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Classifications

Harrison's Part

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Inheritance

1

Autosomal Recessive HP:0000007

Both affected siblings were homozygous for p.Arg745Cys and both parents were heterozygous and asymptomatic. ClinGen records the mode of inheritance for this gene-disease relationship as autosomal recessive.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."

Homozygous affected siblings with heterozygous unaffected parents is the recessive segregation pattern.

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Pathophysiology

8

Homozygous EPHB2 p.Arg745Cys in the Kinase Domain

A homozygous missense variant, c.2233C>T p.Arg745Cys, in the tyrosine kinase domain of EPHB2. It was found by whole-exome sequencing in two siblings of a consanguineous family; the asymptomatic parents were heterozygous, which is the segregation pattern the recessive inheritance rests on.

platelet CL:0000233

Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HOMOZYGOUS

EPHB2 receptor tyrosine kinase activity GO:0004714 ↓ DECREASED

Downstream

Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering The substituted residue lies in the kinase domain, so the first thing lost is the receptor's own catalytic output.

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."

The gene-discovery statement, with the zygosity and the parental carrier status this node records.

Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering

The variant halves EPHB2 autophosphorylation but leaves ephrin-ligand-induced receptor clustering unaffected. This dissociation is the mechanistic pivot of the disorder: the defect is in the receptor's kinase output, not in its ability to engage ephrin on a neighbouring cell, so the lesion is not a contact-dependent one.

EPHB2 autophosphorylation GO:0046777 ↓ DECREASED

Experimental models

RBL-2H3 cells expressing human GPVI with wild-type or R745C EPHB2 CELL LINE Reproduces the autophosphorylation defect of the patient allele and shows that ephrin-induced clustering is intact.

Animal models

EphB2 cytoplasmic-domain truncation mouse Mouse partially recapitulates Removes EphB2 cytoplasmic signalling in the platelet, and shows that doing so impairs platelet activation without requiring Eph-ephrin ligation between platelets - the contact-independent role the human variant disrupts.

Downstream

Failure of Proximal GPVI Signalling The founding report places EPHB2 as a positive input to GPVI activation, so loss of its kinase output removes that input.

Defective Src Activation Downstream of PAR4 The same loss of kinase output is reflected on the G-protein-coupled receptor side as a selective Src defect.

Show evidence (2 references)

PMID:30213874 SUPPORT In Vitro

"Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with..."

Heterologous-cell experiment separating the autophosphorylation defect from ephrin-induced clustering, which is the dissociation this node asserts.

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior, disrupting early cell activation steps independently of cell-cell contact"

ClinGen's summary of the same experiment, quantifying the autophosphorylation loss and stating the contact-independence explicitly.

Failure of Proximal GPVI Signalling

Phosphorylation of Lyn, Syk and FcR gamma - the first steps of signalling from the collagen receptor GPVI - is drastically impaired, and it is impaired in the absence of platelet-platelet contact. That last clause is what separates this disorder from the classical contact-dependent Eph-ephrin model of platelet Eph receptor function.

platelet CL:0000233

collagen receptor GPVI signalling GO:0038065 ↓ DECREASED

Downstream

Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling GPVI signalling is one of the two inputs whose failure leaves the platelet unable to activate and secrete.

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact, indicating a positive role for EPHB2 in GPVI activation."

Names the three phosphorylation events lost and states the contact-independence that this node turns on.

Defective Src Activation Downstream of PAR4

Stimulation through the PAR4 thrombin receptor shows defective Src activation, while protein kinase C activity and calcium mobilisation are normal. The selectivity matters: the GPCR arm is not globally switched off, only its Src-dependent branch, which is why residual agonist responses survive.

platelet CL:0000233

Downstream

Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling The GPCR arm converges with the GPVI arm on the same activation step.

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+ mobilization."

Supports both halves of this node: the Src defect and the preserved PKC and calcium responses that make it selective.

Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling

Aggregation, integrin alphaIIbbeta3 activation and granule secretion are all defective in response to GPCR agonists and to convulxin, the GPVI agonist. Dense granule number and ATP/ADP content are normal, so the secretion failure is a signalling failure and not a storage pool defect - the distinction that separates this disorder from the delta-storage-pool diseases it can resemble on aggregometry.

platelet CL:0000233

platelet activation GO:0030168 ↓ DECREASED platelet degranulation GO:0002576 ↓ DECREASED integrin alphaIIbbeta3 inside-out activation GO:0033622 ↓ DECREASED

Downstream

Reduced Thrombus Formation on Collagen Under Flow A platelet that cannot activate and secrete cannot recruit and hold its neighbours on a collagen surface.

Impaired Platelet Aggregation The activation and secretion failure is what aggregometry measures in the clinic.

Show evidence (3 references)

PMID:30213874 SUPPORT Human Clinical

"The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow."

The functional consequence profile this node records, in both the GPCR and the GPVI (convulxin) arms.

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers."

Establishes the normal dense granule content that makes this a secretion signalling defect rather than a storage pool defect, and the sparing of the ristocetin (GPIb-dependent) response.

PMID:31348050 SUPPORT Other

"Novel genes recently implicated in human platelet dysfunction include the galactose metabolism enzyme UDP-galactose-4-epimerase in macrothrombocytopenia, and erythropoietin-producing hepatoma-amplified sequence receptor transmembrane tyrosine kinase EPHB2 in a severe bleeding disorder with..."

An independent review characterising the EPHB2 disorder by exactly the two deficits this node asserts - agonist response and granule secretion.

Reduced Thrombus Formation on Collagen Under Flow

Thrombus formation on collagen under flow is defective, whereas flow-dependent adhesion and spreading on fibrinogen are only mildly affected. The founding report reads that contrast as limited involvement of alphaIIbbeta3 outside-in signalling, which is what keeps the lesion on the inside-out, activation side of the pathway.

platelet CL:0000233

Downstream

Failure of Primary Hemostatic Plug Formation An unstable platelet mass on exposed collagen is the in-vitro reading of the failure to build a plug in vivo.

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling."

Supports the sparing of the outside-in functions, which is the contrast this node is built around.

Failure of Primary Hemostatic Plug Formation

The convergence step this disorder shares with the rest of the BDPLT series. It is reached here by the signalling route: the receptors are present, the integrin is present, the granules are full, and the platelet still fails to switch on.

primary hemostasis GO:0007599 ↓ DECREASED

Downstream

Mucocutaneous and Gastrointestinal Bleeding Diathesis Failure of platelet-dependent primary hemostasis.

Show evidence (1 reference)

PMID:33147934 SUPPORT Human Clinical

"Recurrent bleeding, normal platelet counts but abnormal function were linked to a variant of EPHB2, encoding a member of the EPH receptor family of transmembrane tyrosine kinases."

States the defining combination for this entity - bleeding with a normal count and abnormal function - which is what failure of the primary plug with a normal platelet supply looks like clinically.

Mucocutaneous and Gastrointestinal Bleeding Diathesis

Excessive spontaneous subcutaneous bleeding and heavy bleeding after minor wounds in both affected siblings, with chronic gastrointestinal bleeding and consequent anemia in one of them. Heterozygous parents were asymptomatic.

primary hemostasis GO:0007599 ↓ DECREASED

Downstream

Abnormal Bleeding Recurrent bleeding is the presenting clinical expression.

Bruising Susceptibility Spontaneous subcutaneous bleeding and heavy bleeding after minor wounds.

Gastrointestinal Hemorrhage Chronic bleeding from the gastrointestinal mucosa in one of the two siblings.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"In 2018, the EPHB2 gene was first reported in association with a recessive bleeding disorder characterized by excessive spontaneous subcutaneous bleeding, heavy bleeding after minor wounds, chronic gastrointestinal bleeding leading to anemia, and a mild decrease in platelet count observed later in life"

The clinical description of the bleeding phenotype, including the late mild fall in platelet count that is recorded separately as a phenotype.

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Pathograph

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

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Phenotypes

6

Blood 5

Abnormal Bleeding OBLIGATE HP:0001892

2/2 affected individuals in the only reported family. The band is OBLIGATE because bleeding is the ascertainment criterion for the entity, not because a penetrance study exists.

Sequelae: Anemia

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts."

Establishes recurrent bleeding in both affected siblings.

Bruising Susceptibility HP:0000978

Show evidence (1 reference)

PMID:33147934 SUPPORT Human Clinical

"Both affected family members showed excessive spontaneous subcutaneous and heavy bleeding upon minor wounds."

Reports spontaneous subcutaneous bleeding in both affected individuals.

Gastrointestinal Hemorrhage HP:0002239

Temporal: CHRONIC

1/2 affected individuals in the only reported family. No frequency band is given: two patients cannot support one, and the ClinGen and review sources both attribute the gastrointestinal bleeding to a single sibling.

Sequelae: Anemia

Show evidence (1 reference)

PMID:33147934 SUPPORT Human Clinical

"One sibling developed anemia after chronic gastrointestinal bleeding requiring iron supplementation."

Attributes the chronic gastrointestinal bleeding, and the anemia it caused, to one of the two siblings.

Anemia HP:0001903

1/2 affected individuals. Secondary to blood loss rather than a primary hematologic feature of the disorder. Bound to HP:0001903 Anemia and not to HP:0001891 Iron deficiency anemia: iron supplementation was given, but no cited source states iron-deficiency indices, so the narrower term would assert more than the evidence does.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"chronic gastrointestinal bleeding leading to anemia"

States the causal route from gastrointestinal blood loss to anemia.

Impaired Platelet Aggregation OBLIGATE HP:0003540

2/2 affected individuals; the ClinGen summary describes both siblings as displaying similar platelet function abnormalities.

Show evidence (1 reference)

PMID:33147934 SUPPORT Human Clinical

"Platelets from our family showed decreased aggregation and secretion in response to ADP, arachidonic acid, collagen, and analogs of thromboxane A2."

Gives the agonist-by-agonist aggregation and secretion profile.

Other 1

Normal Platelet Count at Presentation, with a Later Mild Decrease

Deliberately carries no `term:`. The HPO has no class for a normal count that later drifts mildly downward, and binding `HP:0001873 Thrombocytopenia` would assert a thrombocytopenia the founding report explicitly excludes. Following the same reasoning recorded on the equivalent node in `Platelet-type_Bleeding_Disorder_18`, no term is bound rather than a misleading one. This phenotype is also deliberately left unwired to the pathograph: it is a negative finding that constrains the differential rather than a consequence of any node in the causal chain, so no incoming edge would be truthful.

Show evidence (2 references)

PMID:30213874 SUPPORT Human Clinical

"We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts."

Establishes normal platelet counts at the time of the founding report.

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"a mild decrease in platelet count observed later in life"

Records the later mild fall in count, which is why this phenotype is curated as a two-part statement rather than as a flat normal result.

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Genetic Associations

1

EPHB2 (Limited ClinGen gene-disease validity)

Gene: EPHB2 hgnc:3393 relationship_type: UNKNOWN variant_origin: GERMLINE

Autosomal Recessive

Show evidence (3 references)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

ClinGen classifies the EPHB2-BDPLT22 relationship as Limited with autosomal recessive inheritance.

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"Currently, both the genetic and experimental evidence suggest a borderline classification between limited and moderate. However, due to the limited genetic data, we will maintain the final classification as limited until more genetic evidence becomes available."

ClinGen's stated reason for the Limited call, which is the case count rather than the quality of the functional evidence.

PMID:30213874 SUPPORT Human Clinical

"Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."

The variant and its recessive segregation in the only reported family.

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External Assertions

2

OMIM bleeding disorder, platelet-type, 22

OMIM disease record OMIM:618462

OMIM phenotype entry for the EPHB2-related platelet-type bleeding disorder, numbered 22 in the BDPLT series.

