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.

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

1. Homozygous EPHB2 p.Arg745Cys in the intracellular kinase domain leads to impaired EPHB2 autophosphorylation/kinase signaling.
2. 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.
3. Deficient Src/Lyn activity leads to reduced FcRγ and Syk phosphorylation in the proximal GPVI pathway.
4. Reduced GPVI signaling leads to reduced PLCγ2 and Akt activation and, under GPVI stimulation, impaired calcium-dependent platelet activation.
5. 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.
6. These signaling defects lead to deficient αIIbβ3 inside-out activation, granule secretion/P-selectin exposure, and amplification by ADP/thromboxane pathways.
7. Defective platelet activation leads to reduced aggregation and deficient thrombus growth on collagen under flow.
8. 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

1. Document lifelong bleeding history, family structure, consanguinity, medication exposure, and ISTH-BAT score.
2. 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.
3. Perform light-transmission aggregometry using ADP, collagen, arachidonic acid, thromboxane-pathway agonist, ristocetin, thrombin/PAR agonists, and convulxin/GPVI agonism where available.
4. Assess secretion by ATP release and/or flow-cytometric P-selectin exposure; assess αIIbβ3 activation using an activation-specific antibody or fibrinogen binding.
5. In a specialist/research laboratory, consider platelet electron microscopy, collagen-flow thrombus assays, and phosphosignaling studies.
6. 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

1. 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)
2. 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)
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

1. (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.

2. (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.

3. (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.

4. (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.

5. (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.

6. (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.

7. (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.

8. (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.

All extracted references resolved successfully.

Term Validation

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

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.