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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous carriage of the PLAU tandem duplication is sufficient. In the founder pedigree the duplication segregated with affected status in all tested affected subjects and was absent from unaffected relatives and controls.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:20007542 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This mutation was specific to QPD as it was not present in any unaffected family members (n = 114), unrelated French Canadians (n = 221), or other persons tested (n = 90)."

Complete segregation with affected status and absence from controls is the evidence that heterozygous carriage of the duplication is the inherited determinant of the disorder.

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Discussions and Knowledge Gaps

2

What produces the reduced platelet count in Quebec platelet disorder - intraplatelet proteolysis, shortened platelet survival, or an effect on megakaryopoiesis itself?

KNOWLEDGE GAP OPEN qpd_thrombocytopenia_mechanism

Attached to

pathophysiology#Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation phenotypes#Mild Thrombocytopenia

The fibrinolytic arm of this disorder is established in detail, down to the chromatin contacts that drive it. The thrombocytopenia is not. It is consistently reported and is mild, but the sources that describe it do not separate proteolysis of the platelet's own contents from reduced platelet survival in the circulation or from an effect of uPA overexpression on megakaryocyte output. The distinction matters because it decides whether the low count is a second consequence of the same intraplatelet enzyme or a separate lineage effect, and the entry's causal edge to this phenotype is marked INDIRECT_KNOWN_INTERMEDIATES for exactly that reason.

Does any model reproduce the enhancer adoption that causes QPD, rather than supplying megakaryocyte uPA overexpression directly?

HUMAN MODEL MISMATCH OPEN qpd_no_model_of_the_human_lesion

Attached to

pathophysiology#Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele animal_models#Megakaryocyte-targeted uPA transgenic mouse

The transgenic mouse overexpresses uPA in megakaryocytes by design, so it tests whether that is sufficient to cause bleeding - which it is - but it cannot test the step that actually causes the human disease, because the duplication and the sub-TAD reorganization are absent from it. Everything upstream of "excess platelet uPA" is therefore evidenced only in cultured human megakaryocytes and reporter assays. The mouse also diverges clinically: it shows fetal loss and fatal postpartum hemorrhage, whereas all nine pregnancies among five affected women in the founder-family study were successful. A knock-in carrying the human duplication would close both gaps at once; none was identified.

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Pathophysiology

6

PLAU Tandem Duplication

Mechanism confidence: Established

The initiating lesion is a direct germline tandem duplication of a 78-kb segment of chromosome 10q22 containing PLAU and C10orf55. It is a copy-number gain, not a sequence change: the uPA coding sequence and the transcripts produced from it are structurally normal, which is why the disorder is a regulatory gain of function rather than an altered protein. C10orf55 lies inside the duplicated interval but is not the causal effector.

PLAU hgnc:9052

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

A heterozygous ~78-kb direct tandem duplication. The gain of function is regulatory and lineage-restricted rather than a change in uPA structure or catalytic activity.

Downstream

Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele The duplication disrupts the boundary between the PLAU and VCL sub-topologically associating domains, placing one PLAU copy in a new regulatory neighbourhood.

Show evidence (2 references)

PMID:20007542 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All 38 subjects with QPD had a direct tandem duplication of a 78-kb genomic segment that includes PLAU."

Identifies the duplication as the causal lesion in every affected subject tested.

PMID:28301587 SUPPORT DIRECT PRIMARY RESULT In Vitro

"QPD and control megakaryocytes contained minimal reads for C10orf55, and C10orf55 protein was not increased in QPD megakaryocytes or platelets."

Excludes the second gene in the duplicated interval as the effector, which is what licenses attributing the mechanism to PLAU alone.

Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele

Mechanism confidence: Established

Reorganization of sub-TAD architecture brings the duplicated PLAU copy into preferential contact with a conserved megakaryocyte enhancer that lies within the same topologically associating domain. On the disease chromosome the PLAU promoter loses repressive H3K27me3 and gains transcription-associated H3K36me3. Because the adopted enhancer is active specifically during megakaryopoiesis, the consequence is confined to that lineage - this is the step that explains the cell-type specificity of the whole disorder.

Downstream

Megakaryocyte-Restricted PLAU Overexpression Enhancer adoption drives transcription of the duplicated allele during megakaryopoiesis.

Show evidence (1 reference)

PMID:32663239 SUPPORT DIRECT PRIMARY RESULT In Vitro

"QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD)."

Chromosome-conformation capture in patient-derived megakaryocytes demonstrates the enhancer adoption directly, rather than inferring it from expression alone.

Megakaryocyte-Restricted PLAU Overexpression

Mechanism confidence: Established

QPD megakaryocytes produce more than 100-fold the normal level of structurally normal PLAU transcript, far in excess of the twofold that an extra gene copy alone would predict, and with a strong allelic bias toward the disease chromosome. Leukocytes from the same individuals show only the small increase that copy number predicts. That contrast is the direct evidence that the mechanism is lineage-restricted enhancer adoption and not gene dosage.

megakaryocyte CL:0000556

Downstream

Excess uPA Storage in Platelet Alpha-Granules Overexpressed uPA is packaged into alpha-granules as the megakaryocyte produces platelets.

Show evidence (3 references)

PMID:32663239 SUPPORT DIRECT BACKGROUND In Vitro

"The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes."

States the magnitude and lineage restriction of the overexpression. Quoted from the paper's framing of established knowledge rather than from its own new results.

PMID:28301587 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Rapidly isolated blood leukocytes from QPD subjects showed only a 3.9 fold increase in PLAU transcript levels, in keeping with the normal to minimally increased uPA in affinity purified, QPD leukocytes."

The negative half of the comparison: leukocytes show only the copy-number-predicted increase, establishing that the >100-fold effect is megakaryocyte-specific.

PMID:19029443 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Although QPD CD34(+) progenitors expressed normal amounts of uPA, their differentiation into megakaryocytes abnormally increased expression of the uPA gene but not the flanking genes for vinculin or calcium/calmodulin-dependent protein kinase IIgamma on chromosome 10."

Times the overexpression to megakaryocyte differentiation rather than to the progenitor, and shows the flanking genes are untouched - the two facts that make this a lineage-specific regulatory effect on PLAU alone.

Excess uPA Storage in Platelet Alpha-Granules

Mechanism confidence: Established

Platelets carry more than 100-fold the normal uPA content, stored in alpha-granules, while plasma and urine uPA remain normal. The component lost to the primary hemostatic apparatus is therefore not a receptor but the alpha-granule cargo itself, which is destroyed in situ by the enzyme stored alongside it.

platelet CL:0000233

Downstream

Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation Stored uPA converts plasminogen to plasmin within the granule compartment.

Show evidence (2 references)

PMID:28301587 SUPPORT DIRECT BACKGROUND Human Clinical

"Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine."

The platelet-versus-plasma contrast is what makes this a localized rather than a systemic fibrinolytic disorder.

PMID:19029443 SUPPORT DIRECT PRIMARY RESULT In Vitro

"uPA was localized to QPD alpha-granules and it showed extensive colocalization with alpha-granule proteins in both cultured QPD megakaryocytes and platelets, and with plasminogen in QPD platelets."

Places the enzyme physically inside the granule alongside the cargo it destroys, and alongside its substrate plasminogen. This is the observation that makes the next step a co-localization argument rather than an inference.

Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation

Mechanism confidence: Established

uPA stored with the cargo converts plasminogen to plasmin inside the alpha-granule, and plasmin degrades fibrinogen, factor V, von Willebrand factor, thrombospondin-1, multimerin-1, osteonectin and P-selectin. The degradation is post-translational: transcripts for the alpha-granule proteins are not reduced, so the platelet is built normally and its cargo is destroyed afterwards. This is the step that historically gave the disorder its "factor V Quebec" name, when the deficiency of platelet factor V was mistaken for the primary defect.

plasminogen activation GO:0031639 ↑ INCREASED

Downstream

Accelerated Platelet-Localized Clot Lysis Platelet activation at a site of injury releases active uPA into the forming plug.

Mild Thrombocytopenia Intraplatelet proteolysis, and possibly shortened platelet survival, probably contribute to the reduced platelet count. This link is less directly established than the fibrinolytic arm.

Show evidence (2 references)

PMID:22102275 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins."

States the proteolysis step that links stored uPA to loss of the granule cargo.

PMID:19029443 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In QPD megakaryocytes, cultured without or with plasma as a source of plasminogen, alpha-granule proteins were stored undegraded and this was associated with much less uPA-plasminogen colocalization than in QPD platelets."

Locates the proteolysis in the platelet rather than the megakaryocyte, and ties it to uPA meeting plasminogen. The granule is packaged intact and destroyed later, which is why transcript levels for the cargo are normal.

Accelerated Platelet-Localized Clot Lysis

Mechanism confidence: Established

Activated QPD platelets release uPA into the clot they have just helped build, and the plug is lysed prematurely. Primary hemostasis succeeds and then fails, which is why bleeding is delayed rather than immediate and why it is refractory to platelet transfusion, which adds platelets without suppressing local plasmin generation. Because systemic fibrinolysis is normal, the effect is confined to the site of the plug. This node is deliberately not marked as conforming to primary_hemostatic_plug_failure - that module models a plug that never forms, whereas the defining QPD lesion destroys a plug that did.

fibrinolysis GO:0042730 ↑ INCREASED

Animal models

Megakaryocyte-targeted uPA transgenic mouse Mouse partially recapitulates Reproduces the downstream consequence - platelet uPA overexpression with a bleeding phenotype - and so establishes that ectopic platelet uPA is sufficient to cause the disorder.

Downstream

Delayed-Onset Bleeding After Hemostatic Challenge Premature dissolution of the formed plug produces bleeding hours to days after the challenge.

Joint Bleeding

Hematuria

Epistaxis

Large Spreading Bruises

Prolonged Menstrual Bleeding

Poor Wound Healing Repeated bleeding into a healing wound is the presumed route; the contribution of individual degraded alpha-granule proteins to healing is inferred rather than separately demonstrated.

Show evidence (3 references)

PMID:22102275 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis"

Names the release-and-lysis step that converts the stored enzyme into a bleeding phenotype.

PMID:16689763 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In whole blood perfusion studies, QPD platelets showed normal adherence to fibrin, but their adhesion was followed by accelerated fibrinolysis."

The single most discriminating result for this entry. Adhesion is normal and lysis follows it, which is the direct experimental basis for treating QPD as destruction of a plug that formed rather than failure to form one.

PMID:16689763 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The incorporation of QPD platelets into a forming clot led to progressive disruption of fibrin and platelet aggregates unless drugs were added to inhibit plasmin."

Shows the disruption is plasmin-dependent, because inhibiting plasmin prevents it.

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Pathograph

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

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Phenotypes

8

Blood 6

Delayed-Onset Bleeding After Hemostatic Challenge Prolonged bleeding after surgery HP:0004846

Temporal: RECURRENT

Show evidence (2 references)

PMID:15026313 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or..."

The blinded family questionnaire quantifies delayed post-procedural bleeding as one of the manifestations most strongly associated with affected status.

PMID:22102275 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors."

Identifies delayed onset as the discriminating clinical feature of the disorder.

Joint Bleeding Joint hemorrhage HP:0005261

Show evidence (2 references)

PMID:15026313 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or..."

Joint bleeding ("joint bleeds") is one of the manifestations this sentence assigns an odds ratio above 20 for affected status in the blinded family questionnaire.

PMID:32663239 SUPPORT DIRECT BACKGROUND Human Clinical

"The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that..."

An independent source naming joint bleeds among the risks the QPD mechanism explains, corroborating the family-study odds ratio.

Epistaxis HP:0000421

Large Spreading Bruises Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:15026313 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"bruises that spread lower or as large or larger than an orange or both"

The specific bruise description carrying an odds ratio above 20 for affected status.

Prolonged Menstrual Bleeding Menorrhagia HP:0000132

Show evidence (1 reference)

PMID:32663239 SUPPORT DIRECT BACKGROUND Human Clinical

"The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that..."

Heavy menstrual bleeding is named among the bleeding risks this mechanism accounts for.

Mild Thrombocytopenia HP:0001873

Severity: MILD

Show evidence (1 reference)

PMID:22102275 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes."

Records reduced platelet counts as a recognised feature alongside the fibrinolytic defect.

Genitourinary 1

Hematuria HP:0000790

Temporal: RECURRENT

Show evidence (1 reference)

PMID:32663239 SUPPORT DIRECT BACKGROUND Human Clinical

"The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that..."

The paper's discussion lists spontaneous hematuria among the risks the QPD mechanism explains, and notes it falls on those with the highest platelet uPA. Quoted from the authors' framing of the clinical picture, which they attribute to earlier clinical work, so the grading is HUMAN_CLINICAL with a BACKGROUND role.

Integument 1

Poor Wound Healing HP:0001058

Show evidence (1 reference)

PMID:32663239 SUPPORT DIRECT BACKGROUND Human Clinical

"The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that..."

Wound-healing problems are named among the risks the mechanism explains, and notably as responding to antifibrinolytic therapy - which ties the healing defect to ongoing fibrinolysis rather than to a separate repair deficit.

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Genetic Associations

1

PLAU

Gene: PLAU hgnc:9052 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:20007542 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"QPD is the first bleeding disorder to be associated with a gene duplication event and a PLAU mutation."

Establishes PLAU duplication as the causal genetic lesion, and notes that a duplication mechanism was novel among bleeding disorders.

PMID:32663239 SUPPORT DIRECT In Vitro

"to account for the extra copy gain for peaks overlapping the duplicated region (chr10:75659017-75736956)"

Gives the GRCh37/hg19 coordinates of the duplicated interval. Quoted from the paper's methods, where the region is defined to correct peak calls for the extra copy; `quote_role` is left unset because a methods parameter is neither the paper's finding nor a restatement of someone else's.

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Medical Actions

1

Tranexamic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: tranexamic acid CHEBI:48669

Platform: Small molecule

Antifibrinolytic therapy is the only treatment shown to control QPD bleeding, and it is used both to treat an established bleed and as prophylaxis around a planned hemostatic challenge. Because the bleeding is delayed, cover must continue for days after the challenge rather than stopping once immediate hemostasis is achieved - reported schedules run from three to four days for minor procedures up to ten to fourteen days after intracranial bleeding. Epsilon-aminocaproic acid is a less potent alternative requiring higher doses; it is deliberately left without an ontology binding here because no CHEBI term for it was resolved during curation.

Mechanism Target:

Accelerated Platelet-Localized Clot Lysis — Tranexamic acid blocks plasminogen binding to fibrin, opposing the plasmin-mediated lysis that dissolves the formed plug. It does not correct the PLAU overexpression, so it suppresses episodes without altering the underlying lesion.

Show evidence (2 references)

PMID:22102275 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors."

That the bleeding responds only to fibrinolytic inhibitors is the clinical evidence that the treatable step is the fibrinolytic one. It is an inference from therapeutic response to mechanism, hence INDIRECT.

PMID:16689763 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The incorporation of QPD platelets into a forming clot led to progressive disruption of fibrin and platelet aggregates unless drugs were added to inhibit plasmin."

The ex vivo counterpart of the clinical observation: inhibiting plasmin prevents the clot disruption, which is the step antifibrinolytic therapy targets.

Show evidence (1 reference)

PMID:15026313 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Individuals with QPD and exposure(s) to hemostatic challenges had experienced excessive bleeding only when fibrinolytic inhibitors had not been used."

The observational result behind antifibrinolytic prophylaxis. It is a striking contrast but it comes from retrospective family histories, not a randomized trial.

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Diagnosis

5

Platelet Urokinase Plasminogen Activator Measurement

The biochemical test that defines affected status. Platelet uPA is markedly increased while plasma and urinary uPA are normal, so the assay must be run on platelets rather than on plasma. In the founder-family study, affected and unaffected status was assigned on this assay together with fibrinogen degradation, which is why the resulting bleeding frequencies are anchored to a biochemical rather than a clinical definition.

platelet urokinase plasminogen activator assay NCIT:C25294

Show evidence (2 references)

PMID:15026313 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Data entry was done blinded to affected and unaffected status, determined by assays for platelet urokinase-type plasminogen activator (u-PA) and fibrinogen degradation."

Documents platelet uPA assay plus fibrinogen degradation as the case definition used to assign affected status.

PMID:18791940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The diagnosis of Quebec Platelet Disorder was confirmed by urokinase-specific Western blots."

A worked diagnostic case in which urokinase-specific Western blotting was the confirmatory step.

Light Transmission Aggregometry

Aggregometry is a screening rather than a confirmatory test here. Responses are variably reduced - classically absent secondary aggregation with epinephrine - but the pattern is neither sensitive nor specific, and a normal study does not exclude the diagnosis. Its diagnostic value is mainly in placing the problem in the platelet compartment so that platelet uPA is then measured.

light transmission platelet aggregometry NCIT:C25294

Show evidence (1 reference)

PMID:18791940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Abnormalities were detected in platelet aggregation studies, which revealed variably reduced responses to ADP, collagen and epinephrine with concomitantly decreased ATP/serotonin secretion."

Records the aggregometry pattern in a family subsequently confirmed to have QPD, and the word "variably" is the reason this is a screening test.

Alpha-Granule Protein Degradation Analysis

Demonstrating loss of alpha-granule proteins - multimerin-1, fibrinogen, thrombospondin-1, factor V - separates QPD from disorders in which the granules were never filled. The proteins are absent from the platelet while their transcripts are normal, which is the signature of post-translational destruction rather than failed packaging.

platelet alpha-granule protein analysis NCIT:C25294

Show evidence (1 reference)

PMID:18791940 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Platelet proteomics showed reduced amounts of alpha-granule proteins multimerin, fibrinogen and thrombospondin-1 in patient compared to control samples suggestive of Quebec Platelet Disorder."

Names the specific degraded alpha-granule proteins that raised the diagnosis in an undiagnosed bleeding family.

Global Coagulation and Fibrinolysis Testing (ABSENT)

A negative that matters diagnostically. Routine coagulation times are normal and thromboelastography is not sensitive to the raised platelet uPA, because the defect is localized to the platelet and its clot rather than present in plasma. A QPD patient can therefore pass every global haemostasis screen while bleeding severely after surgery, which is a large part of why the disorder is missed or misattributed. Samples also need appropriate handling, since platelet factor V can be proteolysed ex vivo and confound results.

global coagulation and fibrinolysis testing NCIT:C25294

Show evidence (1 reference)

PMID:16689763 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Thromboelastography was not sensitive to the increased u-PA in QPD blood."

Direct evidence that a global viscoelastic assay does not detect the defect, which is what makes platelet-specific testing necessary rather than merely preferable.

PLAU Duplication Testing

Definitive confirmation. Breakpoint-specific PCR for the tandem duplication is the preferred test in a family with a known lesion, and it can be run on cord blood for newborn testing. The important caveat is technical rather than clinical: the lesion is a non-coding structural variant, so exome sequencing can miss it entirely and a negative exome does not exclude QPD. CNV-aware genome sequencing or a bleeding-disorder panel may detect it depending on probe coverage.

breakpoint-specific PCR for the PLAU tandem duplication NCIT:C17003

Show evidence (2 references)

PMID:20007542 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This new information on the genetic mutation will facilitate diagnostic testing for QPD and studies of its pathogenesis and prevalence."

The paper that identified the duplication states its diagnostic use, which is what made molecular confirmation possible.

PMID:32663239 SUPPORT INDIRECT BACKGROUND In Vitro

"Discovery of the QPD duplication mutation has transformed diagnostic testing for this blood disorder."

Confirms, from a later paper, that molecular testing displaced the biochemical assays as the diagnostic route.

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Quebec Platelet Disorder:

Gray platelet syndrome

Overlapping Features The other alpha-granule disorder in the inherited platelet function group. Gray platelet syndrome fails to package alpha-granule cargo during megakaryopoiesis, whereas QPD packages it normally and then destroys it with a co-stored protease. The distinction is visible on the blood film in gray platelet syndrome and is not in QPD.

von Willebrand disease

Overlapping Features Shares mucocutaneous bleeding and is a common initial consideration. QPD platelets degrade their own von Willebrand factor, so the distinction rests on platelet uPA measurement or PLAU duplication testing rather than on the bleeding pattern.

Hemophilia

Overlapping Features Delayed bleeding and hemarthrosis make QPD resemble a coagulation factor deficiency, which is why it was originally described as "factor V Quebec". Routine coagulation times are normal in QPD.

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Related Datasets

1

Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder ega:EGAS00001004315

Controlled-access raw sequencing data from the study that established enhancer adoption as the QPD mechanism: ChIP-seq for H3K27ac, H3K4me2, H3K36me3, H3K27me3 and CTCF, RNA-seq, and 4C-seq, generated in cultured megakaryocytes from QPD participants and unaffected controls.

human MULTI OMICS

PMID:32663239

Controlled access through the European Genome-phenome Archive; no data files are mirrored into this repository. The accession is recorded from the publication rather than resolved by `just verify-datasets`, which does not cache EGA records.

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Animal Models

1

Megakaryocyte-targeted uPA transgenic mouse

A transgenic mouse engineered to overexpress uPA specifically in megakaryocytes develops a QPD-like bleeding disorder. It tests the sufficiency of ectopic platelet uPA rather than reproducing the human lesion.

Species

Mouse

Genotype

Transgenic overexpression of uPA restricted to the megakaryocyte lineage

Pathograph links

Accelerated Platelet-Localized Clot Lysis partially recapitulates fidelity: moderate observes: organism Reproduces the downstream consequence - platelet uPA overexpression with a bleeding phenotype - and so establishes that ectopic platelet uPA is sufficient to cause the disorder.

Limitations: The model does not carry the tandem duplication and does not reproduce the enhancer adoption that causes lineage-restricted overexpression in humans; the transgene supplies the endpoint directly. Its reproductive phenotype is also more severe than the human disease, with fetal loss and fatal postpartum hemorrhage reported, whereas all nine pregnancies among five affected women in the founder-family study were successful.

Show evidence (1 reference)

PMID:32663239 SUPPORT INDIRECT BACKGROUND Model Organism

"Mice that selectively overexpress PLAU in megakaryocytes have a QPD-like bleeding disorder."

Records the mouse phenocopy. Quoted from this paper's introduction, where it summarises earlier work rather than reporting its own result.

Show evidence (1 reference)

PMID:32663239 SUPPORT INDIRECT BACKGROUND Model Organism

"Mice that selectively overexpress PLAU in megakaryocytes have a QPD-like bleeding disorder."

Establishes that the model exists and phenocopies the disorder. Quoted from this paper's introduction, where it summarises earlier work.

{ }

Source YAML

click to show

name: Quebec Platelet Disorder
creation_date: "2026-09-17T00:00:00Z"
category: Mendelian
description: >-
  Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder caused
  by a 78-kb germline tandem duplication of PLAU. The duplication leaves the
  urokinase plasminogen activator (uPA) coding sequence intact and acts instead by
  rewiring gene regulation: one PLAU copy is relocated into the neighbourhood of a
  conserved megakaryocyte enhancer, which drives a >100-fold, megakaryocyte-restricted
  overexpression of structurally normal PLAU transcripts. Plasma and urinary uPA stay
  normal, so this is a platelet-localized rather than a systemic fibrinolytic defect.
  The excess uPA is packaged into platelet alpha-granules, where plasmin generation
  degrades the granule cargo - fibrinogen, factor V, von Willebrand factor,
  thrombospondin-1, multimerin-1, osteonectin and P-selectin - before release. The
  clinical consequence is a plug that forms and then dissolves: bleeding is
  characteristically delayed by 12 hours to several days after surgery, dental
  extraction or trauma, and responds to antifibrinolytic drugs but not to platelet
  transfusion.
synonyms:
- QPD
- platelet-type bleeding disorder 5
- BDPLT5
- factor V Quebec
- Quebec platelet syndrome
parents:
- inherited bleeding disorder, platelet-type
- alpha granule disease
disease_term:
  preferred_term: Quebec platelet disorder
  term:
    id: MONDO:0011136
    label: Quebec platelet disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous carriage of the PLAU tandem duplication is sufficient. In the founder
    pedigree the duplication segregated with affected status in all tested affected
    subjects and was absent from unaffected relatives and controls.
  evidence:
  - reference: PMID:20007542
    reference_title: "Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This mutation was specific to QPD as it was not present in any unaffected family members (n = 114), unrelated French Canadians (n = 221), or other persons tested (n = 90)."
    explanation: >-
      Complete segregation with affected status and absence from controls is the
      evidence that heterozygous carriage of the duplication is the inherited
      determinant of the disorder.

pathophysiology:
- name: PLAU Tandem Duplication
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion is a direct germline tandem duplication of a 78-kb segment of
    chromosome 10q22 containing PLAU and C10orf55. It is a copy-number gain, not a
    sequence change: the uPA coding sequence and the transcripts produced from it are
    structurally normal, which is why the disorder is a regulatory gain of function
    rather than an altered protein. C10orf55 lies inside the duplicated interval but is
    not the causal effector.
  genes:
  - preferred_term: PLAU
    term:
      id: hgnc:9052
      label: PLAU
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
    zygosity: HETEROZYGOUS
    description: >-
      A heterozygous ~78-kb direct tandem duplication. The gain of function is
      regulatory and lineage-restricted rather than a change in uPA structure or
      catalytic activity.
  evidence:
  - reference: PMID:20007542
    reference_title: "Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All 38 subjects with QPD had a direct tandem duplication of a 78-kb genomic segment that includes PLAU."
    explanation: Identifies the duplication as the causal lesion in every affected subject tested.
  - reference: PMID:28301587
    reference_title: "The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "QPD and control megakaryocytes contained minimal reads for C10orf55, and C10orf55 protein was not increased in QPD megakaryocytes or platelets."
    explanation: >-
      Excludes the second gene in the duplicated interval as the effector, which is what
      licenses attributing the mechanism to PLAU alone.
  downstream:
  - target: Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele
    causal_link_type: DIRECT
    description: >-
      The duplication disrupts the boundary between the PLAU and VCL sub-topologically
      associating domains, placing one PLAU copy in a new regulatory neighbourhood.
    evidence:
    - reference: PMID:32663239
      reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD)."
      explanation: >-
        Attributes the ectopic enhancer contact to the duplication itself, which is the
        claim this edge makes.

- name: Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Reorganization of sub-TAD architecture brings the duplicated PLAU copy into
    preferential contact with a conserved megakaryocyte enhancer that lies within the
    same topologically associating domain. On the disease chromosome the PLAU promoter
    loses repressive H3K27me3 and gains transcription-associated H3K36me3. Because the
    adopted enhancer is active specifically during megakaryopoiesis, the consequence is
    confined to that lineage - this is the step that explains the cell-type specificity
    of the whole disorder.
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD)."
    explanation: >-
      Chromosome-conformation capture in patient-derived megakaryocytes demonstrates the
      enhancer adoption directly, rather than inferring it from expression alone.
  downstream:
  - target: Megakaryocyte-Restricted PLAU Overexpression
    causal_link_type: DIRECT
    description: Enhancer adoption drives transcription of the duplicated allele during megakaryopoiesis.
    evidence:
    - reference: PMID:28301587
      reference_title: "The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "QPD leukocytes expressed PLAU alleles in proportions consistent with an extra copy of PLAU on the disease chromosome, unlike QPD megakaryocytes."
      explanation: >-
        The allelic-proportion contrast between leukocytes and megakaryocytes is the
        direct evidence that something beyond copy number acts in the megakaryocyte
        lineage, which is what this edge asserts.

- name: Megakaryocyte-Restricted PLAU Overexpression
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    QPD megakaryocytes produce more than 100-fold the normal level of structurally normal
    PLAU transcript, far in excess of the twofold that an extra gene copy alone would
    predict, and with a strong allelic bias toward the disease chromosome. Leukocytes
    from the same individuals show only the small increase that copy number predicts.
    That contrast is the direct evidence that the mechanism is lineage-restricted
    enhancer adoption and not gene dosage.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes."
    explanation: >-
      States the magnitude and lineage restriction of the overexpression. Quoted from the
      paper's framing of established knowledge rather than from its own new results.
  - reference: PMID:28301587
    reference_title: "The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Rapidly isolated blood leukocytes from QPD subjects showed only a 3.9 fold increase in PLAU transcript levels, in keeping with the normal to minimally increased uPA in affinity purified, QPD leukocytes."
    explanation: >-
      The negative half of the comparison: leukocytes show only the copy-number-predicted
      increase, establishing that the >100-fold effect is megakaryocyte-specific.
  - reference: PMID:19029443
    reference_title: "Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Although QPD CD34(+) progenitors expressed normal amounts of uPA, their differentiation into megakaryocytes abnormally increased expression of the uPA gene but not the flanking genes for vinculin or calcium/calmodulin-dependent protein kinase IIgamma on chromosome 10."
    explanation: >-
      Times the overexpression to megakaryocyte differentiation rather than to the
      progenitor, and shows the flanking genes are untouched - the two facts that make
      this a lineage-specific regulatory effect on PLAU alone.
  downstream:
  - target: Excess uPA Storage in Platelet Alpha-Granules
    causal_link_type: DIRECT
    description: Overexpressed uPA is packaged into alpha-granules as the megakaryocyte produces platelets.
    evidence:
    - reference: PMID:32663239
      reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis."
      explanation: >-
        States the transcript-to-platelet-store step explicitly, and in the same sentence
        the two steps that follow it.

- name: Excess uPA Storage in Platelet Alpha-Granules
  biological_scale: CELLULAR
  conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
  mechanism_confidence: ESTABLISHED
  description: >-
    Platelets carry more than 100-fold the normal uPA content, stored in alpha-granules,
    while plasma and urine uPA remain normal. The component lost to the primary
    hemostatic apparatus is therefore not a receptor but the alpha-granule cargo itself,
    which is destroyed in situ by the enzyme stored alongside it.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:28301587
    reference_title: "The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine."
    explanation: >-
      The platelet-versus-plasma contrast is what makes this a localized rather than a
      systemic fibrinolytic disorder.
  - reference: PMID:19029443
    reference_title: "Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "uPA was localized to QPD alpha-granules and it showed extensive colocalization with alpha-granule proteins in both cultured QPD megakaryocytes and platelets, and with plasminogen in QPD platelets."
    explanation: >-
      Places the enzyme physically inside the granule alongside the cargo it destroys, and
      alongside its substrate plasminogen. This is the observation that makes the next step
      a co-localization argument rather than an inference.
  downstream:
  - target: Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation
    causal_link_type: DIRECT
    description: Stored uPA converts plasminogen to plasmin within the granule compartment.
    evidence:
    - reference: PMID:22102275
      reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins."
      explanation: >-
        Names the stored uPA as the trigger for the proteolysis, which is the direction
        this edge asserts.

- name: Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation
  biological_scale: MOLECULAR
  conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
  mechanism_confidence: ESTABLISHED
  description: >-
    uPA stored with the cargo converts plasminogen to plasmin inside the alpha-granule,
    and plasmin degrades fibrinogen, factor V, von Willebrand factor, thrombospondin-1,
    multimerin-1, osteonectin and P-selectin. The degradation is post-translational:
    transcripts for the alpha-granule proteins are not reduced, so the platelet is built
    normally and its cargo is destroyed afterwards. This is the step that historically
    gave the disorder its "factor V Quebec" name, when the deficiency of platelet factor
    V was mistaken for the primary defect.
  biological_processes:
  - preferred_term: plasminogen activation
    modifier: INCREASED
    term:
      id: GO:0031639
      label: plasminogen activation
  evidence:
  - reference: PMID:22102275
    reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins."
    explanation: >-
      States the proteolysis step that links stored uPA to loss of the granule cargo.
  - reference: PMID:19029443
    reference_title: "Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "In QPD megakaryocytes, cultured without or with plasma as a source of plasminogen, alpha-granule proteins were stored undegraded and this was associated with much less uPA-plasminogen colocalization than in QPD platelets."
    explanation: >-
      Locates the proteolysis in the platelet rather than the megakaryocyte, and ties it to
      uPA meeting plasminogen. The granule is packaged intact and destroyed later, which is
      why transcript levels for the cargo are normal.
  downstream:
  - target: Accelerated Platelet-Localized Clot Lysis
    causal_link_type: DIRECT
    description: >-
      Platelet activation at a site of injury releases active uPA into the forming plug.
    evidence:
    - reference: PMID:22102275
      reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis"
      explanation: States the release-to-lysis step this edge represents.
  - target: Mild Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Intraplatelet proteolysis, and possibly shortened platelet survival, probably
      contribute to the reduced platelet count. This link is less directly established
      than the fibrinolytic arm.
    evidence:
    - reference: PMID:22102275
      reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes."
      explanation: >-
        Establishes that reduced platelet counts belong to the disorder, but not that the
        intraplatelet proteolysis in this node is what causes them. The quote supports the
        association only; the causal direction is the open question recorded in the
        `qpd_thrombocytopenia_mechanism` discussion, which is why this is INDIRECT.

- name: Accelerated Platelet-Localized Clot Lysis
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Activated QPD platelets release uPA into the clot they have just helped build, and
    the plug is lysed prematurely. Primary hemostasis succeeds and then fails, which is
    why bleeding is delayed rather than immediate and why it is refractory to platelet
    transfusion, which adds platelets without suppressing local plasmin generation.
    Because systemic fibrinolysis is normal, the effect is confined to the site of the
    plug. This node is deliberately not marked as conforming to
    primary_hemostatic_plug_failure - that module models a plug that never forms,
    whereas the defining QPD lesion destroys a plug that did.
  biological_processes:
  - preferred_term: fibrinolysis
    modifier: INCREASED
    term:
      id: GO:0042730
      label: fibrinolysis
  evidence:
  - reference: PMID:22102275
    reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis"
    explanation: >-
      Names the release-and-lysis step that converts the stored enzyme into a bleeding
      phenotype.
  - reference: PMID:16689763
    reference_title: "Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "In whole blood perfusion studies, QPD platelets showed normal adherence to fibrin, but their adhesion was followed by accelerated fibrinolysis."
    explanation: >-
      The single most discriminating result for this entry. Adhesion is normal and lysis
      follows it, which is the direct experimental basis for treating QPD as destruction of
      a plug that formed rather than failure to form one.
  - reference: PMID:16689763
    reference_title: "Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The incorporation of QPD platelets into a forming clot led to progressive disruption of fibrin and platelet aggregates unless drugs were added to inhibit plasmin."
    explanation: >-
      Shows the disruption is plasmin-dependent, because inhibiting plasmin prevents it.
  downstream:
  - target: Delayed-Onset Bleeding After Hemostatic Challenge
    causal_link_type: DIRECT
    description: Premature dissolution of the formed plug produces bleeding hours to days after the challenge.
    evidence:
    - reference: PMID:22102275
      reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis."
      explanation: >-
        Attributes the bleeding phenotype to the accelerated-lysis step, which is exactly
        this edge. Note the source hedges with "thought to be", and the hedge is real:
        the link is a mechanistic synthesis rather than a measured effect size.
  - target: Joint Bleeding
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15026313
      reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or deep cuts, and received or been recommended other treatments (fibrinolytic inhibitors) for bleeding."
      explanation: >-
        Joint bleeds are among the manifestations this sentence ties to affected status with
        an odds ratio above 20, which is the evidence that the QPD defect produces them.
  - target: Hematuria
    causal_link_type: DIRECT
  - target: Epistaxis
    causal_link_type: DIRECT
  - target: Large Spreading Bruises
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15026313
      reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or deep cuts, and received or been recommended other treatments (fibrinolytic inhibitors) for bleeding."
      explanation: >-
        The characteristic large or downward-tracking bruises are named in the same
        odds-ratio sentence, tying them to the disorder rather than to chance.
  - target: Prolonged Menstrual Bleeding
    causal_link_type: DIRECT
  - target: Poor Wound Healing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated bleeding into a healing wound is the presumed route; the contribution of
      individual degraded alpha-granule proteins to healing is inferred rather than
      separately demonstrated.

phenotypes:
- category: Hematologic
  name: Delayed-Onset Bleeding After Hemostatic Challenge
  description: >-
    The defining clinical feature. Bleeding follows an apparently successful initial
    hemostatic response, typically emerging 12 to 24 hours - sometimes three to four
    days - after surgery, dental extraction, trauma or a deep cut, and can then persist
    for days. In the founder-family study, bleeding beyond 24 hours after dental
    extraction or deep cuts was among the manifestations carrying an odds ratio above 20.
  phenotype_term:
    preferred_term: Prolonged bleeding after surgery
    term:
      id: HP:0004846
      label: Prolonged bleeding after surgery
    temporality: RECURRENT
  evidence:
  - reference: PMID:15026313
    reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or deep cuts, and received or been recommended other treatments (fibrinolytic inhibitors) for bleeding."
    explanation: >-
      The blinded family questionnaire quantifies delayed post-procedural bleeding as one
      of the manifestations most strongly associated with affected status.
  - reference: PMID:22102275
    reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors."
    explanation: Identifies delayed onset as the discriminating clinical feature of the disorder.

- category: Hematologic
  name: Joint Bleeding
  description: >-
    Hemarthrosis occurred only in affected relatives in the family study. Recurrent
    episodes can produce destructive arthropathy, which is the main route by which an
    otherwise episodic disorder accumulates permanent damage.
  phenotype_term:
    preferred_term: Joint hemorrhage
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:15026313
    reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Affected individuals had higher mean bleeding scores (P <.0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or deep cuts, and received or been recommended other treatments (fibrinolytic inhibitors) for bleeding."
    explanation: >-
      Joint bleeding ("joint bleeds") is one of the manifestations this sentence assigns
      an odds ratio above 20 for affected status in the blinded family questionnaire.
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that respond to antifibrinolytic therapy."
    explanation: >-
      An independent source naming joint bleeds among the risks the QPD mechanism
      explains, corroborating the family-study odds ratio.

- category: Hematologic
  name: Hematuria
  description: >-
    Often spontaneous and episodic rather than challenge-related. In the family study it
    was among the manifestations significantly associated with affected status, and it
    generally resolves without specific treatment.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
    temporality: RECURRENT
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that respond to antifibrinolytic therapy."
    explanation: >-
      The paper's discussion lists spontaneous hematuria among the risks the QPD
      mechanism explains, and notes it falls on those with the highest platelet uPA.
      Quoted from the authors' framing of the clinical picture, which they attribute to
      earlier clinical work, so the grading is HUMAN_CLINICAL with a BACKGROUND role.

- category: Hematologic
  name: Epistaxis
  description: >-
    Nosebleeds were more frequent in affected relatives, though severe nosebleeds were
    uncommon - a milder mucocutaneous feature than the procedural bleeding that defines
    the disorder.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis

- category: Hematologic
  name: Large Spreading Bruises
  description: >-
    Bruises that track downward or reach the size of an orange were reported only by
    affected participants, and are one of the more specific clinical clues to the
    disorder.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:15026313
    reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "bruises that spread lower or as large or larger than an orange or both"
    explanation: >-
      The specific bruise description carrying an odds ratio above 20 for affected status.

- category: Hematologic
  name: Prolonged Menstrual Bleeding
  description: >-
    Menses lasting longer than seven days were reported more often by affected women,
    although self-described "abundant" menstruation did not itself discriminate affected
    from unaffected participants in the small female sample.
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that respond to antifibrinolytic therapy."
    explanation: >-
      Heavy menstrual bleeding is named among the bleeding risks this mechanism
      accounts for.

- category: Hematologic
  name: Poor Wound Healing
  description: >-
    Delayed wound healing was reported by a minority of affected relatives. Whether this
    reflects repeated bleeding into the healing wound or loss of specific alpha-granule
    proteins with roles in repair is not separately established.
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The mechanism offers an explanation for the >100-fold increased uPA in QPD platelets that increase risks for experiencing challenge-related bleeding, heavy menstrual bleeding, joint bleeds, spontaneous hematuria (in those with the highest platelet uPA levels), and wound-healing problems that respond to antifibrinolytic therapy."
    explanation: >-
      Wound-healing problems are named among the risks the mechanism explains, and
      notably as responding to antifibrinolytic therapy - which ties the healing defect
      to ongoing fibrinolysis rather than to a separate repair deficit.

- category: Hematologic
  name: Mild Thrombocytopenia
  description: >-
    Platelet counts are lower than in unaffected relatives but frequently remain within
    the normal reference interval, so a normal platelet count does not exclude the
    diagnosis. The thrombocytopenia is mild and is not the cause of the bleeding
    phenotype, which tracks the fibrinolytic defect instead.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    severity: MILD
  evidence:
  - reference: PMID:22102275
    reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes."
    explanation: >-
      Records reduced platelet counts as a recognised feature alongside the fibrinolytic
      defect.

diagnosis:
- name: Platelet Urokinase Plasminogen Activator Measurement
  description: >-
    The biochemical test that defines affected status. Platelet uPA is markedly
    increased while plasma and urinary uPA are normal, so the assay must be run on
    platelets rather than on plasma. In the founder-family study, affected and unaffected
    status was assigned on this assay together with fibrinogen degradation, which is why
    the resulting bleeding frequencies are anchored to a biochemical rather than a
    clinical definition.
  diagnosis_term:
    preferred_term: platelet urokinase plasminogen activator assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:15026313
    reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Data entry was done blinded to affected and unaffected status, determined by assays for platelet urokinase-type plasminogen activator (u-PA) and fibrinogen degradation."
    explanation: >-
      Documents platelet uPA assay plus fibrinogen degradation as the case definition used
      to assign affected status.
  - reference: PMID:18791940
    reference_title: The value of proteomics for the diagnosis of a platelet-related bleeding disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The diagnosis of Quebec Platelet Disorder was confirmed by urokinase-specific Western blots."
    explanation: >-
      A worked diagnostic case in which urokinase-specific Western blotting was the
      confirmatory step.

- name: Light Transmission Aggregometry
  description: >-
    Aggregometry is a screening rather than a confirmatory test here. Responses are
    variably reduced - classically absent secondary aggregation with epinephrine - but the
    pattern is neither sensitive nor specific, and a normal study does not exclude the
    diagnosis. Its diagnostic value is mainly in placing the problem in the platelet
    compartment so that platelet uPA is then measured.
  diagnosis_term:
    preferred_term: light transmission platelet aggregometry
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:18791940
    reference_title: The value of proteomics for the diagnosis of a platelet-related bleeding disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Abnormalities were detected in platelet aggregation studies, which revealed variably reduced responses to ADP, collagen and epinephrine with concomitantly decreased ATP/serotonin secretion."
    explanation: >-
      Records the aggregometry pattern in a family subsequently confirmed to have QPD, and
      the word "variably" is the reason this is a screening test.

- name: Alpha-Granule Protein Degradation Analysis
  description: >-
    Demonstrating loss of alpha-granule proteins - multimerin-1, fibrinogen,
    thrombospondin-1, factor V - separates QPD from disorders in which the granules were
    never filled. The proteins are absent from the platelet while their transcripts are
    normal, which is the signature of post-translational destruction rather than failed
    packaging.
  diagnosis_term:
    preferred_term: platelet alpha-granule protein analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:18791940
    reference_title: The value of proteomics for the diagnosis of a platelet-related bleeding disorder.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Platelet proteomics showed reduced amounts of alpha-granule proteins multimerin, fibrinogen and thrombospondin-1 in patient compared to control samples suggestive of Quebec Platelet Disorder."
    explanation: >-
      Names the specific degraded alpha-granule proteins that raised the diagnosis in an
      undiagnosed bleeding family.

- name: Global Coagulation and Fibrinolysis Testing
  description: >-
    A negative that matters diagnostically. Routine coagulation times are normal and
    thromboelastography is not sensitive to the raised platelet uPA, because the defect is
    localized to the platelet and its clot rather than present in plasma. A QPD patient can
    therefore pass every global haemostasis screen while bleeding severely after surgery,
    which is a large part of why the disorder is missed or misattributed. Samples also need
    appropriate handling, since platelet factor V can be proteolysed ex vivo and confound
    results.
  diagnosis_term:
    preferred_term: global coagulation and fibrinolysis testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  presence: ABSENT
  evidence:
  - reference: PMID:16689763
    reference_title: "Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Thromboelastography was not sensitive to the increased u-PA in QPD blood."
    explanation: >-
      Direct evidence that a global viscoelastic assay does not detect the defect, which is
      what makes platelet-specific testing necessary rather than merely preferable.

- name: PLAU Duplication Testing
  description: >-
    Definitive confirmation. Breakpoint-specific PCR for the tandem duplication is the
    preferred test in a family with a known lesion, and it can be run on cord blood for
    newborn testing. The important caveat is technical rather than clinical: the lesion is
    a non-coding structural variant, so exome sequencing can miss it entirely and a
    negative exome does not exclude QPD. CNV-aware genome sequencing or a bleeding-disorder
    panel may detect it depending on probe coverage.
  diagnosis_term:
    preferred_term: breakpoint-specific PCR for the PLAU tandem duplication
    term:
      id: NCIT:C17003
      label: Polymerase Chain Reaction
  evidence:
  - reference: PMID:20007542
    reference_title: "Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This new information on the genetic mutation will facilitate diagnostic testing for QPD and studies of its pathogenesis and prevalence."
    explanation: >-
      The paper that identified the duplication states its diagnostic use, which is what
      made molecular confirmation possible.
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Discovery of the QPD duplication mutation has transformed diagnostic testing for this blood disorder."
    explanation: >-
      Confirms, from a later paper, that molecular testing displaced the biochemical assays
      as the diagnostic route.

datasets:
- accession: ega:EGAS00001004315
  title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
  description: >-
    Controlled-access raw sequencing data from the study that established enhancer
    adoption as the QPD mechanism: ChIP-seq for H3K27ac, H3K4me2, H3K36me3, H3K27me3 and
    CTCF, RNA-seq, and 4C-seq, generated in cultured megakaryocytes from QPD participants
    and unaffected controls.
  data_type: MULTI_OMICS
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:32663239
  notes: >-
    Controlled access through the European Genome-phenome Archive; no data files are
    mirrored into this repository. The accession is recorded from the publication rather
    than resolved by `just verify-datasets`, which does not cache EGA records.

genetic:
- name: PLAU
  gene_term:
    preferred_term: PLAU
    term:
      id: hgnc:9052
      label: PLAU
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PLAU encodes urokinase plasminogen activator. The causal lesion is a ~78-kb germline
    tandem duplication on chromosome 10q22 spanning PLAU and C10orf55, not a sequence
    variant: the transcript and protein are structurally normal and the pathogenic effect
    is entirely at the level of expression. Because the lesion is a non-coding structural
    variant, exome sequencing can miss it, and breakpoint-specific PCR remains the
    preferred confirmatory test in a family with a known duplication. The duplicated
    interval is chr10:75,659,017-75,736,956 on GRCh37/hg19.
  evidence:
  - reference: PMID:20007542
    reference_title: "Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "QPD is the first bleeding disorder to be associated with a gene duplication event and a PLAU mutation."
    explanation: >-
      Establishes PLAU duplication as the causal genetic lesion, and notes that a
      duplication mechanism was novel among bleeding disorders.
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "to account for the extra copy gain for peaks overlapping the duplicated region (chr10:75659017-75736956)"
    explanation: >-
      Gives the GRCh37/hg19 coordinates of the duplicated interval. Quoted from the
      paper's methods, where the region is defined to correct peak calls for the extra
      copy; `quote_role` is left unset because a methods parameter is neither the paper's
      finding nor a restatement of someone else's.

treatments:
- name: Tranexamic Acid
  description: >-
    Antifibrinolytic therapy is the only treatment shown to control QPD bleeding, and it
    is used both to treat an established bleed and as prophylaxis around a planned
    hemostatic challenge. Because the bleeding is delayed, cover must continue for days
    after the challenge rather than stopping once immediate hemostasis is achieved -
    reported schedules run from three to four days for minor procedures up to ten to
    fourteen days after intracranial bleeding. Epsilon-aminocaproic acid is a less potent
    alternative requiring higher doses; it is deliberately left without an ontology
    binding here because no CHEBI term for it was resolved during curation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_mechanisms:
  - target: Accelerated Platelet-Localized Clot Lysis
    description: >-
      Tranexamic acid blocks plasminogen binding to fibrin, opposing the plasmin-mediated
      lysis that dissolves the formed plug. It does not correct the PLAU overexpression,
      so it suppresses episodes without altering the underlying lesion.
    evidence:
    - reference: PMID:22102275
      reference_title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors."
      explanation: >-
        That the bleeding responds only to fibrinolytic inhibitors is the clinical evidence
        that the treatable step is the fibrinolytic one. It is an inference from therapeutic
        response to mechanism, hence INDIRECT.
    - reference: PMID:16689763
      reference_title: "Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "The incorporation of QPD platelets into a forming clot led to progressive disruption of fibrin and platelet aggregates unless drugs were added to inhibit plasmin."
      explanation: >-
        The ex vivo counterpart of the clinical observation: inhibiting plasmin prevents the
        clot disruption, which is the step antifibrinolytic therapy targets.
  evidence:
  - reference: PMID:15026313
    reference_title: Bleeding risks associated with inheritance of the Quebec platelet disorder
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Individuals with QPD and exposure(s) to hemostatic challenges had experienced excessive bleeding only when fibrinolytic inhibitors had not been used."
    explanation: >-
      The observational result behind antifibrinolytic prophylaxis. It is a striking
      contrast but it comes from retrospective family histories, not a randomized trial.
  notes: >-
    Platelet transfusion, plasma and desmopressin have been reported ineffective for
    typical QPD bleeding, because none of them suppresses local uPA and plasmin activity
    at the site of the plug. That negative is diagnostically useful: a bleeding disorder
    that fails to respond to platelet transfusion but responds to an antifibrinolytic is
    behaving as QPD does. These agents are not curated as treatments here precisely
    because the cited sources report them as not working.

animal_models:
- name: Megakaryocyte-targeted uPA transgenic mouse
  species: Mouse
  genotype: Transgenic overexpression of uPA restricted to the megakaryocyte lineage
  description: >-
    A transgenic mouse engineered to overexpress uPA specifically in megakaryocytes
    develops a QPD-like bleeding disorder. It tests the sufficiency of ectopic platelet
    uPA rather than reproducing the human lesion.
  evidence:
  - reference: PMID:32663239
    reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Mice that selectively overexpress PLAU in megakaryocytes have a QPD-like bleeding disorder."
    explanation: >-
      Establishes that the model exists and phenocopies the disorder. Quoted from this
      paper's introduction, where it summarises earlier work.
  modeled_mechanisms:
  - target: Accelerated Platelet-Localized Clot Lysis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the downstream consequence - platelet uPA overexpression with a bleeding
      phenotype - and so establishes that ectopic platelet uPA is sufficient to cause the
      disorder.
    limitations: >-
      The model does not carry the tandem duplication and does not reproduce the enhancer
      adoption that causes lineage-restricted overexpression in humans; the transgene
      supplies the endpoint directly. Its reproductive phenotype is also more severe than
      the human disease, with fetal loss and fatal postpartum hemorrhage reported,
      whereas all nine pregnancies among five affected women in the founder-family study
      were successful.
    evidence:
    - reference: PMID:32663239
      reference_title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Mice that selectively overexpress PLAU in megakaryocytes have a QPD-like bleeding disorder."
      explanation: >-
        Records the mouse phenocopy. Quoted from this paper's introduction, where it
        summarises earlier work rather than reporting its own result.

differential_diagnoses:
- name: Gray platelet syndrome
  description: >-
    The other alpha-granule disorder in the inherited platelet function group. Gray
    platelet syndrome fails to package alpha-granule cargo during megakaryopoiesis,
    whereas QPD packages it normally and then destroys it with a co-stored protease. The
    distinction is visible on the blood film in gray platelet syndrome and is not in QPD.
- name: von Willebrand disease
  description: >-
    Shares mucocutaneous bleeding and is a common initial consideration. QPD platelets
    degrade their own von Willebrand factor, so the distinction rests on platelet uPA
    measurement or PLAU duplication testing rather than on the bleeding pattern.
- name: Hemophilia
  description: >-
    Delayed bleeding and hemarthrosis make QPD resemble a coagulation factor deficiency,
    which is why it was originally described as "factor V Quebec". Routine coagulation
    times are normal in QPD.

notes: >-
  Scope of the module conformance. Two nodes conform to
  `primary_hemostatic_plug_failure`, at the component-loss node and at the granule arm -
  that module's granule-arm description explicitly accommodates disorders "in which the
  granules themselves are absent or their contents degraded", which is what QPD does. The
  accelerated-lysis node is deliberately left unconformed: the module models a plug that
  never forms, and the defining QPD lesion destroys a plug that did form. Conforming that
  node would assert the opposite of the mechanism. This is not only a reading of the
  module's scope - PMID:16689763 perfused whole blood over preformed fibrin and found QPD
  platelets adhered normally, with accelerated fibrinolysis following the adhesion. The
  adhesion arm is intact and measured to be intact, so attaching this node to a
  plug-formation-failure anchor would contradict the experiment.

  Items deliberately left without evidence. Epistaxis and all three differential diagnoses
  carry a description but no evidence block. For epistaxis this is a property of the
  sources: the word appears in none of the eight cached references, and its odds ratio
  falls below the threshold of the McKay summary sentence, so its frequency sits in that
  paper's results tables while the McKay cache is abstract-only. The differentials are a
  curator's clinical framing rather than a claim any cached source makes.

  This justification is scoped to McKay deliberately. An earlier revision generalized
  "the cached record is abstract-only" across every source and used it to excuse four
  uncited phenotypes. That was wrong: PMID:32663239 is cached as full text, and its
  discussion names heavy menstrual bleeding, joint bleeds, spontaneous hematuria and
  wound-healing problems in one sentence, which now evidences three of those four. An
  over-broad justification is worse than none, because it tells the next reader to skip
  the check that would have caught it.

  No prevalence block, and the reason is the source rather than the fetcher. Estimates of
  roughly 1:220,000 in Quebec and 1:655,000 in Canada circulate in the QPD literature, and
  the deep-research report that surfaced them attributes them to Diamandis 2009. That
  bibliography entry carries no journal, no DOI, no volume and no page range - it is
  graduate thesis work, not a published article, so there is no identifier to fetch and no
  abstract to quote. The same source backs the report's per-event antifibrinolytic dosing
  schedules, which is why those appear as prose in the treatment description rather than as
  evidenced claims. Recording either as curated content would attach a citation to
  something no reader could check. The same applies to the reported per-manifestation frequencies and
  odds ratios from the founder-family study: the manifestations are curated as phenotypes
  and the odds-ratio sentence is quoted where it is exact, but individual percentages are
  left in prose rather than asserted as frequency data.

  Evidence qualification. Clinical description rests almost entirely on one French-Canadian
  founder pedigree studied retrospectively, so the frequencies should not be read as
  unbiased population estimates, and the treatment evidence is observational. The
  molecular mechanism is on much firmer ground: segregation in 38 affected subjects,
  patient-derived megakaryocytes, allele-specific expression, chromatin profiling,
  chromosome-conformation capture, and a mouse phenocopy.

discussions:
- discussion_id: qpd_thrombocytopenia_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What produces the reduced platelet count in Quebec platelet disorder - intraplatelet
    proteolysis, shortened platelet survival, or an effect on megakaryopoiesis itself?
  attaches_to:
  - pathophysiology#Intraplatelet Plasmin Generation and Alpha-Granule Protein Degradation
  - phenotypes#Mild Thrombocytopenia
  rationale: >-
    The fibrinolytic arm of this disorder is established in detail, down to the chromatin
    contacts that drive it. The thrombocytopenia is not. It is consistently reported and
    is mild, but the sources that describe it do not separate proteolysis of the platelet's
    own contents from reduced platelet survival in the circulation or from an effect of
    uPA overexpression on megakaryocyte output. The distinction matters because it decides
    whether the low count is a second consequence of the same intraplatelet enzyme or a
    separate lineage effect, and the entry's causal edge to this phenotype is marked
    INDIRECT_KNOWN_INTERMEDIATES for exactly that reason.

- discussion_id: qpd_no_model_of_the_human_lesion
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any model reproduce the enhancer adoption that causes QPD, rather than supplying
    megakaryocyte uPA overexpression directly?
  attaches_to:
  - pathophysiology#Megakaryocyte Enhancer Adoption by the Duplicated PLAU Allele
  - animal_models#Megakaryocyte-targeted uPA transgenic mouse
  rationale: >-
    The transgenic mouse overexpresses uPA in megakaryocytes by design, so it tests whether
    that is sufficient to cause bleeding - which it is - but it cannot test the step that
    actually causes the human disease, because the duplication and the sub-TAD
    reorganization are absent from it. Everything upstream of "excess platelet uPA" is
    therefore evidenced only in cultured human megakaryocytes and reporter assays. The
    mouse also diverges clinically: it shows fetal loss and fatal postpartum hemorrhage,
    whereas all nine pregnancies among five affected women in the founder-family study
    were successful. A knock-in carrying the human duplication would close both gaps at
    once; none was identified.

references:
- reference: PMID:20007542
  title: "Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene."
- reference: PMID:32663239
  title: Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder
- reference: PMID:28301587
  title: "The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes."
- reference: PMID:15026313
  title: Bleeding risks associated with inheritance of the Quebec platelet disorder
- reference: PMID:22102275
  title: "Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment."
- reference: PMID:18791940
  title: The value of proteomics for the diagnosis of a platelet-related bleeding disorder.
- reference: PMID:16689763
  title: "Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis."
- reference: PMID:19029443
  title: "Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation."

📚

References & Deep Research

References

8

PMID:20007542

Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene.