Glanzmann Thrombasthenia

Mendelian MONDO:0100326 Pathograph 12 Show in embeddings browser Inherited Platelet Disorder Bleeding Disorder

Glanzmann thrombasthenia is the prototype inherited disorder of platelet aggregation: an autosomal recessive bleeding syndrome in which quantitative or qualitative loss of the platelet integrin alphaIIbbeta3 leaves platelets unable to bind one another. It is the mechanistic mirror image of Bernard-Soulier syndrome. There the platelet cannot stick to the vessel wall and is large and scarce; here the platelet is present in normal number and normal size, it adheres perfectly well, it activates, and it still cannot form an aggregate, because alphaIIbbeta3 is the receptor that binds the fibrinogen and von Willebrand factor bridging one platelet to the next. That gives the disease a laboratory signature no other disorder reproduces - absent aggregation to every physiological agonist, with normal ristocetin-induced agglutination, a normal platelet count and normal platelet morphology - and it is the reason a diagnosis that is genuinely difficult to make clinically is nearly unmistakable in the aggregometry laboratory. The disease is caused by biallelic variants in either subunit gene, ITGA2B (alphaIIb) or ITGB3 (beta3), which sit adjacent on 17q21; because the two subunits must heterodimerize to leave the endoplasmic reticulum, losing either one removes the whole receptor and the two genotypes are clinically indistinguishable. Severity is strikingly variable - some patients have only minimal bruising while others have frequent, potentially fatal haemorrhage - and it correlates poorly with residual receptor level, so genotype is a poor guide to prognosis. It is rare worldwide but genuinely common in populations where consanguineous marriage is customary, and the clinical problem that dominates long-term management is iatrogenic: repeated platelet transfusion into a patient whose platelets have never displayed alphaIIbbeta3 provokes alloantibodies against an antigen the immune system treats as foreign, after which transfusion stops working.

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1
Inheritance
7
Pathophys.
12
Phenotypes
2
Gaps
12
Pathograph
2
Genes
5
Medical Actions
5
Subtypes
5
Differentials
1
Models
4
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
Biallelic variants in ITGA2B or ITGB3 are required. Heterozygotes have roughly half-normal platelet alphaIIbbeta3 and are mostly asymptomatic. Consanguinity is prominent in affected families and drives the disorder's geographic distribution.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by lack of platelet aggregation."
States the mode of inheritance directly.
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Subtypes

5
Glanzmann thrombasthenia 1 (ITGA2B-related) MONDO:0031332
ITGA2B hgnc:6138 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ITGA2B (hgnc:6138). hgnc:6138 is a gene from the HUGO Gene Nomenclature Committee.
Biallelic ITGA2B variants removing or inactivating the alphaIIb subunit. Clinically indistinguishable from the ITGB3 form, because loss of either subunit prevents surface expression of the heterodimer. Some geographic skewing has been reported - alphaIIb variants dominated an Italian series while beta3 variants, with emphasis on exon 4, characterized an Indian one - which reflects founder effects rather than any mechanistic difference.
Glanzmann thrombasthenia 2 (ITGB3-related) MONDO:0031009
ITGB3 hgnc:6156 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ITGB3 (hgnc:6156). hgnc:6156 is a gene from the HUGO Gene Nomenclature Committee.
Biallelic ITGB3 variants removing or inactivating the beta3 subunit. Because beta3 also partners alphaV to form the vitronectin receptor alphaVbeta3, which is expressed far beyond the platelet, ITGB3-null disease is the arm in which extraplatelet consequences might be expected; in the beta3-null mouse these are real (placental defects and fetal mortality), and whether they translate to patients is an open question rather than an established feature of the human disease.
Type I (severe, <5% residual alphaIIbbeta3)
The classic and commonest form: platelet aggregation is absent and clot retraction is absent, with essentially no surface alphaIIbbeta3. In the detailed Hopital Lariboisiere experience this accounted for 50 of 64 patients (78%). This is a phenotypic severity class cutting across both genes, not a third genotype.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Those patients with absent platelet aggregation and absent clot retraction were subsequently termed as having type I disease; those with absent aggregation but residual clot retraction, type II disease"
Defines the type I/type II split on which this and the following subtype entries rest.
Type II (residual alphaIIbbeta3, clot retraction preserved)
Aggregation is absent but clot retraction is preserved, reflecting residual surface alphaIIbbeta3. Nine of 64 patients (14%) in the Lariboisiere series. Residual receptor does not reliably predict milder bleeding.
Variant GT (receptor present but non-functional)
alphaIIbbeta3 is expressed at near-normal levels but cannot bind ligand, diagnosed by the failure of the receptor to express activation-dependent epitopes. Five of 64 patients (8%) in the Lariboisiere series. This is the subtype in which a purely quantitative flow-cytometry screen is normal and the diagnosis is missed unless receptor function is tested - a practical reason the schema-level distinction is worth carrying.
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Discussions and Knowledge Gaps

2
Why do patients carrying the same ITGA2B or ITGB3 variant differ so widely in bleeding frequency and severity?
KNOWLEDGE GAP gap_severity_not_predicted_by_genotype
Attached to
pathophysiology#Mucocutaneous Bleeding Diathesis
Clinical severity ranges from minimal bruising to fatal haemorrhage, and the source review states directly that individuals with the same mutation may differ widely. That means neither the causal genotype nor the residual receptor level (type I versus type II) is a sufficient predictor, so the modifier is elsewhere. This matters practically: prophylaxis and transplant decisions are severity-driven, and there is currently no molecular basis on which to make them. Candidate explanations include co-inherited prothrombotic variants, which have been reported to modulate the phenotype, and differences in vessel-wall or plasma-phase compensation.
Proposed experiments
Genotype-stratified bleeding-score study with thrombophilia panel
exp_modifier_genotype_bleeding_score
In a multinational registry, pair a standardized bleeding-assessment tool score with the causal genotype, the quantified residual alphaIIbbeta3, and a panel of prothrombotic modifier alleles. Testing whether modifier genotype explains within-variant variance would either yield a usable prognostic model or exclude the leading candidate explanation.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"with the same mutation may differ widely in the frequency and severity of bleeding"
The observation that establishes this as a genuine gap rather than an artefact of imprecise phenotyping.
Do the placental defects and fetal mortality of the beta3-null mouse correspond to any reproductive consequence in human ITGB3-related Glanzmann thrombasthenia?
HUMAN MODEL MISMATCH mismatch_beta3_null_mouse_placental_phenotype
Attached to
pathophysiology#Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3
The beta3-null mouse recapitulates the platelet phenotype faithfully but also shows placental defects leading to fetal mortality, which arise from loss of alphaVbeta3 rather than alphaIIbbeta3. Human ITGB3-null patients likewise lack alphaVbeta3, yet no corresponding placental disease is an established feature of the human disorder - while pregnancy in these patients is hazardous, the documented hazard is haemorrhagic. This is a mismatch of translational validity, not an absence of evidence: the mouse result is solid, and what is unresolved is whether it means anything for patients. The distinction matters because it separates a genuine unstudied risk from a species artefact of constitutional knockout, and because it applies only to the ITGB3 arm, not the ITGA2B arm.
Proposed experiments
Gene-stratified pregnancy outcome analysis
exp_itgb3_pregnancy_outcome_registry
Compare pregnancy outcomes - placental pathology, fetal growth restriction, and loss - between ITGB3-null and ITGA2B-null patients in an international registry, with haemorrhagic complications recorded separately so that a placental signal is not obscured by bleeding-driven outcomes. Equivalent outcomes across the two genotypes would settle the mouse finding as a species artefact.
Show evidence (1 reference)
PMID:9916135 SUPPORT Model Organism
"Implantation appears to be unaffected, but placental defects do occur and lead to fetal mortality."
The model-system finding whose human relevance is the open question.
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Pathophysiology

7
Biallelic Loss of Function in ITGA2B or ITGB3
Pathogenic variants in either of the two adjacent 17q21 genes encoding the alphaIIb and beta3 subunits cause the disease, and the mutational spectrum spans every class - missense, nonsense, frameshift, splice and large deletion - with no region of either gene exempt. Heterozygotes carry roughly half-normal platelet alphaIIbbeta3 and are almost always asymptomatic, so the disease is recessive at the level of receptor dose as well as inheritance. Founder variants dominate in several populations, including the ITGA2B c.1544+1G>A allele of French Gypsy patients.
megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3 Loss of either subunit prevents assembly and surface expression of the obligate heterodimer.
Show evidence (2 references)
PMID:16722529 SUPPORT Human Clinical
"Note that abnormalities are abundant in both αIIb and β3 genes and that no parts of either gene appear to be exempt."
Establishes that the mutational spectrum is unconstrained across both genes, which is why the disorder has no small set of recurrent alleles outside founder populations.
PMID:16722529 SUPPORT Human Clinical
"patients homozygous for mutations causing GT; the heter- ozygous condition is mostly asymptomatic, even though these subjects have only a half-normal concentration of platelet αIIbβ3"
Supports the recessive dose relationship - half-normal receptor is haemostatically sufficient - which is the basis of the carrier statement in this node.
Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3
alphaIIb and beta3 must heterodimerize in the endoplasmic reticulum before the complex can traffic to the platelet surface, so a defect in either subunit removes the whole receptor. Three outcomes are possible and define the phenotypic classes: near-total absence of surface receptor (type I), reduced but measurable receptor (type II), or normal amounts of a receptor that cannot bind ligand (variant GT). The last is why a quantitative flow-cytometry result alone cannot exclude the diagnosis.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
integrin alphaIIbbeta3 fibrinogen-binding activity GO:0005178 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased integrin alphaIIbbeta3 fibrinogen-binding activity, annotated with integrin binding (GO:0005178). GO:0005178 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Interplatelet Fibrinogen Bridging and Aggregation Without a functional receptor, the adhesive proteins that bridge adjacent platelets have nothing to bind.
Impaired Clot Retraction alphaIIbbeta3 also transmits the actomyosin contractile force of the platelet onto the fibrin network, an outside-in function separate from aggregation.
Show evidence (2 references)
PMID:16722529 SUPPORT Human Clinical
"The molecular basis is linked to quantitative and/or qualitative abnormalities of alphaIIb beta3 integrin."
States the quantitative-versus-qualitative distinction this node represents.
PMID:22102273 SUPPORT Human Clinical
"it is caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21-23"
Independent statement of the same receptor-level lesion and its two gene routes, including the chromosomal location asserted here.
Failure of Interplatelet Fibrinogen Bridging and Aggregation
The rate-limiting lesion. Activated alphaIIbbeta3 normally binds fibrinogen and von Willebrand factor, which cross-link adjacent platelets into a growing aggregate; without it, platelets that have adhered and activated normally remain a monolayer. Because this is the final common step of aggregation, the failure is agonist-independent: ADP, collagen, thrombin, arachidonic acid and epinephrine all fail alike, whereas ristocetin-induced agglutination - which depends on GPIb-IX-V and von Willebrand factor rather than on alphaIIbbeta3 - remains normal. That dissociation is what separates this disorder from Bernard-Soulier syndrome at the bench.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet aggregation GO:0070527 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet aggregation (GO:0070527). GO:0070527 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
beta3-null mouse Mouse recapitulates Reproduces defective platelet aggregation and clot retraction, the two integrin-dependent functions lost in the human disease.
Downstream
Failure of Primary Hemostatic Plug Formation No aggregate means no plug beyond the adherent platelet monolayer.
Show evidence (2 references)
PMID:16722529 SUPPORT Human Clinical
"This receptor mediates the binding of adhesive proteins that attach aggregating platelets and ensure thrombus formation at sites of injury in blood vessels."
States the bridging function whose loss constitutes this node.
PMID:16722529 SUPPORT Human Clinical
"GT is the only disease in which platelet aggregation is defective to all agonists, while absent clot retraction is another frequent character- istic."
Supports the agonist-independence claim - the discriminating feature of this node - and the linked clot-retraction defect.
Impaired Clot Retraction
A parallel, outside-in consequence of losing the receptor: alphaIIbbeta3 engaged with fibrin transmits platelet actomyosin contraction to the clot, consolidating and shrinking it. Loss of clot retraction alongside absent aggregation defines type I disease; its preservation despite absent aggregation defines type II, so this node is the discriminator between the two severity classes rather than an independent bleeding mechanism.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
Downstream
Failure of Primary Hemostatic Plug Formation An unretracted clot is mechanically weaker and more easily dislodged.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli is pathognomonic for GT, and abnormal clot retraction is rarely observed in other disorders"
Establishes impaired clot retraction as a real and near-specific feature of the disorder.
Failure of Primary Hemostatic Plug Formation
Platelets adhere to the injured vessel wall normally - GPIb-IX-V and GPVI are intact - but the mass never grows or consolidates into a plug capable of arresting bleeding from small vessels. This is the shared destination of the inherited platelet function disorders reached here by the aggregation route.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
primary hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased primary hemostasis, annotated with hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mucocutaneous Bleeding Diathesis Skin and mucous membranes depend most heavily on platelet-dependent primary hemostasis.
Show evidence (1 reference)
PMID:21781244 SUPPORT Human Clinical
"Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury."
Supports the convergence of a platelet-function defect onto failure of the platelet's haemostatic role and thence to mucocutaneous bleeding.
Mucocutaneous Bleeding Diathesis
Bleeding declares itself at well-defined sites: purpura, epistaxis, gingival haemorrhage and menorrhagia are nearly constant, while gastrointestinal bleeding and haematuria are less common but disproportionately dangerous. Symptoms usually appear soon after birth. Severity varies enormously between patients carrying the same variant, so the clinical course cannot be predicted from the genotype; chronic low-grade loss from gingival oozing or menorrhagia makes iron-deficiency anaemia a frequent accompanying problem.
primary hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased primary hemostasis, annotated with hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
beta3-null mouse Mouse recapitulates Prolonged bleeding times with cutaneous and gastrointestinal bleeding, and anaemia from postnatal haemorrhage.
Downstream
Platelet Alloimmunization Against alphaIIbbeta3 Bleeding drives platelet transfusion, which is the exposure that immunizes; the intervening step is therapeutic rather than biological.
Show evidence (2 references)
PMID:16722529 SUPPORT Human Clinical
"The site of bleeding in GT is clearly defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features; gastrointestinal bleeding and hematuria are less common."
Enumerates the bleeding sites and their relative frequency, which is the content of this node.
PMID:16722529 SUPPORT Human Clinical
"GT is associated with clinical variability: some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages."
Supports the severity-variability claim that makes genotype a poor prognostic guide.
Platelet Alloimmunization Against alphaIIbbeta3
The iatrogenic complication that dominates long-term management and has no counterpart in most inherited disorders. A patient whose platelets have never displayed alphaIIbbeta3 has no tolerance to it, so transfused normal platelets present a foreign antigen; the resulting anti-alphaIIbbeta3 antibodies cause refractoriness to further transfusion and, in women, risk fetal and neonatal alloimmune thrombocytopenia. The beta3 subunit carries the HPA-1 antigen system, and because beta3 also partners alphaV, an HPA-1bb patient who expresses no platelet alphaIIbbeta3 at all can still be immunized against HPA-1a through alphaVbeta3 on their own platelet surface - an exposure route that a purely alphaIIbbeta3-centred model of the disease would predict was closed. This is the reason management is built around avoiding transfusion rather than around delivering it.
Show evidence (2 references)
PMID:33090654 SUPPORT Human Clinical
"we found that HPA-1bb patients who failed to express αIIb β3 on the platelet surface can develop alloantibodies against HPA-1a reacting with β3 as well as αv β3 . This is of particular importance as anti-HPA-1a alloantibodies might cause fetal neonatal alloimmune thrombocytopenia and/or platelet..."
Direct evidence for the alphaVbeta3 immunization route and for the two clinical consequences named in this node.
PMID:16722529 SUPPORT Human Clinical
"In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration."
Supports the claim that avoidance of this complication is what structures first-line management.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Glanzmann Thrombasthenia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Blood 7
Purpura VERY_FREQUENT HP:0000979 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Purpura (HP:0000979). HP:0000979 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
"Nearly constant" maps to the VERY_FREQUENT band (80-99%) for this and the three phenotypes named alongside it.
Epistaxis VERY_FREQUENT HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
Supports the phenotype and the VERY_FREQUENT band.
Gingival Bleeding VERY_FREQUENT HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
Supports the phenotype and the VERY_FREQUENT band.
Menorrhagia VERY_FREQUENT HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16722529 SUPPORT Human Clinical
"purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
Supports the phenotype and the VERY_FREQUENT band.
PMID:16722529 SUPPORT Human Clinical
"Severe menorrhagia is a frequent clinical problem and is usually associated with an excessively proliferative endometrium caused by estrogen dominance."
Supports the mechanism stated in the description and the hormonal treatment rationale.
Gastrointestinal Hemorrhage OCCASIONAL HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"gastrointestinal bleeding and hematuria are less common but can cause serious complications"
Explicitly contrasts these two with the "nearly constant" features, supporting a lower frequency band alongside a higher severity.
Bruising Susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages"
Establishes bruising as the mild end of the disorder's clinical range.
Iron Deficiency Anemia FREQUENT HP:0001891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iron deficiency anemia (HP:0001891). HP:0001891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Iron deficiency anemia, which can develop insidi- ously with gingival oozing or minor menorrhagia, is a fre- quent problem."
Supports both the mechanism given in the description and the FREQUENT band, which the source states directly.
Genitourinary 1
Hematuria OCCASIONAL HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"gastrointestinal bleeding and hematuria are less common but can cause serious complications"
Supports the phenotype and the lower frequency band.
Other 4
Impaired Platelet Aggregation to All Agonists OBLIGATE HP:0003540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired platelet aggregation (HP:0003540). HP:0003540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"GT is the only disease in which platelet aggregation is defective to all agonists"
Supports both the phenotype and its obligate frequency - it is the diagnostic criterion, so no diagnosed patient lacks it.
Decreased Platelet Glycoprotein IIb-IIIa HP:0001975 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased platelet glycoprotein IIb-IIIa (HP:0001975). HP:0001975 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Platelet αIIbβ3 deficiency should always be confirmed in new patients, and this can be done with monoclonal antibod- ies and flow cytometry"
Supports the phenotype and the flow-cytometric method by which it is established.
Prolonged Bleeding After Surgery HP:0004846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after surgery (HP:0004846). HP:0004846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Bleeding following trauma or surgical procedures can be severe and transfusions are often given by precaution or should be available on standby."
Supports post-surgical bleeding as a recognized and clinically managed feature.
Post-Partum Hemorrhage HP:0011891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Post-partum hemorrhage (HP:0011891). HP:0011891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Pregnancy and in partic- ular, delivery, represent a particularly severe hemorrhagic risk."
Supports delivery as a high-risk bleeding event in this disorder.
🧬

Genetic Associations

2
ITGA2B
Gene: ITGA2B hgnc:6138 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ITGA2B (hgnc:6138). hgnc:6138 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:22102273 SUPPORT Human Clinical
"quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21-23"
Establishes ITGA2B as one of the two causal genes and its chromosomal location.
PMID:33090654 SUPPORT Human Clinical
"The c.1544+1G>A mutation was identified in Gypsy Glanzmann thrombasthenia (GT) patients."
Supports the founder variant named in this gene block.
ITGB3
Gene: ITGB3 hgnc:6156 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ITGB3 (hgnc:6156). hgnc:6156 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:22102273 SUPPORT Human Clinical
"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. Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin..."
Supports the boundary drawn in this gene block between classic thrombasthenia alleles and the salt-bridge macrothrombocytopenia alleles.
💊

Medical Actions

5
Local Hemostatic Measures and Desmopressin
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
First-line, and chosen for what it avoids as much as for what it achieves: local measures (fibrin sealants, nasal packing, topical thrombin on gel foam, custom dental splints for extractions) and desmopressin are used wherever possible specifically to keep the patient from being exposed to donor platelets and alloimmunized. Regular dental care is preventive treatment in this disorder, not general advice.
Mechanism Target:
INHIBITS Platelet Alloimmunization Against alphaIIbbeta3 — The mechanism these measures act on is the iatrogenic one: by achieving haemostasis without donor platelets they prevent the alloimmunization that would close off transfusion later.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration."
States exactly this rationale - the measures are selected to avoid alloimmunization.
Platelet Transfusion
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Effective but reserved, because each exposure risks alloimmunization. HLA-compatible concentrates are used when local measures and desmopressin fail, or to cover surgery and delivery.
Mechanism Target:
RESTORES Failure of Interplatelet Fibrinogen Bridging and Aggregation — Supplies platelets that express functional alphaIIbbeta3, transiently restoring the missing bridging function itself rather than bypassing it.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Transfusion of HLA-compatible platelet concentrates may be necessary if these measures are ineffective, or to prevent bleeding during surgery."
Supports the indication and the second-line positioning stated here.
Recombinant Activated Factor VIIa
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
The bypass agent, and the mainstay for patients with platelet antibodies or transfusion refractoriness - precisely the patients for whom transfusion has stopped working. In the international Glanzmann Thrombasthenia Registry it provided effective surgical haemostasis across 206 procedures regardless of antibody or refractoriness status, with a low adverse-event rate; the one treatment-related event was a non-fatal thromboembolism, which is the expected hazard of a prohaemostatic bypass.
Mechanism Target:
BYPASSES Failure of Primary Hemostatic Plug Formation — Drives thrombin generation and fibrin formation on the available activated platelet surface, closing the haemostatic gap without restoring alphaIIbbeta3-mediated aggregation.
Show evidence (1 reference)
PMID:26001792 SUPPORT Human Clinical
"For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (±antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients."
Registry evidence that the agent achieves haemostasis without repairing the receptor defect.
Show evidence (1 reference)
PMID:26001792 SUPPORT Human Clinical
"One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics)."
Supports the thromboembolic hazard named in the description and its observed rarity.
Hormonal Control of Menorrhagia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
High-dose progesterone for severe menorrhagia, followed by maintenance oral contraception. Directed at the oestrogen-dominant proliferative endometrium rather than at the platelet defect, which is why it works where haemostatic agents alone do not.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"It can be effectively treated with high doses of progesterone. Main- tenance treatment with birth control pills should follow."
Supports the regimen described.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: Hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
The only curative option, and reserved for severe phenotypes because it trades a manageable bleeding disorder for transplant risk. The reported experience is small - 19 successful transplants in 18 type I patients, mean age 5 years, all alive at a median 25 months' follow-up - which is encouraging but far too short to establish long-term outcome, and 10 of those patients were already platelet-alloimmunized.
Mechanism Target:
RESTORES Biallelic Loss of Function in ITGA2B or ITGB3 — Replaces the patient's megakaryocyte lineage with donor cells carrying wild-type ITGA2B and ITGB3, correcting the defect at its origin.
Show evidence (1 reference)
PMID:23868573 SUPPORT Human Clinical
"HSCT offers the only curative approach for patients with a severe clinical phenotype."
Supports the curative claim and the restriction to severe phenotypes.
Show evidence (1 reference)
PMID:23868573 SUPPORT Human Clinical
"19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients..."
PARTIAL because the reported series establishes short-term feasibility and survival but, at a 25-month median follow-up in 18 patients, cannot support a long-term outcome claim - which is the caveat this entry states.
🔬

Diagnosis

2
Aggregometry with Normal Count and Morphology
The diagnosis is made on a combination no other disorder reproduces: absent platelet aggregation to all physiological agonists, abnormal clot retraction, and a normal platelet count and morphology. Normal ristocetin-induced agglutination and normal platelet size rule out Bernard-Soulier syndrome; normal coagulation parameters rule out afibrinogenaemia and von Willebrand disease.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"When these two signs are associated with a normal platelet count and morphology, the diag- nosis of GT is clear-cut."
States the diagnostic combination on which this entry rests.
Flow Cytometric Confirmation of alphaIIbbeta3
Surface alphaIIbbeta3 should always be quantified with monoclonal antibodies and flow cytometry. Western blotting for trace intracellular alphaIIb or beta3 can point to which gene is affected, and detection of unprocessed pro-alphaIIb suggests a block in integrin biosynthesis rather than absent transcription. A normal quantitative result does not exclude variant GT, in which activation-dependent epitope expression must be tested instead.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"can give clues to the identity of the affected gene, while the presence of nonprocessed precursor pro-αIIb will suggest a block in integrin biosyn- thesis"
Supports the western-blot and biosynthetic-block inferences described here.
📊

Prevalence

2
Worldwide
Unknown Unknown
Deliberately unquantified. The authoritative review declines to give a worldwide figure because ascertainment is dominated by consanguineous populations - of 177 reviewed patients only 12 were from the United States while 55 were from Israel and Jordan and 42 from South India - so any global rate would average incomparable populations. A prevalence band is left unstated here rather than fabricated from a case series.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"For these reasons, it would be imprudent to give an estimation of worldwide prevalence."
The source's own explicit refusal to estimate, which is why this record carries no rate.
Populations practising consanguineous marriage (South Indian Hindus, Iraqi Jews, French Gypsies, Jordanian nomadic tribes)
Unknown Common
Qualitative band only, and `measure_type` is UNKNOWN because the source states no measure type - it says the disorder "may actually be a common hereditary hemorrhagic disorder" in these groups and cites a single Iranian report of 382 patients, but gives no denominator, so no rate is recorded.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"In certain ethnic groups, such as South Indian Hindus, Iraqi Jews, French gypsies and Jordanian nomadic tribes, thrombasthenia may actually be a common hereditary hemorrhagic disorder."
Supports the qualitative COMMON band in the named populations and the populations listed.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Glanzmann Thrombasthenia:

Bernard-Soulier Syndrome
Overlapping Features The mechanistic mirror image and the first disorder to exclude. Both give mucocutaneous bleeding with abnormal aggregometry, but Bernard-Soulier syndrome is a disorder of adhesion with large platelets and thrombocytopenia and absent ristocetin-induced agglutination, whereas here platelet count, size and ristocetin response are all normal.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Normal ristocetin-induced platelet agglutination and nor- mal platelet size clearly rule out the Bernard-Soulier syn- drome, a disorder of platelet adhesion."
States the exact discriminators used here.
Storage Pool Disease and Agonist-Specific Receptor Defects
Overlapping Features Aggregation defects confined to a single agonist point upstream, to that agonist's receptor or signalling pathway; a defective second wave of aggregation to ADP points to dense-granule storage pool disease; a defective response to arachidonic acid points to a thromboxane A2 synthesis defect - or to recent aspirin, the acquired phenocopy that must be excluded before any of these are diagnosed.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Deficiencies in the platelet response to arachidonic acid can point either to an inherited abnormality in thromboxane A2 formation or a platelet function defect temporarily acquired through aspirin ingestion."
Supports the agonist-specific reasoning and the aspirin phenocopy warning.
von Willebrand Disease and Congenital Afibrinogenemia
Overlapping Features Clotting disorders that can also disturb platelet function; excluded by normal coagulation parameters.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Normal coagulation parameters rule out clotting disorders that can also affect platelet function such as con- genital afibrinogenemia and von Willebrand disease."
States the discriminator.
Acquired Thrombasthenia
Overlapping Features An acquired autoantibody against alphaIIbbeta3, or pharmacological blockade by an alphaIIbbeta3 antagonist, reproduces the functional defect exactly. Must be excluded whenever there is no family history.
Show evidence (1 reference)
PMID:16722529 SUPPORT Human Clinical
"Acquired thrombasthenia must be eliminated in the absence of a family history of the disease."
States the exclusion rule.
🐁

Animal Models

1
beta3-null mouse
The reference model, and a faithful one for the haematological phenotype: beta3-null mice reproduce all the cardinal features of the human disease. They also reveal what a purely platelet-centred view of beta3 misses - because beta3 partners alphaV as well as alphaIIb, the null mouse develops placental defects and fetal mortality that have no established human counterpart.
Species
Mouse
Genotype
Itgb3 knockout (homozygous null)
Publication
PMID:9916135
Pathograph links
Failure of Interplatelet Fibrinogen Bridging and Aggregation recapitulates fidelity: high Reproduces defective platelet aggregation and clot retraction, the two integrin-dependent functions lost in the human disease.
Limitations: The mouse is a complete constitutional null, so it also lacks alphaVbeta3 in every tissue; human patients with ITGA2B variants retain alphaVbeta3 entirely, and the placental phenotype does not correspond to a documented human feature.
Readouts
Platelet aggregation and clot retraction
Direction: DECREASED
Interpretation: Direct functional correlate of the human aggregation defect.
Show evidence (1 reference)
PMID:9916135 SUPPORT Model Organism
"show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding)"
Reports the measured aggregation and clot-retraction defects behind this readout.
Show evidence (1 reference)
PMID:9916135 SUPPORT Model Organism
"In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of beta3 integrins, we have generated a strain of beta3-null mice."
Establishes the model as purpose-built for this disease.
Mucocutaneous Bleeding Diathesis recapitulates fidelity: moderate Prolonged bleeding times with cutaneous and gastrointestinal bleeding, and anaemia from postnatal haemorrhage.
Limitations: Mouse bleeding is cutaneous and gastrointestinal; the mucosal sites that dominate the human picture (epistaxis, gingival haemorrhage, menorrhagia) have no direct murine counterpart, and reduced survival from postnatal haemorrhage exceeds what is seen in treated patients.
Readouts
Bleeding time
Direction: INCREASED
Interpretation: Whole-animal haemostatic correlate of the plug-formation failure.
Show evidence (1 reference)
PMID:9916135 SUPPORT Model Organism
"prolonged bleeding times, and cutaneous and gastrointestinal bleeding"
Reports the bleeding-time measurement and the bleeding sites observed.
Show evidence (1 reference)
PMID:9916135 SUPPORT Model Organism
"Postnatal hemorrhage leads to anemia and reduced survival."
Supports the whole-animal bleeding phenotype and the severity caveat recorded in the limitations.
{ }

Source YAML

click to show 
name: Glanzmann Thrombasthenia
creation_date: "2026-08-24T00:00:00Z"
category: Mendelian
parents:
- Inherited Platelet Disorder
- Bleeding Disorder
disease_term:
  preferred_term: Glanzmann thrombasthenia
  term:
    id: MONDO:0100326
    label: Glanzmann thrombasthenia
synonyms:
- GT
- BDPLT2
- bleeding disorder, platelet-type, 2
- thrombasthenia of Glanzmann and Naegeli
- glycoprotein IIb-IIIa deficiency
- thrombocytasthenia
description: >-
  Glanzmann thrombasthenia is the prototype inherited disorder of platelet
  aggregation: an autosomal recessive bleeding syndrome in which quantitative or
  qualitative loss of the platelet integrin alphaIIbbeta3 leaves platelets
  unable to bind one another. It is the mechanistic mirror image of
  Bernard-Soulier syndrome. There the platelet cannot stick to the vessel wall
  and is large and scarce; here the platelet is present in normal number and
  normal size, it adheres perfectly well, it activates, and it still cannot form
  an aggregate, because alphaIIbbeta3 is the receptor that binds the fibrinogen
  and von Willebrand factor bridging one platelet to the next. That gives the
  disease a laboratory signature no other disorder reproduces - absent
  aggregation to every physiological agonist, with normal ristocetin-induced
  agglutination, a normal platelet count and normal platelet morphology - and it
  is the reason a diagnosis that is genuinely difficult to make clinically is
  nearly unmistakable in the aggregometry laboratory.

  The disease is caused by biallelic variants in either subunit gene, ITGA2B
  (alphaIIb) or ITGB3 (beta3), which sit adjacent on 17q21; because the two
  subunits must heterodimerize to leave the endoplasmic reticulum, losing either
  one removes the whole receptor and the two genotypes are clinically
  indistinguishable. Severity is strikingly variable - some patients have only
  minimal bruising while others have frequent, potentially fatal haemorrhage -
  and it correlates poorly with residual receptor level, so genotype is a poor
  guide to prognosis. It is rare worldwide but genuinely common in populations
  where consanguineous marriage is customary, and the clinical problem that
  dominates long-term management is iatrogenic: repeated platelet transfusion
  into a patient whose platelets have never displayed alphaIIbbeta3 provokes
  alloantibodies against an antigen the immune system treats as foreign, after
  which transfusion stops working.
has_subtypes:
- name: GT1
  display_name: Glanzmann thrombasthenia 1 (ITGA2B-related)
  subtype_term:
    preferred_term: Glanzmann thrombasthenia 1
    term:
      id: MONDO:0031332
      label: Glanzmann thrombasthenia 1
  description: >-
    Biallelic ITGA2B variants removing or inactivating the alphaIIb subunit.
    Clinically indistinguishable from the ITGB3 form, because loss of either
    subunit prevents surface expression of the heterodimer. Some geographic
    skewing has been reported - alphaIIb variants dominated an Italian series
    while beta3 variants, with emphasis on exon 4, characterized an Indian one -
    which reflects founder effects rather than any mechanistic difference.
  genes:
  - preferred_term: ITGA2B
    term:
      id: hgnc:6138
      label: ITGA2B
- name: GT2
  display_name: Glanzmann thrombasthenia 2 (ITGB3-related)
  subtype_term:
    preferred_term: Glanzmann thrombasthenia 2
    term:
      id: MONDO:0031009
      label: Glanzmann thrombasthenia 2
  description: >-
    Biallelic ITGB3 variants removing or inactivating the beta3 subunit. Because
    beta3 also partners alphaV to form the vitronectin receptor alphaVbeta3,
    which is expressed far beyond the platelet, ITGB3-null disease is the arm in
    which extraplatelet consequences might be expected; in the beta3-null mouse
    these are real (placental defects and fetal mortality), and whether they
    translate to patients is an open question rather than an established feature
    of the human disease.
  genes:
  - preferred_term: ITGB3
    term:
      id: hgnc:6156
      label: ITGB3
- name: Type I
  display_name: Type I (severe, <5% residual alphaIIbbeta3)
  description: >-
    The classic and commonest form: platelet aggregation is absent and clot
    retraction is absent, with essentially no surface alphaIIbbeta3. In the
    detailed Hopital Lariboisiere experience this accounted for 50 of 64
    patients (78%). This is a phenotypic severity class cutting across both
    genes, not a third genotype.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those patients with absent platelet aggregation and absent clot retraction were subsequently termed as having type I disease; those with absent aggregation but residual clot retraction, type II disease"
    explanation: >-
      Defines the type I/type II split on which this and the following subtype
      entries rest.
- name: Type II
  display_name: Type II (residual alphaIIbbeta3, clot retraction preserved)
  description: >-
    Aggregation is absent but clot retraction is preserved, reflecting residual
    surface alphaIIbbeta3. Nine of 64 patients (14%) in the Lariboisiere series.
    Residual receptor does not reliably predict milder bleeding.
  review_notes: >-
    No percentage is stated here for the residual receptor, deliberately. The figure
    conventionally quoted for type II is teaching-text lore that the cited
    review does not contain, and nothing else in this entry's evidence base
    quantifies it. Do not reinstate a number here without a source that states
    one.
- name: Variant GT
  display_name: Variant GT (receptor present but non-functional)
  description: >-
    alphaIIbbeta3 is expressed at near-normal levels but cannot bind ligand,
    diagnosed by the failure of the receptor to express activation-dependent
    epitopes. Five of 64 patients (8%) in the Lariboisiere series. This is the
    subtype in which a purely quantitative flow-cytometry screen is normal and
    the diagnosis is missed unless receptor function is tested - a practical
    reason the schema-level distinction is worth carrying.
pathophysiology:
- name: Biallelic Loss of Function in ITGA2B or ITGB3
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >-
    Pathogenic variants in either of the two adjacent 17q21 genes encoding the
    alphaIIb and beta3 subunits cause the disease, and the mutational spectrum
    spans every class - missense, nonsense, frameshift, splice and large
    deletion - with no region of either gene exempt. Heterozygotes carry roughly
    half-normal platelet alphaIIbbeta3 and are almost always asymptomatic, so
    the disease is recessive at the level of receptor dose as well as
    inheritance. Founder variants dominate in several populations, including the
    ITGA2B c.1544+1G>A allele of French Gypsy patients.
  genetic_context:
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Note that abnormalities are abundant in both αIIb and β3 genes and that no parts of either gene appear to be exempt."
    explanation: >-
      Establishes that the mutational spectrum is unconstrained across both
      genes, which is why the disorder has no small set of recurrent alleles
      outside founder populations.
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients homozygous for mutations causing GT; the heter- ozygous condition is mostly asymptomatic, even though these subjects have only a half-normal concentration of platelet αIIbβ3"
    explanation: >-
      Supports the recessive dose relationship - half-normal receptor is
      haemostatically sufficient - which is the basis of the carrier statement
      in this node.
  downstream:
  - target: Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3
    causal_link_type: DIRECT
    description: >-
      Loss of either subunit prevents assembly and surface expression of the
      obligate heterodimer.
- name: Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    alphaIIb and beta3 must heterodimerize in the endoplasmic reticulum before
    the complex can traffic to the platelet surface, so a defect in either
    subunit removes the whole receptor. Three outcomes are possible and define
    the phenotypic classes: near-total absence of surface receptor (type I),
    reduced but measurable receptor (type II), or normal amounts of a receptor
    that cannot bind ligand (variant GT). The last is why a quantitative
    flow-cytometry result alone cannot exclude the diagnosis.
  molecular_functions:
  - preferred_term: integrin alphaIIbbeta3 fibrinogen-binding activity
    term:
      id: GO:0005178
      label: integrin binding
    modifier: DECREASED
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular basis is linked to quantitative and/or qualitative abnormalities of alphaIIb beta3 integrin."
    explanation: >-
      States the quantitative-versus-qualitative distinction this node
      represents.
  - 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: HUMAN_CLINICAL
    snippet: "it is caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21-23"
    explanation: >-
      Independent statement of the same receptor-level lesion and its two gene
      routes, including the chromosomal location asserted here.
  downstream:
  - target: Failure of Interplatelet Fibrinogen Bridging and Aggregation
    causal_link_type: DIRECT
    description: >-
      Without a functional receptor, the adhesive proteins that bridge adjacent
      platelets have nothing to bind.
  - target: Impaired Clot Retraction
    causal_link_type: DIRECT
    description: >-
      alphaIIbbeta3 also transmits the actomyosin contractile force of the
      platelet onto the fibrin network, an outside-in function separate from
      aggregation.
- name: Failure of Interplatelet Fibrinogen Bridging and Aggregation
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Failure of Integrin alphaIIbbeta3-Mediated Platelet Aggregation"
  description: >-
    The rate-limiting lesion. Activated alphaIIbbeta3 normally binds fibrinogen
    and von Willebrand factor, which cross-link adjacent platelets into a
    growing aggregate; without it, platelets that have adhered and activated
    normally remain a monolayer. Because this is the final common step of
    aggregation, the failure is agonist-independent: ADP, collagen, thrombin,
    arachidonic acid and epinephrine all fail alike, whereas ristocetin-induced
    agglutination - which depends on GPIb-IX-V and von Willebrand factor rather
    than on alphaIIbbeta3 - remains normal. That dissociation is what separates
    this disorder from Bernard-Soulier syndrome at the bench.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet aggregation
    term:
      id: GO:0070527
      label: platelet aggregation
    modifier: DECREASED
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This receptor mediates the binding of adhesive proteins that attach aggregating platelets and ensure thrombus formation at sites of injury in blood vessels."
    explanation: >-
      States the bridging function whose loss constitutes this node.
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GT is the only disease in which platelet aggregation is defective to all agonists, while absent clot retraction is another frequent character- istic."
    explanation: >-
      Supports the agonist-independence claim - the discriminating feature of
      this node - and the linked clot-retraction defect.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      No aggregate means no plug beyond the adherent platelet monolayer.
- name: Impaired Clot Retraction
  role: effector
  biological_scale: CELLULAR
  description: >-
    A parallel, outside-in consequence of losing the receptor: alphaIIbbeta3
    engaged with fibrin transmits platelet actomyosin contraction to the clot,
    consolidating and shrinking it. Loss of clot retraction alongside absent
    aggregation defines type I disease; its preservation despite absent
    aggregation defines type II, so this node is the discriminator between the
    two severity classes rather than an independent bleeding mechanism.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli is pathognomonic for GT, and abnormal clot retraction is rarely observed in other disorders"
    explanation: >-
      Establishes impaired clot retraction as a real and near-specific feature
      of the disorder.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      An unretracted clot is mechanically weaker and more easily dislodged.
- name: Failure of Primary Hemostatic Plug Formation
  role: effector
  biological_scale: TISSUE
  conforms_to: "primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation"
  description: >-
    Platelets adhere to the injured vessel wall normally - GPIb-IX-V and GPVI
    are intact - but the mass never grows or consolidates into a plug capable of
    arresting bleeding from small vessels. This is the shared destination of the
    inherited platelet function disorders reached here by the aggregation route.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:21781244
    reference_title: Advances in our understanding of the molecular basis of disorders of platelet function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury."
    explanation: >-
      Supports the convergence of a platelet-function defect onto failure of the
      platelet's haemostatic role and thence to mucocutaneous bleeding.
  downstream:
  - target: Mucocutaneous Bleeding Diathesis
    causal_link_type: DIRECT
    description: >-
      Skin and mucous membranes depend most heavily on platelet-dependent
      primary hemostasis.
- name: Mucocutaneous Bleeding Diathesis
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >-
    Bleeding declares itself at well-defined sites: purpura, epistaxis, gingival
    haemorrhage and menorrhagia are nearly constant, while gastrointestinal
    bleeding and haematuria are less common but disproportionately dangerous.
    Symptoms usually appear soon after birth. Severity varies enormously between
    patients carrying the same variant, so the clinical course cannot be
    predicted from the genotype; chronic low-grade loss from gingival oozing or
    menorrhagia makes iron-deficiency anaemia a frequent accompanying problem.
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The site of bleeding in GT is clearly defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features; gastrointestinal bleeding and hematuria are less common."
    explanation: >-
      Enumerates the bleeding sites and their relative frequency, which is the
      content of this node.
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GT is associated with clinical variability: some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages."
    explanation: >-
      Supports the severity-variability claim that makes genotype a poor
      prognostic guide.
  downstream:
  - target: Platelet Alloimmunization Against alphaIIbbeta3
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bleeding drives platelet transfusion, which is the exposure that
      immunizes; the intervening step is therapeutic rather than biological.
- name: Platelet Alloimmunization Against alphaIIbbeta3
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The iatrogenic complication that dominates long-term management and has no
    counterpart in most inherited disorders. A patient whose platelets have
    never displayed alphaIIbbeta3 has no tolerance to it, so transfused normal
    platelets present a foreign antigen; the resulting anti-alphaIIbbeta3
    antibodies cause refractoriness to further transfusion and, in women, risk
    fetal and neonatal alloimmune thrombocytopenia. The beta3 subunit carries
    the HPA-1 antigen system, and because beta3 also partners alphaV, an
    HPA-1bb patient who expresses no platelet alphaIIbbeta3 at all can still be
    immunized against HPA-1a through alphaVbeta3 on their own platelet surface -
    an exposure route that a purely alphaIIbbeta3-centred model of the disease
    would predict was closed. This is the reason management is built around
    avoiding transfusion rather than around delivering it.
  evidence:
  - reference: PMID:33090654
    reference_title: Immunization against α(IIb) β(3) and α(v) β(3) in Glanzmann thrombasthenia patients carrying the French Gypsy mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found that HPA-1bb patients who failed to express αIIb β3 on the platelet surface can develop alloantibodies against HPA-1a reacting with β3 as well as αv β3 . This is of particular importance as anti-HPA-1a alloantibodies might cause fetal neonatal alloimmune thrombocytopenia and/or platelet transfusion refractoriness."
    explanation: >-
      Direct evidence for the alphaVbeta3 immunization route and for the two
      clinical consequences named in this node.
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration."
    explanation: >-
      Supports the claim that avoidance of this complication is what structures
      first-line management.
phenotypes:
- category: Hematologic
  name: Impaired Platelet Aggregation to All Agonists
  description: >-
    The defining laboratory phenotype: platelet aggregation is absent or
    profoundly reduced in response to every physiological agonist, while
    ristocetin-induced agglutination is preserved.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  frequency: OBLIGATE
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GT is the only disease in which platelet aggregation is defective to all agonists"
    explanation: >-
      Supports both the phenotype and its obligate frequency - it is the
      diagnostic criterion, so no diagnosed patient lacks it.
- category: Hematologic
  name: Decreased Platelet Glycoprotein IIb-IIIa
  description: >-
    Reduced or absent surface alphaIIbbeta3 by flow cytometry, near-total in
    type I and partial in type II. Normal in variant GT, where the receptor is
    present but non-functional, so a normal result does not exclude the
    diagnosis.
  phenotype_term:
    preferred_term: Decreased platelet glycoprotein IIb-IIIa
    term:
      id: HP:0001975
      label: Decreased platelet glycoprotein IIb-IIIa
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet αIIbβ3 deficiency should always be confirmed in new patients, and this can be done with monoclonal antibod- ies and flow cytometry"
    explanation: >-
      Supports the phenotype and the flow-cytometric method by which it is
      established.
- category: Hematologic
  name: Purpura
  phenotype_term:
    preferred_term: Purpura
    term:
      id: HP:0000979
      label: Purpura
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
    explanation: >-
      "Nearly constant" maps to the VERY_FREQUENT band (80-99%) for this and the
      three phenotypes named alongside it.
- category: Hematologic
  name: Epistaxis
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
    explanation: >-
      Supports the phenotype and the VERY_FREQUENT band.
- category: Hematologic
  name: Gingival Bleeding
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
    explanation: >-
      Supports the phenotype and the VERY_FREQUENT band.
- category: Reproductive
  name: Menorrhagia
  description: >-
    Severe menorrhagia is a frequent clinical problem and is usually associated
    with an excessively proliferative oestrogen-dominant endometrium, which is
    why hormonal rather than haemostatic treatment is first-line for it.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features"
    explanation: >-
      Supports the phenotype and the VERY_FREQUENT band.
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe menorrhagia is a frequent clinical problem and is usually associated with an excessively proliferative endometrium caused by estrogen dominance."
    explanation: >-
      Supports the mechanism stated in the description and the hormonal
      treatment rationale.
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal bleeding and hematuria are less common but can cause serious complications"
    explanation: >-
      Explicitly contrasts these two with the "nearly constant" features,
      supporting a lower frequency band alongside a higher severity.
- category: Renal
  name: Hematuria
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal bleeding and hematuria are less common but can cause serious complications"
    explanation: >-
      Supports the phenotype and the lower frequency band.
- category: Hematologic
  name: Bruising Susceptibility
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages"
    explanation: >-
      Establishes bruising as the mild end of the disorder's clinical range.
- category: Hematologic
  name: Iron Deficiency Anemia
  description: >-
    Develops insidiously from chronic low-grade loss - gingival oozing or minor
    menorrhagia - rather than from acute haemorrhage, which is why it is often
    the presenting problem rather than a late complication.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Iron deficiency anemia, which can develop insidi- ously with gingival oozing or minor menorrhagia, is a fre- quent problem."
    explanation: >-
      Supports both the mechanism given in the description and the FREQUENT
      band, which the source states directly.
- category: Hematologic
  name: Prolonged Bleeding After Surgery
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bleeding following trauma or surgical procedures can be severe and transfusions are often given by precaution or should be available on standby."
    explanation: >-
      Supports post-surgical bleeding as a recognized and clinically managed
      feature.
- category: Reproductive
  name: Post-Partum Hemorrhage
  phenotype_term:
    preferred_term: Post-partum hemorrhage
    term:
      id: HP:0011891
      label: Post-partum hemorrhage
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pregnancy and in partic- ular, delivery, represent a particularly severe hemorrhagic risk."
    explanation: >-
      Supports delivery as a high-risk bleeding event in this disorder.
genetic:
- name: ITGA2B
  gene_term:
    preferred_term: ITGA2B
    term:
      id: hgnc:6138
      label: ITGA2B
  relationship_type: CAUSATIVE
  notes: >-
    Encodes the alphaIIb integrin subunit. Biallelic loss-of-function variants
    cause Glanzmann thrombasthenia 1. A founder splice variant, c.1544+1G>A, is
    carried by French Gypsy patients and is linked to the HPA-1b allele of the
    beta3 antigen system, which shapes their alloimmunization risk.
  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: HUMAN_CLINICAL
    snippet: "quantitative and/or qualitative deficiencies of the αIIbβ3 integrin coded by the ITGA2B and ITGB3 genes located at 17q21-23"
    explanation: >-
      Establishes ITGA2B as one of the two causal genes and its chromosomal
      location.
  - reference: PMID:33090654
    reference_title: Immunization against α(IIb) β(3) and α(v) β(3) in Glanzmann thrombasthenia patients carrying the French Gypsy mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The c.1544+1G>A mutation was identified in Gypsy Glanzmann thrombasthenia (GT) patients."
    explanation: >-
      Supports the founder variant named in this gene block.
- name: ITGB3
  gene_term:
    preferred_term: ITGB3
    term:
      id: hgnc:6156
      label: ITGB3
  relationship_type: CAUSATIVE
  notes: >-
    Encodes the beta3 integrin subunit. Biallelic loss-of-function variants
    cause Glanzmann thrombasthenia 2. Distinct, mostly monoallelic variants at
    the cytoplasmic-tail salt bridge (beta3 Asp723, pairing with alphaIIb
    Arg995) do NOT cause classic thrombasthenia: they weaken the link that holds
    the integrin in its bent resting state, raise its activation status, and
    interfere with megakaryocytopoiesis, producing dominant macrothrombocytopenia
    with platelet anisotropy instead. Assigning an ITGB3 variant to this entry
    therefore requires the recessive, aggregation-loss phenotype, not merely a
    variant in the gene.
  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: HUMAN_CLINICAL
    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. Significantly, Arg995 and Asp723 form a salt linkage binding the cytoplasmic tails of αIIbβ3 together keeping the integrin in a bent resting state."
    explanation: >-
      Supports the boundary drawn in this gene block between classic
      thrombasthenia alleles and the salt-bridge macrothrombocytopenia alleles.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic variants in ITGA2B or ITGB3 are required. Heterozygotes have
    roughly half-normal platelet alphaIIbbeta3 and are mostly asymptomatic.
    Consanguinity is prominent in affected families and drives the disorder's
    geographic distribution.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by lack of platelet aggregation."
    explanation: >-
      States the mode of inheritance directly.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Deliberately unquantified. The authoritative review declines to give a
    worldwide figure because ascertainment is dominated by consanguineous
    populations - of 177 reviewed patients only 12 were from the United States
    while 55 were from Israel and Jordan and 42 from South India - so any global
    rate would average incomparable populations. A prevalence band is left
    unstated here rather than fabricated from a case series.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For these reasons, it would be imprudent to give an estimation of worldwide prevalence."
    explanation: >-
      The source's own explicit refusal to estimate, which is why this record
      carries no rate.
- population: Populations practising consanguineous marriage (South Indian Hindus, Iraqi Jews, French Gypsies, Jordanian nomadic tribes)
  measure_type: UNKNOWN
  prevalence_class: COMMON
  notes: >-
    Qualitative band only, and `measure_type` is UNKNOWN because the source
    states no measure type - it says the disorder "may actually be a
    common hereditary hemorrhagic disorder" in these groups and cites a single
    Iranian report of 382 patients, but gives no denominator, so no rate is
    recorded.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In certain ethnic groups, such as South Indian Hindus, Iraqi Jews, French gypsies and Jordanian nomadic tribes, thrombasthenia may actually be a common hereditary hemorrhagic disorder."
    explanation: >-
      Supports the qualitative COMMON band in the named populations and the
      populations listed.
diagnosis:
- name: Aggregometry with Normal Count and Morphology
  description: >-
    The diagnosis is made on a combination no other disorder reproduces: absent
    platelet aggregation to all physiological agonists, abnormal clot
    retraction, and a normal platelet count and morphology. Normal
    ristocetin-induced agglutination and normal platelet size rule out
    Bernard-Soulier syndrome; normal coagulation parameters rule out
    afibrinogenaemia and von Willebrand disease.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When these two signs are associated with a normal platelet count and morphology, the diag- nosis of GT is clear-cut."
    explanation: >-
      States the diagnostic combination on which this entry rests.
- name: Flow Cytometric Confirmation of alphaIIbbeta3
  description: >-
    Surface alphaIIbbeta3 should always be quantified with monoclonal antibodies
    and flow cytometry. Western blotting for trace intracellular alphaIIb or
    beta3 can point to which gene is affected, and detection of unprocessed
    pro-alphaIIb suggests a block in integrin biosynthesis rather than absent
    transcription. A normal quantitative result does not exclude variant GT, in
    which activation-dependent epitope expression must be tested instead.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can give clues to the identity of the affected gene, while the presence of nonprocessed precursor pro-αIIb will suggest a block in integrin biosyn- thesis"
    explanation: >-
      Supports the western-blot and biosynthetic-block inferences described
      here.
treatments:
- name: Local Hemostatic Measures and Desmopressin
  description: >-
    First-line, and chosen for what it avoids as much as for what it achieves:
    local measures (fibrin sealants, nasal packing, topical thrombin on gel
    foam, custom dental splints for extractions) and desmopressin are used
    wherever possible specifically to keep the patient from being exposed to
    donor platelets and alloimmunized. Regular dental care is preventive
    treatment in this disorder, not general advice.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Platelet Alloimmunization Against alphaIIbbeta3
    treatment_effect: INHIBITS
    description: >-
      The mechanism these measures act on is the iatrogenic one: by achieving
      haemostasis without donor platelets they prevent the alloimmunization that
      would close off transfusion later.
    evidence:
    - reference: PMID:16722529
      reference_title: Glanzmann thrombasthenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration."
      explanation: >-
        States exactly this rationale - the measures are selected to avoid
        alloimmunization.
- name: Platelet Transfusion
  description: >-
    Effective but reserved, because each exposure risks alloimmunization.
    HLA-compatible concentrates are used when local measures and desmopressin
    fail, or to cover surgery and delivery.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Failure of Interplatelet Fibrinogen Bridging and Aggregation
    treatment_effect: RESTORES
    description: >-
      Supplies platelets that express functional alphaIIbbeta3, transiently
      restoring the missing bridging function itself rather than bypassing it.
    evidence:
    - reference: PMID:16722529
      reference_title: Glanzmann thrombasthenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Transfusion of HLA-compatible platelet concentrates may be necessary if these measures are ineffective, or to prevent bleeding during surgery."
      explanation: >-
        Supports the indication and the second-line positioning stated here.
- name: Recombinant Activated Factor VIIa
  description: >-
    The bypass agent, and the mainstay for patients with platelet antibodies or
    transfusion refractoriness - precisely the patients for whom transfusion has
    stopped working. In the international Glanzmann Thrombasthenia Registry it
    provided effective surgical haemostasis across 206 procedures regardless of
    antibody or refractoriness status, with a low adverse-event rate; the one
    treatment-related event was a non-fatal thromboembolism, which is the
    expected hazard of a prohaemostatic bypass.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Failure of Primary Hemostatic Plug Formation
    treatment_effect: BYPASSES
    description: >-
      Drives thrombin generation and fibrin formation on the available
      activated platelet surface, closing the haemostatic gap without restoring
      alphaIIbbeta3-mediated aggregation.
    evidence:
    - reference: PMID:26001792
      reference_title: "The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (±antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients."
      explanation: >-
        Registry evidence that the agent achieves haemostasis without repairing
        the receptor defect.
  evidence:
  - reference: PMID:26001792
    reference_title: "The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics)."
    explanation: >-
      Supports the thromboembolic hazard named in the description and its
      observed rarity.
- name: Hormonal Control of Menorrhagia
  description: >-
    High-dose progesterone for severe menorrhagia, followed by maintenance oral
    contraception. Directed at the oestrogen-dominant proliferative endometrium
    rather than at the platelet defect, which is why it works where
    haemostatic agents alone do not.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It can be effectively treated with high doses of progesterone. Main- tenance treatment with birth control pills should follow."
    explanation: >-
      Supports the regimen described.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    The only curative option, and reserved for severe phenotypes because it
    trades a manageable bleeding disorder for transplant risk. The reported
    experience is small - 19 successful transplants in 18 type I patients, mean
    age 5 years, all alive at a median 25 months' follow-up - which is
    encouraging but far too short to establish long-term outcome, and 10 of
    those patients were already platelet-alloimmunized.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Biallelic Loss of Function in ITGA2B or ITGB3
    treatment_effect: RESTORES
    description: >-
      Replaces the patient's megakaryocyte lineage with donor cells carrying
      wild-type ITGA2B and ITGB3, correcting the defect at its origin.
    evidence:
    - reference: PMID:23868573
      reference_title: Indication for allogeneic stem cell transplantation in Glanzmann's thrombasthenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HSCT offers the only curative approach for patients with a severe clinical phenotype."
      explanation: >-
        Supports the curative claim and the restriction to severe phenotypes.
  evidence:
  - reference: PMID:23868573
    reference_title: Indication for allogeneic stem cell transplantation in Glanzmann's thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients showed alloimmunization of thrombocytes. Median follow up is 25 months."
    explanation: >-
      PARTIAL because the reported series establishes short-term feasibility and
      survival but, at a 25-month median follow-up in 18 patients, cannot
      support a long-term outcome claim - which is the caveat this entry states.
animal_models:
- name: beta3-null mouse
  species: Mouse
  genotype: Itgb3 knockout (homozygous null)
  publication: PMID:9916135
  description: >-
    The reference model, and a faithful one for the haematological phenotype:
    beta3-null mice reproduce all the cardinal features of the human disease.
    They also reveal what a purely platelet-centred view of beta3 misses -
    because beta3 partners alphaV as well as alphaIIb, the null mouse develops
    placental defects and fetal mortality that have no established human
    counterpart.
  modeled_mechanisms:
  - target: Failure of Interplatelet Fibrinogen Bridging and Aggregation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces defective platelet aggregation and clot retraction, the two
      integrin-dependent functions lost in the human disease.
    limitations: >-
      The mouse is a complete constitutional null, so it also lacks alphaVbeta3
      in every tissue; human patients with ITGA2B variants retain alphaVbeta3
      entirely, and the placental phenotype does not correspond to a documented
      human feature.
    readouts:
    - name: Platelet aggregation and clot retraction
      target: Failure of Interplatelet Fibrinogen Bridging and Aggregation
      direction: DECREASED
      interpretation: >-
        Direct functional correlate of the human aggregation defect.
      evidence:
      - reference: PMID:9916135
        reference_title: Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding)"
        explanation: >-
          Reports the measured aggregation and clot-retraction defects behind
          this readout.
    evidence:
    - reference: PMID:9916135
      reference_title: Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of beta3 integrins, we have generated a strain of beta3-null mice."
      explanation: >-
        Establishes the model as purpose-built for this disease.
  - target: Mucocutaneous Bleeding Diathesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Prolonged bleeding times with cutaneous and gastrointestinal bleeding, and
      anaemia from postnatal haemorrhage.
    limitations: >-
      Mouse bleeding is cutaneous and gastrointestinal; the mucosal sites that
      dominate the human picture (epistaxis, gingival haemorrhage, menorrhagia)
      have no direct murine counterpart, and reduced survival from postnatal
      haemorrhage exceeds what is seen in treated patients.
    readouts:
    - name: Bleeding time
      target: Mucocutaneous Bleeding Diathesis
      direction: INCREASED
      interpretation: >-
        Whole-animal haemostatic correlate of the plug-formation failure.
      evidence:
      - reference: PMID:9916135
        reference_title: Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "prolonged bleeding times, and cutaneous and gastrointestinal bleeding"
        explanation: >-
          Reports the bleeding-time measurement and the bleeding sites observed.
    evidence:
    - reference: PMID:9916135
      reference_title: Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Postnatal hemorrhage leads to anemia and reduced survival."
      explanation: >-
        Supports the whole-animal bleeding phenotype and the severity caveat
        recorded in the limitations.
differential_diagnoses:
- name: Bernard-Soulier Syndrome
  description: >-
    The mechanistic mirror image and the first disorder to exclude. Both give
    mucocutaneous bleeding with abnormal aggregometry, but Bernard-Soulier
    syndrome is a disorder of adhesion with large platelets and thrombocytopenia
    and absent ristocetin-induced agglutination, whereas here platelet count,
    size and ristocetin response are all normal.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal ristocetin-induced platelet agglutination and nor- mal platelet size clearly rule out the Bernard-Soulier syn- drome, a disorder of platelet adhesion."
    explanation: >-
      States the exact discriminators used here.
- name: Storage Pool Disease and Agonist-Specific Receptor Defects
  description: >-
    Aggregation defects confined to a single agonist point upstream, to that
    agonist's receptor or signalling pathway; a defective second wave of
    aggregation to ADP points to dense-granule storage pool disease; a defective
    response to arachidonic acid points to a thromboxane A2 synthesis defect -
    or to recent aspirin, the acquired phenocopy that must be excluded before
    any of these are diagnosed.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiencies in the platelet response to arachidonic acid can point either to an inherited abnormality in thromboxane A2 formation or a platelet function defect temporarily acquired through aspirin ingestion."
    explanation: >-
      Supports the agonist-specific reasoning and the aspirin phenocopy warning.
- name: von Willebrand Disease and Congenital Afibrinogenemia
  description: >-
    Clotting disorders that can also disturb platelet function; excluded by
    normal coagulation parameters.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal coagulation parameters rule out clotting disorders that can also affect platelet function such as con- genital afibrinogenemia and von Willebrand disease."
    explanation: >-
      States the discriminator.
- name: Acquired Thrombasthenia
  description: >-
    An acquired autoantibody against alphaIIbbeta3, or pharmacological blockade
    by an alphaIIbbeta3 antagonist, reproduces the functional defect exactly.
    Must be excluded whenever there is no family history.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired thrombasthenia must be eliminated in the absence of a family history of the disease."
    explanation: >-
      States the exclusion rule.
- name: ITGA2B/ITGB3-Related Macrothrombocytopenia
  description: >-
    Monoallelic variants disrupting the alphaIIb Arg995-beta3 Asp723 cytoplasmic
    salt bridge cause a dominant macrothrombocytopenia with platelet anisotropy,
    not classic thrombasthenia. The genes are the same and the mechanism is the
    opposite - increased rather than lost integrin activation - so a variant in
    ITGA2B or ITGB3 is not by itself a diagnosis of this disorder.
  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: HUMAN_CLINICAL
    snippet: "Mutations weakening this link (if not abolishing it) increase the activation state of αIIbβ3 and interfere with megakaryocytopoiesis."
    explanation: >-
      States the opposite-direction mechanism that distinguishes these variants
      from thrombasthenia alleles.
discussions:
- discussion_id: gap_severity_not_predicted_by_genotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do patients carrying the same ITGA2B or ITGB3 variant differ so widely in
    bleeding frequency and severity?
  attaches_to:
  - pathophysiology#Mucocutaneous Bleeding Diathesis
  rationale: >-
    Clinical severity ranges from minimal bruising to fatal haemorrhage, and the
    source review states directly that individuals with the same mutation may
    differ widely. That means neither the causal genotype nor the residual
    receptor level (type I versus type II) is a sufficient predictor, so the
    modifier is elsewhere. This matters practically: prophylaxis and transplant
    decisions are severity-driven, and there is currently no molecular basis on
    which to make them. Candidate explanations include co-inherited prothrombotic
    variants, which have been reported to modulate the phenotype, and
    differences in vessel-wall or plasma-phase compensation.
  proposed_experiments:
  - experiment_id: exp_modifier_genotype_bleeding_score
    name: Genotype-stratified bleeding-score study with thrombophilia panel
    description: >-
      In a multinational registry, pair a standardized bleeding-assessment tool
      score with the causal genotype, the quantified residual alphaIIbbeta3, and
      a panel of prothrombotic modifier alleles. Testing whether modifier
      genotype explains within-variant variance would either yield a usable
      prognostic model or exclude the leading candidate explanation.
  evidence:
  - reference: PMID:16722529
    reference_title: Glanzmann thrombasthenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with the same mutation may differ widely in the frequency and severity of bleeding"
    explanation: >-
      The observation that establishes this as a genuine gap rather than an
      artefact of imprecise phenotyping.
- discussion_id: mismatch_beta3_null_mouse_placental_phenotype
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the placental defects and fetal mortality of the beta3-null mouse
    correspond to any reproductive consequence in human ITGB3-related Glanzmann
    thrombasthenia?
  attaches_to:
  - pathophysiology#Quantitative or Qualitative Deficiency of Integrin alphaIIbbeta3
  rationale: >-
    The beta3-null mouse recapitulates the platelet phenotype faithfully but also
    shows placental defects leading to fetal mortality, which arise from loss of
    alphaVbeta3 rather than alphaIIbbeta3. Human ITGB3-null patients likewise
    lack alphaVbeta3, yet no corresponding placental disease is an established
    feature of the human disorder - while pregnancy in these patients is
    hazardous, the documented hazard is haemorrhagic. This is a mismatch of
    translational validity, not an absence of evidence: the mouse result is
    solid, and what is unresolved is whether it means anything for patients. The
    distinction matters because it separates a genuine unstudied risk from a
    species artefact of constitutional knockout, and because it applies only to
    the ITGB3 arm, not the ITGA2B arm.
  proposed_experiments:
  - experiment_id: exp_itgb3_pregnancy_outcome_registry
    name: Gene-stratified pregnancy outcome analysis
    description: >-
      Compare pregnancy outcomes - placental pathology, fetal growth
      restriction, and loss - between ITGB3-null and ITGA2B-null patients in an
      international registry, with haemorrhagic complications recorded
      separately so that a placental signal is not obscured by bleeding-driven
      outcomes. Equivalent outcomes across the two genotypes would settle the
      mouse finding as a species artefact.
  evidence:
  - reference: PMID:9916135
    reference_title: Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Implantation appears to be unaffected, but placental defects do occur and lead to fetal mortality."
    explanation: >-
      The model-system finding whose human relevance is the open question.
notes: >-
  Conformance: this entry conforms to the `primary_hemostatic_plug_failure`
  module through the AGGREGATION arm - `#Failure of Integrin
  alphaIIbbeta3-Mediated Platelet Aggregation` - which is the arm the module
  reserves for a demonstrated failure of the final common aggregation step
  itself, and this is its worked example. It does not conform to the adhesion
  arm: GPIb-IX-V and GPVI are intact and ristocetin-induced agglutination is
  normal.

  Entry scope. MONDO:0100326 (Orphanet:849, OMIMPS:273800) is the umbrella term
  for classic autosomal recessive thrombasthenia and is used as the primary
  `disease_term`; MONDO:0031332 (GT1, ITGA2B) and MONDO:0031009 (GT2, ITGB3) are
  carried as `has_subtypes` because the two genotypes are clinically
  indistinguishable - the subunits are obligate partners, so losing either
  removes the same receptor - and splitting them into separate entries would
  duplicate one pathograph. The type I / type II / variant classes are carried
  as subtypes too, but they are a phenotypic severity axis crossing both genes,
  not additional genotypes; they earn their place because "variant GT" is the
  form a quantitative flow-cytometry screen misses.

  What is deliberately NOT in this entry. The dominant ITGA2B/ITGB3
  macrothrombocytopenias caused by variants at the alphaIIb Arg995-beta3 Asp723
  cytoplasmic salt bridge (OMIM BDPLT16, BDPLT24) are a different disease with
  the opposite mechanism - increased integrin activation interfering with
  megakaryocytopoiesis, rather than lost integrin function - and are recorded
  here only as a differential diagnosis and a caveat in the ITGB3 gene block.
  Leukocyte adhesion deficiency III (FERMT3/kindlin-3) produces a
  thrombasthenia-like platelet phenotype through failure of integrin activation
  with a structurally normal receptor, plus infections; it belongs to the
  signalling arm of the module, not here.

  Prevalence is deliberately left unquantified at worldwide level. The source
  review explicitly declines to estimate it, because ascertainment is dominated
  by consanguineous populations; recording a rate derived from case series would
  be a fabrication dressed as a measurement. The qualitative COMMON band in the
  named populations is recorded separately and carries no numerator.

  Evidence base. The backbone is the Orphanet Journal of Rare Diseases review
  (PMID:16722529), which is cached as full text, so several snippets here are
  drawn from the body rather than the abstract and carry the hyphenation
  artefacts of PDF extraction, where a word broken across a line in the
  original survives as a hyphen plus a space mid-word. These are faithful to
  the cached text and are not transcription errors; the affected snippets are
  in the diagnosis, differential-diagnosis and iron-deficiency-anaemia blocks. Registry-level treatment evidence comes from PMID:26001792, the
  alloimmunization mechanism from PMID:33090654, the macrothrombocytopenia
  boundary from PMID:22102273, and the animal model from PMID:9916135.

  Curation provenance. This entry was curated by direct review of the cached
  full text and abstracts of the references listed in `references:`, not from a
  deep-research provider artifact, so there is no corresponding file under
  `research/`. Candidate PMIDs were located by PubMed search and each was
  fetched with `just fetch-reference` before use; several initially plausible
  identifiers turned out to be unrelated papers and were discarded rather than
  cited on their titles. Every snippet in this entry is an exact substring of
  the cached reference text.
references:
- reference: PMID:16722529
  title: "Glanzmann thrombasthenia."
- reference: PMID:26001792
  title: "The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention."
- reference: PMID:22102273
  title: "Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin."
- reference: PMID:21781244
  title: "Advances in our understanding of the molecular basis of disorders of platelet function."
📚

References & Deep Research

References

4
PMID:16722529
Glanzmann thrombasthenia.
No top-level findings curated for this source.
PMID:26001792
The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention.
No top-level findings curated for this source.
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:21781244
Advances in our understanding of the molecular basis of disorders of platelet function.
No top-level findings curated for this source.