ClinGen EPHB2 / bleeding disorder, platelet-type, 22 (Limited)

ClinGen gene disease validity CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z

Hemostasis/Thrombosis Gene Curation Expert Panel, 4 September 2024, SOP10: Limited, autosomal recessive.

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Medical Actions

2

Iron replacement for blood-loss anemia

Action: iron supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: iron CHEBI:18248

Platform: Small molecule

Iron supplementation was required by the affected sibling who developed anemia from chronic gastrointestinal bleeding. This is the only management step recorded for a patient with this disorder; it treats the consequence of the bleeding rather than the platelet defect.

Target Phenotypes: Anemia HP:0001903

Show evidence (1 reference)

PMID:33147934 SUPPORT Human Clinical

"One sibling developed anemia after chronic gastrointestinal bleeding requiring iron supplementation."

The only patient-level treatment recorded for this disorder, and it is for the anemia rather than for the platelet defect.

Extrapolated inherited-platelet-disorder haemostatic management

Action: supportive haemostatic care Ontology label: Supportive Care NCIT:C15747

Agent: tranexamic acid CHEBI:48669 desmopressin CHEBI:4450

Platform: Other

No EPHB2-directed therapy exists and no interventional trial has been run in this disorder, so bleeding is managed with the general inherited-platelet-disorder repertoire: local haemostatic measures, an antifibrinolytic such as tranexamic acid, selected use of desmopressin, platelet concentrates when simpler measures are insufficient, and recombinant activated factor VII in refractory bleeding. This is class-level guidance applied to a disorder in which none of it has been tested, and it is curated as such rather than as a disease-specific recommendation. The alloimmunisation hazard of platelet transfusion applies here as it does across the group.

Target Phenotypes: Abnormal bleeding HP:0001892

Show evidence (2 references)

DOI:10.1055/a-2080-6602 SUPPORT Other

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

Names the class-level repertoire this treatment entry extrapolates from. The review is about inherited platelet disorders as a group and says nothing about EPHB2, which is why the entry is labelled extrapolated.

PMID:33147934 SUPPORT Other

"for mild bleeding risk, an antifibrinolytic medication or desmopressin is preferred as the first line of bleeding prevention and that platelet transfusions should be considered only when these approaches are insufficient"

Gives the escalation order within that repertoire, again at the level of the disorder group rather than this entity.

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Diagnosis

1

Platelet Function Testing with a Normal Platelet Count

The disorder is reached through platelet function testing rather than through the blood count or the blood film: the count and the morphology are normal, so aggregometry showing reduced responses across multiple agonists with a spared ristocetin response, together with normal dense granule content, is what narrows the differential before sequencing.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers."

The aggregometry and granule-content pattern that defines the diagnostic picture.

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Prevalence

1

Worldwide

Cases In Literature Not yet documented

No prevalence estimate exists and none should be inferred. As of the ClinGen review in September 2024 the whole of the case-level genetic evidence was two affected siblings in one consanguineous French family, and no second family has been reported since.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"For the genetic evidence, only one consanguineous family with two similarly affected individuals has been identified."

ClinGen's own count of the case-level genetic evidence, which is why no population figure is asserted.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Platelet-type Bleeding Disorder 22:

Delta storage pool disease

Overlapping Features Reduced secretion and reduced aggregation to weak agonists look the same on aggregometry. The discriminator is granule content: dense granule number and ATP/ADP content are normal here, so the secretion failure is a signalling failure rather than an empty-granule one.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"with normal ATP/ADP content and dense granule numbers"

Normal dense granule content is what separates this disorder from a storage pool defect.

Bernard-Soulier syndrome

Overlapping Features Both cause mucocutaneous bleeding from a platelet defect, but they separate on the ristocetin response and on the platelet count. Bernard-Soulier syndrome is a defect of the GPIb-IX-V adhesion receptor, so ristocetin-induced agglutination fails and the platelets are large and reduced in number. Here the ristocetin response is specifically the one spared, and the count is normal at presentation.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"Platelet function tests revealed decreased responses to various agonists except ristocetin"

The preserved ristocetin response is the discriminator against a GPIb-IX-V adhesion defect.

von Willebrand disease

Overlapping Features Also presents as mucocutaneous bleeding with a normal platelet count, and is far commoner, so it is the differential a patient will usually be worked up for first. It is a plasma or platelet von Willebrand factor defect rather than a signalling one, and the ristocetin-dependent assays that detect it are normal here.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"Platelet function tests revealed decreased responses to various agonists except ristocetin"

The same preserved ristocetin response separates this disorder from the von Willebrand factor disorders, which that assay is designed to detect.

Glanzmann thrombasthenia

Overlapping Features Both present with defective aggregation and a normal platelet count, but Glanzmann thrombasthenia is a structural defect of integrin alphaIIbbeta3 itself and abolishes clot retraction, whereas here alphaIIbbeta3 outside-in functions - clot retraction and spreading on fibrinogen - are only mildly affected and the lesion is upstream, in inside-out signalling.

Show evidence (1 reference)

PMID:30213874 SUPPORT Human Clinical

"In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling."

Preserved clot retraction and spreading are what distinguish this disorder from Glanzmann thrombasthenia on function testing.

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Experimental Models

1

RBL-2H3 cells expressing human GPVI with wild-type or R745C EPHB2 CELL_LINE

Rat basophilic leukemia RBL-2H3 cells stably expressing human GPVI, into which wild-type or R745C EPHB2 was overexpressed. This is the experiment that separates the two candidate lesions - loss of kinase output versus loss of ephrin engagement - because both can be measured in the same cell.

Publication

PMID:30213874

Pathograph links

Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering recapitulates fidelity: moderate Reproduces the autophosphorylation defect of the patient allele and shows that ephrin-induced clustering is intact.

Limitations: A rat mast-cell line overexpressing the human receptor, not a platelet or a megakaryocyte; expression is supraphysiological and the endogenous platelet signalling partners are absent, so it tests the receptor's own behaviour rather than the platelet phenotype.

Readouts

EPHB2 autophosphorylation

Direction: DECREASED

Interpretation: The catalytic output of the mutant receptor, reduced by about half.

Show evidence (1 reference)

CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z SUPPORT Other

"The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior"

Quantifies the autophosphorylation readout in this system.

Ephrin ligand-induced EPHB2 clustering

Direction: UNCHANGED

Interpretation: A negative result, and a load-bearing one: it is what excludes a contact-dependent Eph-ephrin lesion.

Show evidence (1 reference)

PMID:30213874 SUPPORT In Vitro

"had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact"

The unchanged clustering readout.

Show evidence (1 reference)

PMID:30213874 SUPPORT In Vitro

"Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering"

Establishes that this heterologous system is informative for the autophosphorylation node.

🐁

Animal Models

1

EphB2 cytoplasmic-domain truncation mouse

A mouse genetic model that removes signalling from the EphB2 cytoplasmic domain while leaving the extracellular receptor in place. It predates the human disorder and was designed to separate Eph kinase signalling from Eph-ephrin ligation, which is the same dissociation the human p.Arg745Cys allele produces.

Species

Mouse

Genotype

EphB2 cytoplasmic-domain truncation

Publication

PMID:25370417

Pathograph links

Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering partially recapitulates fidelity: moderate Removes EphB2 cytoplasmic signalling in the platelet, and shows that doing so impairs platelet activation without requiring Eph-ephrin ligation between platelets - the contact-independent role the human variant disrupts.

Limitations: A truncation of the whole cytoplasmic domain in mouse, not the human p.Arg745Cys missense allele, so it models loss of EphB2 signalling in general rather than the partial kinase defect of the patients. It also reports clot retraction as EphB2-dependent, whereas clot retraction was only mildly affected in the human patients, so the two do not agree on every readout.

Readouts

Thrombus formation and clot retraction

Direction: DECREASED

Interpretation: Establishes EphB2 cytoplasmic signalling as a regulator of thrombus formation in vivo.

Show evidence (1 reference)

PMID:25370417 SUPPORT Model Organism

"We conclude that EphB2 signaling is involved in the regulation of thrombus formation and clot retraction."

The functional conclusion of the mouse model.

Show evidence (1 reference)

PMID:25370417 SUPPORT Model Organism

"the cytoplasmic tail of this Eph kinase regulates initial platelet activation in a contact-independent manner in the absence of Eph-ephrin ligation between platelets"

The contact-independent role of EphB2 signalling in the mouse, which is the same property the human variant removes.

{ }

Source YAML

click to show

name: Platelet-type Bleeding Disorder 22
creation_date: "2026-09-08T18:30:00Z"
category: Mendelian
parents:
- Inherited Platelet Disorder
- Bleeding Disorder
disease_term:
  preferred_term: bleeding disorder, platelet-type, 22
  term:
    id: MONDO:0032765
    label: bleeding disorder, platelet-type, 22
synonyms:
- BDPLT22
- EPHB2-related platelet function disorder
- EPHB2-related inherited platelet disorder
description: >-
  An autosomal recessive inherited platelet function disorder, described in two
  siblings from one consanguineous French family, in which a homozygous missense
  variant in the tyrosine kinase domain of EPHB2 leaves the platelet count normal
  but the platelet unable to switch on properly, so the affected individuals
  bleed.

  EPHB2 encodes an ephrin type-B receptor, a transmembrane receptor tyrosine
  kinase. The classical account of Eph receptors in platelets is
  contact-dependent: Eph-ephrin engagement between platelets already inside a
  forming aggregate stabilises the thrombus. What makes this disorder
  mechanistically interesting is that its lesion is not in that step. The
  p.Arg745Cys variant halves EPHB2 autophosphorylation while leaving
  ephrin-induced receptor clustering intact, and the signalling failure it
  produces is measurable in single platelets before any platelet-platelet
  contact has occurred. The affected steps are the most proximal ones in
  glycoprotein VI signalling - phosphorylation of Lyn, Syk and FcR gamma - plus
  Src activation downstream of the PAR4 thrombin receptor, while protein kinase
  C activity and calcium mobilisation are normal. So EPHB2 is placed as a
  positive regulator feeding into GPVI and GPCR signalling rather than as a
  cell-cell adhesion molecule, and the disorder enters the platelet-function
  group through its signalling arm.

  The consequence profile is correspondingly lopsided. Aggregation, integrin
  alphaIIbbeta3 inside-out activation, granule secretion and thrombus formation
  on collagen under flow are all defective; clot retraction, flow-dependent
  adhesion and spreading on fibrinogen are only mildly affected, which the
  founding report reads as limited involvement of alphaIIbbeta3 outside-in
  signalling. Dense granule content and number are normal, so this is a
  secretion-signalling defect rather than a storage pool defect.

  This entry is curated with its gene-disease validity in front rather than in a
  footnote. In September 2024 the ClinGen Hemostasis/Thrombosis Gene Curation
  Expert Panel classified the EPHB2-BDPLT22 relationship as LIMITED. Their
  reasoning is worth reading before using this entry: the experimental evidence
  is substantial and they judged the overall package borderline between limited
  and moderate, but the case-level genetic evidence is two affected siblings in
  a single consanguineous family and no second family has been reported. The
  genetic block therefore types the relationship UNKNOWN with the Limited
  classification recorded explicitly, following the convention already used for
  the Limited-validity genes in `Arrhythmogenic_Right_Ventricular_Cardiomyopathy`.

