Quebec Platelet Disorder

A number sign (#) is used with this entry because Quebec platelet disorder (QPD) is caused by heterozygous tandem duplication of the PLAU gene (191840) on chromosome 10q22.

Description

Quebec platelet disorder is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. The disorder shows a favorable therapeutic response to fibrinolytic inhibitors (summary by Diamandis et al., 2009).

Clinical Features

Hayward et al. (1996) described an autosomal dominant bleeding disorder in a Quebec family that was associated with reduced to normal platelet counts, defective epinephrine aggregation, and multiple glycoprotein abnormalities. This disorder had previously been designated as factor V Quebec by Tracy et al. (1984) because of abnormalities in platelet factor V (612309). Hayward et al. (1997) studied a second family with an unexplained, autosomal dominant bleeding disorder. They found that these patients were deficient in multimerin (601456), a soluble, multimeric factor V binding protein found in platelet alpha-granules and in endothelium. However, in these patients, they also found proteolytic degradation of the platelet alpha-granule proteins factor V, von Willebrand factor (613160), fibrinogen (134820), and thrombospondin (see 188060). Similar findings, including degradation of platelet osteonectin (182120), were reported by Janeway et al. (1996). However, platelet albumin, IgG (see 147100), external membrane glycoproteins, CD63 (155740; a lysosomal and dense granular protein), calpain (see 114220), and plasma von Willebrand factor were normal, indicating restriction in the proteins proteolyzed. Hayward et al. (1997) suggested that pathologic proteolysis of alpha-granular contents, rather than a defect in targeting proteins to alpha-granules, may be the cause of the protein degradation in the Quebec platelet disorder.

To determine bleeding risks and common manifestations of QPD, McKay et al. (2004) developed a history questionnaire which they administered to 127 relatives in a family with QPD. Affected individuals, as identified by assays for platelet urokinase-type plasminogen activator and fibrinogen degradation, had higher mean bleeding scores and a much higher likelihood of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeding, bleeding longer than 24 hours after dental extractions or deep cuts, and received or had been recommended other treatments (fibrinolytic inhibitors) for bleeding. Individuals with QPD and exposure(s) to hemostatic challenges had experienced excessive bleeding only when fibrinolytic inhibitors had not been used. McKay et al. (2004) suggested that QPD is associated with increased risk of bleeding that can be modified by fibrinolytic inhibitors.

Biochemical Features

Kahr et al. (2001) pointed out that QPD is the only inherited bleeding disorder in humans known to be associated with increased urokinase-type plasminogen activator (PLAU; 191840). Unlike normal platelets, QPD platelets contain large amounts of fibrinolytic serine proteases with properties of plasminogen activators. Western blot analysis, zymography, and immunodepletion experiments indicated that this was the result of large amounts of urokinase-type plasminogen activator within a secretory compartment. PLAU antigen was not increased in all QPD plasmas, but was increased more than 100-fold in QPD platelets, which, furthermore, contained increased PLAU mRNA. Although QPD platelets also contained 2-fold more plasminogen activator inhibitor-1 (PAI1; 173360) and 100-fold greater complexes of PLAU with PAI1, they contained excess PLAU activity, predominantly in the form requiring additional PAI1 for full inhibition. Kahr et al. (2001) presented data implicating PLAU in the pathogenesis of alpha-granule protein degradation in QPD. Although patients with QPD have normal to increased PLAU levels in their plasma, without evidence of systemic fibrinogenolysis, their increased platelet PLAU may contribute to bleeding by accelerating fibrinolysis within the hemostatic plug.

Inheritance

Quebec platelet disorder shows autosomal dominant inheritance (Hayward et al., 1996).

Population Genetics

Diamandis et al. (2009) stated that Quebec platelet disorder has a prevalence of 1 in 300,000 in Quebec, Canada.

Mapping

By genotyping markers on chromosome 10q24, which contains the PLAU gene, in patients with QPD, Diamandis et al. (2009) found significant linkage to a 2-Mb region in this area (maximum multipoint LOD score of greater than 11 between markers D10S1432 and D10S1136). QPD was distinctly associated with increased PLAU mRNA levels during megakaryocyte differentiation. However, sequencing and Southern blotting excluded mutations in the PLAU gene and its known regulatory elements as the cause of the disorder. Diamandis et al. (2009) concluded that a mutation in an uncharacterized cis element near PLAU causes QPD.

Molecular Genetics

In 38 patients with Quebec platelet disorder, Paterson et al. (2010) identified a heterozygous 78-kb tandem duplication of the PLAU gene (191840.0002). The authors postulated that the duplication resulted in increased PLAU expression, which has been found in patients with the disorder.