Platelet-type bleeding disorder 18

Mendelian MONDO:0014386 Pathograph 8 Show in embeddings browser Inherited Platelet Disorder Bleeding Disorder

Platelet-type bleeding disorder 18 is an autosomal recessive severe bleeding disorder caused by biallelic loss of RASGRP2, which encodes CalDAG-GEFI - the calcium- and diacylglycerol-regulated guanine nucleotide exchange factor that activates the small GTPase Rap1 downstream of agonist receptors. Rap1 in turn drives integrin alphaIIbbeta3 from its resting to its ligand-binding conformation, so this is a signalling disorder that produces a functional thrombasthenia: the integrin is present in normal amounts and is structurally normal, and it simply never gets switched on. The disorder is a clean natural experiment in how the inside-out pathway is wired, and two features make it more informative than a straightforward knockout. First, the block is not total - PKC- and ADP-dependent pathways provide a parallel route to integrin activation, so patient platelets retain residual responsiveness and can still be activated directly by phorbol ester bypassing the receptor layer entirely. Second, the defect is lineage-restricted to platelets and megakaryocytes with no leukocyte abnormality, which is exactly what separates it from leukocyte adhesion deficiency III, where loss of kindlin-3 breaks integrin activation in white cells as well and adds infection to the bleeding. The therapeutic corollary is striking and runs in the opposite direction: a single normal allele is enough to prevent bleeding entirely, which makes CalDAG-GEFI an unusually attractive antithrombotic target.

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1
Inheritance
7
Pathophys.
3
Phenotypes
8
Pathograph
1
Genes
2
Differentials
1
Models
3
References
👪

Inheritance

1
Autosomal Recessive HP:0000007
Biallelic RASGRP2 loss of function. Recessive in the strong sense - a single normal allele is sufficient to prevent bleeding, even though heterozygote platelets are demonstrably abnormal in flow adhesion and spreading assays.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24958846 SUPPORT Human Clinical
"Heterozygous did not suffer from bleeding and have normal platelet aggregation"
Establishes the clinically recessive inheritance directly.
⚙

