| 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 (pqac-00000002, pqac-00000003) | 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 (pqac-00000002, pqac-00000003) | 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 (pqac-00000003, pqac-00000006) | 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 (pqac-00000003, pqac-00000005) | 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 (pqac-00000003, pqac-00000005) | 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 (pqac-00000002, pqac-00000004) | 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 (pqac-00000002, pqac-00000004, pqac-00000007) | 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 (pqac-00000002, pqac-00000004, pqac-00000007) | 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 (pqac-00000000, pqac-00000002, pqac-00000003) | 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 (pqac-00000000, pqac-00000003) | 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 (pqac-00000008, pqac-00000009) | 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 (pqac-00000002, pqac-00000004) | 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.*