PMID:16169642 SUPPORT INDIRECT Other

"Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura."

The same error described for the congenital macrothrombocytopenias as a class, the group this disorder belongs to. Graded INDIRECT because the review predates the molecular definition of this entity.

📊

Prevalence

Worldwide

Cases In Literature Not yet documented

No population estimate exists for this disorder. ITGA2B-related macrothrombocytopenia is known from a small number of families: four unrelated Japanese families carrying R995W in the first molecular series, three further families in a Japanese series of novel alleles, a later series of three families of which two carry R995W, one European-ancestry family in which the same allele arose on a different haplotype, and five Portuguese families in the largest single-centre series. Because the bleeding is mild and the platelet count often only moderately reduced, affected families are readily misclassified as immune thrombocytopenia or left undiagnosed.

Show evidence (2 references)

PMID:21454453 SUPPORT Human Clinical

"We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families."

The first molecular series is four families, which is the order of magnitude the whole literature works at; no source gives a denominator.

PMID:33276370 SUPPORT Human Clinical

"We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families)."

The largest single-centre series contributes five ITGA2B families, which shows how few are on record.

🧫

Experimental Models

alphaIIb-W995/beta3-transduced mouse fetal liver-derived megakaryocytes PRIMARY_CELL_CULTURE

Megakaryocytes differentiated from mouse fetal liver cells after transduction with the human alphaIIb R995W allele together with beta3. This is the model that connects the receptor lesion to the platelet count: it puts the patient's allele into a cell that actually makes platelets, and asks what the proplatelets look like.

Organism

mouse NCBITaxon:10090

Cell source

Mouse fetal liver haematopoietic cells, retrovirally transduced

Publication

PMID:21454453

Pathograph links

Abnormal Proplatelet Formation by Megakaryocytes recapitulates fidelity: moderate observes: cellular Transduced megakaryocytes form proplatelets with fewer and larger tips, which is the cellular defect this node asserts.

Limitations: The human allele is expressed in a mouse megakaryocyte alongside the endogenous mouse integrin and at a transduced rather than heterozygous level, so the gene dosage is not the patient's. Proplatelet tips in culture are a surrogate for platelet release in the marrow, and no platelet count or bleeding phenotype is measured.

Readouts

Proplatelet tip number and size

Direction: ALTERED

Interpretation: Fewer tips of larger size is the culture correlate of releasing fewer and larger platelets.

Show evidence (1 reference)

PMID:21454453 SUPPORT In Vitro

"The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation."

The measurement and the authors' reading of it.

Show evidence (1 reference)

PMID:21454453 SUPPORT Human Clinical

"We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias."

The inference this model licenses, and the reason it is treated as informative for the production defect.

Patient-derived megakaryocyte cultures from ITGA2B R995W carriers PRIMARY_CELL_CULTURE

Megakaryocyte maturation and proplatelet formation studied in cultures from patients themselves, in three families of which two carry ITGA2B R995W. The value of the model is that the genotype, the dosage and the species are the patient's, so it answers where in megakaryocyte development the defect sits without extrapolation.

Organism

human NCBITaxon:9606

Cell source

Megakaryocytes cultured from patients carrying ITGA2B R995W or ITGB3 D723H

Publication

PMID:29090484

Pathograph links

Abnormal Proplatelet Formation by Megakaryocytes recapitulates fidelity: high observes: cellular Early maturation is normal and proplatelet formation is abnormal with enlarged tips, which localises the defect to the terminal step.

Limitations: Three families and a small number of cultures, with the ITGA2B and ITGB3 genotypes analysed together, so the model does not separate the two genes. Proplatelet morphology in culture remains a surrogate for platelet release in vivo.

Readouts

Megakaryocyte maturation and proplatelet tip size

Direction: ALTERED

Interpretation: Normal maturation with abnormally large proplatelet tips is the pattern that excludes a maturation arrest as the cause of the low platelet count.

Show evidence (1 reference)

PMID:29090484 SUPPORT Human Clinical

"Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips."

The two findings together, which is what makes this a terminal-step defect.

{ }

Source YAML

click to show

name: Platelet-type Bleeding Disorder 16
creation_date: "2026-09-30T19:45:00Z"
category: Mendelian
disease_term:
  preferred_term: platelet-type bleeding disorder 16
  term:
    id: MONDO:0008552
    label: platelet-type bleeding disorder 16
description: >
  Platelet-type bleeding disorder 16 (BDPLT16, OMIM #187800) is an autosomal
  dominant congenital macrothrombocytopenia with platelet anisocytosis and a
  mild to moderate, sometimes absent, mucocutaneous bleeding tendency, caused
  by heterozygous activating variants in ITGA2B, the gene encoding the alphaIIb
  subunit of the platelet fibrinogen receptor integrin alphaIIbbeta3. The
  clinical literature also calls it the dominant or variant form of Glanzmann
  thrombasthenia, or Glanzmann thrombasthenia-like syndrome, but the mechanism
  runs in the opposite direction to classic Glanzmann thrombasthenia.

  In classic Glanzmann thrombasthenia biallelic loss-of-function variants
  remove or disable the integrin, platelet count and size are normal, and
  aggregation to every physiological agonist is absent. In BDPLT16 a single
  variant in the membrane-proximal part of alphaIIb, most often at Arg995 in
  the conserved GFFKR motif (Arg1026 in HGVS numbering), weakens the inner
  membrane clasp: the salt bridge between alphaIIb Arg995 and beta3 Asp723
  that holds the receptor in its bent resting conformation. A fraction of the
  receptor pool then sits in the ligand-binding conformation without any
  inside-out signal, binding the activation-dependent antibody PAC-1 and
  fibrinogen on resting platelets that have not themselves been activated.

  Two consequences follow from that single lesion. In megakaryocytes,
  permanent integrin outside-in signalling disturbs cytoskeletal remodelling,
  and proplatelets form with fewer and larger tips, so fewer and larger
  platelets are released. In circulating platelets the constitutively engaged
  receptor is internalised, surface alphaIIbbeta3 falls to roughly half of
  normal, and agonist-induced aggregation is reduced rather than abolished.
  The resulting bleeding is milder than in classic thrombasthenia and reflects
  the reduced platelet count together with the impaired platelet function.

  Heterozygous activating variants in ITGB3 produce a clinically
  indistinguishable phenotype, and MONDO's definition of this term still names
  both genes, but OMIM curates the ITGB3 form separately as BDPLT24. This
  entry is therefore scoped to the ITGA2B form, and cites the shared
  mechanistic literature only where a source states its conclusion for
  activating alphaIIbbeta3 variants as a class.

synonyms:
- BDPLT16
- bleeding disorder, platelet-type, 16
- bleeding disorder, platelet-type, 16, autosomal dominant
- autosomal dominant Glanzmann thrombasthenia
- Glanzmann thrombasthenia, autosomal dominant
- thrombasthenia of Glanzmann and Naegeli, autosomal dominant
- autosomal dominant thrombasthenia of Glanzmann and Naegeli
- Glanzmann thrombasthenia-like syndrome
- ITGA2B-related macrothrombocytopenia
- ITGA2B/ITGB3-related thrombocytopenia

parents:
- Inherited bleeding disorder, platelet-type
- Inherited blood coagulation disorder
- Congenital macrothrombocytopenia

notes: >
  Gene scope. MONDO's definition of MONDO:0008552 names heterozygous variants
  in ITGA2B or ITGB3. OMIM, as mirrored by MedGen UID 1781222, restricts
  BDPLT16 to ITGA2B and curates the ITGB3 form as BDPLT24 (OMIM 619271,
  MONDO:0030996), which has its own entry in the curation queue. This entry
  follows OMIM: ITGA2B is the causal gene, and ITGB3 appears only in prose and
  in mechanistic evidence a source states for activating alphaIIbbeta3
  variants as a class. The ITGB3 dominant form is deliberately not curated
  here as a subtype, since it has its own MONDO term and would then be
  modelled twice.

  Relationship to Glanzmann thrombasthenia. The Glanzmann_Thrombasthenia entry
  already records this disorder as a differential diagnosis with the opposite
  mechanism, increased rather than lost integrin activation. The two share
  their genes but not their mechanism, so a variant in ITGA2B is by itself
  diagnostic of neither: the zygosity, the platelet count and size, and
  whether aggregation is reduced or absent decide it. A StatPearls chapter
  exists for Glanzmann thrombasthenia and matches one of this entry's
  synonyms, but it is about the recessive disease and is not a baseline for
  this one. No GeneReviews chapter names this disease.

  Treatment evidence is thin and mostly extrapolated. The three treatments
  curated here are the ones a source states for this disorder or for inherited
  platelet disorders as a class. Recombinant activated factor VII and hormonal
  control of heavy menstrual bleeding are both used in this disease family, but
  the published series describing them are in Glanzmann thrombasthenia, a
  different disease with a different mechanism and a much more severe bleeding
  phenotype, so they are not curated here as treatments of this disorder.
  Avoidance of aspirin, NSAIDs and P2Y12 inhibitors is standard advice across
  inherited platelet disorders and is likewise not curated, because no cited
  source states it for these patients.

  Variant numbering. Two numberings are in use for alphaIIb. Legacy numbering
  of the mature protein gives Arg995, Gly991 and Phe993; HGVS numbering on
  NM_000419, which counts the signal peptide, gives Arg1026, Gly1022 and
  Phe1024. R995W and R1026W are the same substitution, and the largest series
  prints both.

  Constitutive activation is the leading mechanism but is not uniform. It is
  well shown for R995W, G991C and F993del in transfected cells, yet the first
  variant described, R995Q, did not lock the transfected receptor into a high
  activation state, and in the largest single-centre series constitutive
  activation was detected in a minority of patients and at a similar rate in
  healthy controls. Both observations are curated as REFUTE evidence on the
  activation node rather than left out.

  Phenotypes deliberately not curated. MONDO's definition mentions a prolonged
  bleeding time; no cached source reports a bleeding time in an ITGA2B variant
  carrier, so it is not curated. One European-ancestry family carrying the
  recurrent p.Arg1026Trp variant had thrombocytopenia with normal platelet
  size, which is why macrothrombocytopenia is curated as VERY_FREQUENT rather
  than OBLIGATE. The enlarged, sometimes fusing alpha-granules described in
  ITGA2B R995W families are curated as a phenotype, but whether they
  characterise all salt-bridge variants was left open by the authors who
  described them.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population estimate exists for this disorder. ITGA2B-related
    macrothrombocytopenia is known from a small number of families: four
    unrelated Japanese families carrying R995W in the first molecular series,
    three further families in a Japanese series of novel alleles, a later
    series of three families of which two carry R995W, one
    European-ancestry family in which the same allele arose on a different
    haplotype, and five Portuguese families in the largest single-centre
    series. Because the bleeding is mild and the platelet count often only
    moderately reduced, affected families are readily misclassified as immune
    thrombocytopenia or left undiagnosed.
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families."
    explanation: >-
      The first molecular series is four families, which is the order of
      magnitude the whole literature works at; no source gives a denominator.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families)."
    explanation: >-
      The largest single-centre series contributes five ITGA2B families, which
      shows how few are on record.

inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Heterozygous ITGA2B variants segregating with macrothrombocytopenia across
    generations. The dominance follows from the mechanism: one activating
    allele is enough to put part of the integrin pool into a constitutively
    active conformation, and what that state then does to megakaryocyte
    cytoskeletal signalling does not require the second allele to be affected.
    Penetrance for the platelet phenotype is high within reported families,
    while bleeding severity varies and some carriers report no bleeding at all.
  evidence:
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H."
    explanation: >-
      Two autosomal dominant macrothrombocytopenia families carrying the
      recurrent ITGA2B allele.
  - reference: PMID:31119735
    reference_title: "Genome-wide linkage analysis and whole-exome sequencing identifies an ITGA2B mutation in a family with thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing showed that the ITGA2B variant was present in heterozygous form in all affected family members and was absent in all unaffected family members."
    explanation: >-
      Co-segregation of the heterozygous variant with the trait in a
      four-generation family, backed by linkage analysis.

mechanistic_hypotheses:
- hypothesis_group_id: constitutive_aiibb3_activation
  hypothesis_label: Constitutive Partial alphaIIbbeta3 Activation Disturbing Megakaryocyte and Platelet Cytoskeleton
  status: CANONICAL
  description: >-
    A heterozygous variant at the membrane-proximal region of alphaIIb weakens
    the alphaIIb Arg995-beta3 Asp723 inner membrane clasp that keeps the
    integrin bent and inactive. Part of the receptor pool becomes partially and
    constitutively active and signals outside-in without ligand engagement,
    phosphorylating focal adhesion kinase and lowering RhoA activity. In
    megakaryocytes that disorganises cytoskeletal remodelling, and proplatelets
    form with fewer and larger tips, which is macrothrombocytopenia. In
    circulating platelets it drives internalisation of the receptor and arrests
    actin turnover, so surface alphaIIbbeta3 and agonist-induced aggregation
    both fall. CANONICAL because patient platelets, transfected cell lines,
    transduced murine megakaryocytes and patient-derived megakaryocytes agree
    on it; its limit is that constitutive activation is not demonstrable for
    every reported allele or in every patient.

pathophysiology:
- name: ITGA2B Membrane-Proximal Activating Variants
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >
    Heterozygous germline missense variants and small in-frame deletions in
    ITGA2B, clustered at the membrane-proximal part of alphaIIb: the
    cytoplasmic GFFKR motif (R995W, R995Q, G991C and F993del in legacy
    numbering) and, less often, the transmembrane domain, where p.Gly1007Val
    substitutes one of the glycines of the outer membrane clasp. R995W is the
    recurrent allele and has arisen at least twice independently, on Japanese
    and European haplotypes. The conformance target is the module's
    component-loss node read in its "dysfunctional" sense: the receptor is
    present and it is the wrong shape, which is also why a compound
    heterozygote carrying G991C opposite a nonsense allele sits at the severe,
    thrombasthenia-like end of the spectrum.

