| Knowledge-base field | Curated finding | Ontology / identifier suggestions | Key evidence |
|---|---|---|---|
| Identity and inheritance | Quebec platelet disorder (QPD) is a rare, nonsyndromic, autosomal-dominant inherited platelet-function disorder characterized by a platelet-dependent gain of fibrinolytic function without systemic hyperfibrinolysis. Historical names include **factor V Quebec**, **Quebec platelet syndrome**, and **platelet disorder, Quebec type**. | MONDO:0011136; OMIM:601709; disease class: inherited platelet function disorder | QPD is described as autosomal dominant and associated with excess platelet urokinase and α-granule proteolysis (DOI: 10.1182/blood-2003-11-4077). (pqac-00000010, pqac-00000025) |
| Causal gene and variant | The established causal lesion is a **germline direct tandem duplication of approximately 78 kb at chromosome 10q22**, encompassing **PLAU** and C10orf55. Reported GRCh37/hg19 coordinates are **chr10:75,659,017–75,736,956**. All 38 tested affected subjects carried the duplication; it was absent from 114 unaffected relatives and 311 unrelated controls. | PLAU; HGNC:9052; NCBI Gene:5328; Ensembl:ENSG00000122861; structural variant/copy-number gain; germline; autosomal dominant | Paterson et al., *Blood*, online 9 Dec 2009/print Feb 2010, PMID:20007542, DOI:10.1182/blood-2009-07-233965; Open Targets recognizes PLAU–QPD association. (pqac-00000000, pqac-00000003, pqac-00000006, pqac-00000030) |
| Variant interpretation | The duplication is disease-causing by **regulatory gain of function**, not by changing the uPA protein sequence. It produces excessive normal PLAU transcripts from the duplicated disease chromosome. Because it is a recurrent founder structural variant, breakpoint-specific testing is more informative than routine coding-region sequencing. | ACMG/AMP concept: pathogenic copy-number gain; molecular consequence: ectopic enhancer adoption / increased gene expression | Human megakaryocyte evidence: Hayward et al., 16 Mar 2017, PMID:28301587, DOI:10.1371/journal.pone.0173991. (pqac-00000002, pqac-00000004, pqac-00000007) |
| Upstream molecular effect | The duplication crosses the normal boundary between **subTADPLAU** and **subTADVCL**, repositioning one PLAU copy near the hematopoietic enhancer **ENHQPD**. Disease-chromosome PLAU contacts ENHQPD preferentially; allele-specific 4C reads were approximately 88–92% disease allele versus 66.6% expected from copy number alone. PLAU also gains H3K36me3 and loses promoter H3K27me3. | GO suggestions: regulation of transcription by RNA polymerase II; chromatin organization; enhancer–promoter interaction. Cell: megakaryocyte (CL:0000556). | Liang et al., *Blood*, Jul 2020, DOI:10.1182/blood.2020005394. (pqac-00000030, pqac-00000031, pqac-00000032, pqac-00000033) |
| Enhancer evidence | ENHQPD is a 5.7-kb megakaryocyte-enriched H3K27ac element about 50 kb from both PLAU and VCL; its approximately 375-bp conserved module binds/associates with FLI1, GATA1, RUNX1, and TAL1. It enhanced PLAU-promoter reporter activity 2.4-fold in K562 cells and was active in cultured human megakaryocytes and thrombocyte-forming zebrafish tissues. | GO suggestions: hematopoietic transcriptional regulation; megakaryocyte differentiation. Model taxon: *Danio rerio* (NCBI Taxon:7955). | DOI:10.1182/blood.2020005394. (pqac-00000027, pqac-00000032, pqac-00000047) |
| Downstream molecular effect | Megakaryocyte PLAU expression and platelet urokinase-type plasminogen activator (uPA) stores increase by **more than 100-fold**. Excess uPA is stored in platelet α-granules, released upon activation, and converts plasminogen to plasmin locally. Plasma and urine uPA and systemic fibrinolysis are generally not increased. | Protein: urokinase plasminogen activator; GO:0042730 fibrinolysis; platelet α-granule (GO:0031091); platelet (CL:0000233); plasminogen activation | Human and patient-derived-cell evidence, DOI:10.1371/journal.pone.0173991. (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000043) |
| Platelet pathology | Intraplatelet plasmin causes proteolysis or loss of α-granule proteins including fibrinogen, factor V, von Willebrand factor, thrombospondin-1, multimerin-1, osteonectin, and P-selectin. Released uPA accelerates platelet-dependent clot lysis, explaining delayed rebleeding after an initially formed hemostatic plug. | HPO suggestion: Abnormality of platelet function; GO suggestions: platelet degranulation, proteolysis, fibrinolysis; platelet α-granule (GO:0031091) | Protein degradation and diagnostic patterns are summarized in disease-focused laboratory evidence. (pqac-00000004, pqac-00000007, pqac-00000035) |
| Hallmark bleeding phenotype | Bleeding is lifelong but variably expressed and commonly appears **12 hours to 4 days after trauma, surgery, dental extraction, or deep cuts**. Episodes can persist for days or weeks without antifibrinolytic therapy. | HPO suggestions: Abnormal bleeding; Prolonged bleeding following procedure; Delayed wound healing | Disease-focused review and family cohort. (pqac-00000019, pqac-00000024, pqac-00000025) |
| Quantified phenotypes | In 23 affected relatives: post-dental-extraction bleeding longer than 24 h occurred in **94% (16/17; OR 176)**; epistaxis in **57% (13/23; OR 4.0)**; prolonged deep-cut bleeding in **56% (9/16; OR 37)**; hematuria in **50% (11/22; OR 7.7)**; joint bleeding in **43% (10/23)**; impaired healing in **26% (6/23; OR 4.9)**; and prior transfusion in **52% (12/23; OR 9.8)**. | HPO: Epistaxis (HP:0000421); Hematuria (HP:0000790); Bruising susceptibility (HP:0000978); Menorrhagia (HP:0000132); Hemarthrosis; Delayed wound healing | McKay et al., *Blood*, 1 Jul 2004, DOI:10.1182/blood-2003-11-4077. (pqac-00000012, pqac-00000013, pqac-00000020) |
| Hematologic laboratory phenotype | Platelet counts are typically low-normal or mildly reduced—about 50% lower than in unaffected relatives. In one cohort, counts were **120–245 ×10⁹/L** (mean 167), while platelet uPA was **142–575 ng/10⁹ platelets** (mean 275; unaffected reference below 1.3). Bleeding score did not correlate strongly with platelet count or uPA level. | HPO: Thrombocytopenia (HP:0001873); laboratory abnormality: increased platelet uPA | Human family study. (pqac-00000003, pqac-00000013, pqac-00000025) |
| Diagnostic hallmarks | PT/INR, aPTT, systemic-fibrinolysis assays, and thromboelastography are usually normal. Aggregometry often shows reduced primary and absent secondary aggregation with epinephrine, but responses can vary and are not specific. Specialized findings are markedly increased platelet uPA and characteristic α-granule-protein degradation. **Definitive testing** is breakpoint PCR or another validated assay that detects the PLAU tandem duplication. | Diagnostic terms: CBC/platelet count; light-transmission aggregometry; platelet uPA immunoassay; immunoblot; copy-number/structural-variant testing | QPD review and modern platelet-diagnostic review, DOI:10.1055/s-0031-1291382 and DOI:10.1080/10408363.2022.2049199. (pqac-00000037, pqac-00000039) |
| Genetic-testing implications | Targeted breakpoint PCR is preferred for known-family testing and can be applied to cord blood. WES may miss the duplication because it is noncoding/structural; WGS or CNV-aware panels may detect it if the pipeline is validated. Routine karyotyping is too low-resolution; CMA could detect a 78-kb gain only if probe coverage is adequate, while FISH is generally unnecessary. Cascade testing is appropriate for at-risk relatives, including minimally symptomatic children. | NCIT suggestions: Genetic Testing; Polymerase Chain Reaction; Whole Genome Sequencing; Copy Number Variation Analysis; Genetic Counseling | Breakpoint-testing and family-screening recommendations derive from disease-focused reviews; sequencing-platform limitations are technical inferences and require laboratory validation. (pqac-00000035, pqac-00000037) |
| Treatment | **Tranexamic acid** is first-line for treatment and peri-procedural prevention; ε-aminocaproic acid is a less-potent alternative. Reported durations are approximately 3–4 days for minor bleeding/surgery, 4–5 days after dental extraction, 5–7 days after major trauma/surgery or joint bleeding, and 10–14 days for intracranial bleeding. | CHEBI:48669 tranexamic acid; NCIT suggestions: Tranexamic Acid; Aminocaproic Acid; Antifibrinolytic Therapy | Observational human evidence: all 19 affected individuals challenged without an antifibrinolytic reported excessive bleeding, whereas all 12 treated during some/all challenges reported no serious bleeding. DOI:10.1182/blood-2003-11-4077. (pqac-00000005, pqac-00000013, pqac-00000020, pqac-00000038) |
| Treatments generally ineffective / cautions | Platelet or plasma transfusion and desmopressin do not correct the underlying platelet-localized fibrinolysis and are reported as ineffective for typical QPD bleeding. Spontaneous hematuria usually resolves without antifibrinolytics. Antifibrinolytics require individualized thrombosis-risk assessment; QPD does not eliminate venous-thromboembolism risk. | NCIT suggestions: Platelet Transfusion; Plasma Transfusion; Desmopressin; Thrombosis Prophylaxis | Disease-focused clinical experience and family cohort. (pqac-00000011, pqac-00000035, pqac-00000036) |
| Epidemiology and founder effect | Most documented cases descend from a founder family from the Sorel/Yamaska/St-François-du-Lac region of Quebec. Historical estimates are approximately **1:220,000 in Quebec** and **1:655,000 in Canada**, probably underestimates; no robust incidence, sex-ratio, global prevalence, or carrier-frequency estimate exists. | Population descriptor: French Canadian founder population | QPD review. (pqac-00000003) |
| Penetrance and expressivity | Molecular penetrance appears high, but clinical expressivity is strongly variable and exposure-dependent. Young carriers may have low bleeding scores before surgery, trauma, dental extraction, menstruation, or childbirth. No genetic anticipation or established modifier gene is known. | HPO suggestion: Variable expressivity | The cohort included ages 1–89 years; two affected children aged 3 and 6 had bleeding scores below 2. (pqac-00000010, pqac-00000013) |
| Prognosis and morbidity | QPD is chronic and lifelong; quantitative survival or life-expectancy data are unavailable. With recognition and antifibrinolytic prophylaxis, major challenge-related bleeding is often preventable. Morbidity includes transfusions, lifestyle restriction, delayed healing, destructive arthropathy from recurrent hemarthroses, anemia, compartment bleeding, and rare intracranial hemorrhage. | HPO suggestions: Anemia; Hemarthrosis; Intracranial hemorrhage; Arthropathy | Human cohort and expert review. (pqac-00000009, pqac-00000011, pqac-00000025) |
| Evidence gaps / current status | Searches identified no QPD-specific interventional clinical trial and no approved disease-modifying, gene, RNA, or cell therapy. No established environmental cause, protective allele, modifier gene, pharmacogenomic rule, single-cell/spatial-omics study, validated prognostic biomarker, or naturally occurring nonhuman QPD is reported. The principal advanced datasets remain patient-derived RNA-seq, ChIP-seq and 4C-seq; 2023–2024 publications mainly review inherited platelet-disorder diagnosis/management rather than report new QPD-specific cohorts or therapies. | Research-gap annotations: natural history study; clinical trial; single-cell transcriptomics; gene therapy | Recent expert literature continues to classify QPD as an inherited platelet disorder and emphasizes comprehensive platelet-function plus genetic testing; disease-specific evidence remains dominated by small founder-family studies. (pqac-00000039, pqac-00000040, pqac-00000042, pqac-00000047) |


*Table: Compact disease knowledge-base table integrating the causal PLAU duplication, enhancer-rewiring mechanism, quantified clinical manifestations, diagnostic approach, treatment, epidemiology, ontology suggestions, and major evidence gaps.*