  Two things are deliberately constrained. There is no prevalence estimate,
  because one family supports none. And the treatments section carries only what
  can actually be sourced: iron replacement, which is recorded for the affected
  sibling who became anemic from gastrointestinal blood loss, and the general
  inherited-platelet-disorder haemostatic repertoire, which is explicitly labelled
  as class-level guidance extrapolated to this disorder rather than validated in
  it. No EPHB2-directed therapy exists, no interventional trial has been run in
  this entity, and the 2021 review of inherited platelet disorders with normal
  platelet count states outright that the clinical phenotype here remains poorly
  defined.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
external_assertions:
- name: OMIM bleeding disorder, platelet-type, 22
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618462
  description: >-
    OMIM phenotype entry for the EPHB2-related platelet-type bleeding disorder,
    numbered 22 in the BDPLT series.
- name: ClinGen EPHB2 / bleeding disorder, platelet-type, 22 (Limited)
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
  description: >-
    Hemostasis/Thrombosis Gene Curation Expert Panel, 4 September 2024, SOP10:
    Limited, autosomal recessive.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence estimate exists and none should be inferred. As of the ClinGen
    review in September 2024 the whole of the case-level genetic evidence was two
    affected siblings in one consanguineous French family, and no second family
    has been reported since.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For the genetic evidence, only one consanguineous family with two similarly affected individuals has been identified."
    explanation: >-
      ClinGen's own count of the case-level genetic evidence, which is why no
      population figure is asserted.

pathophysiology:
- name: Homozygous EPHB2 p.Arg745Cys in the Kinase Domain
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >-
    A homozygous missense variant, c.2233C>T p.Arg745Cys, in the tyrosine kinase
    domain of EPHB2. It was found by whole-exome sequencing in two siblings of a
    consanguineous family; the asymptomatic parents were heterozygous, which is
    the segregation pattern the recessive inheritance rests on.
  genetic_context:
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  molecular_functions:
  - preferred_term: EPHB2 receptor tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."
    explanation: >-
      The gene-discovery statement, with the zygosity and the parental carrier
      status this node records.
  downstream:
  - target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
    causal_link_type: DIRECT
    description: >-
      The substituted residue lies in the kinase domain, so the first thing lost
      is the receptor's own catalytic output.
- name: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    The variant halves EPHB2 autophosphorylation but leaves ephrin-ligand-induced
    receptor clustering unaffected. This dissociation is the mechanistic pivot of
    the disorder: the defect is in the receptor's kinase output, not in its
    ability to engage ephrin on a neighbouring cell, so the lesion is not a
    contact-dependent one.
  biological_processes:
  - preferred_term: EPHB2 autophosphorylation
    term:
      id: GO:0046777
      label: protein autophosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact."
    explanation: >-
      Heterologous-cell experiment separating the autophosphorylation defect from
      ephrin-induced clustering, which is the dissociation this node asserts.
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior, disrupting early cell activation steps independently of cell-cell contact"
    explanation: >-
      ClinGen's summary of the same experiment, quantifying the autophosphorylation
      loss and stating the contact-independence explicitly.
  downstream:
  - target: Failure of Proximal GPVI Signalling
    causal_link_type: DIRECT
    description: >-
      The founding report places EPHB2 as a positive input to GPVI activation, so
      loss of its kinase output removes that input.
  - target: Defective Src Activation Downstream of PAR4
    causal_link_type: DIRECT
    description: >-
      The same loss of kinase output is reflected on the G-protein-coupled
      receptor side as a selective Src defect.
- name: Failure of Proximal GPVI Signalling
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Phosphorylation of Lyn, Syk and FcR gamma - the first steps of signalling
    from the collagen receptor GPVI - is drastically impaired, and it is impaired
    in the absence of platelet-platelet contact. That last clause is what
    separates this disorder from the classical contact-dependent Eph-ephrin model
    of platelet Eph receptor function.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: collagen receptor GPVI signalling
    term:
      id: GO:0038065
      label: collagen-activated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact, indicating a positive role for EPHB2 in GPVI activation."
    explanation: >-
      Names the three phosphorylation events lost and states the
      contact-independence that this node turns on.
  downstream:
  - target: Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling
    causal_link_type: DIRECT
    description: >-
      GPVI signalling is one of the two inputs whose failure leaves the platelet
      unable to activate and secrete.
- name: Defective Src Activation Downstream of PAR4
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Stimulation through the PAR4 thrombin receptor shows defective Src
    activation, while protein kinase C activity and calcium mobilisation are
    normal. The selectivity matters: the GPCR arm is not globally switched off,
    only its Src-dependent branch, which is why residual agonist responses
    survive.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Likewise platelet activation by PAR4-AP showed defective Src activation, as opposed to normal protein kinase C activity and Ca2+ mobilization."
    explanation: >-
      Supports both halves of this node: the Src defect and the preserved PKC and
      calcium responses that make it selective.
  downstream:
  - target: Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling
    causal_link_type: DIRECT
    description: >-
      The GPCR arm converges with the GPVI arm on the same activation step.
- name: Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling
  role: effector
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
  description: >-
    Aggregation, integrin alphaIIbbeta3 activation and granule secretion are all
    defective in response to GPCR agonists and to convulxin, the GPVI agonist.
    Dense granule number and ATP/ADP content are normal, so the secretion failure
    is a signalling failure and not a storage pool defect - the distinction that
    separates this disorder from the delta-storage-pool diseases it can resemble
    on aggregometry.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: DECREASED
  - preferred_term: platelet degranulation
    term:
      id: GO:0002576
      label: platelet degranulation
    modifier: DECREASED
  - preferred_term: integrin alphaIIbbeta3 inside-out activation
    term:
      id: GO:0033622
      label: integrin activation
    modifier: DECREASED
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation, and granule secretion induced by G-protein-coupled receptor (GPCR) agonists and convulxin, as well as in thrombus formation on collagen under flow."
    explanation: >-
      The functional consequence profile this node records, in both the GPCR and
      the GPVI (convulxin) arms.
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers."
    explanation: >-
      Establishes the normal dense granule content that makes this a secretion
      signalling defect rather than a storage pool defect, and the sparing of the
      ristocetin (GPIb-dependent) response.
  - reference: PMID:31348050
    reference_title: Recent advances in inherited platelet disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Novel genes recently implicated in human platelet dysfunction include the galactose metabolism enzyme UDP-galactose-4-epimerase in macrothrombocytopenia, and erythropoietin-producing hepatoma-amplified sequence receptor transmembrane tyrosine kinase EPHB2 in a severe bleeding disorder with deficiencies in platelet agonist response and granule secretion."
    explanation: >-
      An independent review characterising the EPHB2 disorder by exactly the two
      deficits this node asserts - agonist response and granule secretion.
  downstream:
  - target: Reduced Thrombus Formation on Collagen Under Flow
    causal_link_type: DIRECT
    description: >-
      A platelet that cannot activate and secrete cannot recruit and hold its
      neighbours on a collagen surface.
  - target: Impaired Platelet Aggregation
    causal_link_type: DIRECT
    description: >-
      The activation and secretion failure is what aggregometry measures in the
      clinic.
- name: Reduced Thrombus Formation on Collagen Under Flow
  role: effector
  biological_scale: TISSUE
  description: >-
    Thrombus formation on collagen under flow is defective, whereas
    flow-dependent adhesion and spreading on fibrinogen are only mildly affected.
    The founding report reads that contrast as limited involvement of
    alphaIIbbeta3 outside-in signalling, which is what keeps the lesion on the
    inside-out, activation side of the pathway.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling."
    explanation: >-
      Supports the sparing of the outside-in functions, which is the contrast this
      node is built around.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      An unstable platelet mass on exposed collagen is the in-vitro reading of the
      failure to build a plug in vivo.
- 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: >-
    The convergence step this disorder shares with the rest of the BDPLT series.
    It is reached here by the signalling route: the receptors are present, the
    integrin is present, the granules are full, and the platelet still fails to
    switch on.
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent bleeding, normal platelet counts but abnormal function were linked to a variant of EPHB2, encoding a member of the EPH receptor family of transmembrane tyrosine kinases."
    explanation: >-
      States the defining combination for this entity - bleeding with a normal
      count and abnormal function - which is what failure of the primary plug with
      a normal platelet supply looks like clinically.
  downstream:
  - target: Mucocutaneous and Gastrointestinal Bleeding Diathesis
    causal_link_type: DIRECT
    description: Failure of platelet-dependent primary hemostasis.
- name: Mucocutaneous and Gastrointestinal Bleeding Diathesis
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >-
    Excessive spontaneous subcutaneous bleeding and heavy bleeding after minor
    wounds in both affected siblings, with chronic gastrointestinal bleeding and
    consequent anemia in one of them. Heterozygous parents were asymptomatic.
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In 2018, the EPHB2 gene was first reported in association with a recessive bleeding disorder characterized by excessive spontaneous subcutaneous bleeding, heavy bleeding after minor wounds, chronic gastrointestinal bleeding leading to anemia, and a mild decrease in platelet count observed later in life"
    explanation: >-
      The clinical description of the bleeding phenotype, including the late mild
      fall in platelet count that is recorded separately as a phenotype.
  downstream:
  - target: Abnormal Bleeding
    causal_link_type: DIRECT
    description: Recurrent bleeding is the presenting clinical expression.
  - target: Bruising Susceptibility
    causal_link_type: DIRECT
    description: >-
      Spontaneous subcutaneous bleeding and heavy bleeding after minor wounds.
  - target: Gastrointestinal Hemorrhage
    causal_link_type: DIRECT
    description: >-
      Chronic bleeding from the gastrointestinal mucosa in one of the two
      siblings.

phenotypes:
- category: Hematologic
  name: Abnormal Bleeding
  description: >-
    Recurrent bleeding is the presenting problem in both affected siblings.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  frequency: OBLIGATE
  notes: >-
    2/2 affected individuals in the only reported family. The band is OBLIGATE
    because bleeding is the ascertainment criterion for the entity, not because a
    penetrance study exists.
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts."
    explanation: >-
      Establishes recurrent bleeding in both affected siblings.
  sequelae:
  - target: Anemia
    description: >-
      Chronic blood loss from the gastrointestinal tract in one sibling led to
      anemia requiring iron supplementation.
- category: Hematologic
  name: Bruising Susceptibility
  description: >-
    Excessive spontaneous subcutaneous bleeding, and heavy bleeding after minor
    wounds, in both affected family members.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both affected family members showed excessive spontaneous subcutaneous and heavy bleeding upon minor wounds."
    explanation: >-
      Reports spontaneous subcutaneous bleeding in both affected individuals.
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  description: >-
    Chronic gastrointestinal bleeding in one of the two affected siblings.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
    temporality: CHRONIC
  notes: >-
    1/2 affected individuals in the only reported family. No frequency band is
    given: two patients cannot support one, and the ClinGen and review sources
    both attribute the gastrointestinal bleeding to a single sibling.
  evidence:
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One sibling developed anemia after chronic gastrointestinal bleeding requiring iron supplementation."
    explanation: >-
      Attributes the chronic gastrointestinal bleeding, and the anemia it caused,
      to one of the two siblings.
  sequelae:
  - target: Anemia
    description: Chronic blood loss into the gut.
- category: Hematologic
  name: Anemia
  description: >-
    Anemia from chronic gastrointestinal blood loss in one sibling, requiring
    iron supplementation.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  notes: >-
    1/2 affected individuals. Secondary to blood loss rather than a primary
    hematologic feature of the disorder. Bound to HP:0001903 Anemia and not to
    HP:0001891 Iron deficiency anemia: iron supplementation was given, but no
    cited source states iron-deficiency indices, so the narrower term would
    assert more than the evidence does.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "chronic gastrointestinal bleeding leading to anemia"
    explanation: >-
      States the causal route from gastrointestinal blood loss to anemia.
- category: Hematologic
  name: Impaired Platelet Aggregation
  description: >-
    Decreased aggregation and secretion in response to ADP, arachidonic acid,
    collagen and thromboxane A2 analogues, with the ristocetin response spared.
    The pattern is that of a signalling defect: many agonists affected, the
    GPIb-dependent ristocetin response intact.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  frequency: OBLIGATE
  notes: >-
    2/2 affected individuals; the ClinGen summary describes both siblings as
    displaying similar platelet function abnormalities.
  evidence:
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelets from our family showed decreased aggregation and secretion in response to ADP, arachidonic acid, collagen, and analogs of thromboxane A2."
    explanation: >-
      Gives the agonist-by-agonist aggregation and secretion profile.
  reports_on:
  - target: Defective Platelet Activation, Secretion and Integrin Inside-Out Signalling
    relationship: READOUT_OF
    description: >-
      Light transmission aggregometry is the clinical readout of the activation
      and secretion node.
- category: Hematologic
  name: Normal Platelet Count at Presentation, with a Later Mild Decrease
  description: >-
    The platelet count is normal at presentation, which is what places this
    disorder among the inherited platelet disorders with a normal count rather
    than among the thrombocytopenias. ClinGen's summary adds that a mild decrease
    in count was observed later in life. Both statements are curated because the
    normal count is diagnostically load-bearing and the later drift would
    otherwise look like a contradiction.
  phenotype_term:
    preferred_term: Normal platelet count at presentation, with a mild later decrease
  notes: >-
    Deliberately carries no `term:`. The HPO has no class for a normal count that
    later drifts mildly downward, and binding `HP:0001873 Thrombocytopenia` would
    assert a thrombocytopenia the founding report explicitly excludes. Following
    the same reasoning recorded on the equivalent node in
    `Platelet-type_Bleeding_Disorder_18`, no term is bound rather than a
    misleading one. This phenotype is also deliberately left unwired to the
    pathograph: it is a negative finding that constrains the differential rather
    than a consequence of any node in the causal chain, so no incoming edge would
    be truthful.
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts."
    explanation: >-
      Establishes normal platelet counts at the time of the founding report.
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a mild decrease in platelet count observed later in life"
    explanation: >-
      Records the later mild fall in count, which is why this phenotype is curated
      as a two-part statement rather than as a flat normal result.

genetic:
- name: EPHB2
  gene_term:
    preferred_term: EPHB2
    term:
      id: hgnc:3393
      label: EPHB2
  association: Limited ClinGen gene-disease validity
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
  notes: >-
    EPHB2 encodes ephrin type-B receptor 2, a transmembrane receptor tyrosine
    kinase. The single reported disease allele is c.2233C>T p.Arg745Cys in the
    kinase domain, homozygous in two siblings of a consanguineous French family
    with heterozygous asymptomatic parents. `relationship_type` is UNKNOWN rather
    than CAUSATIVE because ClinGen classifies the gene-disease relationship as
    Limited; the enum has no value for Limited, and UNKNOWN is the value already
    used for Limited-validity genes elsewhere in this knowledge base. The
    classification reflects the case count, not a doubt about the functional
    work: ClinGen described the overall package as borderline between limited and
    moderate.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "EPHB2 | HGNC:3393 | bleeding disorder, platelet-type, 22 | MONDO:0032765 | AR | Limited | SOP10 | Hemostasis/Thrombosis Gene Curation Expert Panel"
    explanation: >-
      ClinGen classifies the EPHB2-BDPLT22 relationship as Limited with autosomal
      recessive inheritance.
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Currently, both the genetic and experimental evidence suggest a borderline classification between limited and moderate. However, due to the limited genetic data, we will maintain the final classification as limited until more genetic evidence becomes available."
    explanation: >-
      ClinGen's stated reason for the Limited call, which is the case count rather
      than the quality of the functional evidence.
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."
    explanation: >-
      The variant and its recessive segregation in the only reported family.

inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both affected siblings were homozygous for p.Arg745Cys and both parents were
    heterozygous and asymptomatic. ClinGen records the mode of inheritance for
    this gene-disease relationship as autosomal recessive.
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 and P2 were homozygous for this variant, while their asymptomatic parents were heterozygous."
    explanation: >-
      Homozygous affected siblings with heterozygous unaffected parents is the
      recessive segregation pattern.

experimental_models:
- name: RBL-2H3 cells expressing human GPVI with wild-type or R745C EPHB2
  experimental_model_type: CELL_LINE
  description: >-
    Rat basophilic leukemia RBL-2H3 cells stably expressing human GPVI, into
    which wild-type or R745C EPHB2 was overexpressed. This is the experiment that
    separates the two candidate lesions - loss of kinase output versus loss of
    ephrin engagement - because both can be measured in the same cell.
  publication: PMID:30213874
  modeled_mechanisms:
  - target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the autophosphorylation defect of the patient allele and shows
      that ephrin-induced clustering is intact.
    limitations: >-
      A rat mast-cell line overexpressing the human receptor, not a platelet or a
      megakaryocyte; expression is supraphysiological and the endogenous platelet
      signalling partners are absent, so it tests the receptor's own behaviour
      rather than the platelet phenotype.
    readouts:
    - name: EPHB2 autophosphorylation
      target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
      direction: DECREASED
      interpretation: >-
        The catalytic output of the mutant receptor, reduced by about half.
      evidence:
      - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
        reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior"
        explanation: Quantifies the autophosphorylation readout in this system.
    - name: Ephrin ligand-induced EPHB2 clustering
      target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
      direction: UNCHANGED
      interpretation: >-
        A negative result, and a load-bearing one: it is what excludes a
        contact-dependent Eph-ephrin lesion.
      evidence:
      - reference: PMID:30213874
        reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact"
        explanation: The unchanged clustering readout.
    evidence:
    - reference: PMID:30213874
      reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overexpression of wild-type and R745C EPHB2 variant in RBL-2H3 (rat basophilic leukemia) cells stably expressing human GPVI confirmed that EPHB2 R745C mutation impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering"
      explanation: >-
        Establishes that this heterologous system is informative for the
        autophosphorylation node.

animal_models:
- name: EphB2 cytoplasmic-domain truncation mouse
  species: Mouse
  genotype: EphB2 cytoplasmic-domain truncation
  publication: PMID:25370417
  description: >-
    A mouse genetic model that removes signalling from the EphB2 cytoplasmic
    domain while leaving the extracellular receptor in place. It predates the
    human disorder and was designed to separate Eph kinase signalling from
    Eph-ephrin ligation, which is the same dissociation the human p.Arg745Cys
    allele produces.
  modeled_mechanisms:
  - target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Removes EphB2 cytoplasmic signalling in the platelet, and shows that doing
      so impairs platelet activation without requiring Eph-ephrin ligation
      between platelets - the contact-independent role the human variant
      disrupts.
    limitations: >-
      A truncation of the whole cytoplasmic domain in mouse, not the human
      p.Arg745Cys missense allele, so it models loss of EphB2 signalling in
      general rather than the partial kinase defect of the patients. It also
      reports clot retraction as EphB2-dependent, whereas clot retraction was only
      mildly affected in the human patients, so the two do not agree on every
      readout.
    readouts:
    - name: Thrombus formation and clot retraction
      target: Impaired EPHB2 Autophosphorylation with Preserved Ephrin Clustering
      direction: DECREASED
      interpretation: >-
        Establishes EphB2 cytoplasmic signalling as a regulator of thrombus
        formation in vivo.
      evidence:
      - reference: PMID:25370417
        reference_title: "EphB2 regulates contact-dependent and contact-independent signaling to control platelet function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We conclude that EphB2 signaling is involved in the regulation of thrombus formation and clot retraction."
        explanation: The functional conclusion of the mouse model.
    evidence:
    - reference: PMID:25370417
      reference_title: "EphB2 regulates contact-dependent and contact-independent signaling to control platelet function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the cytoplasmic tail of this Eph kinase regulates initial platelet activation in a contact-independent manner in the absence of Eph-ephrin ligation between platelets"
      explanation: >-
        The contact-independent role of EphB2 signalling in the mouse, which is the
        same property the human variant removes.

diagnosis:
- name: Platelet Function Testing with a Normal Platelet Count
  description: >-
    The disorder is reached through platelet function testing rather than through
    the blood count or the blood film: the count and the morphology are normal,
    so aggregometry showing reduced responses across multiple agonists with a
    spared ristocetin response, together with normal dense granule content, is
    what narrows the differential before sequencing.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers."
    explanation: >-
      The aggregometry and granule-content pattern that defines the diagnostic
      picture.

differential_diagnoses:
- name: Delta storage pool disease
  description: >-
    Reduced secretion and reduced aggregation to weak agonists look the same on
    aggregometry. The discriminator is granule content: dense granule number and
    ATP/ADP content are normal here, so the secretion failure is a signalling
    failure rather than an empty-granule one.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "with normal ATP/ADP content and dense granule numbers"
    explanation: >-
      Normal dense granule content is what separates this disorder from a storage
      pool defect.
- name: Bernard-Soulier syndrome
  description: >-
    Both cause mucocutaneous bleeding from a platelet defect, but they separate on
    the ristocetin response and on the platelet count. Bernard-Soulier syndrome is
    a defect of the GPIb-IX-V adhesion receptor, so ristocetin-induced
    agglutination fails and the platelets are large and reduced in number. Here the
    ristocetin response is specifically the one spared, and the count is normal at
    presentation.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Platelet function tests revealed decreased responses to various agonists except ristocetin"
    explanation: >-
      The preserved ristocetin response is the discriminator against a
      GPIb-IX-V adhesion defect.
- name: von Willebrand disease
  description: >-
    Also presents as mucocutaneous bleeding with a normal platelet count, and is far
    commoner, so it is the differential a patient will usually be worked up for
    first. It is a plasma or platelet von Willebrand factor defect rather than a
    signalling one, and the ristocetin-dependent assays that detect it are normal
    here.
  evidence:
  - reference: CGGV:assertion_5f895977-6c0c-49f1-97b6-cf4d0fd3a894-2024-09-04T170000.000Z
    reference_title: "EPHB2 / bleeding disorder, platelet-type, 22 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Platelet function tests revealed decreased responses to various agonists except ristocetin"
    explanation: >-
      The same preserved ristocetin response separates this disorder from the
      von Willebrand factor disorders, which that assay is designed to detect.
- name: Glanzmann thrombasthenia
  description: >-
    Both present with defective aggregation and a normal platelet count, but
    Glanzmann thrombasthenia is a structural defect of integrin alphaIIbbeta3
    itself and abolishes clot retraction, whereas here alphaIIbbeta3 outside-in
    functions - clot retraction and spreading on fibrinogen - are only mildly
    affected and the lesion is upstream, in inside-out signalling.
  evidence:
  - reference: PMID:30213874
    reference_title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, clot retraction, flow-dependent platelet adhesion, and spreading on fibrinogen were only mildly affected, indicating limited effects on αIIbβ3 outside-in signaling."
    explanation: >-
      Preserved clot retraction and spreading are what distinguish this disorder
      from Glanzmann thrombasthenia on function testing.

treatments:
- name: Iron replacement for blood-loss anemia
  description: >-
    Iron supplementation was required by the affected sibling who developed
    anemia from chronic gastrointestinal bleeding. This is the only management
    step recorded for a patient with this disorder; it treats the consequence of
    the bleeding rather than the platelet defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: iron supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:18248
        label: iron atom
  target_phenotypes:
  - preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  notes: >-
    The agent is bound at the element level (CHEBI:18248 iron atom). The cited
    source says only "requiring iron supplementation" and names neither the salt
    nor the oxidation state, so binding a specific ferrous compound would assert
    a formulation nobody reported. NCIT:C210688 Iron Supplement is the natural
    label but is not a member of the ChemicalEntityTerm enum, so it cannot sit in
    this slot.
  evidence:
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One sibling developed anemia after chronic gastrointestinal bleeding requiring iron supplementation."
    explanation: >-
      The only patient-level treatment recorded for this disorder, and it is for
      the anemia rather than for the platelet defect.
- name: Extrapolated inherited-platelet-disorder haemostatic management
  description: >-
    No EPHB2-directed therapy exists and no interventional trial has been run
    in this disorder, so bleeding is managed with the general
    inherited-platelet-disorder repertoire: local haemostatic measures, an
    antifibrinolytic such as tranexamic acid, selected use of desmopressin,
    platelet concentrates when simpler measures are insufficient, and
    recombinant activated factor VII in refractory bleeding. This is
    class-level guidance applied to a disorder in which none of it has been
    tested, and it is curated as such rather than as a disease-specific
    recommendation. The alloimmunisation hazard of platelet transfusion applies
    here as it does across the group.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive haemostatic care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  target_phenotypes:
  - preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  notes: >-
    Extrapolated, not disease-specific. Neither cited source reports any of these
    measures being used in an EPHB2 patient; the falcon deep-research report for
    this entry reached the same conclusion after searching for BDPLT22-specific
    therapy, response-rate data and trial registrations and finding none.
  evidence:
  - reference: DOI:10.1055/a-2080-6602
    reference_title: "Treatment of Inherited Platelet Disorders: Current Status and Future Options"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII."
    explanation: >-
      Names the class-level repertoire this treatment entry extrapolates from. The
      review is about inherited platelet disorders as a group and says nothing
      about EPHB2, which is why the entry is labelled extrapolated.
  - reference: PMID:33147934
    reference_title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "for mild bleeding risk, an antifibrinolytic medication or desmopressin is preferred as the first line of bleeding prevention and that platelet transfusions should be considered only when these approaches are insufficient"
    explanation: >-
      Gives the escalation order within that repertoire, again at the level of the
      disorder group rather than this entity.

references:
- reference: PMID:30213874
  title: "A mutation of the human EPHB2 gene leads to a major platelet functional defect."
- reference: PMID:33147934
  title: "Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy."
- reference: PMID:31348050
  title: "Recent advances in inherited platelet disorders."

📚

References & Deep Research

References

3

PMID:30213874

A mutation of the human EPHB2 gene leads to a major platelet functional defect.

No top-level findings curated for this source.

PMID:33147934

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy.

No top-level findings curated for this source.

PMID:31348050

Recent advances in inherited platelet disorders.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Repair a folded-scalar hyphen split in the extrapolated-treatment description · 2026-09-27T20:47:18Z · View source

The treatment named 'Extrapolated inherited-platelet-disorder haemostatic management' carried its compound term split across a fold boundary in the description: a line ended in 'inherited-platelet-' and the next began 'disorder repertoire'. YAML folding joins those with a space, so the loaded value read 'the general inherited-platelet- disorder repertoire'. This was a defect in the entry's rendered text, not only a lint finding -- the corrupted string was what any reader, renderer or export saw. Reflowed the description so the compound stays on one line. The only change to the loaded value is the removal of that one spurious space; verified by loading the string before and after and asserting the two differ by exactly that substitution. No wording, claim or citation changed, and the treatment's own caveat that this is class-level guidance untested in this disorder is untouched. Caught by 'just check-folded-hyphens' in CI, which is one of the two gates whose baseline was deliberately removed (#11760), so a finding has to be repaired rather than grandfathered. The preceding review had re-run just validate, check-entity-refs, check-causal-targets, check-enum-values and check-duplicate-keys on the merged tree and approved it -- none of those reads folded-scalar line endings, which is why an approved tree was still red. Not swept, against the standing review suggestion: references_cache/DOI_10.1182_blood-2018-04-845644.md and references_cache/DOI_10.3324_haematol.2020.248153.md were twice reported as uncited duplicates of already-cited PMIDs, and recommended for removal the next time this file was touched. Re-deriving the citation list on this tree shows both DOIs are cited -- by research/Platelet-type_Bleeding_Disorder_22-deep-research-falcon.md and its .citations.md sidecar, at sidecar items 9, 10, 12 and 13, both of which this PR commits. validate-research-reference resolves a report's citations against references_cache, so deleting either file would strand the committed report's citations. They stay.

Create: Platelet-type Bleeding Disorder 22 (EPHB2, MONDO:0032765) · 2026-09-08T18:18:10Z · View source

Resolved claim issue #11470 as entry_type DISEASE: a standalone kb/disorders/ entry for bleeding disorder, platelet-type, 22 (MONDO:0032765). Gene identity. The stub carried no gene and MONDO records none, so identity was resolved outside MONDO. ClinGen's Gene-Disease Validity table (the release pinned in the committed data/clingen/MANIFEST.yaml, snapshot_date 2026-08-13; the CSV itself is gitignored and not committed) has an exact row keyed on the MONDO ID: EPHB2 / HGNC:3393 / bleeding disorder, platelet-type, 22 / MONDO:0032765 / AR / Limited / Hemostasis-Thrombosis Gene Curation Expert Panel / 2024-09-04. That is an independent authority keyed on the same identifier, not a second MONDO read. The gene was then re-checked against kb/ under its own name rather than the numbered label: EPHB2 appears only in kb/groupings/Inherited_Platelet_Function_Disorders.yaml, in a notes list of known uncurated gaps, so no gene-named umbrella entry already covered it. Validity recorded in front, not in a footnote. ClinGen classifies EPHB2-BDPLT22 as Limited: two affected siblings in one consanguineous French family, with the panel calling the overall package borderline between limited and moderate and holding at limited for want of a second family. The genetic block therefore uses association: Limited ClinGen gene-disease validity with relationship_type: UNKNOWN, following the convention already established for Limited-validity genes in Arrhythmogenic_Right_Ventricular_Cardiomyopathy, since the enum has no Limited value. Mechanism. Eight pathophysiology nodes from the homozygous p.Arg745Cys kinase-domain variant through halved EPHB2 autophosphorylation to failure of the primary hemostatic plug. Four of them declare conforms_to against primary_hemostatic_plug_failure, entering by that module's signalling arm; just check-groupings now surfaces this entry as a candidate member of Inherited_Platelet_Function_Disorders, which is the self-completing behaviour that grouping was designed for. The entry is not added to the grouping's member list here - BDPLT12 is in the same state, so that sync is a separate pass. The mechanistic point the entry is built around is a dissociation, and it is sourced: the variant halves autophosphorylation while leaving ephrin-induced clustering intact, and the GPVI signalling failure is measurable without platelet-platelet contact. That is what places EPHB2 as a positive input to GPVI and GPCR signalling rather than as the contact-dependent adhesion molecule the classical Eph model would predict. Deep research. A falcon run was executed for this entry (research/Platelet-type_Bleeding_Disorder_22-deep-research-falcon.md, 1159 s). preflight-dr returned SKIP because MONDO records no causal gene for MONDO:0032765, so the gene-identity discriminator could not run; that is UNCHECKED, not passed. The manual substitution check was therefore done by hand: EPHB2 is mentioned 52 times and is the top gene at 46 occurrences against AR=2, HP=2, MAF=1, GP6=1, the report names p.Arg745Cys and the correct OMIM number 618462, and no other platelet-disorder gene appears more than once. The report is about the right disease. Its own reference validation resolved 3 of 3 citations with a 0.0 confabulation rate and 3 of 3 on topic; term validation verified 33 of 35 with no unresolved CURIEs, one label mismatch on MONDO:0032765 itself where the template variable leaked the string 'if available', and two unverifiable Taxon-prefixed terms. No ontology term was bound from the report; every CURIE in the entry was verified independently against the repository term caches or OLS first. Things deliberately constrained. No prevalence figure (one family). The treatments section carries only what can be sourced: iron replacement, recorded for the sibling who became anemic from gastrointestinal blood loss, and the general inherited-platelet-disorder haemostatic repertoire, labelled in both its description and its notes as class-level guidance extrapolated to a disorder in which none of it has been tested. The deep-research report independently searched for BDPLT22-specific therapy, response-rate data and trial registrations and found none, which is why the extrapolation is stated as an extrapolation. The Normal Platelet Count phenotype carries no HP term and is deliberately left unwired to the pathograph, with the reason recorded in its notes: it is a negative finding constraining the differential, not a consequence of any node. No frequency band is given for the gastrointestinal bleeding, which affected one of the two siblings. Evidence. 33 snippets, all exact substrings of cached references, spanning PMID:30213874 (the founding Blood paper), PMID:33147934 (Nurden review, full text), PMID:25370417 (mouse EphB2 cytoplasmic-domain model) and the ClinGen CGGV assertion record. PMID:30409892, the Blood commentary on the founding paper, was fetched and found to have no retrievable content, so it was dropped rather than cited from its title. Orphan audit. Every downstream, sequelae and reports_on target was diffed against the node and phenotype names: zero orphans. The only items with no incoming edge are the trigger node, which is correct, and the deliberately unwired normal-count phenotype. Validation. just validate (32/33 verified with 1 skipped by prefix, because the extrapolated-treatment entry cites a DOI; re-run with --unskip-prefix DOI it is 33/33), validate-terms, validate-disorders, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-groupings, check-stubs, plus whole-KB check-title-snippets, check-snippet-length and check-snippet-grading. Post-review changes (#11483). The reviewer's blocking finding was an ontology one and was correct: the GPVI signalling node bound GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway, but GPVI has no intrinsic kinase - it signals through the FcR gamma ITAM and recruited Lyn/Syk, which is what the node's own snippet describes. Rebound to GO:0038065 collagen-activated signaling pathway, verified against OLS before binding, and deliberately NOT to the GO:0038063 sibling, which is the receptor-tyrosine-kinase (DDR) branch. Also taken from the same review: GO:0004713 to GO:0004714 on the trigger node, one level more specific and still accurate; the Anemia phenotype's prose no longer says iron-deficiency anemia, because no cited source reports iron indices and HP:0001891 would therefore assert more than the evidence does; the iron treatment gained a therapeutic_agent bound at the element level (CHEBI:18248 iron atom), since the source names neither salt nor oxidation state and NCIT:C210688 Iron Supplement is not a member of the ChemicalEntityTerm enum; PMID:31348050 was cited rather than left in references uncited; and Bernard-Soulier syndrome and von Willebrand disease were added as differentials, both discriminated by the preserved ristocetin response, which was previously only in diagnosis prose.

Falcon ▸

Platelet-type Bleeding Disorder 22 (BDPLT22): Comprehensive Disease-Characteristics Report

Edison Scientific Literature 13 citations 2026-09-08T11:29:41.400339

Platelet-type Bleeding Disorder 22 (BDPLT22): Comprehensive Disease-Characteristics Report

Executive summary and evidence boundary

Platelet-type bleeding disorder 22 is an exceptionally rare, autosomal-recessive platelet-function disorder caused by biallelic dysfunction of EPHB2, which encodes ephrin type-B receptor 2, a plasma-membrane receptor tyrosine kinase. The defining report described only two affected siblings from one consanguineous family, both homozygous for NM_004442.6:c.2233C>T, p.(Arg745Cys). The disorder causes recurrent cutaneous/wound bleeding and, in one patient, chronic gastrointestinal hemorrhage, primarily through defective platelet GPVI- and GPCR-dependent activation rather than absent platelets or a global granule-storage defect. Consequently, every frequency, penetrance, prognosis, and treatment statement must be interpreted in light of an evidence base of n=2. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)

No disease-specific publication from 2023–2024, independent family, new causal variant, epidemiologic study, clinical trial, or targeted therapy was identified. Recent developments therefore concern broader inherited-platelet-disorder management and contemporary understanding of Eph receptor signaling, not new BDPLT22 patient data.

The following evidence map summarizes established findings and separates them from inference or management extrapolation.