Pathophysiology

7
Biallelic Loss of Function in RASGRP2
Biallelic RASGRP2 variants abolish CalDAG-GEFI. The index family carried c.G742T, identified by whole-exome sequencing in three siblings with severe bleeding; nonsense (p.Q236X) and missense (p.C296Y) alleles have since been reported homozygously with no detectable CalDAG-GEFI protein in platelet lysates. Both null and expressed-but-dysfunctional alleles occur, so protein absence is not a requirement for the diagnosis.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology. megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Failure of CalDAG-GEFI-Dependent Rap1 Activation CalDAG-GEFI is the calcium-responsive exchange factor for Rap1 in platelets, so its loss removes that activation route.
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI)."
The gene-discovery statement establishing RASGRP2 as causal.
PMID:28762304 SUPPORT Human Clinical
"Genetic analysis identified two new homozygous variants in RASGRP2: c.706C>T (p.Q236X) and c.887G>A (p.C296Y). In both patients, CalDAG-GEFI protein was not detectable in platelet lysates"
Supports the additional alleles and the loss of detectable protein described in this node.
Failure of CalDAG-GEFI-Dependent Rap1 Activation
The rate-limiting lesion. CalDAG-GEFI is activated by rising cytoplasmic calcium downstream of phospholipase-C-coupled agonist receptors, and its main target is Rap1, the small GTPase that regulates integrin-mediated adhesion. Patient platelets show reduced ability to activate Rap1, and expressing the mutant protein in HEK293T cells abolishes Rap1 activation on stimulation - a heterologous confirmation that separates the molecular defect from anything else in the patient's platelet.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
Rap protein signal transduction GO:0032486 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Rap protein signal transduction (GO:0032486). GO:0032486 is a biological process from the Gene Ontology. ↓ DECREASED
CalDAG-GEFI guanine nucleotide exchange factor activity GO:0005085 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves CalDAG-GEFI guanine nucleotide exchange factor activity, annotated with guanyl-nucleotide exchange factor activity (GO:0005085), qualified as loss of function. GO:0005085 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Experimental models
Patient megakaryocyte culture with wild-type RASGRP2 rescue PRIMARY CELL CULTURE Restoring wild-type CalDAG-GEFI in patient megakaryocytes corrects the functional defect, establishing sufficiency of the gene for the phenotype.
Downstream
Impaired Integrin alphaIIbbeta3 Inside-Out Activation Rap1 is the immediate upstream regulator of talin/kindlin-mediated integrin activation.
Impaired Rac1-Dependent Platelet Spreading and Adhesion Under Flow A second, cytoskeletal consequence, reported as following from reduced Rac1 GTP-binding rather than directly from Rap1.
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling."
Direct patient evidence for the Rap1 activation defect and its coupling to integrin inside-out signalling.
PMID:24958846 SUPPORT In Vitro
"Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation."
Heterologous confirmation that the variant itself, rather than some other platelet abnormality, causes the Rap1 defect.
Impaired Integrin alphaIIbbeta3 Inside-Out Activation
The integrin is expressed normally - major glycoprotein receptor levels are normal in patients - but fibrinogen binding is greatly impaired in response to every agonist tested except phorbol ester. That single exception is mechanistically the most informative result in the disorder: phorbol ester activates protein kinase C directly, downstream of the missing exchange factor, and it restores aggregation, which localizes the block precisely to the CalDAG-GEFI step and demonstrates that a parallel PKC route to the same integrin exists and is intact.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
integrin inside-out activation GO:0033622 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased integrin inside-out activation, annotated with integrin activation (GO:0033622). GO:0033622 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Primary Hemostatic Plug Formation Without integrin activation the platelets cannot bridge into an aggregate.
Show evidence (2 references)
PMID:28762304 SUPPORT Human Clinical
"platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA"
States both the integrin activation defect and the phorbol-ester exception that localizes the block, which is the core claim of this node.
PMID:28762304 SUPPORT Human Clinical
"normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients)"
Supports the combination that defines a functional rather than structural thrombasthenia - normal receptor expression with lost aggregation.
Residual PKC- and ADP-Dependent Platelet Activation
The compensating pathway, and a real one rather than a theoretical possibility. PKC- and ADP-dependent signalling allows residual platelet activation in the absence of functional CalDAG-GEFI, which is why the aggregation defect is severe but not absolute and why the disorder's severity varies. Its existence is also what makes CalDAG-GEFI a plausible antithrombotic target: a pathway with a backup can be blocked without abolishing haemostasis outright.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Integrin alphaIIbbeta3 Inside-Out Activation Partially offsets the activation defect rather than abolishing it, which is why this node is curated as an escape route into the same effector.
Show evidence (1 reference)
PMID:24958846 SUPPORT Human Clinical
"Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI."
States the residual pathway and its persistence despite loss of the exchange factor.
Impaired Rac1-Dependent Platelet Spreading and Adhesion Under Flow
A cytoskeletal arm separate from integrin activation: patient platelets fail to form thrombi under flow and fail to spread normally, and this is attributed to reduced Rac1 GTP-binding rather than to the Rap1-integrin route. It is the more sensitive readout of the two - heterozygotes, who do not bleed and whose platelet aggregation is normal, nonetheless fail to adhere under flow and to spread like their homozygous relatives, so this arm detects a defect that the aggregation arm does not.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Primary Hemostatic Plug Formation Contributes to the haemostatic failure, though the heterozygote data show it is not on its own sufficient to cause bleeding.
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding."
States the flow and spreading defects and their attribution to Rac1, which is what separates this node from the Rap1-integrin arm.
PMID:24958846 SUPPORT Human Clinical
"Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading."
Supports the claim that this arm is the more sensitive readout, being abnormal in non-bleeding heterozygotes.
Failure of Primary Hemostatic Plug Formation
Reached by the signalling route: normal receptors, normal integrin, no activation. Prolonged PFA-100 closure times are the whole-blood expression of it.
primary hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased primary hemostasis, annotated with hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Severe Bleeding Diathesis Failure of platelet-dependent primary hemostasis.
Show evidence (1 reference)
PMID:28762304 SUPPORT Human Clinical
"Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors"
The whole-blood haemostatic measurement, alongside the normal receptor expression that makes the failure a signalling one.
Severe Bleeding Diathesis
Severe bleeding is what brought the index family to attention, and the disorder sits at the severe end of the platelet function disorders despite the residual PKC/ADP pathway. Crucially, heterozygous carriers do not bleed at all.
primary hemostasis GO:0007599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased primary hemostasis, annotated with hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding."
Establishes the severity of the presenting phenotype.
PMID:24958846 SUPPORT Human Clinical
"Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis."
Supports the carrier statement and the antithrombotic-target corollary drawn in this entry's description.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Platelet-type bleeding disorder 18 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Blood 1
Abnormal Bleeding OBLIGATE HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24958846 SUPPORT Human Clinical
"three siblings affected by severe bleeding"
Establishes bleeding as the presenting feature in the index family.
Other 2
Impaired Platelet Aggregation with Normal Receptor Expression OBLIGATE HP:0003540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired platelet aggregation (HP:0003540). HP:0003540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28762304 SUPPORT Human Clinical
"severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected"
Reports the aggregation profile including the PMA exception, in both reported patients - supporting the OBLIGATE band for the aggregation defect itself.
Normal Platelet Count and Morphology
Deliberately carries NO `term:`. The previous binding (`HP:0011869 Abnormal platelet function`) was wrong twice over: it asserts an abnormality where a normal result is the curated finding, and it describes function where this finding is about count and morphology. The HPO has no class for a normal count-and-morphology result, so no term is bound rather than a misleading one; a new-term request would be the durable fix.
Show evidence (1 reference)
PMID:28762304 SUPPORT Human Clinical
"The homozygous patients had normal platelet and neutrophil counts and morphology."
Supports normal counts and morphology in both lineages, which is what makes this a pure function disorder.
🧬

Genetic Associations

1
RASGRP2
Gene: RASGRP2 hgnc:9879 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RASGRP2 (hgnc:9879). hgnc:9879 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3."
Supports the lineage restriction and the explicit contrast with LAD-III drawn in this gene block.
PMID:28762304 SUPPORT Human Clinical
"Patient neutrophils showed normal integrin expression, but impaired Mn2+-induced fibrinogen binding."
PARTIAL - it qualifies the "no leukocyte alteration" statement by demonstrating a detectable in vitro neutrophil abnormality without clinical consequence, which is the nuance this block records.
🔬

Diagnosis

1
Aggregometry with a Phorbol-Ester Arm, Plus Receptor Quantitation
The disorder imitates Glanzmann thrombasthenia on a standard workup, and two additions separate them. First, quantify surface alphaIIbbeta3 - it is normal here and deficient there. Second, include a phorbol ester (PMA) arm on the aggregometry panel: PMA activates protein kinase C downstream of the missing exchange factor, so aggregation is preserved with PMA while failing to ADP, collagen and the other physiological agonists. Prolonged PFA-100 closure times with a normal platelet count and morphology complete the picture, and sequencing confirms. Without the PMA arm the two disorders are not distinguishable by aggregometry alone.
Show evidence (2 references)
PMID:28762304 SUPPORT Human Clinical
"Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors"
Establishes the two findings that open the workup - an abnormal global closure time with normal receptor expression.
PMID:28762304 SUPPORT Human Clinical
"platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA"
Supports the discriminating PMA arm on which this diagnostic entry turns.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Platelet-type bleeding disorder 18:

Glanzmann Thrombasthenia
Overlapping Features The disorder this one imitates. Both give absent or severely reduced aggregation with a normal platelet count and morphology; here the integrin is expressed normally and PMA-induced aggregation is preserved, whereas in Glanzmann thrombasthenia the receptor itself is deficient or non-functional and no agonist works. Flow cytometry for alphaIIbbeta3 plus a PMA arm on aggregometry separates them.
Show evidence (1 reference)
PMID:28762304 SUPPORT Human Clinical
"normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected"
Documents both discriminating features - preserved receptor expression and preserved PMA response.
Leukocyte Adhesion Deficiency III (FERMT3/kindlin-3)
Overlapping Features The other inherited disorder of integrin inside-out activation, and the closest mechanistic relative. Kindlin-3 loss breaks integrin activation in leukocytes as well as platelets, so LAD-III adds recurrent infection to a thrombasthenia-like bleeding phenotype. This disorder is platelet-restricted.
Show evidence (2 references)
PMID:24958846 SUPPORT Human Clinical
"Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3."
States the contrast that is the discriminator between the two disorders.
PMID:21781244 SUPPORT Human Clinical
"Leukocyte adhesion deficiency-III combines Glanzmann thrombasthenia with infections and defects of kindlin-3, a mediator of integrin activation."
Independent statement of the LAD-III phenotype used for this differential.
🧫

Experimental Models

1
Patient megakaryocyte culture with wild-type RASGRP2 rescue PRIMARY_CELL_CULTURE
Cultured megakaryocytes from patients, transfected with wild-type RASGRP2. The rescue corrects the functional deficiency, which closes the causal loop between the variant and the platelet phenotype in the patient's own cells rather than in a heterologous line.
Pathograph links
Failure of CalDAG-GEFI-Dependent Rap1 Activation rescues fidelity: high Restoring wild-type CalDAG-GEFI in patient megakaryocytes corrects the functional defect, establishing sufficiency of the gene for the phenotype.
Limitations: Cultured megakaryocytes, not circulating platelets, so the rescue is measured in the precursor rather than in the anucleate cell that does the haemostatic work; and transfection gives supraphysiological, transient expression rather than the endogenous regulation the gene normally has.
Readouts
CalDAG-GEFI-dependent functional response after wild-type transfection
Direction: RESTORED
Interpretation: Correction of the defect by the wild-type gene in the patient's own cells.
Show evidence (1 reference)
PMID:24958846 SUPPORT In Vitro
"Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2."
Reports the rescue measurement behind this readout.
Show evidence (1 reference)
PMID:24958846 SUPPORT In Vitro
"Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2."
Establishes the model as informative for the node by demonstrating gene-specific correction.
{ }

Source YAML

click to show 
name: Platelet-type bleeding disorder 18
creation_date: "2026-08-24T00:00:00Z"
category: Mendelian
parents:
- Inherited Platelet Disorder
- Bleeding Disorder
disease_term:
  preferred_term: platelet-type bleeding disorder 18
  term:
    id: MONDO:0014386
    label: platelet-type bleeding disorder 18
synonyms:
- BDPLT18
- bleeding disorder due to CalDAG-GEFI deficiency
- RASGRP2-related platelet function disorder
- bleeding disorder due to calcium- and DAG-regulated guanine exchange factor-1 deficiency
description: >-
  Platelet-type bleeding disorder 18 is an autosomal recessive severe bleeding
  disorder caused by biallelic loss of RASGRP2, which encodes CalDAG-GEFI - the
  calcium- and diacylglycerol-regulated guanine nucleotide exchange factor that
  activates the small GTPase Rap1 downstream of agonist receptors. Rap1 in turn
  drives integrin alphaIIbbeta3 from its resting to its ligand-binding
  conformation, so this is a signalling disorder that produces a functional
  thrombasthenia: the integrin is present in normal amounts and is structurally
  normal, and it simply never gets switched on.