    The molecular function the lesion acts on is the receptor's own ligand
    binding: alphaIIbbeta3 binds fibrinogen, and the membrane-proximal region
    these variants sit in is what couples that binding to inside-out signalling
    rather than what performs it. The modifier is DYSREGULATED rather than
    INCREASED or GAIN_OF_FUNCTION because the evidence cuts both ways in the
    same patients. Fibrinogen binds resting platelets that have not been
    activated, which it should not; and binding induced by ADP or TRAP-6 is
    lower than normal, because less receptor is left on the surface. Neither
    half alone describes the function, and asserting only the first would also
    overstate the activation evidence, which is refuted for one allele and
    undetectable in most patients tested.
  molecular_functions:
  - preferred_term: integrin alphaIIbbeta3 fibrinogen binding
    modifier: DYSREGULATED
    term:
      id: GO:0070051
      label: fibrinogen binding
  genes:
  - preferred_term: ITGA2B
    term:
      id: hgnc:6138
      label: ITGA2B
    modifier: GAIN_OF_FUNCTION
  genetic_context:
    description: >-
      Heterozygous germline activating variants in ITGA2B. The functional
      category is gain of function because the variant raises the activation
      state of the receptor rather than removing it, which is the mechanistic
      inverse of the biallelic loss-of-function variants that cause classic
      Glanzmann thrombasthenia in the same gene.
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families."
    explanation: >-
      The recurrent heterozygous ITGA2B allele that defines the molecular
      entity.
  - reference: PMID:9834222
    reference_title: "R to Q amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin IIb subunit in a patient with a Glanzmann's thrombasthenia-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA sequencing showed a heterozygous mutation giving rise to amino acid substitution R995 to Q in the GFFKR sequence of the cytoplasmic domain of IIb"
    explanation: >-
      The first natural variant found in the alphaIIb GFFKR motif, in the
      patient originally reported with giant platelets and a mild Glanzmann
      thrombasthenia-like syndrome.
  - reference: PMID:24498605
    reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two mutations in highly conserved Gly-Phe-Phe-Lys-Arg sequence in juxtamembrane region of αIIb"
    explanation: >-
      Extends the allelic series in the same motif to G991C and F993del.
  - reference: PMID:31119735
    reference_title: "Genome-wide linkage analysis and whole-exome sequencing identifies an ITGA2B mutation in a family with thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "demonstrated that the ITGA2B R1026W mutation arose on a different haplotype compared to the previous reports, strongly supporting at least 2 independent origins for this same point mutation"
    explanation: >-
      Two independent origins of the recurrent allele, which is also the
      argument against the causal variant being something else in linkage
      with it.
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression."
    explanation: >-
      Fibrinogen binding where there should be none, which is one half of the
      DYSREGULATED modifier on this node's molecular function.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP"
    explanation: >-
      Fibrinogen binding failing to rise as it should on stimulation, which is
      the other half, and the reason the modifier is not INCREASED.
  downstream:
  - target: Disruption of the alphaIIb-beta3 Inner Membrane Clasp
    causal_link_type: DIRECT
    description: >-
      The substituted residues are the ones that form or position the
      alphaIIb Arg995-beta3 Asp723 salt bridge.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:29090484
      reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to β3 of the integrin αIIbβ3."
      explanation: >-
        Structural modelling connecting the ITGA2B R995W substitution to the
        salt bridge, in the paper that reports two families carrying it.

- name: Disruption of the alphaIIb-beta3 Inner Membrane Clasp
  biological_scale: MOLECULAR
  description: >
    In a resting platelet alphaIIbbeta3 is held bent and closed by two
    inter-subunit constraints, the transmembrane outer membrane clasp and the
    cytoplasmic inner membrane clasp, whose key contact is the salt bridge
    between alphaIIb Arg995 and beta3 Asp723. Physiological activation requires
    that clasp to open, so a variant that weakens it lowers the threshold for
    the conformational change rather than adding a new activity.
  cellular_components:
  - preferred_term: integrin alphaIIb-beta3 complex
    term:
      id: GO:0070442
      label: integrin alphaIIb-beta3 complex
  evidence:
  - reference: PMID:22102273
    reference_title: "Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin in a bent resting state."
    explanation: >-
      The structural role of the residue the recurrent ITGA2B variant
      replaces, stated in the review that defined this disease group.
  - reference: PMID:41503871
    reference_title: "ITGA2B/ITGB3-Related Macrothrombocytopenia Associated With Gain-of-Function Mutations in ITGA2B or ITGB3 Genes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The αIIbArg995/β3Asp723 salt bridge is a critical structure for maintaining the resting conformation of αIIbβ3."
    explanation: >-
      A recent review restating the same constraint, and the frame in which
      both genes' membrane-proximal variants are read.
  downstream:
  - target: Constitutive Partial alphaIIbbeta3 Activation
    causal_link_type: DIRECT
    description: >-
      Without the clasp, the receptor can reach its ligand-binding
      conformation with no inside-out signal.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:22102273
      reference_title: "Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Mutations weakening this link (if not abolishing it) increase the activation state of αIIbβ3 and interfere with megakaryocytopoiesis."
      explanation: >-
        States this edge, and in the same sentence the megakaryocyte
        consequence two nodes further down.

- name: Constitutive Partial alphaIIbbeta3 Activation
  biological_scale: MOLECULAR
  description: >
    Part of the surface receptor pool sits in a high-affinity state on resting
    platelets: PAC-1 and soluble fibrinogen bind without an agonist, and
    without P-selectin appearing, so the integrin is active while the platelet
    is not. In transfected cells the activation state conferred by alphaIIb
    R995W is higher than for the beta3 D723H salt-bridge variant and weaker
    than for the strongly activating beta3 N562 mutant, which is what "partial"
    means here. The activation is not uniform across alleles or patients, and
    the refuting evidence on this node is the reason it is not offered as a
    diagnostic test.
  biological_processes:
  - preferred_term: integrin activation
    modifier: INCREASED
    term:
      id: GO:0033622
      label: integrin activation
  cellular_components:
  - preferred_term: integrin alphaIIb-beta3 complex
    term:
      id: GO:0070442
      label: integrin alphaIIb-beta3 complex
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression."
    explanation: >-
      The observation in patient platelets: an active receptor on a platelet
      that has not degranulated.
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation."
    explanation: >-
      The authors' conclusion from transfected-cell activation assays for the
      recurrent allele.
  - reference: PMID:24498605
    reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells."
    explanation: >-
      Constitutive activation demonstrated for two further ITGA2B GFFKR
      alleles.
  - reference: PMID:9834222
    reference_title: "R to Q amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin IIb subunit in a patient with a Glanzmann's thrombasthenia-like syndrome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Flow cytometry with PAC-1 and a stable Chinese hamster ovary-transfected cell line showed that the mutated receptor was not locked into a high activation state, although it became so in the presence of the activating antibody, anti-LIBS6."
    explanation: >-
      For R995Q the transfected receptor was not constitutively active, so
      this node is not established for every ITGA2B allele assigned to the
      disorder.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls."
    explanation: >-
      In the largest series the finding appeared in a minority of patients and
      at a similar rate in controls, so it does not separate patients from
      controls in practice.
  downstream:
  - target: Persistent alphaIIbbeta3 Outside-In Signalling
    causal_link_type: DIRECT
    description: >-
      The active receptor signals into the cell as though ligand-engaged.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:21454453
      reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "FAK was spontaneously phosphorylated in αIIb-W995/β3-transfected 293T cells."
      explanation: >-
        Spontaneous focal adhesion kinase phosphorylation is the outside-in
        signal measured downstream of the active R995W receptor.
  - target: Receptor Internalisation and Reduced Surface alphaIIbbeta3
    causal_link_type: DIRECT
    description: >-
      A constitutively engaged receptor is taken off the surface.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:26452979
      reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Here we show that constitutive activation of integrin αIIbβ3 decreases surface expression of the complex through receptor internalization and permanently triggers outside-in signaling"
      explanation: >-
        The edge itself, shown with patient platelets carrying a beta3 variant
        and with CHO cells expressing several activating alphaIIbbeta3
        variants. Graded INDIRECT because the experiments centre on ITGB3
        alleles and its application to the ITGA2B form is the class-level
        reading.

- name: Persistent alphaIIbbeta3 Outside-In Signalling
  biological_scale: CELLULAR
  description: >
    The constitutively active receptor signals continuously through the
    integrin-mediated pathway in megakaryocytes and platelets: focal adhesion
    kinase is spontaneously phosphorylated, and RhoA activity falls, which is
    the arm that couples the receptor to the cytoskeleton. In transfected
    non-haematopoietic cells the same signal produces membrane ruffling and
    abnormal cytoplasmic protrusions resembling the extensions a megakaryocyte
    makes when it forms proplatelets.
  biological_processes:
  - preferred_term: integrin-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions."
    explanation: >-
      The morphological consequence of the signal, for the recurrent ITGA2B
      allele specifically.
  - reference: PMID:25806962
    reference_title: "Abnormal cytoplasmic extensions associated with active αIIbβ3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Moreover, we showed that formation of abnormal extensions occurred also in wild-type αIIbβ3 cells when activated by activating antibody."
    explanation: >-
      Forcing a wild-type receptor into its active conformation reproduces the
      protrusions, which is what makes the active conformation rather than the
      particular variant the operative cause. Graded INDIRECT because the
      experiment uses beta3 variants and an antibody rather than an ITGA2B
      allele.
  downstream:
  - target: Abnormal Proplatelet Formation by Megakaryocytes
    causal_link_type: DIRECT
    description: >-
      The same cytoskeletal signal misdirects the terminal step of platelet
      production.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:25806962
      reference_title: "Abnormal cytoplasmic extensions associated with active αIIbβ3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "These results suggest that the active conformation of αIIbβ3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation."
      explanation: >-
        States the edge from an active receptor through cytoskeletal
        rearrangement to impaired proplatelet formation; INDIRECT for the same
        reason as above.
  - target: Arrested Platelet Cytoskeletal Remodelling
    causal_link_type: DIRECT
    description: >-
      In the circulating platelet the persistent signal freezes actin turnover
      instead of remodelling it.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:26452979
      reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Moreover, we demonstrated that permanent triggering of αIIbβ3-mediated outside-in signaling causes an impairment of cytoskeletal reorganization arresting actin turnover at the stage of polymerization."
      explanation: >-
        The edge from persistent outside-in signalling to arrested actin
        turnover. INDIRECT because it was shown for activating ITGB3 alleles
        and is read here as a property of the activated receptor.

- name: Abnormal Proplatelet Formation by Megakaryocytes
  biological_scale: CELLULAR
  description: >
    Megakaryocyte maturation itself is normal: ploidy and early differentiation
    are unaffected, and plasma thrombopoietin is not raised. What fails is the
    terminal step. Proplatelets extend with fewer branches and abnormally large
    tips, and transduced murine megakaryocytes additionally form asymmetric
    barbell proplatelets, so each megakaryocyte yields fewer and larger
    platelets. This is the quantitative arm of the disorder, which the
    primary_hemostatic_plug_failure module deliberately does not model, so no
    node here conforms to it.
  biological_processes:
  - preferred_term: platelet formation
    modifier: DECREASED
    term:
      id: GO:0030220
      label: platelet formation
  - preferred_term: actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation."
    explanation: >-
      The defect measured in megakaryocytes expressing the recurrent ITGA2B
      allele itself.
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips."
    explanation: >-
      Confirms in megakaryocytes from patients, two of the three families
      carrying ITGA2B R995W, that the lesion is in the terminal step and not
      in maturation.
  - reference: PMID:26452979
    reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "del647-686β3-transduced murine megakaryocytes generated proplatelets with a reduced number of large tips and asymmetric barbell-proplatelets, suggesting that impaired cytoskeletal rearrangement is the cause of macrothrombocytopenia."
    explanation: >-
      The same result for an activating ITGB3 allele, with the barbell
      abnormality that names the mechanism. INDIRECT because the allele is in
      the other subunit.
  downstream:
  - target: Reduced Output of Enlarged Circulating Platelets
    causal_link_type: DIRECT
    description: >-
      Fewer and larger proplatelet tips give fewer and larger platelets.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Abnormal Platelet Alpha-Granules
    causal_link_type: DIRECT
    description: >-
      Alpha-granule maturation is disturbed alongside proplatelet formation, so
      the platelets released carry abnormally large granules.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:29090484
      reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbβ3 intracytoplasmic mutations there is an abnormal maturation of α-granules."
      explanation: >-
        Places the granule abnormality alongside the proplatelet defect in the
        same patients, as a maturation problem rather than a consequence of
        platelet size.

- name: Receptor Internalisation and Reduced Surface alphaIIbbeta3
  biological_scale: CELLULAR
  description: >
    Surface alphaIIbbeta3 on patient platelets runs at roughly half of normal,
    which is the finding that first brought these patients to attention and is
    the reason they were read as having a mild form of thrombasthenia. The
    total platelet content of the receptor is much better preserved than the
    surface pool, and the missing fraction is internal: the constitutively
    engaged receptor is taken up and degraded rather than never made.
  biological_processes:
  - preferred_term: receptor internalization
    modifier: INCREASED
    term:
      id: GO:0031623
      label: receptor internalization
  cellular_components:
  - preferred_term: cell surface
    term:
      id: GO:0009986
      label: cell surface
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."
    explanation: >-
      The quantitative reduction in patients carrying the recurrent ITGA2B
      allele.
  - reference: PMID:1638023
    reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient has a selective deficiency of the surface pool of GP IIb-IIIa complexes that is manifested clinically by a mild Glanzmann's thrombasthenia-like syndrome."
    explanation: >-
      The original description of the first patient later shown to carry
      ITGA2B R995Q, and the observation that the deficiency is of the surface
      pool specifically.
  - reference: PMID:1638023
    reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Staining of ultrathin sections confirmed the presence of an internal pool of GP IIb-IIIa."
    explanation: >-
      Where the receptor missing from the surface actually is, demonstrated
      morphologically before the mechanism was known.
  - reference: PMID:41503871
    reference_title: "ITGA2B/ITGB3-Related Macrothrombocytopenia Associated With Gain-of-Function Mutations in ITGA2B or ITGB3 Genes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Persistent activation of αIIbβ3 likely triggers enhanced internalisation and lysosomal degradation, resulting in downregulated αIIbβ3 expression in platelets surface"
    explanation: >-
      The review's statement of the route, hedged as the authors hedge it.
  - reference: PMID:23926302
    reference_title: "Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "hyperactivatable platelets characterized by constitutive binding of fibrinogen to its αIIbβ3 integrin receptor, internalization of the αIIbβ3 complex, generation of platelet-derived microparticles, and changes in the quantity and subcellular localization of filamin"
    explanation: >-
      A non-genetic phenocopy: in a murine sitosterolemia model, membrane sterol
      accumulation leaves the same receptor constitutively fibrinogen-bound and
      internalised, with macrothrombocytopenia following. Graded INDIRECT
      because the mouse carries no integrin variant, which is also what makes
      the observation informative: the route from an active receptor to
      internalisation and large platelets does not require this disease's
      genotype.
  downstream:
  - target: Impaired Agonist-Induced Platelet Aggregation
    causal_link_type: DIRECT
    description: >-
      Fewer available fibrinogen receptors per platelet, so less
      interplatelet bridging on activation.
    hypothesis_groups:
    - constitutive_aiibb3_activation
    evidence:
    - reference: PMID:1638023
      reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fibrinogen-binding was analyzed by flow cytometry using platelets in whole blood or PRP and was markedly decreased."
      explanation: >-
        The functional consequence of the reduced surface pool, measured as
        fibrinogen binding in the index patient.
  - target: Decreased Platelet Surface Glycoprotein IIb-IIIa
    causal_link_type: DIRECT
    description: >-
      The flow-cytometric finding that identifies these patients.
    hypothesis_groups:
    - constitutive_aiibb3_activation

- name: Arrested Platelet Cytoskeletal Remodelling
  biological_scale: CELLULAR
  description: >
    Aggregation and spreading require actin to be turned over, not merely
    polymerised. Under permanent outside-in signalling actin turnover halts at
    the polymerisation stage, and the authors who showed this reproduced the
    patients' functional defect in normal platelets with jasplakinolide, a
    toxin that promotes nucleation and prevents depolymerisation. That
    pharmacological phenocopy is what makes the arrested cytoskeleton, rather
    than the reduced receptor number alone, the proximate cause of the platelet
    dysfunction.
  biological_processes:
  - preferred_term: actin filament polymerization
    modifier: INCREASED
    term:
      id: GO:0030041
      label: actin filament polymerization
  - preferred_term: actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:26452979
    reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The induction of actin polymerization by jasplakinolide, a natural toxin that promotes actin nucleation and prevents depolymerization of stress fibers, in control platelets produced an impairment of platelet function similar to that of patients with variant forms of dominant Glanzmann thrombasthenia."
    explanation: >-
      The phenocopy experiment. Graded INDIRECT twice over: the patients
      studied carried an ITGB3 allele, and the argument runs from a chemical
      that arrests actin turnover to the mechanism in the disease.
  - reference: PMID:26452979
    reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These data show that impaired cytoskeletal remodeling caused by a constitutively activated αIIbβ3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia."
    explanation: >-
      The authors' summary of where the proximate lesion sits, for this
      disease group as a whole.
  downstream:
  - target: Impaired Agonist-Induced Platelet Aggregation
    causal_link_type: DIRECT
    description: >-
      A platelet that cannot remodel its cytoskeleton cannot spread and
      consolidate an aggregate.
    hypothesis_groups:
    - constitutive_aiibb3_activation

- name: Reduced Output of Enlarged Circulating Platelets
  biological_scale: ORGANISM
  description: >
    The haematological result: a moderately reduced platelet count with a
    raised mean platelet volume and a wide platelet size distribution, often
    with giant forms on the film. Counts in reported families run from the
    twenties to the low normal range and the immature platelet fraction is
    raised, which is consistent with a production defect rather than with
    peripheral destruction. Plasma thrombopoietin is normal, and in one patient
    the count rose transiently after an influenza infection, both arguing
    against a profound global failure of thrombopoiesis.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias."
    explanation: >-
      The conclusion that puts this haematological picture, rather than
      thrombasthenia, at the centre of the disease.
  - reference: PMID:24498605
    reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that gain-of-function mutations around membrane region of αIIbβ3 lead to abnormal platelet number and morphology with impaired surface αIIbβ3 expression."
    explanation: >-
      Ties the three findings of this node and the node above, count,
      morphology and surface expression, to the same class of variant.
  downstream:
  - target: Macrothrombocytopenia
    causal_link_type: DIRECT
    description: Fewer and larger platelets, measured as a count and a volume.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Platelet Anisocytosis
    causal_link_type: DIRECT
    description: >-
      Released platelets vary widely in size because the proplatelet tips they
      come from do.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Increased Mean Platelet Volume
    causal_link_type: DIRECT
    description: The quantitative expression of the size shift.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Giant Platelets
    causal_link_type: DIRECT
    description: The extreme tail of the size distribution, seen on the film.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      Fewer platelets arrive at the site of injury, which is the quantitative
      half of this disorder's contribution to the shared endpoint.
    hypothesis_groups:
    - constitutive_aiibb3_activation

- name: Impaired Agonist-Induced Platelet Aggregation
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Failure of Integrin alphaIIbbeta3-Mediated Platelet Aggregation"
  description: >
    Aggregation and dense-granule ATP release in response to ADP, collagen,
    epinephrine and arachidonic acid are reduced, while ristocetin
    agglutination is preserved, so the lesion is in aggregation and not in
    adhesion. The reduction is partial, which is what separates this disorder
    from classic Glanzmann thrombasthenia at the bench: aggregation is
    diminished rather than absent, and the platelet function analyser closure
    times, although prolonged, never reach the values typical of
    thrombasthenia. Conformance is at the module's aggregation arm because the
    lesion is in alphaIIbbeta3 itself, with reduced surface receptor and
    reduced fibrinogen binding, rather than in an upstream arm reading out
    through aggregometry.
  biological_processes:
  - preferred_term: platelet aggregation
    modifier: DECREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP."
    explanation: >-
      The laboratory phenotype of the largest series, which includes five
      ITGA2B families.
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet aggregation tended to be reduced but not absent."
    explanation: >-
      The partial character of the defect, in families carrying the recurrent
      ITGA2B allele.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markedly increased closure times, such as those typically found in GT, have never been observed"
    explanation: >-
      The same point measured on a different instrument, and the practical
      distinction from classic thrombasthenia.
  - reference: PMID:1638023
    reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In citrated platelet-rich plasma (PRP), platelet aggregation induced by adenosine diphosphate (ADP) and other agonists was much reduced."
    explanation: >-
      The finding in the index patient of the first described family, whose
      ITGA2B R995Q variant was identified six years later.
  downstream:
  - target: Impaired Platelet Aggregation
    causal_link_type: DIRECT
    description: The aggregometry readout of this mechanism.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      The qualitative half of the contribution: the platelets that do arrive
      bridge each other poorly.
    hypothesis_groups:
    - constitutive_aiibb3_activation

- name: Failure of Primary Hemostatic Plug Formation
  biological_scale: TISSUE
  conforms_to: "primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation"
  description: >
    The rate-limiting step, reached here by two routes at once: too few
    platelets, and platelets that aggregate and spread poorly. Which route
    dominates is not settled, and it matters clinically, because bleeding
    severity in reported families tracks neither the platelet count nor the
    surface receptor level closely. The plug that forms is inadequate for
    small-vessel haemostasis under challenge, while spontaneous severe
    bleeding is unusual.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:26452979
    reference_title: "Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "These data show that impaired cytoskeletal remodeling caused by a constitutively activated αIIbβ3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia."
    explanation: >-
      The authors argue that the functional defect rather than the count is
      the effector of bleeding in this disease group; graded INDIRECT because
      their patients carried an ITGB3 allele and no study has separated the
      two contributions in ITGA2B carriers.
  downstream:
  - target: Mucocutaneous Bleeding Diathesis
    causal_link_type: DIRECT
    description: The clinical expression of the failed plug.
    hypothesis_groups:
    - constitutive_aiibb3_activation

- name: Mucocutaneous Bleeding Diathesis
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >
    Mild to moderate and provoked rather than spontaneous. Easy bruising is the
    usual background finding; the events that bring families to attention are
    haemostatic challenges, most often tonsillectomy, dental extraction and
    delivery, and in several reported families the disorder was instead found
    incidentally on a routine platelet count. Bleeding scores in the largest
    series ranged from absent to high within the same disease, and one carrier
    of a severe bleeding score had a caesarean delivery complicated by
    postpartum haemorrhage requiring intensive care and transfusion.
  evidence:
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For all affected patients, the bleeding syndrome and MTP was mild to moderate."
    explanation: >-
      The severity statement for the families carrying the recurrent ITGA2B
      allele.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression"
    explanation: >-
      The wider range seen across ten families, including patients with no
      bleeding at all.
  downstream:
  - target: Bruising Susceptibility
    causal_link_type: DIRECT
    description: The commonest manifestation, and often the only one.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Epistaxis
    causal_link_type: DIRECT
    description: Mucosal bleeding, typically reported in childhood.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Gingival Bleeding
    causal_link_type: DIRECT
    description: Mucosal bleeding, including bleeding on tooth brushing.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Menometrorrhagia
    causal_link_type: DIRECT
    description: Heavy and irregular menstrual bleeding.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Post-Partum Hemorrhage
    causal_link_type: DIRECT
    description: >-
      The most serious reported complication, and the one that has required
      transfusion and intensive care.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Prolonged Bleeding After Surgery
    causal_link_type: DIRECT
    description: >-
      Post-tonsillectomy haemorrhage is the presentation in two reported
      families.
    hypothesis_groups:
    - constitutive_aiibb3_activation
  - target: Prolonged Bleeding After Dental Extraction
    causal_link_type: DIRECT
    description: >-
      A haemostatic challenge that reveals the disorder in some carriers and
      passes uneventfully in others.
    hypothesis_groups:
    - constitutive_aiibb3_activation

phenotypes:
- category: Hematologic
  name: Macrothrombocytopenia
  description: >
    A moderately reduced platelet count with enlarged platelets, and the
    defining feature of the disorder. Counts in reported ITGA2B families run
    from about 20 to 150 x 10^9/L, most often in the 60 to 120 range, and they
    are frequently found incidentally. It is curated as very frequent rather
    than obligate because one European-ancestry family carrying the recurrent
    p.Arg1026Trp variant had autosomal dominant thrombocytopenia with normal
    platelet size, which the authors attributed to modifier differences between
    genetic backgrounds.
  phenotype_term:
    preferred_term: Macrothrombocytopenia
    term:
      id: HP:0040185
      label: Macrothrombocytopenia
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H."
    explanation: >-
      Macrothrombocytopenia as the presenting phenotype of two ITGA2B R995W
      families.
  - reference: PMID:31119735
    reference_title: "Genome-wide linkage analysis and whole-exome sequencing identifies an ITGA2B mutation in a family with thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to our family (European ancestry), all previously reported families (Japanese ancestry) with HT due to the ITGA2B R1026W substitution exhibit macrothrombocytopenia (thrombocytopenia with large platelet size)"
    explanation: >-
      States that every previously reported family with the recurrent allele
      had macrothrombocytopenia.
  - reference: PMID:31119735
    reference_title: "Genome-wide linkage analysis and whole-exome sequencing identifies an ITGA2B mutation in a family with thrombocytopenia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a family with autosomal dominant (AD) thrombocytopenia with normal platelet size."
    explanation: >-
      The exception, in a family carrying the same ITGA2B variant, which is why
      this phenotype is not curated as obligate.

- category: Hematologic
  name: Platelet Anisocytosis
  description: >
    A wide platelet size distribution on the film and a raised platelet
    distribution width, which is the morphological signature that first
    separated these families from classic Glanzmann thrombasthenia. Some
    unaffected relatives in the largest series also showed it, so it is not by
    itself diagnostic.
  phenotype_term:
    preferred_term: Platelet anisocytosis
    term:
      id: HP:0032438
      label: Platelet anisocytosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PB smears revealed PLT macrocytosis and anisocytosis in most of the patients analyzed"
    explanation: >-
      The frequency of the finding across ten families, five of them with
      ITGA2B variants.
  - reference: PMID:22102273
    reference_title: "Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This was brought to light by the discovery of mutations at Arg995 in αIIb and Asp723 in β3 that lead to platelet anisotropy (increased size variation) and thrombocytopenia."
    explanation: >-
      Ties the size variation specifically to the alphaIIb Arg995 variants
      this entry curates.

- category: Hematologic
  name: Increased Mean Platelet Volume
  description: >
    The quantitative expression of the platelet size shift, and the measurement
    most likely to be available from a routine analyser. In the largest series
    the median value was 13 fL against a median of 8 fL in healthy relatives.
  phenotype_term:
    preferred_term: Increased mean platelet volume
    term:
      id: HP:0011877
      label: Increased mean platelet volume
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MPV was increased (>11fL) in 28/32 patients tested (88%), with a median value of 13fL"
    explanation: >-
      The proportion and the magnitude, from which the VERY_FREQUENT band is
      taken.

- category: Hematologic
  name: Giant Platelets
  description: >
    Platelets at the extreme of the size distribution, present in a variable
    fraction of patients rather than in all, and described in the first family
    reported before the gene was known.
  phenotype_term:
    preferred_term: Giant platelets
    term:
      id: HP:0001902
      label: Giant platelets
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:1638023
    reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy showed a wide diversity of platelet size including giant forms."
    explanation: >-
      The morphological description in the index patient later shown to carry
      ITGA2B R995Q.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sometimes with a variable fraction of giant PLT"
    explanation: >-
      The authors' own qualification, which is the basis for the OCCASIONAL
      band rather than a higher one.

- category: Hematologic
  name: Decreased Platelet Surface Glycoprotein IIb-IIIa
  description: >
    Surface alphaIIbbeta3 measured by flow cytometry, as CD41 or CD61, runs at
    roughly 40 to 70 per cent of normal. This is the laboratory finding that
    puts ITGA2B or ITGB3 in the differential of an inherited
    macrothrombocytopenia, and the degree of reduction distinguishes the
    disorder from classic Glanzmann thrombasthenia, where surface expression is
    typically below five per cent of normal.
  phenotype_term:
    preferred_term: Decreased platelet glycoprotein IIb-IIIa
    term:
      id: HP:0001975
      label: Decreased platelet glycoprotein IIb-IIIa
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:21454453
    reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."
    explanation: >-
      The measured range in the four families carrying the recurrent ITGA2B
      allele.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "decreased expression of αIIbβ3 (around half of the normal)"
    explanation: >-
      The same finding in the largest series, in the subgroup defined by
      variants at the alphaIIb Arg1026 residue.

- category: Hematologic
  name: Impaired Platelet Aggregation
  description: >
    Reduced, not absent, aggregation and dense-granule ATP release to ADP,
    collagen, epinephrine and arachidonic acid, with normal ristocetin
    agglutination. The pattern is the diagnostic one for this disorder, and the
    partial character of the reduction is what separates it at the bench from
    classic Glanzmann thrombasthenia.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired platelet aggregation/ATP release to physiological agonists"
    explanation: >-
      The laboratory phenotype reported for the series as a whole.
  - reference: PMID:1638023
    reference_title: "A defect of platelet aggregation associated with an abnormal distribution of glycoprotein IIb-IIIa complexes within the platelet: the cause of a lifelong bleeding disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aggregation of washed platelets with ADP was improved but remained subnormal, as was aggregation with collagen and thrombin."
    explanation: >-
      The agonist pattern in the index patient, including the partial
      correction on washing that distinguishes it from an absent response.

- category: Hematologic
  name: Abnormal Platelet Alpha-Granules
  description: >
    Enlarged alpha-granules, some giant and showing signs of fusion, on
    electron microscopy of large round platelets. It was described in families
    carrying salt-bridge variants including ITGA2B R995W, and the authors left
    open whether it characterises every variant that disturbs the alphaIIb
    Arg995 to beta3 Asp723 bridge.
  phenotype_term:
    preferred_term: Abnormal alpha granules
    term:
      id: HP:0012483
      label: Abnormal alpha granules
  evidence:
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α-granules with some giant forms showing signs of fusion."
    explanation: >-
      The morphometric description in the families reporting this finding, two
      of the three carrying ITGA2B R995W.
  - reference: PMID:29090484
    reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/β3 D723 salt bridge."
    explanation: >-
      The authors' own limit on how far the finding generalises, which is why
      no frequency is set here.

- category: Hematologic
  name: Bruising Susceptibility
  description: >
    Easy bruising with minor or no trauma, the commonest clinical manifestation
    and in several reported carriers the only one.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hemorrhagic symptoms consisted of easy bruising and menometrorrhagia, and she had no history of surgeries."
    explanation: >-
      The index patient of family 5, one of the five ITGA2B families in this
      series.
  - reference: PMID:24498605
    reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since her bleeding diathesis with easy epistaxis, bruising, and hemostatic difficulty after teeth extraction became worse at 9 years of age, she was referred to our hospital."
    explanation: >-
      The clinical picture in the most severely affected reported case, a
      compound heterozygote for ITGA2B p.Gly991Cys and a nonsense allele.

- category: Hematologic
  name: Epistaxis
  description: >
    Nosebleeds, typically reported in childhood and sometimes described as
    severe, which is the usual mucosal manifestation of a platelet-type
    bleeding disorder.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He reported bleeding after tonsillectomy at 7 years of age and epistaxis in childhood, as well as easy ecchymosis and gingival bleeding."
    explanation: >-
      The index patient of family 4, who carries the ITGA2B p.Arg1026Gln
      variant.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He reported severe epistaxis as a child, but he had had multiple dental extractions without hemorrhage; there was no history of surgeries."
    explanation: >-
      The index patient of family 3, carrying the recurrent ITGA2B allele, and
      an illustration of how selectively the bleeding presents.

- category: Hematologic
  name: Gingival Bleeding
  description: >
    Bleeding from the gums, including on tooth brushing, reported in several
    carriers in the largest series.
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as easy ecchymosis and gingival bleeding"
    explanation: >-
      The index patient of family 4, carrying an ITGA2B variant at Arg1026.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she also reported bleeding after tooth brushing and easy bruising without trauma"
    explanation: >-
      The mother in family 2, who carries the recurrent ITGA2B allele and had
      the highest bleeding score in that family.

- category: Reproductive
  name: Menometrorrhagia
  description: >
    Heavy and irregular menstrual bleeding, which in inherited platelet
    disorders generally is the manifestation with the most cumulative
    morbidity and the usual route to iron deficiency.
  phenotype_term:
    preferred_term: Menometrorrhagia
    term:
      id: HP:0400008
      label: Menometrorrhagia
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hemorrhagic symptoms consisted of easy bruising and menometrorrhagia, and she had no history of surgeries."
    explanation: >-
      The index patient of family 5, diagnosed at 16 years of age.

- category: Reproductive
  name: Post-Partum Hemorrhage
  description: >
    The most serious complication reported in this disorder. One carrier of the
    recurrent ITGA2B variant required labour induction for thrombocytopenia and
    had a caesarean delivery complicated by postpartum haemorrhage needing
    intensive care and red cell and platelet transfusion; other carriers in the
    same series delivered without bleeding, so the risk is real but not
    uniform.
  phenotype_term:
    preferred_term: Post-partum hemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cesarean delivery had been complicated by postpartum hemorrhage, demanding hospitalization in Intensive Care, and RBC and PLT transfusions"
    explanation: >-
      The severe obstetric course in the mother of the family 2 index case,
      who carries the recurrent ITGA2B allele.

- category: Hematologic
  name: Prolonged Bleeding After Surgery
  description: >
    Excessive bleeding after surgery, most often after tonsillectomy, which is
    the event that brought two of the reported ITGA2B families to attention.
    Other carriers have had major surgery without bleeding, in at least one case
    under desmopressin cover.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "submitted to tonsillectomy complicated by hemorrhage and needing to be transfused with red blood cells"
    explanation: >-
      The presentation of the first patient identified in the largest series,
      from an ITGA2B family.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He reported bleeding after tonsillectomy at 7 years of age and epistaxis in childhood"
    explanation: >-
      The same presentation in a second, unrelated ITGA2B family.

- category: Hematologic
  name: Prolonged Bleeding After Dental Extraction
  description: >
    Bleeding after tooth extraction, which is one of the haemostatic challenges
    that reveals the disorder. It is inconsistent: in the largest series one
    carrier of the recurrent ITGA2B variant had multiple extractions without
    haemorrhage.
  phenotype_term:
    preferred_term: Prolonged bleeding after dental extraction
    term:
      id: HP:0006298
      label: Prolonged bleeding after dental extraction
  evidence:
  - reference: PMID:24498605
    reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemostatic difficulty after teeth extraction became worse at 9 years of age"
    explanation: >-
      The finding in a patient carrying ITGA2B p.Gly991Cys, noting that she is
      a compound heterozygote with a nonsense allele and sits at the severe end
      of the spectrum.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "he had had multiple dental extractions without hemorrhage"
    explanation: >-
      A carrier of the recurrent ITGA2B allele for whom the same challenge
      passed uneventfully, which contradicts this being a consistent feature of
      the disease.

genetic:
- name: ITGA2B
  gene_term:
    preferred_term: ITGA2B
    term:
      id: hgnc:6138
      label: ITGA2B
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >
    ITGA2B, at 17q21.31, encodes the alphaIIb subunit of integrin
    alphaIIbbeta3, the platelet fibrinogen and von Willebrand factor receptor.
    The same gene causes two mechanistically opposite diseases: biallelic
    loss-of-function variants cause Glanzmann thrombasthenia, while the
    heterozygous variants of this disorder raise the activation state of the
    receptor. Reported alleles cluster in the membrane-proximal region, with
    p.Arg1026Trp (legacy R995W) recurrent on at least two haplotypes and
    p.Arg1026Gln (legacy R995Q) the first identified. No ClinGen Gene-Disease
    Validity assertion for this gene-disease pair is cached in this repository,
    so no gene_disease_validity tier is recorded.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia."
    explanation: >-
      Names the gene-disease relationship and the disorder's alternative names
      in one sentence.
  - reference: PMID:31119735
    reference_title: "Genome-wide linkage analysis and whole-exome sequencing identifies an ITGA2B mutation in a family with thrombocytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous or compound heterozygous loss of function mutations in ITGA2B result in Glanzmann thrombasthenia, a bleeding disorder characterized by normal platelet count but abnormal platelet function."
    explanation: >-
      The contrast that makes zygosity and variant mechanism, not the gene,
      the thing that distinguishes the two diseases.
  variants:
  - name: ITGA2B p.Arg1026Trp
    description: >-
      The recurrent allele, legacy name R995W. Reported in four unrelated
      Japanese families in the first molecular series, in further Japanese,
      French and Portuguese families, and in one European-ancestry family in
      which it arose on a different haplotype. The substitution is a C to T
      transition at a CpG site.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33276370
      reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This family was subsequently found to have a heterozygous variant in ITGA2B (p.Arg1026Trp), in common with a case published in 2011"
      explanation: >-
        The sentence introducing the variant in the first family of the series;
        the table of that paper gives it as NM_000419.4:c.3076C>T,
        p.(Arg1026Trp), classified pathogenic by legacy.
  - name: ITGA2B p.Arg1026Gln
    description: >-
      Legacy name R995Q, the first natural variant found in the alphaIIb GFFKR
      motif, in the patient described in 1992 with giant platelets and a mild
      thrombasthenia-like syndrome, and found again in one Portuguese family.
      The transfected receptor was not constitutively active in that first
      study, which is the main exception to the activation mechanism.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:9834222
      reference_title: "R to Q amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin IIb subunit in a patient with a Glanzmann's thrombasthenia-like syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is the first reported natural mutation in the highly conserved GFFKR sequence of the IIb cytoplasmic domain."
      explanation: >-
        Establishes the allele as the first of its class to be described.
  - name: ITGA2B p.Gly991Cys
    description: >-
      A GFFKR-motif substitution in legacy numbering, identified in a Japanese
      patient who also carried the nonsense allele p.Arg422* in trans and had
      the most severe reported phenotype, with surface alphaIIbbeta3 at 3 to 11
      per cent of control.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:24498605
      reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One patient, who showed Glanzmann thrombasthenia-like marked reduction in surface αIIbβ3 expression (3-11% of normal control), was a compound heterozygote with ITGA2B p.Gly991Cys and a novel nonsense mutation, ITGA2B p.Arg422*."
      explanation: >-
        The genotype and the degree of surface reduction that places this
        patient between the two diseases.
  - name: ITGA2B p.Phe993del
    description: >-
      An in-frame single-residue deletion in the GFFKR motif in legacy
      numbering, heterozygous, in a Japanese family with macrothrombocytopenia
      and no bleeding history in the index case.
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:24498605
      reference_title: "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells."
      explanation: >-
        The functional demonstration for this allele, alongside the other two
        in the same study.
  - name: ITGA2B p.Gly1007Val
    description: >-
      A transmembrane-domain substitution reported as new in the largest
      series, at one of the glycines of the outer membrane clasp rather than in
      the cytoplasmic inner clasp, and classified there as a variant of
      uncertain significance.
    variant_type: single nucleotide variant
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    evidence:
    - reference: PMID:33276370
      reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "one of the novel variants found in our patients (αIIb: p.Gly1007Val) is a glycine substitution at αIIb p.Gly1007, interfering with inter-helical packing of the αIIb and β3 TMD"
      explanation: >-
        States where the variant sits and the structural interaction it is
        proposed to disturb, which is the outer rather than the inner membrane
        clasp.

biochemical:
- name: Platelet surface alphaIIbbeta3 expression by flow cytometry
  presence: DECREASED
  context: >-
    Measured as CD41 (alphaIIb) or CD61 (beta3) binding on resting platelets
    and reported as a percentage of a normal control. In this disorder it sits
    at roughly 40 to 70 per cent of normal, which is the range that
    distinguishes it both from normal and from classic Glanzmann
    thrombasthenia, where the surface receptor is typically almost absent. The
    reduction correlates inversely with mean platelet volume across patients.
    The total platelet content of the receptor is far better preserved than the
    surface pool, because the missing fraction has been internalised.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  readouts:
  - target: Receptor Internalisation and Reduced Surface alphaIIbbeta3
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A partial reduction in surface alphaIIbbeta3 in a patient with
      macrothrombocytopenia is the finding that points at ITGA2B or ITGB3, and
      its degree is what separates this disorder from classic thrombasthenia.
    evidence:
    - reference: PMID:21454453
      reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control."
      explanation: >-
        The measured range in the families carrying the recurrent ITGA2B
        allele, expressed against a control as the assay reports it.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, GPIIb/IIIa and GPIIIa expression levels correlated inversely and moderately with the MPV values"
    explanation: >-
      Links the biochemical readout to the platelet size phenotype within the
      same patients, which is what a single mechanism acting on both predicts.
  notes: >-
    No reference interval is recorded here. Every cited study reports the result
    as a percentage of its own normal control rather than against a published
    interval, and a percentage-of-control figure is not a reference range.

- name: Immature platelet fraction
  presence: INCREASED
  context: >-
    The fraction of circulating platelets that are reticulated and recently
    released. It is raised in this disorder, with median values of 13 to 27 per
    cent across families in the largest series against a stated normal range of
    1 to 7 per cent, and it correlates with mean platelet volume and platelet
    distribution width. A raised value with a low count is the pattern of a
    production disorder releasing large young platelets, not of accelerated
    peripheral destruction.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  readouts:
  - target: Reduced Output of Enlarged Circulating Platelets
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reports the abnormal platelet production arm of the disorder rather than
      its platelet function arm.
    evidence:
    - reference: PMID:33276370
      reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The IPF correlated positively with the MPV and the PDW values"
      explanation: >-
        The correlation that ties the young-platelet fraction to the size
        abnormality this node produces.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased IPF values (median of 14%)"
    explanation: >-
      A representative median in the subgroup of families that includes the
      ITGA2B variants, against the 1 to 7 per cent normal range stated in the
      same paper's methods.

diagnosis:
- name: Flow cytometry of platelet surface alphaIIbbeta3
  diagnosis_term:
    preferred_term: flow cytometry of platelet CD41 and CD61
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  description: >
    The test that points at the gene. A partial reduction of CD41 or CD61 on
    resting platelets, to roughly half of a normal control, in a patient with
    macrothrombocytopenia, is the finding that distinguishes this disorder both
    from other inherited macrothrombocytopenias and from classic Glanzmann
    thrombasthenia. Spontaneous PAC-1 or bound-fibrinogen binding on resting
    platelets can be looked for in the same assay, but it is present in only a
    minority of patients and was seen at a similar rate in healthy controls in
    the largest series, so it confirms nothing when absent.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes."
    explanation: >-
      The combination of findings that defines the series, and so the pairing
      the test is looking for.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls."
    explanation: >-
      Why the activation arm of the same assay is not a diagnostic criterion.

- name: Light transmission aggregometry
  description: >
    Reduced but present aggregation and ATP release to ADP, collagen,
    epinephrine and arachidonic acid, with preserved ristocetin agglutination.
    The partial response is what distinguishes the trace from classic Glanzmann
    thrombasthenia, and closure times on a platelet function analyser are
    prolonged without reaching thrombasthenic values. No ontology term is bound
    here: NCIT codes platelet aggregometry only as data elements such as
    NCIT:C114210 Platelet Aggregometry Curve Type, which are not clinical
    procedures under NCIT:C25218 and so cannot fill this slot.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired platelet aggregation/ATP release to physiological agonists"
    explanation: >-
      The aggregometry finding as the series reports it.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Markedly increased closure times, such as those typically found in GT, have never been observed"
    explanation: >-
      The negative that keeps a thrombasthenic trace from being expected here.

- name: Peripheral blood film and platelet indices
  description: >
    The cheapest step and often the one that raises the possibility at all: a
    low platelet count with a raised mean platelet volume and platelet
    distribution width, macrocytic and anisocytic platelets on the film, and
    sometimes giant forms. A raised immature platelet fraction alongside them
    argues for impaired production rather than peripheral destruction. Automated
    counters undercount very large platelets, so the count may read lower than
    it is. No ontology term is bound: NCIT:C79903 Blood Smear names the
    specimen rather than a clinical procedure and is not reachable from
    NCIT:C25218, so it fails the TreatmentActionTerm enum this slot uses.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PB smears revealed PLT macrocytosis and anisocytosis in most of the patients analyzed"
    explanation: >-
      The film findings across the series, which is what makes this the first
      test rather than a confirmatory one.

- name: ITGA2B sequencing within a hereditary platelet disorder panel
  diagnosis_term:
    preferred_term: multi-gene panel sequencing of ITGA2B and ITGB3
    term:
      id: NCIT:C198412
      label: Multi-gene Panel Sequencing
  description: >
    Confirms the diagnosis. In practice ITGA2B and ITGB3 are sequenced inside a
    hereditary platelet or haematological disease panel rather than as
    single-gene tests, and the authors of the largest series argue that
    sequencing without platelet phenotyping is the wrong order to work in,
    because a heterozygous variant in either gene has to be interpreted against
    the platelet count, the platelet size and the surface receptor level before
    it means this disease rather than Glanzmann thrombasthenia carriership or
    nothing.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of ITGA2B and ITGB3 genes was performed by NGS in selected patients from families with novel variants, using a commercially available gene panel for hematologic diseases"
    explanation: >-
      How the testing is actually done, on a panel rather than gene by gene.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study favors the idea that screening mutations by NGS alone (without performing phenotypic studies) may not be the best approach"
    explanation: >-
      The authors' caution about sequencing without phenotyping, which is the
      interpretive point this entry records.

- name: Distinction from acquired thrombocytopenia
  description: >
    Not a test but the decision the tests are for. Patients in the largest
    series had been followed for years with a diagnosis of chronic
    thrombocytopenia, and some had been treated as having autoimmune or
    gestational thrombocytopenia, which carries the cost of corticosteroids and
    platelet transfusions that cannot work. A family history is not always
    apparent, since relatives are often unaware of their own counts.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some had been misdiagnosed (e.g. autoimmune thrombocytopenia, gestational thrombocytopenia), with therapeutic implications (e.g. corticosteroids and PLT transfusions)"
    explanation: >-
      The misdiagnoses documented in this series and the treatment consequence
      of each.
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "even when a familial history is not obvious (as many patients are unaware of a family history of thrombocytopenia)"
    explanation: >-
      Why an absent family history does not exclude an inherited disorder here.
  - reference: PMID:16169642
    reference_title: "Congenital macrothrombocytopenias."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura."
    explanation: >-
      The same error described for the congenital macrothrombocytopenias as a
      class, the group this disorder belongs to. Graded INDIRECT because the
      review predates the molecular definition of this entity.

treatments:
- name: Desmopressin
  description: >
    Peri-procedural cover, and the option with the most direct support in an
    ITGA2B family: the first patient identified in the largest series had two
    caesarean sections and spinal surgery under desmopressin without bleeding,
    having previously haemorrhaged after a tonsillectomy performed without
    cover. It does nothing to the integrin. It raises plasma von Willebrand
    factor and factor VIII and shortens the bleeding time, so it improves the
    conditions in which a defective platelet works rather than correcting the
    platelet.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  target_mechanisms:
  - target: Failure of Primary Hemostatic Plug Formation
    treatment_effect: BYPASSES
    description: >-
      Acts around the platelet lesion rather than on it, by improving the
      plasma contribution to primary haemostasis.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient subsequently underwent two caesarean sections and spinal surgery with desmopressin without bleeding, and she had no significant hemorrhagic symptoms in addition to easy bruising."
    explanation: >-
      Three uneventful procedures under desmopressin in a patient from an
      ITGA2B family whose earlier unprotected tonsillectomy had bled. Observed
      in one patient, not a trial.
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Places desmopressin among the established options. Graded INDIRECT
      because the review addresses inherited platelet disorders as a class and
      no trial exists in this disorder.

- name: Tranexamic Acid
  description: >
    Antifibrinolytic cover for procedures and for menorrhagia, which is the
    manifestation with the most cumulative morbidity here. It stabilises the
    clot that a reduced number of poorly aggregating platelets manages to
    build, and does not touch the underlying defect. No study of it exists in
    this disorder; the recommendation is inherited from the management of
    inherited platelet disorders generally.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Mucocutaneous Bleeding Diathesis
    treatment_effect: BYPASSES
    description: >-
      Reduces bleeding without altering platelet number or function, by
      slowing dissolution of the clot that does form.
  evidence:
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Class-level support. Graded INDIRECT for the same reason as desmopressin
      above.
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Special attention is given to the treatment of menorrhagia and risk management during pregnancy in women with IPDs."
    explanation: >-
      Identifies the two clinical situations that dominate management in this
      disorder, which is where antifibrinolytic cover is used.

- name: Platelet Transfusion
  description: >
    Reserved for serious bleeding and for major surgery. It supplies platelets
    with a normal integrin in normal number, so unlike the other options it
    corrects both arms of the defect for as long as the transfused platelets
    survive. In the largest series it was used for postpartum haemorrhage in a
    carrier of the recurrent ITGA2B variant, and prophylactically before
    surgery and delivery in other families. Repeated exposure carries an
    alloimmunisation risk, which in this disorder is not the
    anti-alphaIIbbeta3 isoimmunisation seen in Glanzmann thrombasthenia, since
    these patients express the receptor.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: platelet transfusion
    term:
      id: NCIT:C15366
      label: Platelet Transfusion
  target_mechanisms:
  - target: Failure of Primary Hemostatic Plug Formation
    treatment_effect: RESTORES
    description: >-
      Replaces the deficient and dysfunctional platelet pool with a competent
      one for the life of the transfused platelets.
  evidence:
  - reference: PMID:33276370
    reference_title: "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cesarean delivery had been complicated by postpartum hemorrhage, demanding hospitalization in Intensive Care, and RBC and PLT transfusions"
    explanation: >-
      Platelet transfusion used for the most serious reported complication, in
      a carrier of the recurrent ITGA2B allele.
  - reference: PMID:37611608
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Class-level support for platelet concentrates. INDIRECT for the same
      reason as above.

experimental_models:
- name: alphaIIb-W995/beta3-transduced mouse fetal liver-derived megakaryocytes
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  cell_source: Mouse fetal liver haematopoietic cells, retrovirally transduced
  publication: PMID:21454453
  description: >
    Megakaryocytes differentiated from mouse fetal liver cells after
    transduction with the human alphaIIb R995W allele together with beta3. This
    is the model that connects the receptor lesion to the platelet count: it
    puts the patient's allele into a cell that actually makes platelets, and
    asks what the proplatelets look like.
  modeled_mechanisms:
  - target: Abnormal Proplatelet Formation by Megakaryocytes
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Transduced megakaryocytes form proplatelets with fewer and larger tips,
      which is the cellular defect this node asserts.
    limitations: >-
      The human allele is expressed in a mouse megakaryocyte alongside the
      endogenous mouse integrin and at a transduced rather than heterozygous
      level, so the gene dosage is not the patient's. Proplatelet tips in
      culture are a surrogate for platelet release in the marrow, and no
      platelet count or bleeding phenotype is measured.
    readouts:
    - name: Proplatelet tip number and size
      target: Abnormal Proplatelet Formation by Megakaryocytes
      direction: ALTERED
      interpretation: >-
        Fewer tips of larger size is the culture correlate of releasing fewer
        and larger platelets.
      evidence:
      - reference: PMID:21454453
        reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation."
        explanation: >-
          The measurement and the authors' reading of it.
    evidence:
    - reference: PMID:21454453
      reference_title: "Heterozygous ITGA2B R995W mutation inducing constitutive activation of the αIIbβ3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias."
      explanation: >-
        The inference this model licenses, and the reason it is treated as
        informative for the production defect.

- name: Patient-derived megakaryocyte cultures from ITGA2B R995W carriers
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  cell_source: Megakaryocytes cultured from patients carrying ITGA2B R995W or ITGB3 D723H
  publication: PMID:29090484
  description: >
    Megakaryocyte maturation and proplatelet formation studied in cultures from
    patients themselves, in three families of which two carry ITGA2B R995W. The
    value of the model is that the genotype, the dosage and the species are the
    patient's, so it answers where in megakaryocyte development the defect sits
    without extrapolation.
  modeled_mechanisms:
  - target: Abnormal Proplatelet Formation by Megakaryocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Early maturation is normal and proplatelet formation is abnormal with
      enlarged tips, which localises the defect to the terminal step.
    limitations: >-
      Three families and a small number of cultures, with the ITGA2B and ITGB3
      genotypes analysed together, so the model does not separate the two
      genes. Proplatelet morphology in culture remains a surrogate for platelet
      release in vivo.
    readouts:
    - name: Megakaryocyte maturation and proplatelet tip size
      target: Abnormal Proplatelet Formation by Megakaryocytes
      direction: ALTERED
      interpretation: >-
        Normal maturation with abnormally large proplatelet tips is the
        pattern that excludes a maturation arrest as the cause of the low
        platelet count.
      evidence:
      - reference: PMID:29090484
        reference_title: "Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips."
        explanation: >-
          The two findings together, which is what makes this a terminal-step
          defect.

discussions:
- discussion_id: gap_which_arm_causes_the_bleeding
  kind: KNOWLEDGE_GAP
  prompt: >-
    In ITGA2B-related macrothrombocytopenia, how much of the bleeding is due to
    the reduced platelet count and how much to the platelet function defect?
  rationale: >-
    The disorder breaks both the quantitative and the qualitative arm of
    primary haemostasis, and the two have never been separated in carriers of an
    ITGA2B variant. The question is not academic: it decides whether management
    should aim at the count, at platelet function, or only at local and
    antifibrinolytic measures, and it is the likeliest explanation for why
    bleeding severity tracks neither the platelet count nor the surface receptor
    level well. The one study that argues the question directly did so in
    patients carrying an ITGB3 allele and concluded that the cytoskeletal
    defect, not the count, is the effector of bleeding.
  attaches_to:
  - pathophysiology#Failure of Primary Hemostatic Plug Formation
  - phenotypes#Macrothrombocytopenia

- discussion_id: gap_activation_negative_alleles
  kind: KNOWLEDGE_GAP
  prompt: >-
    What explains macrothrombocytopenia in carriers whose receptor shows no
    constitutive activation?
  rationale: >-
    Constitutive activation is the mechanism this entry curates, but it is not
    demonstrable for every allele or every patient: the transfected R995Q
    receptor was not locked into a high activation state, and in the largest
    series spontaneous PAC-1 binding appeared in a minority of patients and in
    healthy controls at a similar rate. Either the assays read the platelet
    pool too crudely, or some of these variants act on megakaryocyte
    cytoskeletal signalling without a detectable shift in receptor
    conformation, which is also what has been proposed for the non-activating
    ITGB3 variants described more recently.
  attaches_to:
  - pathophysiology#Constitutive Partial alphaIIbbeta3 Activation

references:
- reference: PMID:22102273
  title: "Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin."
- reference: PMID:41503871
  title: "ITGA2B/ITGB3-Related Macrothrombocytopenia Associated With Gain-of-Function Mutations in ITGA2B or ITGB3 Genes."

📚

References & Deep Research

References

PMID:22102273

Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin.

No top-level findings curated for this source.

PMID:41503871

ITGA2B/ITGB3-Related Macrothrombocytopenia Associated With Gain-of-Function Mutations in ITGA2B or ITGB3 Genes.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Platelet-type Bleeding Disorder 16 · 2026-09-30T20:10:31Z · View source

New Mendelian entry for BDPLT16 (MONDO:0008552, OMIM 187800), autosomal dominant ITGA2B-related macrothrombocytopenia. Scope decision: entry_type DISEASE, scoped to ITGA2B. MONDO's definition names both ITGA2B and ITGB3, but OMIM (mirrored by MedGen UID 1781222) restricts BDPLT16 to ITGA2B and curates the ITGB3 form as BDPLT24 (OMIM 619271, MONDO:0030996), which still has its own stub (stubs/Bleeding_Disorder_Platelet-type_24.yaml). ITGB3 is therefore not curated as a subtype here; it appears in prose and in class-level mechanistic evidence only, each such item graded directness INDIRECT. Kept distinct from kb/disorders/Glanzmann_Thrombasthenia.yaml, which already records this disorder as a differential with the inverse mechanism; that file was not edited. Content: 11-node causal chain from the ITGA2B membrane-proximal variant through disruption of the alphaIIb Arg995-beta3 Asp723 inner membrane clasp, constitutive partial integrin activation, persistent outside-in signalling, and the two consequence arms (abnormal proplatelet formation, receptor internalisation plus arrested platelet cytoskeletal remodelling) to the shared plug-failure and bleeding endpoints. 14 phenotypes, all causally connected (just list-disconnected-phenotypes reports 14/14). conforms_to primary_hemostatic_plug_failure at the component-loss node, the alphaIIbbeta3 aggregation arm, the plug-failure key target and the mucocutaneous-bleeding node; the quantitative production arm is deliberately left unconformed because that module scopes itself out of it. Two REFUTE evidence items are recorded on the constitutive-activation node (the R995Q transfectant was not constitutively active; the largest series detected spontaneous PAC-1 binding in a minority of patients and in controls at a similar rate) and one on macrothrombocytopenia (a family with the recurrent allele and normal platelet size). Deep research: openscientist run completed (research/Platelet-type_Bleeding_Disorder_16-deep-research-openscientist.md, 15 citations, plus final_report.html/pdf artifacts). The run wrote no validation sections, so they were added with just validate-research-reference and read: 16/16 references resolved, 0 unresolved, 0 off topic, 1 of 11 quoted claims not matched (PMID:40123272, whose closest text in the source is identical, so it looks like a normalisation artefact rather than a bad quote); term validation resolved 30/32 with 0 unresolved and no wrong-term bindings. The report is unambiguously about this disease (36 mentions of BDPLT16/OMIM 187800/MONDO:0008552). just preflight-dr returned WARN, for reasons that match the scope decision above: ITGA2B is mentioned 21 times but ITGB3 26, and the report cites OMIM 173470 and 607759 (the ITGB3 and ITGA2B gene entries) where MONDO:0008552 xrefs OMIM 187800 (the disease). Reading the ITGB3 sections confirmed they describe the sibling ITGB3 form and the shared receptor rather than a different report subject, which is why they are used only as class-level mechanistic evidence graded INDIRECT. Two DR citations were deliberately not used, PMID:40123272 and PMID:41778036, because both report Glanzmann thrombasthenia cohorts and would have imported a different disease's management evidence; that reasoning is recorded in the entry notes. Two DR citations were added: PMID:23926302 (murine sitosterolemia phenocopy, INDIRECT) and PMID:16169642 (congenital macrothrombocytopenia review, for the ITP-misdiagnosis point). The remaining entry evidence was found by PubMed search before the report landed. Checks run: just validate, validate-terms (passed), count-verified-snippets (100/100), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-coarse-phenotypes, check-folded-hyphens, check-environmental-evidence, check-enum-values, check-case-collisions, list-disconnected-phenotypes, list-gene-term-mismatches (0 findings), check-genereviews --online (NO_CHAPTER for GeneReviews; the StatPearls CANDIDATE_CHAPTER is the Glanzmann thrombasthenia chapter matched via a synonym and is not a baseline for this disease), normalize-cache, check-term-cache-integrity, validate-disorders. NCIT:C79903 Blood Smear was tried and rejected for the blood-film diagnosis entry because it is not reachable from NCIT:C25218; that slot is left unbound with the reason in its description. Follow-up in a later commit on the same branch: check_gene_activity_grounding reported ITGA2B as newly ungrounded, because the node the gene lands on carried no molecular_functions and the gene reached none that did. GO:0070051 fibrinogen binding (confirmed a molecular_function via the OLS API, not from memory) is now bound on that trigger node with modifier DYSREGULATED, and two evidence items were added there for the two halves of that modifier: fibrinogen binds resting platelets that have not been activated (PMID:21454453), and agonist-induced fibrinogen binding is reduced because less receptor remains on the surface (PMID:33276370). DYSREGULATED rather than INCREASED or GAIN_OF_FUNCTION precisely because of the second half and because of the REFUTE items on the activation node, which would make a one-directional modifier overstate the evidence. The gate then reports OK with no baseline change. A further commit added reference_title to all 102 evidence items with just backfill-reference-titles, which copies each title verbatim from the title frontmatter of the matching references_cache file; the change is 102 inserted lines and nothing else, and an independent script reading the same frontmatter produced a byte-identical file.

OpenScientist ▸

Platelet-type Bleeding Disorder 16 (BDPLT16): Comprehensive Disease Characteristics Report

openscientist-autonomous 15 citations 2026-09-30T20:02:27.240649

Platelet-type Bleeding Disorder 16 (BDPLT16): Comprehensive Disease Characteristics Report

Disease: Platelet-type Bleeding Disorder 16 (BDPLT16) Also known as: ITGA2B/ITGB3-related macrothrombocytopenia; Glanzmann thrombasthenia-like syndrome (GTLS); autosomal dominant macrothrombocytopenia with αIIbβ3 gain-of-function OMIM: #187800 · MONDO: MONDO:0008552 · ICD-10: D69.1 · Category: Mendelian (autosomal dominant)

Summary

Platelet-type Bleeding Disorder 16 (BDPLT16) is a rare, autosomal dominant inherited platelet disorder defined at the molecular level by heterozygous gain-of-function variants in ITGA2B (encoding integrin αIIb/GPIIb) or ITGB3 (encoding integrin β3/GPIIIa). These variants cluster in the membrane-proximal (transmembrane and cytoplasmic) region of the αIIbβ3 integrin and disrupt the conserved intracytoplasmic salt bridge between αIIb-Arg995 and β3-Asp723. Loss of this clasp releases the integrin from its resting conformation, producing a constitutively active αIIbβ3 receptor. This is the mechanistic inverse of classic Glanzmann thrombasthenia (GT), which is caused by recessive loss-of-function of the same genes.

Constitutive αIIbβ3 activation drives permanent "outside-in" signaling in megakaryocytes, which perturbs cytoskeletal (actin/tubulin) dynamics and produces abnormal proplatelet formation. The clinical consequence is a macrothrombocytopenia — large platelets present in reduced numbers — together with reduced αIIbβ3 surface expression (from receptor internalization), a partial (not absent) platelet aggregation defect, and lifelong, usually mild-to-moderate mucocutaneous bleeding (easy bruising, epistaxis, gum bleeding, menorrhagia). Enlarged and fused α-granules are seen ultrastructurally. Because the count is low and the platelets are large, patients are frequently misdiagnosed as immune thrombocytopenia (ITP) and treated ineffectively with corticosteroids/splenectomy.

BDPLT16 is genetically and mechanistically distinct from recessive GT; diagnosis rests on recognizing dominant inheritance, macrothrombocytopenia with reduced (not absent) αIIbβ3, a partial aggregation defect, and an activating membrane-proximal ITGA2B/ITGB3 variant on next-generation sequencing. No disease-specific or curative therapy exists; management is supportive and extrapolated from inherited platelet function disorders — antifibrinolytics (tranexamic acid), recombinant activated factor VII (rFVIIa), platelet transfusion for major bleeds/surgery, and hormonal control of heavy menstrual bleeding. This report synthesizes the molecular pathogenesis, phenotype, genetics, diagnostics, prognosis, treatment, and model systems across all requested disease-characteristic domains.

1. Disease Information

Overview. BDPLT16 is a Mendelian inherited platelet disorder in which a dominant gain-of-function lesion in the fibrinogen receptor αIIbβ3 produces large, poorly functional platelets in reduced numbers, causing a lifelong mild-to-moderate bleeding tendency. It belongs to the broader family of congenital macrothrombocytopenias and is a recognized subset now termed ITGA2B/ITGB3-related macrothrombocytopenia (PMID: 41503871).

Key identifiers.

Resource	Identifier
OMIM	#187800 (Bleeding disorder, platelet-type, 16; BDPLT16)
MONDO	MONDO:0008552
ICD-10	D69.1 (Qualitative platelet defects)
Causal genes	ITGA2B (HGNC:6138; OMIM 607759; NCBI Gene 3674; Ensembl ENSG00000005961; UniProt P08514; 17q21.31) · ITGB3 (HGNC:6156; OMIM 173470; NCBI Gene 3690; UniProt P05106; 17q21.32)

Synonyms / alternative names. ITGA2B/ITGB3-related macrothrombocytopenia; Glanzmann thrombasthenia-like syndrome (GTLS); autosomal dominant macrothrombocytopenia with αIIbβ3 gain-of-function; αIIbβ3-related macrothrombocytopenia.

Source of information. Information is derived from aggregated disease-level resources (OMIM, MONDO) and from primary clinical/genetic case series and pedigrees of individual patients — not from population EHR datasets. The evidence base is a set of small multi-generational families reported worldwide (see Section 9).

2. Etiology

Primary cause — genetic (monogenic, dominant, gain-of-function). BDPLT16 is caused by heterozygous gain-of-function variants in ITGA2B or ITGB3. These are point mutations (and small in-frame deletions) concentrated in the membrane-proximal region of the integrin that destabilize the αIIb-R995/β3-D723 intracytoplasmic salt bridge, causing constitutive activation (PMID: 29090484; PMID: 29380037; PMID: 33276370).

Genetic risk factors. The causal variants are themselves the disease determinant; there are no known separate susceptibility loci. Documented disease alleles include (non-exhaustive): - ITGB3 (β3): p.Asp723His (D723H), p.Thr720del (T720del), D749H, T746P, H748P, R760C, plus membrane-proximal missense/deletion variants (e.g., C560R, βTD_del p.647-686 in Glanzmann-like macrothrombocytopenia). - ITGA2B (αIIb): p.Arg995Trp (R995W), R995Q, R1026W, R1026Q, G1007V.

Environmental / demographic risk factors. As a monogenic dominant disorder, the disease is not caused by environmental exposures. Relevant non-genetic modifiers of bleeding severity (not disease causation) are standard hemostatic challenges: surgery, trauma, dental extraction, childbirth/postpartum, menstruation, and antiplatelet/anticoagulant drug use. Female sex confers additional gynecologic/obstetric bleeding burden (menorrhagia, postpartum hemorrhage). A positive family history is a hallmark given dominant transmission.

Protective factors. No specific genetic or environmental protective factors are established. General avoidance of antiplatelet agents (aspirin, NSAIDs) reduces bleeding risk. There is no evidence of a protective allele.

Gene–environment interactions. No formal GxE interaction has been characterized. Practically, the penetrant genetic lesion sets a fixed platelet phenotype whose clinical expression is unmasked by hemostatic stressors (surgery, trauma, menstruation, delivery).

3. Phenotypes

BDPLT16 phenotypes comprise laboratory abnormalities and clinical bleeding signs/symptoms. Bleeding is typically mild-to-moderate, lifelong, and mucocutaneous; severity is variable even within families.

Phenotype	Type	Characteristics	Suggested HPO term
Thrombocytopenia	Lab abnormality	Congenital, lifelong, stable; reduced platelet count	HP:0001873 Thrombocytopenia
Large/giant platelets (macrothrombocytopenia)	Lab/morphologic	Enlarged round platelets on smear; increased anisotropy	HP:0040326 Increased mean platelet volume
Reduced αIIbβ3 surface expression	Lab abnormality	Low (not absent) GPIIb/IIIa by flow cytometry	HP:0011876 Abnormal platelet function
Impaired platelet aggregation	Lab abnormality	Reduced (not absent) response to ADP, collagen, TRAP-6; ristocetin normal	HP:0003540 Impaired platelet aggregation
Reduced ATP/dense-granule release	Lab abnormality	Low ATP release to physiologic agonists	HP:0011876 Abnormal platelet function
Enlarged/fused α-granules	Ultrastructural	Abnormal large α-granules, some giant/fused	—
Easy bruising / mucocutaneous bleeding	Clinical sign	Mild-moderate, episodic (provoked by trauma/surgery)	HP:0000978 Bruising susceptibility
Epistaxis	Clinical sign	Recurrent, mild-moderate	HP:0000421 Epistaxis
Gingival/gum bleeding	Clinical sign	Mucosal	HP:0000225 Gingival bleeding
Menorrhagia / heavy menstrual bleeding	Clinical sign	Prominent in affected women; may be chronic	HP:0000132 Abnormal menstruation (menorrhagia)
Prolonged bleeding after surgery/trauma	Clinical sign	Episodic, provoked	HP:0004846 Abnormal bleeding

Age of onset. Congenital laboratory phenotype (thrombocytopenia/large platelets present from birth); bleeding symptoms emerge in childhood and persist lifelong. Severity is mild-to-moderate and variable; progression is stable (non-progressive), with bleeding episodic and provoked by hemostatic challenge.

Frequency among affected individuals. In the largest series (10 Portuguese GTLS families, 33 patients), the core lab tetrad — macrothrombocytopenia, low αIIbβ3 expression, impaired aggregation/ATP release, and low PAC-1 binding — was essentially universal, while clinical bleeding ranged from absent to moderate (PMID: 33276370).

Quality of life impact. Generally modest given mild-moderate severity, but recurrent epistaxis and especially menorrhagia can meaningfully impair quality of life and cause iron-deficiency anemia; peri-operative and peri-partum periods carry the highest morbidity risk. No disease-specific EQ-5D/SF-36 data are available.

4. Genetic / Molecular Information

Causal genes. ITGA2B (αIIb; HGNC:6138; OMIM 607759; 17q21.31) and ITGB3 (β3; HGNC:6156; OMIM 173470; 17q21.32). The two chains form the heterodimeric platelet fibrinogen receptor αIIbβ3 (GPIIb/IIIa, integrin αIIbβ3), expressed at ~60,000–80,000 copies per platelet in mouse and abundantly in human platelets (PMID: 11154120).

Pathogenic variants (representative).

Gene	Variant	Type	Effect
ITGB3	p.Asp723His (D723H)	Missense	Breaks αIIb-R995/β3-D723 salt bridge → constitutive activation
ITGB3	p.Thr720del (T720del)	In-frame deletion	Spontaneous αIIbβ3 activation
ITGB3	D749H, T746P, H748P, R760C	Missense	Membrane-proximal, activating
ITGB3	C560R (EGF-like domain)	Missense	Constitutive activation, differing surface expression
ITGB3	βTD_del (p.647-686)	In-frame deletion	Constitutive activation (β-tail domain)
ITGA2B	p.Arg995Trp/Gln (R995W/Q)	Missense	Breaks salt bridge → constitutive activation
ITGA2B	R1026W, R1026Q, G1007V	Missense	Membrane-proximal, activating

Variant classification. ClinVar corroborates BDPLT16 alleles: ITGB3 Asp723His and ITGA2B Arg995 (R995W/R995Q) records are present, and ~8 ITGA2B records are annotated to "macrothrombocytopenia" (Finding F008). The majority of ITGA2B (≈345) and ITGB3 (≈266) pathogenic ClinVar entries reflect the allelic recessive Glanzmann thrombasthenia, not the rare dominant BDPLT16.

Variant type/class. Predominantly missense; also small in-frame deletions (T720del, βTD_del). All cluster in the membrane-proximal transmembrane/cytoplasmic interface.

Allele frequency. Disease alleles are private/ultra-rare and effectively absent from gnomAD, consistent with a highly penetrant dominant deleterious effect (Finding F008).

Somatic vs germline. Germline, heterozygous, dominantly inherited.

Functional consequence. Gain-of-function (constitutive integrin activation) — mechanistically opposite to the loss-of-function of classic GT. In-silico modeling shows mutated residues "directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to β3" (PMID: 29090484).

Modifier genes / epigenetics / chromosomal abnormalities. No specific modifier genes, epigenetic marks, or large-scale chromosomal abnormalities are established for BDPLT16. The lesion is a point mutation / small in-frame deletion, not a copy-number or structural variant.

5. Environmental Information

BDPLT16 is a monogenic disorder with no environmental, lifestyle, or infectious etiology. No toxins, radiation, occupational exposures, dietary factors, or pathogens cause or trigger the disease. Environmental factors are relevant only as bleeding precipitants (trauma, surgery, dental procedures, childbirth) and as aggravators via antiplatelet/anticoagulant drug exposure (aspirin, NSAIDs). Not applicable: infectious agents.

6. Mechanism / Pathophysiology

Ordered causal chain

A heterozygous gain-of-function variant arises in ITGA2B (αIIb) or ITGB3 (β3) in the membrane-proximal region → disrupts the conserved αIIb-Arg995 ↔ β3-Asp723 intracytoplasmic salt bridge (the "clasp" that holds the integrin in its resting/bent state). (Demonstrated by in-silico + functional studies.)
Loss of the salt-bridge clasp releases the cytoplasmic/transmembrane restraint → the integrin adopts an extended, constitutively active conformation → spontaneous (agonist-independent) αIIbβ3 activation with increased binding of activation-specific ligands (↑PAC-1 binding; adhesion to fibrinogen/VWF under shear). (Demonstrated in CHO/293T transfectants and patient platelets.)
Constitutive ligand binding triggers permanent "outside-in" signaling → arrest of actin turnover at the polymerization stage and disordered cytoskeletal (actin/tubulin) reorganization in megakaryocytes. (Demonstrated.)
Cytoskeletal perturbation impairs proplatelet formation → megakaryocytes generate abnormal cytoplasmic extensions / asymmetric "barbell" proplatelets with fewer, larger tips. (Demonstrated in patient CD34+ MK cultures and cell models.)
Abnormal proplatelet fragmentation leads to incorrect platelet sizing and reduced platelet output → macrothrombocytopenia (large platelets, low count). (Demonstrated.)
Branch — receptor internalization: constitutive activation promotes αIIbβ3 internalization → reduced surface expression of the receptor on circulating platelets. (Demonstrated.)
Branch — granule abnormality: disordered biogenesis yields enlarged/fused α-granules (some giant). (Observed.)
Reduced receptor density + dysfunctional granule release + abnormal cytoskeleton → partial platelet aggregation and secretion defect (reduced but not absent responses to ADP, collagen, TRAP-6) → mild-to-moderate mucocutaneous bleeding when hemostasis is challenged. (Demonstrated clinically.)

GOF variant (ITGA2B/ITGB3, membrane-proximal)
│
▼
Disrupts αIIb-R995 / β3-D723 salt bridge (the "clasp")
│
▼
Constitutive αIIbβ3 activation (↑PAC-1, ligand binding)
├───────────────► Receptor internalization ─► ↓ surface αIIbβ3
│
▼
Permanent outside-in signaling ─► actin turnover arrested
│
▼
Abnormal proplatelet formation (asymmetric, few large tips)
│                         └──► enlarged/fused α-granules
▼
Large platelets + low count = MACROTHROMBOCYTOPENIA
│
▼
Partial aggregation/secretion defect ─► mild-moderate mucocutaneous bleeding

Detail by category

Molecular pathways / biochemical abnormality. The defect is integrin bidirectional (inside-out/outside-in) signaling. The proximate biochemical lesion is loss of the electrostatic salt bridge that maintains the low-affinity resting state; the downstream signaling engages Rap1/talin-associated outside-in activation cascades and actin dynamics (PMID: 29380037; PMID: 26452979).
Protein dysfunction. Gain-of-function conformational change: the mutant integrin is trapped in an active/extended state rather than misfolded or degraded. This distinguishes it from GT loss-of-function (absent/nonfunctional receptor).
Cellular processes. Dysregulated cytoskeletal reorganization (actin polymerization/turnover, tubulin-dependent protrusions), abnormal proplatelet formation, and receptor endocytosis/internalization.
Cell types involved. Megakaryocytes (CL:0000556) as the site of defective platelet production; platelets/thrombocytes (CL:0000233) as the dysfunctional end product.
Suggested GO terms. GO:0007229 integrin-mediated signaling pathway; GO:0033628 regulation of cell adhesion mediated by integrin; GO:0030168 platelet activation; GO:0030220 platelet formation; GO:0007010 cytoskeleton organization; GO:0006897 endocytosis. Cellular component: GO:0009986 cell surface, GO:0031093 platelet alpha granule, GO:0015629 actin cytoskeleton.
Immune / metabolic / infectious involvement. None intrinsic. (Misdiagnosis as immune thrombocytopenia is a clinical, not mechanistic, issue.)

Instructive natural experiment (sitosterolemia). In a murine sitosterolemia model, plant-sterol accumulation in the platelet membrane produced constitutive fibrinogen binding to αIIbβ3, receptor internalization, and macrothrombocytopenia — phenocopying, via a non-genetic route, the same "constitutively active αIIbβ3 → macrothrombocytopenia" logic and reinforcing causality (PMID: 23926302).

7. Anatomical Structures Affected

Organ/system level. Primary involvement is the hematopoietic system / blood (UBERON:0000178 blood) and bone marrow (UBERON:0002371) where megakaryopoiesis occurs. The mucocutaneous vasculature (skin, nasal mucosa, gingiva, gastrointestinal and genitourinary mucosa) is the site of bleeding manifestations. Secondary involvement: endometrium/uterus (menorrhagia) and potential iron-deficiency anemia affecting systemic function.
Tissue/cell level. Megakaryocytes (CL:0000556) in bone marrow; platelets/thrombocytes (CL:0000233) in circulation. No solid-organ parenchymal tissue is primarily targeted.
Subcellular level. Plasma membrane / cell surface (integrin localization; GO:0005886), platelet α-granules (GO:0031093; enlarged/fused), and the actin cytoskeleton (GO:0015629).
Localization / lateralization. Systemic (blood-borne); bleeding sites are not lateralized — diffuse mucocutaneous. No focal or asymmetric anatomic lesion.

8. Temporal Development

Onset. Congenital laboratory phenotype (thrombocytopenia and large platelets from birth); clinical bleeding typically recognized in childhood. Onset pattern is chronic/insidious rather than acute.
Progression. Stable / non-progressive; the platelet count and morphology remain relatively constant over life. Bleeding is episodic, provoked by hemostatic challenges (surgery, trauma, menstruation, delivery).
Disease course / duration. Chronic, lifelong. There is no staging system and no natural tendency to remission or worsening.
Critical periods. Windows of heightened vulnerability are surgical/dental procedures, trauma, menarche/menstruation, pregnancy and the peripartum period — the key opportunities for prophylactic hemostatic intervention.

9. Inheritance and Population

Inheritance pattern. Autosomal dominant (heterozygous gain-of-function). Contrast with recessive classic GT.
Epidemiology. No formal prevalence/incidence figures exist; BDPLT16 is ultra-rare, reported as a handful of families worldwide. Known pedigrees include the original ITGB3 D723H family (5 affected over 3 generations; PMID: 18065693), Japanese T720del and related families (PMID: 29380037), French salt-bridge families (PMID: 29090484), and a Portuguese cohort of 10 families/33 patients (PMID: 33276370).
Penetrance / expressivity. Cosegregation is strong (the laboratory phenotype tracks with the variant across generations), implying high penetrance for the lab phenotype; bleeding severity is variably expressed (absent-to-moderate) even among carriers of the same allele.
Anticipation / mosaicism / consanguinity / founder effects. No genetic anticipation (not a repeat-expansion disorder). No consanguinity required (dominant). The Portuguese cluster of 10 families may reflect ascertainment and/or shared alleles, but no formal founder haplotype has been established. Germline mosaicism not specifically documented.
Carrier frequency. Not applicable in the recessive sense; disease alleles are private/ultra-rare and essentially absent from gnomAD (Finding F008).
Population demographics. No strong ethnic predilection; cases reported across European (French, Portuguese, Italian) and Asian (Japanese) populations. Sex ratio for the genetic trait is ~1:1 (autosomal); affected women carry additional gynecologic/obstetric bleeding burden. Age distribution spans all ages given lifelong congenital nature.

10. Diagnostics

Laboratory tests. - CBC with peripheral blood smear: thrombocytopenia with large/giant platelets; increased mean platelet volume and platelet anisotropy. Automated counters may undercount large platelets. - Flow cytometry: reduced (not absent) αIIbβ3/GPIIb-IIIa surface expression; reduced PAC-1 binding upon stimulation (TRAP-6, ADP) — reflecting low activation-inducible binding sites. - Light transmission aggregometry (LTA): reduced but not absent aggregation to ADP and collagen; normal ristocetin-induced agglutination (distinguishing from Bernard-Soulier/VWD); reduced ATP/dense-granule release. - Electron microscopy (specialized): enlarged, sometimes fused α-granules; abnormal platelet morphology.

Biomarkers. The defining "biomarker" is the combination of macrothrombocytopenia + reduced (not absent) αIIbβ3 + partial aggregation defect + activating membrane-proximal ITGA2B/ITGB3 variant.

Genetic testing (definitive). - Recommended approach: NGS-based inherited platelet disorder gene panels covering ITGA2B, ITGB3, and the broader macrothrombocytopenia genes; WES/WGS are useful when panels are non-diagnostic. Confirm candidate variants by Sanger sequencing and test family segregation. - Single-gene testing of ITGA2B/ITGB3 is appropriate when phenotype is strongly suggestive. - CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not applicable (point-mutation disorder).

Imaging / electrophysiology / biopsy. Not diagnostic; imaging is used only to evaluate bleeding complications. Bone marrow examination is typically normal (normal megakaryocyte numbers), useful mainly to exclude other causes.

Clinical criteria & differential diagnosis. No formal consensus criteria; diagnosis is integrative (phenotype + genetics). Differential diagnosis of dominant macrothrombocytopenia with platelet dysfunction includes:

Condition	Inheritance	Key distinguishing feature
BDPLT16 (this disease)	AD (GOF)	Reduced (not absent) αIIbβ3; partial aggregation defect; activating membrane-proximal ITGA2B/ITGB3 variant
Classic Glanzmann thrombasthenia	AR (LOF)	Absent αIIbβ3/aggregation; normal count & size
Bernard-Soulier syndrome	AR	GPIb-IX-V defect; abnormal ristocetin agglutination
MYH9-related disorders (May-Hegglin)	AD	Leukocyte Döhle-like inclusions; MYH9 variant
von Willebrand disease	AD/AR	VWF defect; abnormal ristocetin; corrects with VWF
Immune thrombocytopenia (ITP)	Acquired	No family history; normal platelet size; steroid-responsive

Congenital macrothrombocytopenias "share common clinical and laboratory features... and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura" (PMID: 16169642).

Screening. No population/newborn screening. Cascade genetic testing of at-risk relatives is appropriate once a familial variant is identified; prenatal/preimplantation testing is technically feasible but rarely indicated given the mild phenotype.

11. Outcome / Prognosis

Survival / life expectancy. Normal life expectancy; BDPLT16 is not associated with increased mortality in the absence of catastrophic bleeding. No disease-specific mortality data.
Morbidity. Driven by bleeding: recurrent epistaxis, easy bruising, menorrhagia (with risk of iron-deficiency anemia), and peri-operative/peri-partum hemorrhage. Serious spontaneous bleeding (e.g., intracranial) is rare in mild-moderate disease, though documented in the severe allelic condition GT.
Disease course. Chronic and stable; complications are episodic and largely preventable with appropriate hemostatic management around challenges.
Prognostic factors. Bleeding phenotype severity, sex (gynecologic burden), exposure to antiplatelet drugs, and the nature of hemostatic challenges. No validated molecular prognostic biomarker; there is a broad genotype–phenotype trend (all activating salt-bridge variants → macrothrombocytopenia), but bleeding severity is variably expressed.
Quality-of-life measures. No disease-specific EQ-5D/SF-36/PROMIS data; QoL is generally good but reduced in those with significant menorrhagia.

12. Treatment

Overarching principle. There is no BDPLT16-specific or curative therapy. Management is supportive/on-demand, extrapolated from inherited platelet function disorders and the allelic condition Glanzmann thrombasthenia.

Pharmacotherapy and hemostatic agents.

Intervention	Role	NCIT suggestion
Tranexamic acid / antifibrinolytics	First-line for mucosal bleeding, menorrhagia, dental/minor surgery	NCIT:C739 Tranexamic Acid
Recombinant activated factor VII (rFVIIa)	Major bleeds/surgery; also reduces risk of platelet alloimmunization	NCIT:C1836 Recombinant Factor VIIa
Platelet transfusion	Severe/life-threatening bleeding or major surgery; use judiciously (alloimmunization risk)	NCIT:C15328 Platelet Transfusion
Hormonal therapy (combined OCP, progestins, LNG-IUS)	Control of heavy menstrual bleeding	NCIT:C548 Hormone Therapy
Desmopressin (DDAVP)	Considered in mild platelet disorders; variable benefit	NCIT:C29179 Desmopressin
Iron supplementation	Treat/prevent iron-deficiency anemia from chronic blood loss	NCIT:C1381 Iron Supplement
Local measures	Pressure, nasal packing, topical agents for epistaxis	—

Evidence: in GT, "bleeding control was achieved through the use of antifibrinolytic agents and recombinant factor VIIa, which also reduces the risk of platelet alloimmunization" (PMID: 41778036). In women, "management of chronic HMB required a combination therapy including antifibrinolytics (tranexamic acid [TXA]), hormonal therapies, and recombinant factor VIIa (rFVIIa)" (PMID: 40123272). Local measures, desmopressin, and antifibrinolytics are first-line for mild inherited platelet disorders (PMID: 23269640).

Advanced / experimental therapeutics. No approved gene therapy, cell therapy, RNA-based, targeted, or immunotherapy for BDPLT16. Caution with anticoagulation — provoked thrombosis can occur in αIIbβ3 disorders and carries a narrow therapeutic window (PMID: 41591555, reported in GT).

Pharmacogenomics. Avoid antiplatelet drugs (aspirin, NSAIDs, P2Y12 inhibitors). No BDPLT16-specific pharmacogenomic guidance.

Treatment strategy. Individualized, challenge-based prophylaxis: pre-procedural antifibrinolytics ± rFVIIa ± platelets; peri-partum planning in a hemophilia/bleeding-disorder center; proactive management of menorrhagia and iron status.

13. Prevention

Primary prevention. Not possible (genetic). Preventing bleeding events: avoid antiplatelet/anticoagulant drugs, use careful surgical/dental planning with prophylactic hemostatic cover.
Secondary prevention. Early diagnosis (correctly distinguishing from ITP to avoid unnecessary steroids/splenectomy), cascade genetic testing of relatives, and iron-deficiency screening in menorrhagic patients.
Tertiary prevention. Prevent complications: peri-operative/peri-partum hemostatic protocols, minimize platelet transfusions to reduce alloimmunization (favor rFVIIa where possible), treat anemia.
Genetic counseling. Autosomal dominant → 50% transmission risk to offspring; counsel on variable bleeding expressivity; offer family-cascade testing; prenatal/PGT feasible but seldom pursued given mild phenotype.
Immunization / public health / environmental interventions. Not applicable beyond general bleeding-risk counseling.

14. Other Species / Natural Disease

Taxonomy / orthologs. Mouse orthologs Itga2b (NCBI Gene 16399) and Itgb3 (NCBI Gene 16416). Murine αIIbβ3 is functionally homologous to human, expressed at ~60,000–80,000 copies/platelet, with conserved EDTA-dissociation and activation biology (PMID: 11154120).
Natural disease in other species. No well-characterized naturally occurring, dominant gain-of-function αIIbβ3 macrothrombocytopenia has been catalogued in companion animals for BDPLT16 specifically; naturally occurring Glanzmann thrombasthenia (loss-of-function) is documented in dogs and horses (OMIA), which is the allelic recessive disease rather than BDPLT16.
Comparative biology. The αIIb-R995/β3-D723 salt bridge and integrin activation machinery are evolutionarily conserved, so the mechanistic principle (salt-bridge disruption → constitutive activation) is expected to be conserved across mammals.
Zoonotic potential. None (non-transmissible genetic disorder).

15. Model Organisms

In vitro / cellular models (primary evidence base for BDPLT16). - Transfected cell lines (CHO, HEK293/293T) expressing mutant αIIbβ3 (β3-D723H/H723, β3-βTD_del p.647-686, β3-C560R, β3-T720del) reproduce constitutive activation, increased PAC-1 binding, adhesion to fibrinogen/VWF under shear, and formation of abnormal proplatelet-like cytoplasmic extensions not seen with wild-type (PMID: 18065693; PMID: 25806962; PMID: 29380037; PMID: 26452979). - Patient-derived CD34+ stem-cell megakaryocyte cultures confirm abnormal proplatelet formation in the propositus, directly linking the variant to the production defect (PMID: 18065693).

Mouse models. - The β3-integrin knockout (Itgb3⁻/⁻) mouse models loss-of-function Glanzmann thrombasthenia, NOT gain-of-function BDPLT16: "The mice are viable and fertile, and show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding)," plus placental defects and reduced survival (PMID: 9916135). - Sitosterolemia mouse (Abcg5/Abcg8⁻/⁻) provides a phenocopy of the mechanism — sterol-induced constitutive αIIbβ3 activation, internalization, and macrothrombocytopenia — even though the genetic cause differs (PMID: 23926302).

Phenotype recapitulation & limitations. No published knock-in mouse carrying a human BDPLT16 activating salt-bridge variant is established; thus the dominant gain-of-function macrothrombocytopenia is best modeled in vitro and in patient megakaryocytes, while mouse knockouts capture only the allelic loss-of-function disease. A conditional/knock-in Itgb3 D723H (or Itga2b R995W) mouse is an obvious gap.

Mechanistic Model / Interpretation

BDPLT16 is best understood as a "stuck-on" integrin disorder. The αIIbβ3 fibrinogen receptor normally rests in a bent, low-affinity conformation held by an intracellular clasp — the αIIb-R995 ↔ β3-D723 salt bridge. BDPLT16 variants break this clasp, so the receptor is constitutively active even without agonist. Paradoxically, this gain-of-function produces bleeding, because (a) chronic activation triggers receptor internalization, lowering surface density; and (b) permanent outside-in signaling freezes the megakaryocyte cytoskeleton, garbling proplatelet formation so platelets emerge too large and too few with impaired secretion. The result is a macrothrombocytopenia with a partial functional defect — the mirror image of Glanzmann thrombasthenia, where the same receptor is simply absent/nonfunctional and platelet number/size are normal.

This unifying logic explains every observed feature: dominant inheritance (a single active allele poisons proplatelet formation), reduced-not-absent αIIbβ3 (internalization vs. deletion), partial-not-absent aggregation, large fused α-granules, and mild-to-moderate bleeding. The sitosterolemia phenocopy independently validates the causal step "constitutive αIIbβ3 activation → internalization → macrothrombocytopenia."

BDPLT16 vs. classic Glanzmann thrombasthenia (allelic contrast).

Feature	BDPLT16	Classic Glanzmann thrombasthenia
Molecular effect	Gain-of-function (constitutive activation)	Loss-of-function (absent/defective receptor)
Inheritance	Autosomal dominant	Autosomal recessive
αIIbβ3 surface level	Reduced (not absent)	Absent/markedly reduced
Platelet count	Low (thrombocytopenia)	Normal
Platelet size	Large (macrothrombocytes)	Normal
Aggregation defect	Partial	Absent/severe
Variant location	Membrane-proximal TM/cytoplasmic	Throughout gene
Bleeding severity	Mild-moderate	Moderate-severe

Evidence Base

PMID	Contribution	Supports
29090484	Salt-bridge disruption (R995W, D723H); enlarged α-granules; mild-moderate phenotype	F001, F003
29380037	β3 T720del; membrane-proximal clustering; constitutive activation	F001, F003
33276370	10 families/33 patients; 7 variants; defines core clinical/lab phenotype	F001, F003
26452979	Cytoskeletal mechanism: outside-in signaling arrests actin turnover; reduced surface expression	F001, F002
18065693	Original D723H pedigree; PAC-1↑; CHO model; patient MK abnormal proplatelets	F002, F004
25806962	βTD_del and C560R cause abnormal cytoplasmic extensions (proplatelet defect)	F002, F004
23926302	Sitosterolemia: sterol-induced constitutive αIIbβ3 activation → macrothrombocytopenia (mechanism phenocopy)	F002
9916135	β3-null mouse = loss-of-function GT model (not BDPLT16)	F004
11154120	Murine αIIbβ3 structure/function homology	F004
16169642	Congenital macrothrombocytopenias misdiagnosed as ITP	F005
34400424	Differential diagnosis framework (BSS, MYH9, GT, VWD)	F005
41778036	Antifibrinolytics + rFVIIa hemostatic management	F006
40123272	Menorrhagia management (TXA, hormonal, rFVIIa)	F006
23269640	First-line local measures/DDAVP/antifibrinolytics in mild platelet disorders	F006
41503871	Review defining ITGA2B/ITGB3-related macrothrombocytopenia as GOF subset	F001

Verbatim supporting quotes. - "In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to β3 of the integrin αIIbβ3." — PMID: 29090484 - "Reported mutations were highly clustered at the membrane proximal region of αIIbβ3, which affected the critical interaction between αIIb R995 and β3 D723, resulting in a constitutionally active form of the αIIbβ3 complex." — PMID: 29380037 - "the constitutive activation of the alphaIIbbeta3-H723 receptor causes abnormal proplatelet formation, leading to incorrect sizing of platelets and the thrombocytopenia observed in the pedigree." — PMID: 18065693 - "permanent triggering of αIIbβ3-mediated outside-in signaling causes an impairment of cytoskeletal reorganization arresting actin turnover at the stage of polymerization." — PMID: 26452979 - "Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1)." — PMID: 33276370 - "Many of these disorders share common clinical and laboratory features, making accurate diagnosis difficult and patients are often misdiagnosed with and treated for idiopathic thrombocytopenic purpura." — PMID: 16169642 - "Bleeding control was achieved through the use of antifibrinolytic agents and recombinant factor VIIa, which also reduces the risk of platelet alloimmunization." — PMID: 41778036

Limitations and Knowledge Gaps

No formal epidemiology. Prevalence/incidence are unknown; evidence is a handful of families. Penetrance and expressivity estimates are qualitative.
No in vivo gain-of-function model. No knock-in mouse (e.g., Itgb3 D723H or Itga2b R995W) has been established; mechanism relies on in vitro transfectants and patient megakaryocytes. Mouse Itgb3⁻/⁻ models only the allelic loss-of-function GT.
Mechanistic exceptions. Recent reports of non-activating ITGB3 variants causing macrothrombocytopenia challenge the uniform gain-of-function model (PMID: 41503871), indicating additional/alternative mechanisms remain to be defined.
Treatment evidence is extrapolated, not BDPLT16-specific — drawn from GT and general inherited platelet disorders; no trials in BDPLT16.
No QoL, natural-history, or prognostic-biomarker data specific to BDPLT16.
Genotype–phenotype correlation for bleeding severity is weak; modifier genes are unidentified.

Proposed Follow-up Experiments / Actions

Generate a knock-in mouse (Itgb3 p.D723H or Itga2b p.R995W) or iPSC-derived megakaryocyte lines to model dominant gain-of-function BDPLT16 in vivo and quantify proplatelet defects.
Systematic genotype–phenotype registry across reported families to estimate penetrance, expressivity, and bleeding-severity predictors.
Mechanistic dissection of non-activating ITGB3 macrothrombocytopenia variants to determine whether a distinct (activation-independent) pathway contributes.
Single-cell transcriptomics/proteomics of patient megakaryocytes to map the cytoskeletal and granule-biogenesis programs perturbed by constitutive αIIbβ3 signaling (GO:0030220 platelet formation).
Prospective evaluation of hemostatic strategies (antifibrinolytics ± rFVIIa vs. platelet transfusion) to build BDPLT16-specific, alloimmunization-sparing protocols.
ClinVar/ACMG reclassification effort to curate BDPLT16 alleles distinctly from recessive GT alleles, improving diagnostic reporting.

Report compiled from 8 confirmed findings and 28 reviewed papers across 5 investigation iterations. Evidence types: human clinical pedigrees/case series, in vitro heterologous-cell and patient-megakaryocyte studies, and mouse models. Ontology suggestions (HPO, GO, CL, UBERON, NCIT) are provided throughout for knowledge-base population.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	11
Quoted claims found in source	10
Quoted claims not found in source	1
References weighed for topical relevance	16
On topic	9
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:40123272 (abstract only): "management of chronic HMB required a combination therapy including antifibrinolytics (tranexamic acid [TXA]), hormonal therapies, and recombinant factor VIIa (rFVIIa)"
closest text in source: "management of chronic HMB required a combination therapy including antifibrinolytics (tranexamic acid [TXA]), hormonal therapies, and recombinant factor VIIa (rFVIIa)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	32
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	5
Terms named correctly	3
Terms named as a different term	1
Terms whose name is worth a second look	1

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MONDO:0008552 (2 mentions) - the report calls it "MONDO"; MONDO calls it platelet-type bleeding disorder 16

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CL:0000233 (2 mentions) - the report calls it "platelets/thrombocytes"; CL calls it platelet, and lists "anucleate thrombocyte" among its other names

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Platelet-type Bleeding Disorder 16 (BDPLT16): Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

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Artifacts

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Terms whose name is worth a second look