An autosomal dominant, qualitative platelet disorder associated with multimerin deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen and an epinephrine aggregation defect

Abstract

Multimerin is a massive soluble, multimeric protein found in platelets and endothelial cells. Recent studies identified multimerin as a specific coagulation factor V binding protein, complexed with platelet, but not plasma, factor V. These findings led us to investigate individuals with inherited factor V deficiencies for possible multimerin abnormalities. Platelet proteins were evaluated using immunoassays, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, immunoprecipitation, and direct binding studies. Patients with factor V Quebec, a disorder with abnormal platelet factor V, had a quantitative deficiency in multimerin (n = 11 tested; mean, 12.5%; range, 5% to 27% of the normal pool; normal range, 45% to 214%) with a normal multimer pattern. Quantitative and qualitative abnormalities were detected in their platelet factor V. An unrelated patient who was deficient in platelet and plasma factor V had normal platelet multimerin. The levels of platelet beta- thromboglobulin, von Willebrand factor, thrombospondin, and fibrinogen antigen were normal in the factor V Quebec patients. However, proteins with abnormal mobility were detected in their platelet lysate and releasate, and their platelet thrombospondin, von Willebrand factor, and fibrinogen showed evidence of proteolytic degradation. Platelet counts of the factor V Quebec patients ranged from mildly thrombocytopenic to low normal (mean, 159 x 10(9)/L; range, 104 to 198 x 10(9)/L). In addition, their platelets failed to aggregate in response to 6 to 10 micromol/L epinephrine despite normal numbers of platelet alpha 2-adrenergic receptors. These data indicate that patients with factor V Quebec have an inherited bleeding disorder distinct from other platelet disorders and associated with multiple abnormalities, including multimerin deficiency, abnormal platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen, and an epinephrine aggregation defect.

The storage defects in grey platelet syndrome and αδ‐storage pool deficiency affect α‐granule factor V and multimerin storage without altering their proteolytic processing

“…Normal ranges for platelet lysate were determined using 20 healthy controls. Assays of normal and factor V-deficient plasmas (George King Biomedical) and platelets (Hayward et al, 1996) confirmed that this ELISA was specific for factor V. Its lower limit of detection was 2±3 ng of factor V/ml sample.…”

“…27% of normal pooled platelet lysate). These data indicated that the storage defect in GPS allowed multimerin to associate with the plasma pool of factor V. (Hayward et al, 1996). ²Values outside the normal range (mean^2 S.D.).…”

“…Multimerin was measured using an enzyme-linked immunosorbent assay (ELISA) and a pooled platelet lysate standard [one milliunit (mU) of multimerin antigen was defined as the amount in 10 6 pooled, normal platelets] (Hayward et al, 1996). The lower limit of detection of this ELISA was 4±5 mU of multimerin/ml sample.…”

Fibrinogen degradation products in patients with the Quebec platelet disorder

“…The Quebec platelet disorder is an autosomal dominant bleeding disorder (previously known as factor V Quebec) associated with mildly-reduced to low-normal platelet counts, abnormal epinephrine aggregation, platelet multimerin deficiency, and pathologic proteolysis of many proteins stored in platelet a-granules, including factor V, thrombospondin, fibrinogen, von Willebrand factor, osteonectin, fibronectin and P-selectin (Hayward et al, 1996(Hayward et al, , 1997Janeway et al, 1996;Tracy et al, 1984). Patients with this disorder suffer from mucocutaneous bleeding, moderatesevere bleeding following surgery or trauma, and, less commonly, haemarthroses and intracranial haemorrhage (Hayward et al, 1996(Hayward et al, , 1997Janeway et al, 1996;Tracy et al, 1984). Recognition of this disorder is important for several reasons.…”

“…First, in contrast to many platelet disorders, patients with Quebec platelet disorder do not respond to platelet transfusions (Hayward et al, 1996(Hayward et al, , 1997Janeway et al, 1996). However, many bleeding episodes can be successfully treated or prevented with fibrinolytic inhibitors (Hayward et al, 1996(Hayward et al, , 1997. Furthermore, as this disorder is inherited as an autosomal dominant trait, recognition is important for genetic counselling.…”