Inherited Platelet Function Disorders (Platelet-Type Bleeding Disorders)

name: Inherited Platelet Function Disorders
display_name: Inherited Platelet Function Disorders (Platelet-Type Bleeding Disorders)
creation_date: "2026-08-24T00:00:00Z"
description: >-
  The inherited platelet function disorders - the platelet-type bleeding
  disorders, catalogued in OMIM as the BDPLT series - are Mendelian disorders in
  which a component of the platelet's primary-hemostatic apparatus is lost or
  dysfunctional, so that platelets fail to arrest bleeding after vessel injury.
  The components differ completely between members: an adhesion receptor
  (GPIb-IX-V in Bernard-Soulier syndrome), the aggregation receptor (integrin
  alphaIIbbeta3 in Glanzmann thrombasthenia), an activating receptor or its
  signalling machinery (P2Y12 in BDPLT8, CalDAG-GEFI in BDPLT18), the secretory
  granules (gray platelet syndrome, Quebec platelet disorder), the megakaryocyte
  transcription factors that build the platelet (FLI1 in BDPLT21), or the
  phospholipid scramblase that makes the platelet procoagulant (ANO6 in Scott
  syndrome).

  They are grouped because that heterogeneity converges. Every member funnels
  through failure of primary hemostatic plug formation onto a mucocutaneous
  bleeding diathesis, which is precisely why they are so hard to tell apart
  clinically and why the group has a shared diagnostic pathway built on platelet
  function testing rather than on presentation. The grouping exists to make that
  convergence auditable and to make the boundary explicit: mucocutaneous
  bleeding on its own does not put a disorder here.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on a shared final-common pathway: each member conforms to the
  `primary_hemostatic_plug_failure` module, entering through one of its four
  non-interchangeable arms and converging on failure of the primary hemostatic
  plug. Members are kept as separate Disease entries because they differ in
  which arm is interrupted, in the causal gene, in whether the platelet count
  and morphology are also abnormal, and - critically - in management: the
  aggregation-arm disorders carry an alloimmunization hazard from platelet
  transfusion that the signalling-arm disorders do not, and Scott syndrome is
  invisible to the aggregometry that diagnoses the rest.

  The defining criterion is deliberately NECESSARY_AND_SUFFICIENT on module
  conformance rather than on phenotype. A phenotype-based criterion would be
  both too wide and too narrow: too wide because coagulation-factor
  deficiencies, plasma von Willebrand disease, the vascular and
  connective-tissue bleeding disorders and immune thrombocytopenia all produce
  the same mucocutaneous bleeding; too narrow because Scott syndrome has normal
  platelet aggregation and would be excluded by any aggregometry-based rule.
  Making conformance the criterion means the sufficient direction can be used to
  find candidate members - any disorder curated as conforming to the module and
  not yet listed here is surfaced by `just check-groupings` - which is the
  mechanism that keeps the union complete as the BDPLT series is curated out.

