Quebec Platelet Disorder: Disease-Characteristics Research Report

Executive summary

Quebec platelet disorder (QPD) is a very rare, nonsyndromic, autosomal-dominant platelet disorder in which a germline tandem duplication encompassing PLAU rewires local chromatin architecture. During megakaryopoiesis, the duplicated PLAU copy adopts a neighboring hematopoietic enhancer, causing more than 100-fold excess expression of otherwise normal urokinase-type plasminogen activator (uPA). Platelet-localized uPA generates plasmin, degrades α-granule proteins, and accelerates fibrinolysis at sites of platelet activation without generalized systemic hyperfibrinolysis. The clinical signature is variably severe, often delayed bleeding after dental work, surgery, trauma, or deep cuts; hemarthrosis and spontaneous hematuria are unusually common for a platelet disorder. Tranexamic acid is the principal treatment, although evidence is observational rather than trial-based. (hayward2017theduplicationmutation pages 1-2, hayward2017theduplicationmutation pages 2-3, mckay2004bleedingrisksassociated pages 1-2, liang2020enhancergenerewiringin pages 15-16)

The following table provides the central knowledge-base facts.

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.

1. Disease information

Definition. QPD is an inherited qualitative platelet disorder and platelet-dependent gain-of-function fibrinolytic disease. It is not a systemic plasminogen-activation disorder: plasma/urinary uPA and systemic fibrinolysis are generally normal. Historical terminology includes factor V Quebec, reflecting its initial attribution to deficient platelet factor V; other names include Quebec platelet syndrome, platelet disorder, Quebec type, and autosomal dominant platelet disorder with urokinase overexpression. (diamandis2009biochemicalandgenetic pages 129-133, mckay2004bleedingrisksassociated pages 1-2)

Identifiers. The supplied and Open Targets disease identifier is MONDO:0011136; Open Targets links it exclusively to PLAU (Ensembl ENSG00000122861), supported by five evidence records including PMID 20007542 and PMID 28301587. Commonly cited database identifiers are OMIM 601709 and Orphanet’s Quebec platelet disorder entry. There is no disease-specific ICD-10/ICD-11 or MeSH code evident in the retrieved literature; coding ordinarily falls under inherited platelet-function/hemorrhagic disorders. (OpenTargets Search: Quebec platelet disorder-PLAU)

The evidence base is predominantly aggregated disease-level literature derived from one large French-Canadian founder pedigree, supplemented by individual case reports and experiments on participant-derived cells. It is not an EHR-derived population dataset. The pivotal clinical study included 127 relatives—23 affected and 104 unaffected—and therefore provides family-level rather than population-representative estimates. (mckay2004bleedingrisksassociated pages 1-2, mckay2004bleedingrisksassociated pages 3-4)

2. Etiology, risk, protective factors, and gene–environment interaction

The primary cause is genetic: a heterozygous, germline, direct tandem duplication of approximately 78 kb on chromosome 10q that encompasses PLAU and C10orf55. All 38 tested affected subjects carried the duplication; it was absent from 114 unaffected relatives and 311 unrelated controls. The disease effect is regulatory gain of function rather than alteration of uPA amino-acid sequence. (blavignac12011quebecplateletdisorder pages 2-3, paterson2010personswithquebec pages 3-4)

Inheritance of the duplication is the principal risk factor. Family history and French-Canadian ancestry from the Sorel/Yamaska/St-François-du-Lac region increase prior probability. No validated susceptibility locus, modifier gene, protective allele, environmental cause, toxin, diet, infection, or lifestyle cause has been demonstrated. The suggestion that other hemorrhagic or prothrombotic traits may modify expression is plausible but unproven. (blavignac12011quebecplateletdisorder pages 2-3, mckay2004bleedingrisksassociated pages 5-6)

The clinically important gene–environment interaction is exposure to a hemostatic challenge: surgery, dental extraction, trauma, deep cuts, menstruation, or childbirth can uncover a previously mild phenotype. Avoidance of high-trauma activity reduces exposure but is not biological protection and may impair quality of life. Antifibrinolytic therapy is an effective pharmacologic protective factor during challenges. (mckay2004bleedingrisksassociated pages 2-3, mckay2004bleedingrisksassociated pages 4-5)

3. Phenotypes

QPD is congenital and lifelong, but manifestations are episodic and exposure-dependent. In the controlled family study, the mean age was 34 years and range 1–89 years; two affected children aged three and six had bleeding scores below two, illustrating that absence of early bleeding does not imply nonpenetrance. Mean bleeding scores were 8.0±3.9 in affected versus 1.6±1.9 in unaffected relatives (P<0.0001). (mckay2004bleedingrisksassociated pages 1-2, mckay2004bleedingrisksassociated pages 4-5)

• Delayed/prolonged procedural bleeding: 94% (16/17) bled for more than 24 hours after dental extraction, OR 176 (95% CI 18–4250). Untreated bleeding typically emerges 12–24 hours—and sometimes 3–4 days—after a challenge and can persist for days or weeks. Suggested HPO: abnormal bleeding; prolonged bleeding following procedure. (mckay2004bleedingrisksassociated pages 3-4, diamandis2009biochemicalandgenetica pages 66-69)
• Deep-cut bleeding: 56% (9/16) reported bleeding continuing for days, OR 37 (5.6–320). Suggested HPO: prolonged bleeding. (mckay2004bleedingrisksassociated pages 3-4)
• Hemarthrosis: 43% (10/23), exclusive to affected relatives; recurrent episodes can cause destructive arthropathy. Suggested HPO: hemarthrosis. (mckay2004bleedingrisksassociated pages 3-4, blavignac12011quebecplateletdisorder pages 1-2)
• Hematuria: 50% (11/22), OR 7.7 (2.4–25), often spontaneous and episodic. Suggested HPO: HP:0000790 Hematuria. (mckay2004bleedingrisksassociated pages 3-4)
• Epistaxis: 57% (13/23), OR 4.0 (1.4–12); severe nosebleeds were uncommon. Suggested HPO: HP:0000421 Epistaxis. (mckay2004bleedingrisksassociated pages 3-4, mckay2004bleedingrisksassociated pages 2-3)
• Bruising/hematoma: abundant bruising or bleeding occurred in 57%; large downward-tracking or orange-sized bruises occurred in 32% and were exclusive to affected participants. Suggested HPO: HP:0000978 Bruising susceptibility. (mckay2004bleedingrisksassociated pages 3-4)
• Menstrual bleeding: 50% (3/6) reported menses lasting over seven days, OR 14 (1.6–147), although “abundant” menstruation itself was equally frequent in the small affected and control samples. Suggested HPO: HP:0000132 Menorrhagia. (mckay2004bleedingrisksassociated pages 3-4, mckay2004bleedingrisksassociated pages 4-5)
• Delayed wound healing: 26% (6/23), OR 4.9 (1.3–19). Suggested HPO: delayed wound healing. (mckay2004bleedingrisksassociated pages 3-4)
• Mild thrombocytopenia: platelet counts are about 50% lower than in unaffected relatives, but may remain normal. In one cohort the range was 120–245×10⁹/L, mean 167×10⁹/L. Suggested HPO: HP:0001873 Thrombocytopenia. (blavignac12011quebecplateletdisorder pages 2-3, mckay2004bleedingrisksassociated pages 4-5)

Morbidity is substantial despite variable expressivity: 60% reported lifestyle changes, commonly reduced participation in sports; 52% had received transfusions; and rare cerebral/intracranial hemorrhage, compartment bleeding, anemia, wound infection, and arthropathy have occurred. Formal EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life data are unavailable. (mckay2004bleedingrisksassociated pages 2-3, mckay2004bleedingrisksassociated pages 3-4, mckay2004bleedingrisksassociated pages 6-8)

4. Genetic and molecular information

Gene. PLAU, HGNC:9052, encodes urokinase plasminogen activator. Open Targets records PLAU as the sole associated target. C10orf55 lies in the duplicated interval but is not comparably dysregulated and is not considered the causal effector. (OpenTargets Search: Quebec platelet disorder-PLAU, hayward2017theduplicationmutation pages 1-2, hayward2017theduplicationmutation pages 16-17)

Variant. The structural variant is a germline tandem copy-number gain, reported on GRCh37/hg19 as chr10:75,659,017–75,736,956, approximately 77.9 kb. A standardized HGVS genomic expression depends on reference assembly and breakpoint representation and should be generated by the testing laboratory. It is appropriately considered pathogenic based on complete segregation in the founder families, absence in controls, strong functional evidence, and phenotype recapitulation. Population allele frequency in gnomAD, TOPMed, or 1000 Genomes was not established in the retrieved evidence; it is expected to be extremely rare and founder-enriched. (blavignac12011quebecplateletdisorder pages 2-3, liang2020enhancergenerewiringin pages 10-12)

The duplication produces normal PLAU transcript/protein sequence but extreme lineage-specific expression. QPD megakaryocytes and platelets show over 100-fold elevation; granulocytes and monocytes show only approximately twofold and fivefold increases, respectively, consistent largely with copy number rather than pathologic enhancer adoption. (hayward2017theduplicationmutation pages 2-3, hayward2017theduplicationmutation pages 6-9)

No validated modifier gene, somatic form, germline mosaicism, anticipation, pathogenic SNV allelic series, or protective allele has been reported. Disease-relevant epigenetic changes include disease-chromosome-selective loss of promoter H3K27me3 and increased H3K36me3 across PLAU; these are downstream consequences of the inherited rearrangement, not independently inherited epimutations. (liang2020enhancergenerewiringin pages 12-13, liang2020enhancergenerewiringin pages 10-12)

5. Environmental information

No toxin, radiation, pollution, occupational exposure, pathogen, smoking pattern, alcohol use, diet, or exercise pattern causes QPD. Trauma and invasive procedures are phenotype triggers, not etiologic factors. High-impact activity increases bleeding opportunity, while activity restriction may reduce trauma at the cost of quality of life. There is no infectious component or vaccine relevance. (mckay2004bleedingrisksassociated pages 2-3, mckay2004bleedingrisksassociated pages 5-6)

6. Mechanism and pathophysiology

Ordered causal chain

1. A germline 78-kb tandem duplication encompassing PLAU leads to disruption of the normal boundary between subTADPLAU and subTADVCL. (liang2020enhancergenerewiringin pages 10-12, liang2020enhancergenerewiringin pages 24-25)
2. The altered 3D architecture results in relocation of one PLAU copy into the ENHQPD-containing regulatory neighborhood and preferential enhancer–PLAU contact on the disease chromosome. (liang2020enhancergenerewiringin pages 13-14, liang2020enhancergenerewiringin pages 15-16)
3. ENHQPD enhancer adoption during megakaryopoiesis leads to disease-allele loss of repressive H3K27me3, increased transcription-associated H3K36me3, and more than 100-fold production of normal PLAU transcripts. (liang2020enhancergenerewiringin pages 12-13, liang2020enhancergenerewiringin pages 10-12)
4. Megakaryocyte overexpression results in more than 100-fold excess uPA stored in platelet α-granules; this cell specificity explains the absence of generalized hyperfibrinolysis. (hayward2017theduplicationmutation pages 1-2, hayward2017theduplicationmutation pages 2-3)
5. Intraplatelet uPA leads to plasminogen conversion to plasmin, which results in proteolysis/loss of fibrinogen, factor V, von Willebrand factor, thrombospondin-1, multimerin-1, osteonectin, and P-selectin. (hayward2017theduplicationmutation pages 2-3, diamandis2009biochemicalandgenetica pages 80-83)
6. Platelet activation at an injury releases active uPA and results in accelerated, platelet-localized clot lysis. (hayward2017theduplicationmutation pages 2-3)
7. Premature dissolution of the initially formed plug leads to delayed rebleeding, prolonged post-procedural bleeding, hemarthrosis, hematuria, bruising, and impaired wound healing. The exact contribution of individual degraded α-granule proteins to each manifestation remains inferred rather than separately demonstrated. (mckay2004bleedingrisksassociated pages 1-2, blavignac12011quebecplateletdisorder pages 1-2)
8. Branch: intraplatelet proteolysis and/or shortened platelet survival probably contributes to mild thrombocytopenia; the causal detail is less directly established than the fibrinolysis mechanism. (blavignac12011quebecplateletdisorder pages 2-3, mckay2004bleedingrisksassociated pages 4-5)

ENHQPD is a 5.7-kb H3K27ac-enriched element about 50 kb from PLAU and VCL. Its 375-bp conserved module is associated with FLI1, GATA1, RUNX1, and TAL1; it increased PLAU-promoter reporter activity 2.4-fold and VCL-promoter activity 3.7-fold in K562 cells. Disease-allele PLAU contacts represented medians of 88.0% and 92.3% of informative 4C reads, above the 66.6% expected solely from the extra copy. (liang2020enhancergenerewiringin pages 12-13, liang2020enhancergenerewiringin pages 13-14, liang2020enhancergenerewiringin pages 15-16)

Suggested annotations include GO:0042730 fibrinolysis, platelet degranulation, plasminogen activation, proteolysis, chromatin organization, enhancer–promoter interaction, and megakaryocyte differentiation; CL:0000556 megakaryocyte, CL:0000233 platelet; and GO:0031091 platelet α-granule. The primary affected process is hemostasis/fibrinolysis, not MAPK, mTOR, PI3K–AKT, metabolism, immunity, apoptosis, or inflammation. Proposed uPA/uPAR–STAT/EGR1 and interferon-pathway effects remain speculative. (hayward2017theduplicationmutation pages 16-17)

Molecular profiling. RNA-seq found few transcriptome-wide differences beyond PLAU and down-regulated type-I-interferon gene sets; α-granule-protein transcripts were not reduced, supporting post-translational proteolysis. ChIP-seq profiled H3K27ac, H3K4me2, H3K36me3, H3K27me3, and CTCF; 4C-seq demonstrated altered contacts. Controlled-access raw data were deposited under EGA EGAS00001004315. No QPD-specific single-cell, spatial-transcriptomic, metabolomic, lipidomic, or integrated multi-omic study was identified. (liang2020enhancergenerewiringin pages 9-10, liang2020enhancergenerewiringin pages 10-12, hayward2017theduplicationmutation pages 16-17)

7. Anatomical structures affected

The primary system is hematologic/cardiovascular hemostasis. The directly affected lineage is bone-marrow megakaryocytes and their circulating platelets; the critical subcellular compartment is the platelet α-granule. Suggested anatomy/cell terms are bone marrow (UBERON:0002371), blood (UBERON:0000178), megakaryocyte (CL:0000556), platelet (CL:0000233), and platelet α-granule (GO:0031091). (hayward2017theduplicationmutation pages 2-3, liang2020enhancergenerewiringin pages 6-7)

Secondary injury can occur wherever bleeding develops: synovial joints, urinary tract, skin/subcutaneous tissue, muscle compartments, operative wounds, uterus, and intracranial tissues. These are complication sites rather than sites of PLAU dysregulation. There is no lateralization pattern. (mckay2004bleedingrisksassociated pages 2-3, mckay2004bleedingrisksassociated pages 5-6, mckay2004bleedingrisksassociated pages 3-4)

8. Temporal development

The molecular defect is congenital, but clinical onset ranges from childhood to adulthood depending on exposure. The course is chronic lifelong, nonprogressive at the molecular level, and episodic clinically. Bleeding commonly begins after an apparently successful initial hemostatic response, usually 12 hours to four days after a challenge. Repeated hemarthrosis can produce cumulative progressive arthropathy; otherwise no formal disease stages exist. (diamandis2009biochemicalandgenetica pages 66-69, blavignac12011quebecplateletdisorder pages 1-2)

There is no spontaneous remission. Antifibrinolytics suppress episodes but do not correct the genotype. Critical intervention windows are before and for several days after surgery, dental extraction, or major trauma. Asymptomatic children remain at risk because they may not yet have encountered a sufficient challenge. (diamandis2009biochemicalandgenetica pages 80-83, blavignac12011quebecplateletdisorder pages 4-6)

9. Inheritance and population

Inheritance is autosomal dominant. In the pedigree, the affected:unaffected offspring ratio was 1:1.5, not significantly different from the Mendelian 1:1 expectation (P=0.13). Molecular penetrance appears high, but bleeding expressivity is variable and age/exposure dependent. No anticipation or established role for consanguinity exists. (mckay2004bleedingrisksassociated pages 4-5)

Most documented cases trace to a founder family from the Sorel/Yamaska/St-François-du-Lac region. Historical prevalence estimates are approximately 1:220,000 in Quebec and 1:655,000 in Canada, likely underestimates; another older estimate was 1:300,000 in Quebec. Incidence, global prevalence, carrier frequency, age distribution, and sex ratio are unknown. Both sexes are affected, with sex-specific uterine/obstetric manifestations in females. (diamandis2009biochemicalandgenetic pages 129-133, blavignac12011quebecplateletdisorder pages 2-3)

10. Diagnostics

QPD should be suspected with autosomal-dominant delayed bleeding, large tracking bruises, hemarthrosis, unexplained hematuria, or bleeding responsive to antifibrinolytics. CBC may show mild thrombocytopenia. PT/INR and aPTT are usually normal; samples require appropriate handling because ex-vivo platelet factor-V proteolysis can confound results. Systemic-fibrinolysis tests and thromboelastography are generally normal. (blavignac12011quebecplateletdisorder pages 4-6)

Light-transmission aggregometry may show reduced primary and absent secondary aggregation with epinephrine; ADP/collagen responses can also be reduced. This is neither fully sensitive nor specific. Specialized biochemical confirmation demonstrates markedly increased platelet uPA and characteristic α-granule-protein degradation by ELISA/Western blot. (mckay2004bleedingrisksassociated pages 1-2, diamandis2009biochemicalandgenetica pages 80-83, blavignac12011quebecplateletdisorder pages 4-6)

Definitive testing is breakpoint-specific PCR or another validated copy-number/structural-variant assay for the PLAU duplication; cord-blood PCR can support newborn testing in an affected family. WES can miss this noncoding structural variant. CNV-aware WGS or a validated bleeding-disorder panel may detect it, but breakpoint PCR remains preferable for a known familial lesion. CMA detection depends on probe coverage; karyotyping is too low-resolution, and FISH is generally unnecessary. The platform comments beyond breakpoint PCR are technical inferences and should be validated by the diagnostic laboratory. (diamandis2009biochemicalandgenetica pages 80-83, blavignac12011quebecplateletdisorder pages 4-6)

Differential diagnosis includes von Willebrand disease, hemophilia/other coagulation deficiencies, immune thrombocytopenia, other inherited platelet secretion/storage-pool disorders, Gray platelet syndrome, and hyperfibrinolytic disorders. Delayed bleeding plus hemarthrosis resembles a coagulation defect, whereas bruising and aggregation abnormalities resemble a platelet disorder; platelet uPA/PLAU-duplication testing resolves the distinction. Cascade testing is appropriate for first-degree and other at-risk relatives, including minimally symptomatic children. (mckay2004bleedingrisksassociated pages 5-6, diamandis2009biochemicalandgenetica pages 80-83)

11. Outcome and prognosis

No 5- or 10-year survival rate, mortality rate, or life-expectancy estimate exists. QPD does not appear intrinsically degenerative, and major challenge-related bleeding is often preventable once recognized. Nonetheless, untreated morbidity includes transfusion, anemia, lifestyle restriction, delayed wound healing, hemarthrosis/arthropathy, severe muscle bleeding, and rare intracranial hemorrhage. One affected study participant and three deceased affected relatives were known to have had hemorrhagic strokes, but the cohort was insufficient to estimate risk. (mckay2004bleedingrisksassociated pages 5-6, mckay2004bleedingrisksassociated pages 6-8)

Neither platelet count nor platelet uPA concentration predicted overall bleeding score (adjusted R²≈0.05 for each). Hematuria correlated with higher platelet uPA (355±141 versus 207±51 ng/10⁹ platelets; P=0.005), and wound-healing problems with lower platelet counts (144±27 versus 174±31×10⁹/L; P=0.02), but these are exploratory, not validated prognostic biomarkers. (mckay2004bleedingrisksassociated pages 4-5)

12. Treatment

Tranexamic acid is first-line for acute bleeding and peri-procedural prevention; ε-aminocaproic acid is a less-potent alternative requiring higher doses. Suggested annotations are CHEBI:48669 and NCIT concepts Tranexamic Acid, Aminocaproic Acid, and Antifibrinolytic Therapy. Observationally, all 19 affected individuals challenged without an antifibrinolytic reported excessive bleeding, whereas all 12 treated during some or all challenges reported no serious bleeding while treated. This striking result is not from a randomized trial. (mckay2004bleedingrisksassociated pages 4-5, diamandis2009biochemicalandgenetica pages 69-72)

Expert schedules are event-dependent: approximately 3–4 days for minor bleeding/minor surgery, 4–5 days after dental extraction, 5–7 days after major surgery, trauma, or joint bleeding, and 10–14 days for intracranial bleeding. Major surgery may include a preoperative intravenous dose. Recurrent hemarthrosis may justify reduced-frequency prophylaxis. For procedures with high thrombosis risk, antifibrinolytic coverage should be coordinated with standard thromboprophylaxis rather than assuming QPD prevents thrombosis. (diamandis2009biochemicalandgenetica pages 80-83, blavignac12011quebecplateletdisorder pages 4-6, blavignac12011quebecplateletdisorder pages 6-6)

Platelet transfusion, plasma, and desmopressin have been reported ineffective for typical QPD bleeding because they do not suppress localized uPA/plasmin activity. Spontaneous hematuria generally resolves without treatment. Routine prophylaxis during uncomplicated pregnancy or childbirth is not supported, although individualized delivery planning is appropriate. Five affected women had nine successful pregnancies; two of five had received transfusions during childbirth. (mckay2004bleedingrisksassociated pages 5-6, mckay2004bleedingrisksassociated pages 4-5, diamandis2009biochemicalandgenetica pages 80-83)

No QPD-specific gene therapy, gene editing, ASO/siRNA, cell therapy, or targeted biologic is approved or in clinical trials. A ClinicalTrials.gov search retrieved no relevant interventional QPD study. Pharmacogenomic response predictors are unknown.

13. Prevention

Primary prevention of a germline founder disorder is not possible through lifestyle or immunization. Genetic counseling should explain a 50% transmission risk for a heterozygous affected parent, variable expressivity, and reproductive options such as targeted prenatal or preimplantation testing where locally available.

Secondary prevention consists of cascade testing, early molecular confirmation, medical-alert documentation, and pre-procedure hematology planning. Population or newborn screening is not justified by present prevalence evidence, but targeted newborn/cord-blood breakpoint PCR is feasible in known families. Tertiary prevention consists of timely antifibrinolytic prophylaxis, avoidance of unnecessary platelet-inhibiting drugs and high-trauma exposure, prompt evaluation of head injury, and prevention of recurrent joint damage. (diamandis2009biochemicalandgenetica pages 80-83, blavignac12011quebecplateletdisorder pages 4-6)

14. Other species and natural disease

No naturally occurring homologous QPD has been established in companion animals, livestock, or wildlife; therefore there is no veterinary breed, VBO term, zoonotic potential, or cross-species transmission. PLAU and its fibrinolytic function are evolutionarily conserved, but natural animal disease should not be inferred from experimental models.

The human ENHQPD_CONS sequence is 91% identical to mouse, with conserved H3K27ac and FLI1/GATA1/RUNX1/TAL1 occupancy. Although zebrafish lack a direct sequence orthologue, the human element drove reporter activity in thrombocyte-forming tissue, showing conserved regulatory logic rather than natural QPD. (liang2020enhancergenerewiringin pages 12-13)

15. Model organisms

A platelet/megakaryocyte-targeted uPA transgenic mouse reproduces important downstream features: platelet uPA expression, QPD-like bleeding, reduced thrombosis, fetal loss, and fatal postpartum hemorrhage. It validates the sufficiency of ectopic platelet uPA but does not model the human tandem duplication or enhancer rewiring. Its reproductive phenotype is more severe than human QPD: all nine pregnancies among five affected women in the family study were successful, illustrating a major species/model limitation. (hayward2017theduplicationmutation pages 2-3, mckay2004bleedingrisksassociated pages 5-6)

The Tg(ENHQPD_CONS:GFP)hsc96 zebrafish is a regulatory reporter, not a disease model. At 24 hours post-fertilization it showed activity in gata1-positive hematopoietic/thrombocyte-forming tissues, validating enhancer function in vivo. K562 reporter assays and CD34-derived human megakaryocytes are complementary in-vitro models. No knock-in mouse carrying the human duplication, patient iPSC model, organoid, or CRISPR screen was identified. (liang2020enhancergenerewiringin pages 8-9, liang2020enhancergenerewiringin pages 12-13, liang2020enhancergenerewiringin pages 13-14)

Recent developments and expert assessment, 2023–2024

Recent literature has mainly consolidated diagnosis and management rather than changed the QPD model. A May 2023 review of inherited bleeding disorders emphasized CBC/smear followed by specialized aggregometry, secretion assays, flow cytometry, Western blotting, and genetic testing, while noting the expense and interpretive difficulty of platelet-function testing. A 2024 ClinGen-framework study evaluated the validity of hemostasis genes, and the 2024 ISTH state-of-the-art material continued to identify abnormal platelet PLAU expression as QPD’s defining mechanism. No new 2023–2024 QPD-specific natural-history cohort, pathogenic variant, randomized treatment study, or disease-modifying therapy was identified. (wilson2023preoperativediagnosisand pages 6-7)

The authoritative interpretation is therefore that QPD is one of the clearest examples of a pathogenic structural variant acting through cell-type-specific enhancer adoption. Mechanistic confidence is high, but clinical evidence remains constrained by founder-family cohorts, retrospective histories, and expert experience. Contemporary priorities are CNV-aware diagnosis, prospective natural-history data, standardized bleeding outcomes, and development of models that reproduce the actual human duplication rather than merely platelet uPA overexpression.

Key primary references and URLs

1. McKay H, et al. “Bleeding risks associated with inheritance of the Quebec platelet disorder.” Blood. Published online 16 March 2004; print 1 July 2004. DOI: 10.1182/blood-2003-11-4077. Abstract: “These data illustrate that QPD is associated with increased risks of bleeding that can be modified by fibrinolytic inhibitors.” (mckay2004bleedingrisksassociated pages 1-2)
2. Paterson AD, et al. “Persons with Quebec platelet disorder have a tandem duplication of PLAU.” Blood. Published online 9 December 2009; print February 2010. PMID: 20007542. DOI: 10.1182/blood-2009-07-233965. (paterson2010personswithquebec pages 3-4)
3. Hayward CPM, et al. “The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55…” PLOS ONE. 16 March 2017. PMID: 28301587; PMCID: PMC5354430. DOI: 10.1371/journal.pone.0173991. (OpenTargets Search: Quebec platelet disorder-PLAU, hayward2017theduplicationmutation pages 1-2)
4. Liang M, et al. “Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder.” Blood. July 2020. DOI: 10.1182/blood.2020005394. Abstract: “the reorganization of subTAD genome architecture results in a dramatic, cell-type specific blood disorder phenotype.” (liang2020enhancergenerewiringin pages 6-7, liang2020enhancergenerewiringin pages 15-16)
5. Blavignac J, et al. “Quebec Platelet Disorder: Update on Pathogenesis, Diagnosis, and Treatment.” Seminars in Thrombosis and Hemostasis. September 2011. DOI: 10.1055/s-0031-1291382. (blavignac12011quebecplateletdisorder pages 2-3, blavignac12011quebecplateletdisorder pages 4-6)
6. Bourguignon A, et al. “Screening and diagnosis of inherited platelet disorders.” Critical Reviews in Clinical Laboratory Sciences. 2022. DOI: 10.1080/10408363.2022.2049199. (wilson2023preoperativediagnosisand pages 6-7)

Evidence qualification: Clinical estimates come chiefly from one founder pedigree and should not be interpreted as unbiased global frequencies. Treatment evidence is observational. Molecular causality is substantially stronger, supported by segregation, patient-derived megakaryocytes, allele-specific expression, chromatin profiling, chromosome-conformation capture, reporter experiments, and downstream animal phenocopy.

References

1. (hayward2017theduplicationmutation pages 1-2): Catherine P. M. Hayward, Minggao Liang, Subia Tasneem, Asim Soomro, John S. Waye, Andrew D. Paterson, Georges E. Rivard, and Michael D. Wilson. The duplication mutation of quebec platelet disorder dysregulates plau, but not c10orf55, selectively increasing production of normal plau transcripts by megakaryocytes but not granulocytes. PLOS ONE, 12(3):e0173991, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173991, doi:10.1371/journal.pone.0173991. This article has 27 citations and is from a peer-reviewed journal.

2. (hayward2017theduplicationmutation pages 2-3): Catherine P. M. Hayward, Minggao Liang, Subia Tasneem, Asim Soomro, John S. Waye, Andrew D. Paterson, Georges E. Rivard, and Michael D. Wilson. The duplication mutation of quebec platelet disorder dysregulates plau, but not c10orf55, selectively increasing production of normal plau transcripts by megakaryocytes but not granulocytes. PLOS ONE, 12(3):e0173991, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173991, doi:10.1371/journal.pone.0173991. This article has 27 citations and is from a peer-reviewed journal.

3. (mckay2004bleedingrisksassociated pages 1-2): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

4. (liang2020enhancergenerewiringin pages 15-16): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

5. (blavignac12011quebecplateletdisorder pages 1-2): Jessica Blavignac1, Natalia Bunimov1, Georges Rivard2, and Catherine P.M. Hayward1. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost, 37:713-720, Sep 2011. URL: https://doi.org/10.1055/s-0031-1291382, doi:10.1055/s-0031-1291382. This article has 79 citations.

6. (OpenTargets Search: Quebec platelet disorder-PLAU): Open Targets Query (Quebec platelet disorder-PLAU, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

7. (blavignac12011quebecplateletdisorder pages 2-3): Jessica Blavignac1, Natalia Bunimov1, Georges Rivard2, and Catherine P.M. Hayward1. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost, 37:713-720, Sep 2011. URL: https://doi.org/10.1055/s-0031-1291382, doi:10.1055/s-0031-1291382. This article has 79 citations.

8. (paterson2010personswithquebec pages 3-4): Andrew D. Paterson, Johanna M. Rommens, Bhupinder Bharaj, Jessica Blavignac, Isidro Wong, Maria Diamandis, John S. Waye, Georges E. Rivard, and Catherine P. M. Hayward. Persons with quebec platelet disorder have a tandem duplication of plau, the urokinase plasminogen activator gene. Blood, 115 6:1264-6, Feb 2010. URL: https://doi.org/10.1182/blood-2009-07-233965, doi:10.1182/blood-2009-07-233965. This article has 116 citations and is from a highest quality peer-reviewed journal.

9. (liang2020enhancergenerewiringin pages 10-12): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

10. (hayward2017theduplicationmutation pages 16-17): Catherine P. M. Hayward, Minggao Liang, Subia Tasneem, Asim Soomro, John S. Waye, Andrew D. Paterson, Georges E. Rivard, and Michael D. Wilson. The duplication mutation of quebec platelet disorder dysregulates plau, but not c10orf55, selectively increasing production of normal plau transcripts by megakaryocytes but not granulocytes. PLOS ONE, 12(3):e0173991, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173991, doi:10.1371/journal.pone.0173991. This article has 27 citations and is from a peer-reviewed journal.

11. (liang2020enhancergenerewiringin pages 6-7): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

12. (liang2020enhancergenerewiringin pages 13-14): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

13. (liang2020enhancergenerewiringin pages 12-13): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

14. (diamandis2009biochemicalandgenetic pages 129-133): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

15. (hayward2017theduplicationmutation pages 6-9): Catherine P. M. Hayward, Minggao Liang, Subia Tasneem, Asim Soomro, John S. Waye, Andrew D. Paterson, Georges E. Rivard, and Michael D. Wilson. The duplication mutation of quebec platelet disorder dysregulates plau, but not c10orf55, selectively increasing production of normal plau transcripts by megakaryocytes but not granulocytes. PLOS ONE, 12(3):e0173991, Mar 2017. URL: https://doi.org/10.1371/journal.pone.0173991, doi:10.1371/journal.pone.0173991. This article has 27 citations and is from a peer-reviewed journal.

16. (diamandis2009biochemicalandgenetica pages 80-83): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

17. (diamandis2009biochemicalandgenetica pages 66-69): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

18. (diamandis2009biochemicalandgenetic pages 66-69): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

19. (mckay2004bleedingrisksassociated pages 3-4): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

20. (mckay2004bleedingrisksassociated pages 4-5): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

21. (diamandis2009biochemicalandgenetica pages 69-72): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

22. (blavignac12011quebecplateletdisorder pages 4-6): Jessica Blavignac1, Natalia Bunimov1, Georges Rivard2, and Catherine P.M. Hayward1. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost, 37:713-720, Sep 2011. URL: https://doi.org/10.1055/s-0031-1291382, doi:10.1055/s-0031-1291382. This article has 79 citations.

23. (wilson2023preoperativediagnosisand pages 6-7): MD MSc R. Douglas Wilson. Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults. Canadian Journal of Surgery, 66:E246-E263, May 2023. URL: https://doi.org/10.1503/cjs.005922, doi:10.1503/cjs.005922. This article has 7 citations and is from a peer-reviewed journal.

24. (blavignac12011quebecplateletdisorder pages 6-6): Jessica Blavignac1, Natalia Bunimov1, Georges Rivard2, and Catherine P.M. Hayward1. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost, 37:713-720, Sep 2011. URL: https://doi.org/10.1055/s-0031-1291382, doi:10.1055/s-0031-1291382. This article has 79 citations.

25. (mckay2004bleedingrisksassociated pages 5-6): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

26. (diamandis2009biochemicalandgenetic pages 80-83): M Diamandis. Biochemical and genetic studies. Unknown journal, 2009.

27. (mckay2004bleedingrisksassociated pages 2-3): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

28. (liang2020enhancergenerewiringin pages 23-24): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

29. (mckay2004bleedingrisksassociated pages 6-8): Heather McKay, Francine Derome, M. Anwar Haq, Susan Whittaker, Emmy Arnold, Frédéric Adam, Nancy M. Heddle, Georges E. Rivard, and Catherine P. M. Hayward. Bleeding risks associated with inheritance of the quebec platelet disorder. Blood, 104 1:159-65, Jul 2004. URL: https://doi.org/10.1182/blood-2003-11-4077, doi:10.1182/blood-2003-11-4077. This article has 133 citations and is from a highest quality peer-reviewed journal.

30. (liang2020enhancergenerewiringin pages 24-25): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

31. (liang2020enhancergenerewiringin pages 9-10): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

32. (liang2020enhancergenerewiringin pages 8-9): Minggao Liang, Asim Usman Soomro, Subia Tasneem, Luis E Abatti, Azad Alizada, Xuefei Yuan, Liis Uusküla-Reimand, Lina Antounians, Sana Akhtar Alvi, Andrew David Paterson, Georges E Rivard, Ian C Scott, Jennifer A Mitchell, Catherine P M Hayward, and Michael Davies Wilson. Enhancer-gene rewiring in the pathogenesis of quebec platelet disorder. Blood, Jul 2020. URL: https://doi.org/10.1182/blood.2020005394, doi:10.1182/blood.2020005394. This article has 41 citations and is from a highest quality peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

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

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0011136 (3 mentions) - the report calls it "if available"; MONDO calls it Quebec platelet disorder

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0001873 (2 mentions) - the report calls it "HPO: Thrombocytopenia"; HP calls it Thrombocytopenia

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Gene, Taxon.