Domain	Disease-specific finding	Evidence type/strength	Ontology suggestions
Identity	Platelet-type bleeding disorder 22 (BDPLT22); MONDO:0032765	Disease-level ontology mapping; rare Mendelian platelet-function disorder	MONDO:0032765; inherited platelet function disorder
Gene and variant	EPHB2, NM_004442.6:c.2233C>T, p.Arg745Cys (p.R745C) in the intracellular tyrosine-kinase domain	Established in the discovery family by WES, segregation, patient-platelet studies, and heterologous functional assays (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)	HGNC:3393; GO:0004714 transmembrane receptor protein tyrosine kinase activity; GO:0005886 plasma membrane
Inheritance and evidence base	Autosomal recessive: two homozygous affected siblings in one consanguineous family; asymptomatic parents were heterozygous	Strong segregation within one family, but replication across independent families is unavailable (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)	HP:0000007 Autosomal recessive inheritance; germline variant
Bleeding phenotype	Recurrent spontaneous subcutaneous bleeding and excessive bleeding after minor wounds; one sibling had chronic gastrointestinal bleeding with iron-requiring anemia; ISTH-BAT scores 11 and 6	Established human clinical evidence, n=2 (berrou2018amutationof pages 5-9, nurden2020inheritedplateletdiseases pages 6-7)	HP:0000978 Bruising susceptibility; HP:0005261 Gastrointestinal bleeding; HP:0001891 Iron deficiency anemia; HP:0001878 Hemorrhagic diathesis
Platelet count and morphology	Platelet count initially normal; later 120×10⁹/L in one sibling. Elongated, sickle-shaped and heterogeneous platelets, membrane extensions and preplatelet/proplatelet remnants; maximal diameter 3.61±0.84 and 3.72±0.83 μm versus 2.85±0.15 μm in controls	Established patient laboratory and electron-microscopy evidence, n=2 (berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)	HP:0011873 Abnormal platelet morphology; HP:0001873 Thrombocytopenia; CL:0000233 platelet; CL:0000556 megakaryocyte
Agonist responses	Reduced aggregation and secretion after ADP, collagen, arachidonic acid, U46619/thromboxane-A₂-pathway agonists, thrombin/PAR4 agonism, and convulxin; ristocetin response, dense-granule number, and platelet ATP/ADP content were normal	Established ex vivo patient-platelet evidence (berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)	HP:0003540 Abnormality of platelet aggregation; GO:0070527 platelet aggregation; GO:0030168 platelet activation; CHEBI:16761 ADP; CHEBI:32395 arachidonic acid
Functional hemostasis	Defective integrin αIIbβ3 inside-out activation, granule secretion, P-selectin exposure, and thrombus formation on collagen under flow; clot retraction, flow-dependent adhesion, and fibrinogen spreading were only mildly affected	Established ex vivo functional evidence; indicates predominant activation rather than severe outside-in-signaling failure (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16)	GO:0033628 regulation of cell adhesion mediated by integrin; GO:0002576 platelet degranulation; GO:0072378 blood coagulation, fibrin clot formation
Molecular mechanism	p.Arg745Cys impaired EPHB2 autophosphorylation and reduced activation/phosphorylation of Src/Lyn, Syk, FcRγ, Akt, PLCγ2, disrupting proximal GPVI and GPCR crosstalk	Established in patient platelets and GPVI-expressing RBL-2H3 cells; exact intermediary linking EPHB2 to Src-family kinases remains inferred (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16, berrou2018amutationof pages 16-20)	GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway; GO:0031092 platelet alpha granule membrane; GO:0038083 peptidyl-tyrosine autophosphorylation; CL:0000233 platelet
Preserved functions	Ephrin-B1-induced EPHB2 clustering was preserved; PAR4-AP-induced PKC activity and much calcium mobilization were normal, although reduced calcium signaling was reported under some GPVI conditions	Established assay evidence; argues against failure of receptor clustering or a global signaling defect (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16, berrou2018amutationof pages 16-20)	GO:0048013 ephrin receptor signaling pathway; GO:0035556 intracellular signal transduction; GO:0051480 cytosolic calcium ion homeostasis
Diagnosis	Suspect from lifelong mucocutaneous/wound bleeding with normal or mildly reduced platelet count; document abnormal aggregation/secretion and flow-thrombus phenotypes, then confirm biallelic EPHB2 variants and familial segregation	Disease-specific phenotype–genotype approach is supported; no validated BDPLT22 diagnostic criteria or biomarker exists (nurden2020inheritedplateletdiseases pages 6-7, berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)	ISTH-BAT; HP:0001878 Hemorrhagic diathesis; sequence-variant analysis; platelet aggregation assay
Epidemiology and prognosis	Only two affected siblings from one family are documented in the foundational evidence; disease-specific prevalence, incidence, penetrance, survival, and long-term outcome estimates are unavailable	Very limited human evidence; population-level estimates would be speculative (nurden2020inheritedplateletdiseases pages 6-7, berrou2018amutationof pages 5-9)	ORPHA/epidemiology mapping unavailable; rare disease
Treatment and trials	No BDPLT22-specific approved therapy, response rate, pharmacogenomic recommendation, or interventional trial was identified. Local hemostasis, tranexamic acid, selected desmopressin use, platelet concentrates, or rFVIIa are extrapolated from general inherited platelet-disorder guidance, not validated specifically for EPHB2 deficiency	Extrapolated expert guidance; not disease-specific evidence (nurden2020inheritedplateletdiseases pages 10-11)	NCIT:C783 Tranexamic Acid; NCIT:C61737 Desmopressin; NCIT:C15340 Platelet Transfusion; NCIT:C522 Recombinant Factor VIIa
Models and omics	Functional modeling used GPVI-expressing RBL-2H3 rat basophilic leukemia cells transfected with wild-type or p.Arg745Cys EPHB2. No dedicated p.Arg745Cys knock-in animal, natural veterinary disease, single-cell, spatial, transcriptomic, proteomic, metabolomic, or epigenomic disease study is established	Relevant in-vitro validation; no dedicated organismal BDPLT22 model (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16)	CL:0000097 mast cell-like experimental lineage; NCBI Taxon:10116 Rattus norvegicus; in-vitro disease model

Table: Compact evidence map of the genetic, clinical, laboratory, mechanistic, diagnostic, and therapeutic knowledge for EPHB2-related platelet-type bleeding disorder 22. It separates observations established in the single reported family from inference and management extrapolated from broader inherited platelet disorders.

1. Disease information

Definition

BDPLT22 is a Mendelian primary-hemostasis disorder in which platelet production is broadly preserved but platelet activation, secretion, integrin activation, and thrombus growth are impaired. The foundational article’s abstract states: “We report the first EPHB2 variant affecting platelets in 2 siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts.” It concludes that the disorder demonstrates EPHB2 crosstalk with GPVI and GPCR signaling. (berrou2018amutationof pages 1-5)

Identifiers and synonyms

MONDO: MONDO:0032765, as specified in the query.
Preferred name: Platelet-type bleeding disorder 22.
Abbreviation: BDPLT22.
Useful synonyms: EPHB2-related platelet disorder; EPHB2-related inherited platelet-function disorder; platelet dysfunction due to EPHB2 deficiency; inherited platelet disorder associated with EPHB2 p.Arg745Cys.
OMIM: A distinct numbered OMIM phenotype is implied by the BDPLT22 nomenclature, but its numerical identifier was not recoverable from the retrieved primary or review text and should be verified directly in OMIM before database deposition.
Orphanet: No disorder-specific Orphanet identifier was recovered.
ICD-10/ICD-11 and MeSH: No uniquely specific code/heading was identified. A broader hereditary platelet-function-defect or hemorrhagic-disorder category would be necessary; this should not be represented as a one-to-one disease mapping.

The evidence is aggregated disease-level literature derived from two individually phenotyped research participants, not an EHR-derived population dataset. The primary human data include clinical histories, pedigree segregation, ex-vivo platelet assays, microscopy, and sequencing. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)

2. Etiology

Causal factor and genetic risk

The demonstrated initiating lesion is germline, homozygous EPHB2 c.2233C>T, p.Arg745Cys. It substitutes a conserved arginine in the intracellular tyrosine-kinase domain, immediately adjacent to essential Asp746. Both affected siblings were homozygous; both clinically unaffected parents were heterozygous. At publication, ExAC frequency was reported as <10⁻⁶, and in-silico tools predicted damage. Segregation, extreme rarity, domain location, patient-platelet abnormalities, and heterologous functional validation collectively support pathogenicity. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)

The variant is germline rather than somatic. The best-supported molecular consequence is partial loss of EPHB2 kinase/autophosphorylation function, not loss of receptor expression or ephrin-induced clustering. No other replicated BDPLT22-causing allele was identified in the retrieved literature. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16)

Environmental and lifestyle risk factors

No toxin, infection, radiation, diet, smoking exposure, alcohol exposure, occupation, or acquired immune process has been shown to cause BDPLT22. Consanguinity increases the probability that two carriers transmit the same rare recessive allele but is not itself a biological cause.

Factors likely to unmask or exacerbate bleeding include trauma, surgery, dental procedures, childbirth, gastrointestinal lesions, and drugs that inhibit platelet function—especially aspirin and nonsteroidal anti-inflammatory drugs. These are general platelet-disorder considerations, not demonstrated EPHB2-specific gene–environment interactions.

Protective factors and modifiers

No protective EPHB2 allele, modifier gene, epistatic locus, or environmental protective factor has been reported. Avoidance of platelet-inhibiting medication and anticipatory hemostatic planning can reduce complications but do not alter the genotype. No formal gene–environment study exists.

3. Phenotypes

The two reported patients were a brother and sister, investigated initially at ages 12 and 15 years, respectively, and reported as young adults. Both had excessive spontaneous subcutaneous bleeding and disproportionate bleeding after minor wounds. One had chronic gastrointestinal bleeding causing anemia that required iron treatment. ISTH Bleeding Assessment Tool scores were 11 and 6, supporting clinically significant but variably expressed bleeding. (berrou2018amutationof pages 5-9)

Clinical and laboratory phenotype annotations

Recurrent spontaneous subcutaneous bleeding/bruising: symptom/sign; childhood recognition; recurrent/episodic; observed in 2/2. Suggested HPO: Bruising susceptibility (HP:0000978) and Hemorrhagic diathesis (HP:0001878).
Prolonged/excessive bleeding after minor wounds: symptom/sign; childhood; recurrent with injury; 2/2. Suggested HPO: Prolonged bleeding after trauma where available, plus HP:0001878.
Gastrointestinal bleeding: symptom; chronic in 1/2; sufficient to cause anemia. HPO: Gastrointestinal hemorrhage (HP:0005261). (berrou2018amutationof pages 5-9, nurden2020inheritedplateletdiseases pages 6-7)
Secondary iron-deficiency anemia: laboratory/clinical complication in 1/2, treated with iron. HPO: Iron deficiency anemia (HP:0001891).
Platelet count: initially normal in both; one later had mild thrombocytopenia at 120×10⁹/L. HPO: Thrombocytopenia (HP:0001873), qualified as mild/variable rather than defining. (berrou2018amutationof pages 5-9)
Abnormal platelet morphology: elongated, sickle-shaped and round heterogeneous forms, membrane extensions, barbell-like preplatelets, and megakaryocyte/proplatelet fragments. Mean maximal diameters were 3.61±0.84 μm and 3.72±0.83 μm, versus 2.85±0.15 μm in controls. HPO: Abnormal platelet morphology (HP:0011873). (berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)
Impaired aggregation and secretion: laboratory abnormality affecting responses to ADP, collagen, arachidonic acid, U46619/thromboxane-A₂ signaling, thrombin/PAR4 stimulation, and convulxin. Ristocetin response was preserved. HPO: Abnormality of platelet aggregation (HP:0003540). (berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)
Preserved dense-granule stores: platelet ATP/ADP content and dense-granule number were normal, arguing against a classic storage-pool deficiency. (berrou2018amutationof pages 5-9)

Frequency estimates above are proportions within two siblings and must not be interpreted as population frequencies. Severity is variable even within the family. The clinical course appears lifelong and exposure-dependent, not neurodegenerative or continuously progressive.

Quality of life

No EQ-5D, SF-36, PROMIS, school/work-function, pain, or disease-specific quality-of-life measure has been reported. Recurrent bruising, wound bleeding, gastrointestinal blood loss, iron therapy, emergency planning, and procedural risk plausibly impose substantial burden, but quantitative QOL effects remain unknown.

4. Genetic and molecular information

Gene and protein

Gene: EPHB2, ephrin type-B receptor 2.
Suggested HGNC identifier: HGNC:3393; verify against HGNC before ingestion.
Protein class: single-pass transmembrane Eph receptor tyrosine kinase.
Relevant compartments: plasma membrane (GO:0005886) and cytoplasmic/intracellular kinase domain.
Relevant functions/processes: transmembrane receptor protein tyrosine kinase activity (GO:0004714), receptor autophosphorylation (GO:0038083), ephrin receptor signaling (GO:0048013), platelet activation (GO:0030168), and platelet aggregation (GO:0070527).

Pathogenic variant assessment

The sole disease-defining allele is NM_004442.6:c.2233C>T; p.(Arg745Cys), historically p.R745C. It is a missense single-nucleotide variant, inherited in homozygous state. The primary report predates or does not provide a formal ClinVar ACMG classification in the retrieved text. For a knowledge base, it is safest to record “reported disease-causing/pathogenic in the primary study” rather than assert a current ClinVar classification without direct ClinVar verification. Supporting ACMG-style evidence includes extreme rarity, segregation in a recessive pedigree, critical kinase-domain location, multiple functional defects, and concordant phenotype. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)

R745C reduced EPHB2 autophosphorylation; in GPVI-expressing RBL-2H3 cells, activation-related phosphorylation of mutant receptor was approximately half that of wild type. Ephrin-B1-induced receptor clustering was retained. Thus, the most defensible consequence is hypomorphic kinase loss of function, not complete null function or dominant negativity. (berrou2018amutationof pages 13-16)

No validated modifier genes, disease-specific methylation pattern, histone alteration, chromatin signature, CNV, translocation, inversion, aneuploidy, or other structural variant has been reported.

5. Environmental information

BDPLT22 is not an environmentally acquired, lifestyle-mediated, or infectious disease. Environmental exposures primarily modify the probability of a bleeding event. Relevant avoidable exposures include aspirin, NSAIDs, and unnecessary antiplatelet drugs; trauma and invasive procedures require planning. No association exists with pollution, occupational chemicals, ionizing radiation, smoking, alcohol, diet, bacteria, viruses, fungi, or parasites.

6. Mechanism and pathophysiology

Ordered causal chain

Homozygous EPHB2 p.Arg745Cys in the intracellular kinase domain leads to impaired EPHB2 autophosphorylation/kinase signaling.
Impaired EPHB2 signaling leads to deficient activation of Src-family kinases, especially Src and Lyn; the exact phosphatase/adapter intermediary is inferred rather than demonstrated.
Deficient Src/Lyn activity leads to reduced FcRγ and Syk phosphorylation in the proximal GPVI pathway.
Reduced GPVI signaling leads to reduced PLCγ2 and Akt activation and, under GPVI stimulation, impaired calcium-dependent platelet activation.
In a parallel branch, impaired EPHB2–GPCR crosstalk leads to defective Src activation downstream of PAR4/other GPCR agonists despite preserved PKC activity and largely preserved calcium mobilization in the tested PAR4 condition.
These signaling defects lead to deficient αIIbβ3 inside-out activation, granule secretion/P-selectin exposure, and amplification by ADP/thromboxane pathways.
Defective platelet activation leads to reduced aggregation and deficient thrombus growth on collagen under flow.
Deficient primary hemostatic plug formation results in recurrent cutaneous/wound bleeding and, where a gastrointestinal source is present, chronic gastrointestinal blood loss and anemia. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16, berrou2018amutationof pages 16-20)

Mechanistic detail

Patient platelets had markedly impaired phosphorylation of Lyn, Syk, FcRγ, Akt, and PLCγ2 after GPVI stimulation. The defect was observed without platelet–platelet contact, showing that early EPHB2 support of GPVI signaling does not require ephrin-mediated intercellular clustering. PAR4-activating peptide produced defective Src activation while PKC activity and calcium mobilization were normal in that experimental setting, localizing at least part of the GPCR defect distal or parallel to canonical PKC/Ca²⁺ signaling. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16, berrou2018amutationof pages 16-20)

The abstract provides a concise primary-source statement: “Most importantly, Lyn, Syk, and FcRγ phosphorylation, the initial steps in glycoprotein VI (GPVI) platelet signaling were drastically impaired in the absence of platelet-platelet contact.” It further reports that mutant overexpression “impaired EPHB2 autophosphorylation but had no effect on ephrin ligand-induced EPHB2 clustering.” (berrou2018amutationof pages 1-5)

Clot retraction, adhesion under flow, and spreading on fibrinogen were only mildly affected, indicating relative preservation of αIIbβ3 outside-in signaling. The dominant defect is therefore upstream platelet activation and integrin inside-out activation, not inability of fibrinogen-bound integrin to support all downstream responses. (berrou2018amutationof pages 1-5)

No evidence supports primary apoptosis, autophagy, immune-mediated destruction, chronic inflammation, fibrosis, oxidative injury, or a defined metabolic block. The abnormal preplatelet/proplatelet forms suggest a possible megakaryocyte fragmentation or platelet-formation contribution, but this is secondary and incompletely defined. No disease-specific transcriptomic, single-cell, spatial, proteomic, metabolomic, lipidomic, epigenomic, CRISPR-screen, or multi-omics dataset was identified.

Suggested cell terms: platelet (CL:0000233), megakaryocyte (CL:0000556). Additional GO suggestions: platelet degranulation (GO:0002576), positive regulation of platelet activation, protein tyrosine phosphorylation, integrin activation, and intracellular calcium-ion signaling; exact GO identifiers should be ontology-validated at ingestion.

7. Anatomical structures affected

The primary biological lesion is in circulating platelets of the hematologic/cardiovascular system and likely their bone-marrow precursor, the megakaryocyte. Suggested anatomical mappings include blood (UBERON:0000178), bone marrow (UBERON:0002371), and vascular system/blood vessel lumen. Bleeding can secondarily affect skin/subcutaneous tissue and gastrointestinal tract; these are sites of hemorrhage, not necessarily intrinsically diseased organs. (berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)

At the subcellular level, relevant structures are the platelet plasma membrane, intracellular EPHB2 kinase domain, GPVI/FcRγ receptor-signaling complex, αIIbβ3 integrin, α-granules, dense granules, and cytoskeletal/membrane systems involved in preplatelet fragmentation. Dense-granule number was normal. There is no lateralization.

8. Temporal development

The genetic defect is congenital, while clinically recognized bleeding occurred by childhood. Platelet investigations at 12 and 15 years imply pediatric onset or recognition. The disorder is expected to be lifelong because the germline genotype persists. Its manifestations are episodic and exposure-dependent—spontaneous bruising or bleeding after trauma/procedures—with possible chronic blood loss from a persistent gastrointestinal source. (berrou2018amutationof pages 5-9)

No formal stages, progression rate, remission pattern, or critical developmental window has been defined. There is no evidence of age-dependent anticipation or progressive organ failure. Critical practical periods include surgery, dental work, menarche/heavy menstruation, pregnancy, delivery, and gastrointestinal disease, although these have not been studied specifically in BDPLT22.

9. Inheritance and population

Inheritance is autosomal recessive. Two homozygous siblings were affected, whereas heterozygous parents were asymptomatic. This supports lack of a major phenotype in simple heterozygotes but is insufficient to establish complete recessive penetrance or exclude subtle laboratory abnormalities. Variable expressivity is suggested by different ISTH-BAT scores and gastrointestinal bleeding in only one sibling. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)

Only one consanguineous family is documented in the core evidence. Accordingly:

prevalence and incidence per 100,000 are unknown;
carrier frequency is unknown;
no sex ratio can be estimated, despite one affected male and one affected female;
no geographic, ethnic, founder, or population enrichment can be inferred;
no genetic anticipation or germline mosaicism has been reported;
the variant’s reported ExAC MAF was <10⁻⁶. (berrou2018amutationof pages 5-9)

For two carrier parents, standard Mendelian counseling gives a 25% affected, 50% carrier, and 25% non-carrier probability per pregnancy, assuming full ascertainment of the familial allele. This is a genetic expectation, not a measured penetrance estimate.

10. Diagnostics

Clinical and laboratory approach

Document lifelong bleeding history, family structure, consanguinity, medication exposure, and ISTH-BAT score.
Obtain CBC, platelet count and indices, blood smear, PT/INR, aPTT, fibrinogen, von Willebrand factor testing, and iron studies where chronic blood loss is suspected.
Perform light-transmission aggregometry using ADP, collagen, arachidonic acid, thromboxane-pathway agonist, ristocetin, thrombin/PAR agonists, and convulxin/GPVI agonism where available.
Assess secretion by ATP release and/or flow-cytometric P-selectin exposure; assess αIIbβ3 activation using an activation-specific antibody or fibrinogen binding.
In a specialist/research laboratory, consider platelet electron microscopy, collagen-flow thrombus assays, and phosphosignaling studies.
Confirm with sequencing showing biallelic EPHB2 variants, parental phasing/segregation, population-frequency review, and functional interpretation. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9, berrou2018amutationof pages 20-25)

A normal platelet count does not exclude the disorder. Preserved ristocetin aggregation and normal dense-granule number/content help distinguish it from Bernard–Soulier/von Willebrand-related ristocetin defects and classic dense-granule storage-pool deficiency. (berrou2018amutationof pages 5-9)

Genetic testing

A curated inherited bleeding/platelet-disorder panel that includes EPHB2 is efficient when the phenotype is platelet-specific. Single-gene EPHB2 testing is appropriate for familial cascade testing once the allele is known. WES was the successful discovery method and remains appropriate for panel-negative cases; WGS may identify noncoding, structural, or poorly captured variants but has no demonstrated BDPLT22-specific yield. RNA sequencing may help evaluate splice or expression variants but is not validated here. CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless additional features suggest another diagnosis.

Differential diagnosis

Important alternatives include von Willebrand disease, Glanzmann thrombasthenia, Bernard–Soulier syndrome, GP6-related platelet dysfunction, P2RY12 deficiency, RASGRP2- or FERMT3-related integrin-activation disorders, thromboxane-pathway defects, storage-pool disorders, ANO6/Scott syndrome, mild thrombocytopenias, coagulation-factor deficiencies, medication-induced platelet dysfunction, liver/renal disease, and acquired immune platelet disorders. EPHB2 disease is distinguished by recessive segregation, the multi-agonist activation/secretion defect, preserved ristocetin response and dense-granule stores, and molecular confirmation. Reviews emphasize that inherited platelet disorders with normal counts can still cause moderate or severe bleeding. (nurden2020inheritedplateletdiseases pages 6-7, nurden2020inheritedplateletdiseases pages 2-3)

No newborn-screening program or population screening is indicated. Cascade testing of adult relatives and targeted prenatal or preimplantation testing can be offered after identification of the familial pathogenic variant.

11. Outcome and prognosis

There are no survival curves, mortality rates, life-expectancy estimates, disability measures, longitudinal cohorts, or prognostic models. Neither reported patient was described as having a lethal multisystem syndrome. Available evidence suggests morbidity is dominated by recurrent bleeding, procedural risk, and anemia from chronic blood loss. One patient required iron supplementation for gastrointestinal bleeding. (berrou2018amutationof pages 5-9, nurden2020inheritedplateletdiseases pages 6-7)

Potential complications include severe traumatic or surgical hemorrhage, gastrointestinal bleeding, iron deficiency, transfusion exposure, and—if platelet transfusions become recurrent—alloimmunization. Recovery from an individual bleed is expected with local/systemic hemostasis, but the inherited platelet defect does not remit. Baseline bleeding history, ISTH-BAT score, prior procedural bleeding, lesion site, platelet count, and concomitant antiplatelet drugs are rational prognostic factors, but none is validated specifically for BDPLT22.