  The disorder is a clean natural experiment in how the inside-out pathway is
  wired, and two features make it more informative than a straightforward
  knockout. First, the block is not total - PKC- and ADP-dependent pathways
  provide a parallel route to integrin activation, so patient platelets retain
  residual responsiveness and can still be activated directly by phorbol ester
  bypassing the receptor layer entirely. Second, the defect is
  lineage-restricted to platelets and megakaryocytes with no leukocyte
  abnormality, which is exactly what separates it from leukocyte adhesion
  deficiency III, where loss of kindlin-3 breaks integrin activation in white
  cells as well and adds infection to the bleeding. The therapeutic corollary is
  striking and runs in the opposite direction: a single normal allele is enough
  to prevent bleeding entirely, which makes CalDAG-GEFI an unusually attractive
  antithrombotic target.
pathophysiology:
- name: Biallelic Loss of Function in RASGRP2
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  description: >-
    Biallelic RASGRP2 variants abolish CalDAG-GEFI. The index family carried
    c.G742T, identified by whole-exome sequencing in three siblings with severe
    bleeding; nonsense (p.Q236X) and missense (p.C296Y) alleles have since been
    reported homozygously with no detectable CalDAG-GEFI protein in platelet
    lysates. Both null and expressed-but-dysfunctional alleles occur, so protein
    absence is not a requirement for the diagnosis.
  genetic_context:
    allele_type: SNV
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI)."
    explanation: >-
      The gene-discovery statement establishing RASGRP2 as causal.
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis identified two new homozygous variants in RASGRP2: c.706C>T (p.Q236X) and c.887G>A (p.C296Y). In both patients, CalDAG-GEFI protein was not detectable in platelet lysates"
    explanation: >-
      Supports the additional alleles and the loss of detectable protein
      described in this node.
  downstream:
  - target: Failure of CalDAG-GEFI-Dependent Rap1 Activation
    causal_link_type: DIRECT
    description: >-
      CalDAG-GEFI is the calcium-responsive exchange factor for Rap1 in
      platelets, so its loss removes that activation route.
- name: Failure of CalDAG-GEFI-Dependent Rap1 Activation
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    The rate-limiting lesion. CalDAG-GEFI is activated by rising cytoplasmic
    calcium downstream of phospholipase-C-coupled agonist receptors, and its
    main target is Rap1, the small GTPase that regulates integrin-mediated
    adhesion. Patient platelets show reduced ability to activate Rap1, and
    expressing the mutant protein in HEK293T cells abolishes Rap1 activation on
    stimulation - a heterologous confirmation that separates the molecular
    defect from anything else in the patient's platelet.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  molecular_functions:
  - preferred_term: CalDAG-GEFI guanine nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: Rap protein signal transduction
    term:
      id: GO:0032486
      label: Rap protein signal transduction
    modifier: DECREASED
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling."
    explanation: >-
      Direct patient evidence for the Rap1 activation defect and its coupling to
      integrin inside-out signalling.
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation."
    explanation: >-
      Heterologous confirmation that the variant itself, rather than some other
      platelet abnormality, causes the Rap1 defect.
  downstream:
  - target: Impaired Integrin alphaIIbbeta3 Inside-Out Activation
    causal_link_type: DIRECT
    description: >-
      Rap1 is the immediate upstream regulator of talin/kindlin-mediated
      integrin activation.
  - target: Impaired Rac1-Dependent Platelet Spreading and Adhesion Under Flow
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A second, cytoskeletal consequence, reported as following from reduced
      Rac1 GTP-binding rather than directly from Rap1.
- name: Impaired Integrin alphaIIbbeta3 Inside-Out Activation
  role: effector
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
  description: >-
    The integrin is expressed normally - major glycoprotein receptor levels are
    normal in patients - but fibrinogen binding is greatly impaired in response
    to every agonist tested except phorbol ester. That single exception is
    mechanistically the most informative result in the disorder: phorbol ester
    activates protein kinase C directly, downstream of the missing exchange
    factor, and it restores aggregation, which localizes the block precisely to
    the CalDAG-GEFI step and demonstrates that a parallel PKC route to the same
    integrin exists and is intact.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: integrin inside-out activation
    term:
      id: GO:0033622
      label: integrin activation
    modifier: DECREASED
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA"
    explanation: >-
      States both the integrin activation defect and the phorbol-ester exception
      that localizes the block, which is the core claim of this node.
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients)"
    explanation: >-
      Supports the combination that defines a functional rather than structural
      thrombasthenia - normal receptor expression with lost aggregation.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: DIRECT
    description: >-
      Without integrin activation the platelets cannot bridge into an aggregate.
- name: Residual PKC- and ADP-Dependent Platelet Activation
  role: adaptive_escape
  biological_scale: CELLULAR
  description: >-
    The compensating pathway, and a real one rather than a theoretical
    possibility. PKC- and ADP-dependent signalling allows residual platelet
    activation in the absence of functional CalDAG-GEFI, which is why the
    aggregation defect is severe but not absolute and why the disorder's
    severity varies. Its existence is also what makes CalDAG-GEFI a plausible
    antithrombotic target: a pathway with a backup can be blocked without
    abolishing haemostasis outright.
  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
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI."
    explanation: >-
      States the residual pathway and its persistence despite loss of the
      exchange factor.
  downstream:
  - target: Impaired Integrin alphaIIbbeta3 Inside-Out Activation
    causal_link_type: DIRECT
    description: >-
      Partially offsets the activation defect rather than abolishing it, which
      is why this node is curated as an escape route into the same effector.
- name: Impaired Rac1-Dependent Platelet Spreading and Adhesion Under Flow
  role: effector
  biological_scale: CELLULAR
  description: >-
    A cytoskeletal arm separate from integrin activation: patient platelets fail
    to form thrombi under flow and fail to spread normally, and this is
    attributed to reduced Rac1 GTP-binding rather than to the Rap1-integrin
    route. It is the more sensitive readout of the two - heterozygotes, who do
    not bleed and whose platelet aggregation is normal, nonetheless fail to
    adhere under flow and to spread like their homozygous relatives, so this arm
    detects a defect that the aggregation arm does not.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: DECREASED
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding."
    explanation: >-
      States the flow and spreading defects and their attribution to Rac1, which
      is what separates this node from the Rap1-integrin arm.
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading."
    explanation: >-
      Supports the claim that this arm is the more sensitive readout, being
      abnormal in non-bleeding heterozygotes.
  downstream:
  - target: Failure of Primary Hemostatic Plug Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Contributes to the haemostatic failure, though the heterozygote data show
      it is not on its own sufficient to cause bleeding.
- 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: >-
    Reached by the signalling route: normal receptors, normal integrin, no
    activation. Prolonged PFA-100 closure times are the whole-blood expression of
    it.
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors"
    explanation: >-
      The whole-blood haemostatic measurement, alongside the normal receptor
      expression that makes the failure a signalling one.
  downstream:
  - target: Severe Bleeding Diathesis
    causal_link_type: DIRECT
    description: Failure of platelet-dependent primary hemostasis.
- name: Severe Bleeding Diathesis
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "primary_hemostatic_plug_failure#Mucocutaneous Bleeding Diathesis"
  description: >-
    Severe bleeding is what brought the index family to attention, and the
    disorder sits at the severe end of the platelet function disorders despite
    the residual PKC/ADP pathway. Crucially, heterozygous carriers do not bleed
    at all.
  biological_processes:
  - preferred_term: primary hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding."
    explanation: >-
      Establishes the severity of the presenting phenotype.
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis."
    explanation: >-
      Supports the carrier statement and the antithrombotic-target corollary
      drawn in this entry's description.
phenotypes:
- category: Hematologic
  name: Impaired Platelet Aggregation with Normal Receptor Expression
  description: >-
    Severely reduced aggregation to ADP and collagen with normal expression of
    the major platelet glycoprotein receptors - the combination that defines a
    functional rather than a structural thrombasthenia. Aggregation to PMA is
    unaffected.
  phenotype_term:
    preferred_term: Impaired platelet aggregation
    term:
      id: HP:0003540
      label: Impaired platelet aggregation
  frequency: OBLIGATE
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected"
    explanation: >-
      Reports the aggregation profile including the PMA exception, in both
      reported patients - supporting the OBLIGATE band for the aggregation
      defect itself.
- category: Hematologic
  name: Normal Platelet Count and Morphology
  description: >-
    Curated as a positive finding because it is diagnostically load-bearing:
    unlike Bernard-Soulier syndrome or gray platelet syndrome, there is no
    thrombocytopenia and no morphological clue, so the disorder can only be
    reached through function testing and sequencing.
  phenotype_term:
    preferred_term: Normal platelet count and morphology
  notes: >-
    Deliberately carries NO `term:`. The previous binding
    (`HP:0011869 Abnormal platelet function`) was wrong twice over: it asserts an
    abnormality where a normal result is the curated finding, and it describes
    function where this finding is about count and morphology. The HPO has no
    class for a normal count-and-morphology result, so no term is bound rather
    than a misleading one; a new-term request would be the durable fix.
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The homozygous patients had normal platelet and neutrophil counts and morphology."
    explanation: >-
      Supports normal counts and morphology in both lineages, which is what
      makes this a pure function disorder.
- category: Hematologic
  name: Abnormal Bleeding
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  frequency: OBLIGATE
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three siblings affected by severe bleeding"
    explanation: >-
      Establishes bleeding as the presenting feature in the index family.
genetic:
- name: RASGRP2
  gene_term:
    preferred_term: RASGRP2
    term:
      id: hgnc:9879
      label: RASGRP2
  relationship_type: CAUSATIVE
  notes: >-
    Encodes CalDAG-GEFI. Biallelic loss of function causes the disorder;
    reported alleles include c.G742T, c.706C>T (p.Q236X) and c.887G>A (p.C296Y).
    The gene is expressed in neutrophils as well as platelets and CalDAG-GEFI is
    described as critical for integrin signalling in both, yet the clinical
    phenotype is platelet-restricted - patient neutrophils show normal integrin
    expression, with the abnormality detectable only as impaired
    manganese-induced fibrinogen binding in vitro. This dissociation, not the
    gene's expression pattern, is what distinguishes the disorder from leukocyte
    adhesion deficiency III.
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3."
    explanation: >-
      Supports the lineage restriction and the explicit contrast with LAD-III
      drawn in this gene block.
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient neutrophils showed normal integrin expression, but impaired Mn2+-induced fibrinogen binding."
    explanation: >-
      PARTIAL - it qualifies the "no leukocyte alteration" statement by
      demonstrating a detectable in vitro neutrophil abnormality without
      clinical consequence, which is the nuance this block records.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic RASGRP2 loss of function. Recessive in the strong sense - a single
    normal allele is sufficient to prevent bleeding, even though heterozygote
    platelets are demonstrably abnormal in flow adhesion and spreading assays.
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous did not suffer from bleeding and have normal platelet aggregation"
    explanation: >-
      Establishes the clinically recessive inheritance directly.
experimental_models:
- name: Patient megakaryocyte culture with wild-type RASGRP2 rescue
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Cultured megakaryocytes from patients, transfected with wild-type RASGRP2.
    The rescue corrects the functional deficiency, which closes the causal loop
    between the variant and the platelet phenotype in the patient's own cells
    rather than in a heterologous line.
  modeled_mechanisms:
  - target: Failure of CalDAG-GEFI-Dependent Rap1 Activation
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Restoring wild-type CalDAG-GEFI in patient megakaryocytes corrects the
      functional defect, establishing sufficiency of the gene for the phenotype.
    limitations: >-
      Cultured megakaryocytes, not circulating platelets, so the rescue is
      measured in the precursor rather than in the anucleate cell that does the
      haemostatic work; and transfection gives supraphysiological, transient
      expression rather than the endogenous regulation the gene normally has.
    readouts:
    - name: CalDAG-GEFI-dependent functional response after wild-type transfection
      target: Failure of CalDAG-GEFI-Dependent Rap1 Activation
      direction: RESTORED
      interpretation: >-
        Correction of the defect by the wild-type gene in the patient's own
        cells.
      evidence:
      - reference: PMID:24958846
        reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2."
        explanation: >-
          Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:24958846
      reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2."
      explanation: >-
        Establishes the model as informative for the node by demonstrating
        gene-specific correction.
diagnosis:
- name: Aggregometry with a Phorbol-Ester Arm, Plus Receptor Quantitation
  description: >-
    The disorder imitates Glanzmann thrombasthenia on a standard workup, and two
    additions separate them. First, quantify surface alphaIIbbeta3 - it is
    normal here and deficient there. Second, include a phorbol ester (PMA) arm
    on the aggregometry panel: PMA activates protein kinase C downstream of the
    missing exchange factor, so aggregation is preserved with PMA while failing
    to ADP, collagen and the other physiological agonists. Prolonged PFA-100
    closure times with a normal platelet count and morphology complete the
    picture, and sequencing confirms. Without the PMA arm the two disorders are
    not distinguishable by aggregometry alone.
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors"
    explanation: >-
      Establishes the two findings that open the workup - an abnormal global
      closure time with normal receptor expression.
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "platelet αIIbβ3 activation, as assessed by fibrinogen binding, was greatly impaired in response to all agonists except PMA"
    explanation: >-
      Supports the discriminating PMA arm on which this diagnostic entry turns.
differential_diagnoses:
- name: Glanzmann Thrombasthenia
  description: >-
    The disorder this one imitates. Both give absent or severely reduced
    aggregation with a normal platelet count and morphology; here the integrin
    is expressed normally and PMA-induced aggregation is preserved, whereas in
    Glanzmann thrombasthenia the receptor itself is deficient or non-functional
    and no agonist works. Flow cytometry for alphaIIbbeta3 plus a PMA arm on
    aggregometry separates them.
  evidence:
  - reference: PMID:28762304
    reference_title: Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected"
    explanation: >-
      Documents both discriminating features - preserved receptor expression and
      preserved PMA response.
- name: Leukocyte Adhesion Deficiency III (FERMT3/kindlin-3)
  description: >-
    The other inherited disorder of integrin inside-out activation, and the
    closest mechanistic relative. Kindlin-3 loss breaks integrin activation in
    leukocytes as well as platelets, so LAD-III adds recurrent infection to a
    thrombasthenia-like bleeding phenotype. This disorder is
    platelet-restricted.
  evidence:
  - reference: PMID:24958846
    reference_title: Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3."
    explanation: >-
      States the contrast that is the discriminator between the two disorders.
  - reference: PMID:21781244
    reference_title: Advances in our understanding of the molecular basis of disorders of platelet function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Leukocyte adhesion deficiency-III combines Glanzmann thrombasthenia with infections and defects of kindlin-3, a mediator of integrin activation."
    explanation: >-
      Independent statement of the LAD-III phenotype used for this
      differential.
notes: >-
  Conformance: this entry conforms to `primary_hemostatic_plug_failure` through
  the SIGNALLING arm - `#Impaired Platelet Activation, Granule Secretion, and
  Integrin Inside-Out Signalling` - which the module reserves for lesions
  upstream of the integrin. It deliberately does NOT conform to
  `#Failure of Integrin alphaIIbbeta3-Mediated Platelet Aggregation` even though
  aggregation fails, because the module gates that arm on failure of the
  aggregation step itself and here the integrin is normal and PMA-induced
  aggregation is preserved. This entry is the module's worked example of exactly
  the distinction that arm's guidance is written to protect.

  Curation note on the `Residual PKC- and ADP-Dependent Platelet Activation`
  node. It is given `role: adaptive_escape` and an edge into the integrin node
  because it is a genuine parallel route that partially offsets the block, not a
  separate disease mechanism. It matters twice over: it explains why the
  aggregation defect is severe rather than absolute, and it is the basis of the
  therapeutic inversion the source draws - a pathway with an intact backup is a
  safer antithrombotic target than one without.

  The antithrombotic-target claim in the description is the source's own
  conclusion and is reported as such; nothing here should be read as evidence
  that a CalDAG-GEFI inhibitor exists or has been tested clinically.

  Evidence base: the index family and mechanism from PMID:24958846, two further
  alleles with detailed platelet phenotyping from PMID:28762304, and the LAD-III
  contrast independently from PMID:21781244. No prevalence record is included -
  the disorder is known from a small number of families and no denominator has
  been published.

  No `treatments:` block, deliberately. There is no disorder-specific management
  evidence in this repository's reference cache: both cited sources are
  mechanistic, and neither abstract names an agent or a regimen for these
  patients. Management in practice follows the general approach used across the
  inherited platelet function disorders (antifibrinolytics, desmopressin,
  platelet transfusion, rFVIIa in refractory bleeding), but citing a general
  source for a
  disease-specific claim, or writing the block without a verified snippet, are
  both worse than the gap. Note that this entry also does NOT inherit the
  module's rFVIIa pattern: `primary_hemostatic_plug_failure` states explicitly
  that its treatment is a mechanistic target pattern evidenced in Glanzmann
  thrombasthenia and that conformers do not inherit it as a recommendation.

  Curation provenance. This entry was curated by direct review of the cached
  full text and abstracts of the references listed in `references:`, not from a
  deep-research provider artifact, so there is no corresponding file under
  `research/`. Candidate PMIDs were located by PubMed search and each was
  fetched with `just fetch-reference` before use; several initially plausible
  identifiers turned out to be unrelated papers and were discarded rather than
  cited on their titles. Every snippet in this entry is an exact substring of
  the cached reference text.
references:
- reference: PMID:24958846
  title: "Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding."
- reference: PMID:28762304
  title: "Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis."
- reference: PMID:21781244
  title: "Advances in our understanding of the molecular basis of disorders of platelet function."
📚

References & Deep Research

References

3
PMID:24958846
Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
No top-level findings curated for this source.
PMID:28762304
Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis.
No top-level findings curated for this source.
PMID:21781244
Advances in our understanding of the molecular basis of disorders of platelet function.
No top-level findings curated for this source.