  Scope note: the inherited THROMBOCYTOPENIAS are not members unless a
  qualitative functional defect is also curated. Several members do carry both
  (Bernard-Soulier syndrome, gray platelet syndrome, BDPLT21), and the module
  covers only their functional arm; a disorder whose sole lesion is reduced
  platelet production belongs to a different mechanism and is out of scope here.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000009
      label: inherited bleeding disorder, platelet-type
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch rather than exactMatch. MONDO:0000009 (OMIMPS:231200) is the
      ontology's class for the same clinical family and is the natural alignment
      target, but the two boundaries are drawn differently: this grouping is
      defined by conformance to a mechanism module, whereas the MONDO class is
      an OMIM phenotypic-series descendant set that includes entities whose
      lesion is quantitative rather than functional. Deliberately NOT
      narrowMatch or exactMatch, so the mapping does not retire MONDO:0000009
      from the curation queue.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO:0000009 has 32 descendants at the time of writing, most of which
        are not yet curated in dismech; that descendant set is a useful worklist
        for this grouping but should not be treated as a definition of its
        membership, since arm-level conformance is what is actually being
        asserted.
membership_criteria:
- description: >-
    A disorder is an inherited platelet function disorder if and only if it
    conforms to the primary hemostatic plug failure module - that is, an
    inherited lesion in a component of the platelet primary-hemostatic apparatus
    causes failure of primary hemostatic plug formation.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: primary_hemostatic_plug_failure#Failure of Primary Hemostatic Plug Formation
    description: >-
      Conforms to the primary hemostatic plug failure module at its central
      effector node.
- description: >-
    Every member is an inherited (germline) disorder presenting with abnormal
    bleeding. Stated as a NECESSARY condition only - it audits the listed
    members and must not be used to classify candidates, because abnormal
    bleeding is shared with the coagulation-factor, vascular and immune bleeding
    disorders that this grouping explicitly excludes.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_PHENOTYPE
    phenotype_term:
      preferred_term: Abnormal bleeding
      term:
        id: HP:0001892
        label: Abnormal bleeding
    description: >-
      Presents with abnormal bleeding (satisfied by any HPO descendant, e.g.
      epistaxis, menorrhagia, purpura).
members:
- member: Bernard-Soulier Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The ADHESION arm. Loss of the GPIb-IX-V complex removes the receptor that
      captures von Willebrand factor under arterial shear, so the platelet is
      never recruited to the vessel wall. The same complex anchors the membrane
      skeleton during proplatelet formation, so the disorder is also
      quantitative - giant platelets and thrombocytopenia - which distinguishes
      it from Glanzmann thrombasthenia at the bench. Ristocetin-induced
      agglutination is absent and is not corrected by normal plasma.
    module: primary_hemostatic_plug_failure#Impaired Platelet Adhesion to the Injured Vessel Wall
    gene:
      preferred_term: GP1BA
      term:
        id: hgnc:4439
        label: GP1BA
- member: Platelet-Type von Willebrand Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The ADHESION arm reached from the opposite direction, and the reason that
      arm is worth stating carefully. GP1BA gain-of-function variants make
      GPIbalpha hyperresponsive to von Willebrand factor, so constitutive
      binding depletes the high-molecular-weight VWF multimers and the platelets
      bound to them from the circulation - gain of function at the receptor
      producing loss of function at the vessel wall. Ristocetin-induced
      agglutination is enhanced rather than absent, the mirror image of
      Bernard-Soulier syndrome.
    module: primary_hemostatic_plug_failure#Impaired Platelet Adhesion to the Injured Vessel Wall
    gene:
      preferred_term: GP1BA
      term:
        id: hgnc:4439
        label: GP1BA
    modifier: GAIN_OF_FUNCTION
- member: Glanzmann Thrombasthenia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The AGGREGATION arm, and the only member that enters through the final
      common step of aggregation itself. Loss of integrin alphaIIbbeta3 removes
      the receptor that binds the fibrinogen bridging one platelet to the next,
      so aggregation fails to every physiological agonist while
      ristocetin-induced agglutination, platelet count and platelet morphology
      are all normal. Uniquely in the group, the dominant long-term problem is
      iatrogenic: patients have no tolerance to alphaIIbbeta3 and become
      alloimmunized by platelet transfusion.
    module: primary_hemostatic_plug_failure#Failure of Integrin alphaIIbbeta3-Mediated Platelet Aggregation
    gene:
      preferred_term: ITGA2B
      term:
        id: hgnc:6138
        label: ITGA2B
- member: Platelet-type bleeding disorder 18
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The SIGNALLING arm, and the disorder that proves the arm distinction is
      real rather than bookkeeping. Loss of CalDAG-GEFI abolishes
      calcium-driven Rap1 activation, so integrin alphaIIbbeta3 - present in
      normal amount and structurally normal - is never switched on. The
      phenotype is a functional thrombasthenia, separated from the real thing by
      normal receptor expression and by preserved aggregation to phorbol ester,
      which activates protein kinase C downstream of the missing step.
    module: primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling
    gene:
      preferred_term: RASGRP2
      term:
        id: hgnc:9879
        label: RASGRP2
- member: Platelet-type bleeding disorder 8
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The SIGNALLING arm entered at the agonist receptor. Loss of the Gi-coupled
      ADP receptor P2Y12 removes the sustained, irreversible phase of ADP
      aggregation and the potentiation of secretion by other agonists, while the
      Gq-coupled P2Y1 shape change and first wave remain - giving incomplete,
      reversible aggregation even at high ADP. It is the congenital counterpart
      of clopidogrel, prasugrel and ticagrelor, so its closest differential is
      an acquired drug phenocopy rather than another inherited disorder.
    module: primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling
    gene:
      preferred_term: P2RY12
      term:
        id: hgnc:18124
        label: P2RY12
- member: Gray Platelet Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The SECRETION arm, entered through granule biogenesis rather than
      signalling. Loss of NBEAL2 leaves the megakaryocyte unable to pack
      endogenously synthesized cargo into alpha-granules, so the platelet cannot
      amplify haemostasis by secretion. Its distinguishing feature is that the
      bleeding is not the worst of it: progressive marrow fibrosis and
      splenomegaly, plus a granule defect extending to leukocytes, make it the
      only member of this grouping with a systemic non-haemostatic arm.
    module: primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling
    gene:
      preferred_term: NBEAL2
      term:
        id: hgnc:31928
        label: NBEAL2
- member: Bleeding disorder, platelet-type, 21
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The SECRETION arm entered furthest upstream of all. FLI1 is the ETS
      transcription factor driving terminal megakaryocyte maturation and
      directly transactivating platelet genes including GP6, GP9 and ITGA2B, so
      losing it does not break one component but under-builds the platelet
      wholesale - fewer platelets, defective granules, poor secretion. It is the
      monogenic counterpart of Paris-Trousseau thrombocytopenia, where FLI1 is
      lost within the contiguous 11q23 deletion.
    module: primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling
    gene:
      preferred_term: FLI1
      term:
        id: hgnc:3749
        label: FLI1
- member: GFI1B-related platelet-type bleeding disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The SECRETION arm entered through transcriptional control, and the second
      megakaryocyte transcription-factor member alongside FLI1/BDPLT21. Loss of
      GFI1B repressor function arrests megakaryocyte maturation, yielding large,
      alpha-granule-deficient platelets that stain poorly and ectopically retain
      the progenitor marker CD34. Its distinguishing feature within the family is
      that the two genetic routes are not interchangeable: heterozygous
      zinc-finger variants act as dominant negatives over wild-type GFI1B, while
      the recessive form is an isoform-selective loss of full-length p37 with the
      shorter p32 isoform retained - which is why erythropoiesis is spared in
      that kindred. Phenotypically grey-platelet-like, but mechanistically
      distinct from NBEAL2 gray platelet syndrome: there the granule-packing
      machinery fails, here the maturation programme that builds the platelet
      does.
    module: primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling
    gene:
      preferred_term: GFI1B
      term:
        id: hgnc:4238
        label: GFI1B
- member: Scott Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The PROCOAGULANT arm, and the member that would be excluded by any
      aggregometry-based definition of this group. Loss of the ANO6/TMEM16F
      scramblase leaves the activated platelet unable to externalize
      phosphatidylserine, so the surface on which the tenase and prothrombinase
      complexes assemble is never presented and local thrombin generation
      collapses - with adhesion, activation, secretion and aggregation all
      normal. Historically described as a coagulation defect ("prothrombin
      consumption deficiency") for exactly this reason.
    module: primary_hemostatic_plug_failure#Impaired Platelet Procoagulant Membrane Response
    gene:
      preferred_term: ANO6
      term:
        id: hgnc:25240
        label: ANO6
notes: >-
  Coverage. This grouping lists the members curated in dismech at the time of
  writing and is deliberately incomplete relative to the OMIM BDPLT series
  (which runs to BDPLT25) and to MONDO:0000009 (32 descendants). Known gaps with
  open stubs include Quebec platelet disorder (BDPLT5, PLAU tandem duplication),
  MYH9-related disease / May-Hegglin anomaly (BDPLT6), the thromboxane pathway
  defects (BDPLT12 cyclooxygenase-1, BDPLT13 TBXA2R, BDPLT14 TBXAS1), GPVI
  deficiency (BDPLT11), the ITGA2/glycoprotein Ia-IIa defect (BDPLT9), CD36
  deficiency (BDPLT10), ACTN1 (BDPLT15), PRKACG (BDPLT19),
  SLFN14 (BDPLT20), EPHB2 (BDPLT22) and TPM4 (BDPLT25). Because the defining
  criterion is SUFFICIENT as well as necessary, each will be surfaced as a
  candidate member by `just check-groupings` as soon as it is curated with a
  conforming node - the union is designed to complete itself rather than to
  need manual synchronization.

  Members already curated elsewhere that are NOT listed here, and why. The
  storage pool diseases of lysosome-related organelle origin - Hermansky-Pudlak
  syndrome, Chediak-Higashi syndrome, Griscelli syndrome - have dense-granule
  defects that would qualify them for the secretion arm, but their entries
  currently conform to `lysosome_related_organelle_biogenesis` rather than to
  this module, and that is the mechanistically primary account of them: the
  platelet defect is one manifestation of a general organelle-trafficking lesion
  that also produces hypopigmentation and, in two of the three, a lethal immune
  phenotype. Adding a parallel conformance to this module would be defensible
  and would make them candidates here; that is a curation decision for those
  entries, not one to make from inside this grouping, so they are left off
  rather than listed as unevaluated members. The same applies to Wiskott-Aldrich
  syndrome (cytoskeletal, with immunodeficiency dominating) and to ARC syndrome
  (VPS33B/VIPAS39 alpha-granule deficiency within a multisystem developmental
  disorder).

  Why membership is criterion-checked rather than gene-listed. An earlier and
  more obvious design would enumerate the BDPLT genes as a `HAS_GENE`
  disjunction. That fails on both edges of this family: ITGA2B and ITGB3 cause
  both this grouping's flagship member and a dominant macrothrombocytopenia that
  is mechanistically its opposite (increased integrin activation interfering
  with megakaryocytopoiesis), and GP1BA causes both Bernard-Soulier syndrome and
  platelet-type von Willebrand disease through loss and gain of function
  respectively. Gene identity does not determine membership here; conformance
  does.