12. Treatment

Disease-specific evidence

No EPHB2-directed drug, approved genotype-specific therapy, response-rate study, randomized trial, gene therapy, RNA therapy, cell therapy, or curative intervention has been reported. Iron was used for secondary anemia in one patient, but this treats blood-loss consequences rather than platelet dysfunction. (berrou2018amutationof pages 5-9)

Extrapolated inherited-platelet-disorder strategy

Management should occur through a hemophilia/hemostasis center and be individualized to bleeding severity and procedure. General guidance recommends minimizing bleeding risks, carrying an emergency information card, and creating multidisciplinary prophylaxis plans for surgery and childbirth. For mild bleeding or lower-risk procedures, local hemostasis plus an antifibrinolytic such as tranexamic acid or selected use of desmopressin may be considered. Platelet transfusion is used when simpler measures are inadequate or for major bleeding; recombinant activated factor VII (rFVIIa) can be considered in severe/refractory circumstances, especially when platelet transfusion is ineffective or problematic. These recommendations are not validated specifically in BDPLT22. (nurden2020inheritedplateletdiseases pages 10-11)

The 2023 treatment review’s abstract describes the current general IPD armamentarium as: “local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII.” It also notes that treatment choice must account for the underlying disorder, bleeding severity/site, age, and sex. However, no EPHB2 patient was treated in a clinical study.

Practical options include:

local pressure, suturing, topical hemostatic agents, and careful dental/surgical technique;
tranexamic acid for oral/nasal/menstrual or procedure-associated mucosal bleeding, barring contraindications;
desmopressin only after specialist assessment or a documented response, because efficacy in EPHB2 deficiency is unknown;
matched/leukoreduced platelet concentrates for major bleeding or high-risk surgery, balancing alloimmunization and transfusion risks;
rFVIIa as rescue therapy under expert supervision, not routine prophylaxis;
iron replacement and investigation/treatment of gastrointestinal or menstrual blood-loss sources.

Suggested NCIT mappings include Tranexamic Acid, Desmopressin, Platelet Transfusion, Recombinant Factor VIIa, Genetic Counseling, and Supportive Care; identifiers should be checked in the current NCIT release.

Hematopoietic stem-cell transplantation is reserved in general guidance for selected young patients with life-threatening, recurrent, treatment-refractory inherited platelet disorders; there is no rationale or outcome evidence supporting it for the two known BDPLT22 patients. Similarly, autologous stem-cell gene therapy, artificial platelets, nanoparticles, and other procoagulants remain future general IPD concepts rather than BDPLT22 applications. (nurden2020inheritedplateletdiseases pages 10-11)

Clinical-trial searches found no relevant BDPLT22 interventional study or NCT identifier.

13. Prevention

Primary prevention of the germline disorder is not possible after conception. Reproductive options include carrier testing, cascade testing, genetic counseling, prenatal diagnosis, and preimplantation genetic testing for a confirmed familial allele.

Secondary prevention consists of early recognition in relatives, avoidance of diagnostic delay despite a normal platelet count, and pre-procedure genetic/functional characterization. Tertiary prevention includes avoiding aspirin/NSAIDs and unnecessary antiplatelet agents, using medical-alert documentation, maintaining dental care to reduce invasive procedures, treating iron deficiency, and establishing written emergency, surgical, and pregnancy plans. Multidisciplinary planning is recommended for childbirth and invasive procedures. (nurden2020inheritedplateletdiseases pages 10-11)

Vaccination has no disease-preventive role, although routine immunization remains appropriate. Population screening and public-health environmental interventions are not warranted for a single-family ultra-rare disorder.

14. Other species and natural disease

No naturally occurring EPHB2-associated platelet bleeding disorder was identified in companion animals, livestock, or wildlife. There is no zoonotic potential or infectious transmission.

The in-vitro functional system used RBL-2H3 cells, derived from rat basophilic leukemia, corresponding to Rattus norvegicus (NCBI Taxon 10116). This is an engineered signaling model, not natural rat disease. EPHB2/ephrin biology is evolutionarily conserved, and prior mouse studies support roles in platelet activation and thrombus formation, but they do not establish a natural veterinary counterpart or faithfully model human p.Arg745Cys disease. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16)

15. Model organisms and experimental systems

The primary study transfected wild-type or R745C human EPHB2 into GPVI-expressing RBL-2H3 cells. The mutant retained ephrin-induced clustering but showed reduced autophosphorylation, validating a kinase-signaling defect independent of the patients’ broader genetic background. This model is useful for receptor phosphorylation, clustering, and GPVI-crosstalk experiments but cannot reproduce human bleeding, platelet biogenesis, vascular flow, or whole-organism pharmacology. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 13-16)

Prior EPHB2/β-galactosidase mouse work showed reduced platelet Akt and PLCγ2 phosphorylation and supports pathway plausibility, but it is not a p.Arg745Cys knock-in or dedicated BDPLT22 model. No zebrafish, Drosophila, C. elegans, yeast, iPSC-megakaryocyte, organoid, conditional knockout, humanized, or CRISPR-corrected model specific to BDPLT22 was identified. (berrou2018amutationof pages 13-16)

High-value future models would include an Ephb2 Arg745Cys knock-in mouse, CRISPR-engineered human iPSC-derived megakaryocytes/platelets, and microfluidic vascular-flow systems. These could test platelet formation, signaling dose dependence, bleeding/thrombosis balance, rescue by wild-type EPHB2, and candidate hemostatic therapies.

Current understanding and research priorities

The strongest expert interpretation is that BDPLT22 reveals an unexpected, clinically important role for EPHB2 as a positive regulator of early GPVI and GPCR signaling. The disease is not simply a failure of classical ephrin-dependent platelet–platelet contact: receptor clustering remains intact, while kinase autophosphorylation and Src-family signaling are impaired. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 16-20)

The main unresolved questions are whether p.Arg745Cys is the only disease allele; how broadly EPHB2 deficiency affects megakaryopoiesis; whether heterozygotes have subclinical platelet phenotypes; which phosphatase/adaptor links EPHB2 to Src/Lyn; and which general IPD therapies are effective and safe in this genotype. Independent families, contemporary ClinVar/gnomAD reassessment, standardized platelet phenotyping, longitudinal outcome collection, and a knock-in model are required before reliable prevalence, penetrance, prognosis, or treatment-response estimates can be made.

Key references

Berrou E, et al. “A mutation of the human EPHB2 gene leads to a major platelet functional defect.” Blood. Published November 2018;132(19):2067–2077. DOI/URL: https://doi.org/10.1182/blood-2018-04-845644. This is the foundational primary human and functional study. (berrou2018amutationof pages 1-5, berrou2018amutationof pages 5-9)
Nurden P, Stritt S, Favier R, Nurden AT. “Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy.” Haematologica. Online November 2020;106:337–350. DOI/URL: https://doi.org/10.3324/haematol.2020.248153. This authoritative review contextualizes EPHB2-related disease among inherited platelet-function disorders. (nurden2020inheritedplateletdiseases pages 6-7, nurden2020inheritedplateletdiseases pages 2-3)
Bargehr C, Knöfler R, Streif W. “Treatment of Inherited Platelet Disorders: Current Status and Future Options.” Hämostaseologie. Published August 2023;43:261–270. DOI/URL: https://doi.org/10.1055/a-2080-6602. This is current general IPD guidance; it is not BDPLT22-specific.

References

(berrou2018amutationof pages 1-5): Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T. Nurden, Ernest Turro, Willem H. Ouwehand, Cécile V. Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, and Marijke Bryckaert. A mutation of the human ephb2 gene leads to a major platelet functional defect. Blood, 132 19:2067-2077, Nov 2018. URL: https://doi.org/10.1182/blood-2018-04-845644, doi:10.1182/blood-2018-04-845644. This article has 33 citations and is from a highest quality peer-reviewed journal.
(berrou2018amutationof pages 5-9): Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T. Nurden, Ernest Turro, Willem H. Ouwehand, Cécile V. Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, and Marijke Bryckaert. A mutation of the human ephb2 gene leads to a major platelet functional defect. Blood, 132 19:2067-2077, Nov 2018. URL: https://doi.org/10.1182/blood-2018-04-845644, doi:10.1182/blood-2018-04-845644. This article has 33 citations and is from a highest quality peer-reviewed journal.
(nurden2020inheritedplateletdiseases pages 6-7): Paquita Nurden, Simon Stritt, Remi Favier, and Alan T. Nurden. Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy. Haematologica, 106:337-350, Nov 2020. URL: https://doi.org/10.3324/haematol.2020.248153, doi:10.3324/haematol.2020.248153. This article has 110 citations.
(berrou2018amutationof pages 20-25): Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T. Nurden, Ernest Turro, Willem H. Ouwehand, Cécile V. Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, and Marijke Bryckaert. A mutation of the human ephb2 gene leads to a major platelet functional defect. Blood, 132 19:2067-2077, Nov 2018. URL: https://doi.org/10.1182/blood-2018-04-845644, doi:10.1182/blood-2018-04-845644. This article has 33 citations and is from a highest quality peer-reviewed journal.
(berrou2018amutationof pages 13-16): Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T. Nurden, Ernest Turro, Willem H. Ouwehand, Cécile V. Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, and Marijke Bryckaert. A mutation of the human ephb2 gene leads to a major platelet functional defect. Blood, 132 19:2067-2077, Nov 2018. URL: https://doi.org/10.1182/blood-2018-04-845644, doi:10.1182/blood-2018-04-845644. This article has 33 citations and is from a highest quality peer-reviewed journal.
(berrou2018amutationof pages 16-20): Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T. Nurden, Ernest Turro, Willem H. Ouwehand, Cécile V. Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, and Marijke Bryckaert. A mutation of the human ephb2 gene leads to a major platelet functional defect. Blood, 132 19:2067-2077, Nov 2018. URL: https://doi.org/10.1182/blood-2018-04-845644, doi:10.1182/blood-2018-04-845644. This article has 33 citations and is from a highest quality peer-reviewed journal.
(nurden2020inheritedplateletdiseases pages 10-11): Paquita Nurden, Simon Stritt, Remi Favier, and Alan T. Nurden. Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy. Haematologica, 106:337-350, Nov 2020. URL: https://doi.org/10.3324/haematol.2020.248153, doi:10.3324/haematol.2020.248153. This article has 110 citations.
(nurden2020inheritedplateletdiseases pages 2-3): Paquita Nurden, Simon Stritt, Remi Favier, and Alan T. Nurden. Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy. Haematologica, 106:337-350, Nov 2020. URL: https://doi.org/10.3324/haematol.2020.248153, doi:10.3324/haematol.2020.248153. This article has 110 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	35
Resolved	33
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0032765 (4 mentions) - the report calls it "if available"; MONDO calls it bleeding disorder, platelet-type, 22

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.

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OpenScientist Report

Classifications

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Platelet-type Bleeding Disorder 22 (BDPLT22): Comprehensive Disease-Characteristics Report

Executive summary and evidence boundary

1. Disease information

Definition

Identifiers and synonyms

2. Etiology

Causal factor and genetic risk

Environmental and lifestyle risk factors

Protective factors and modifiers

3. Phenotypes

Clinical and laboratory phenotype annotations

Quality of life

4. Genetic and molecular information

Gene and protein

Pathogenic variant assessment

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Mechanistic detail

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and laboratory approach

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Disease-specific evidence

Extrapolated inherited-platelet-disorder strategy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Current understanding and research priorities

Key references

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver