Factor V (Quebec): a bleeding diathesis associated with a qualitative platelet Factor V deficiency.

Abstract

Abstract. Studies were performed on a FrenchCanadian family afflicted with a bleeding disorder exhibiting an autosomal dominant inheritance pattern and a severe bleeding diathesis after trauma. Clinical laboratory coagulation tests were unimpressive; the only persistent abnormalities include mild thrombocytopenia and moderately reduced Factor V clotting activities. Some individuals had prolonged Stypven times when platelet-rich plasma was used, suggesting that their platelets could not support functional prothrombinase complex assembly. Detailed studies were performed by use of plasma and isolated, washed platelets from a sister and brother. Bioassay data indicate that both individuals had Factor V activities of -40 and 36% of normal, respectively. A comparison of the Factor V radioimmunoassay and bioassay data on the brother's plasma indicated that the circulating amount of Factor V functional activity was low relative to Factor V antigen concentration (-65-75%). In both individuals, the platelet Factor V functional activities were extremely low (2-4%) relative to antigen levels present as determined by radioimmunoassay. These discrepancies between Factor V activities and antigen concentration do not appear to be due to an unstable Factor V molecule or to the presence of a Factor V or Factor Va inhibitor or inactivator. Kinetics of prothrombin activation by use of purified clotting factors indicated that thrombinactivated platelets from both individuals supported prothrombinase complex assembly identical to controls in the presence of added purified Factor Va. Consequently, their bleeding diathesis appears to reflect their platelet, rather than their plasma, Factor V activity. These results suggest that platelet Factor V is an essential component in maintaining stable and prolonged hemostasis after trauma.

Bleeding risks associated with inheritance of the Quebec platelet disorder

“…One hundred twenty-seven relatives within 2 families with known inheritance of QPD 11,12 participated in the study. When information for the updated pedigree was acquired, a common ancestor was identified, allowing the 2 pedigrees to be merged ( Figure 1).…”

“…[11][12][13][14][15][16] The cases initially reported had moderate to severe delayed bleeding problems that responded to treatment with fibrinolytic inhibitors. [11][12][13] Although these bleeding problems were initially attributed to a deficiency of functional platelet factor V, and hence the designation factor V Quebec, the disorder is now known to be associated with a complex spectrum of unique platelet and fibrinolytic abnormalities that include increased megakaryocyte expression and storage of urokinase-type plasminogen activator (u-PA), ␣-granule protein degradation associated with intraplatelet generation of plasmin, normal to increased plasma u-PA without increased plasma D-dimers, normal to reduced platelet counts, absent platelet aggregation responses to 6 M epinephrine, and normal to abnormal aggregation responses to collagen and adenosine diphosphate (ADP). [11][12][13][14][15][16][17] Access to affected and unaffected individuals within families with QPD, the large pedigree sizes, and definitive blood tests for QPD [12][13][14] provided a unique opportunity to investigate bleeding risks for an autosomal dominant trait and to gather data on responses of QPD bleeding to fibrinolytic inhibitor therapy.…”

Platelets from patients with the Quebec platelet disorder contain and secrete abnormal amounts of urokinase-type plasminogen activator

“…1,[4][5][6] This disorder was initially designated as factor V Quebec because of the abnormalities found in platelet factor V of these patients. 7 Two families from Quebec have been identified with this condition, which is now known to be associated with other platelet abnormalities that include reduced to low-normal platelet counts, proteolytic degradation of soluble and membrane proteins stored in platelet ␣-granules, an apparent quantitative deficiency of the ␣-granule protein multimerin, and defective aggregation with epinephrine. 1,[4][5][6]8 Although patients with the QPD have elevated levels of fibrinogen degradation products (FDPs) in their serum (because of platelet fibrinogen degradation), their plasma contains normal amounts of FDPs and D-dimers.…”

Unique in Vivo Modifications of Coagulation Factor V Produce a Physically and Functionally Distinct Platelet-derived Cofactor

“…Its paramount importance in the maintenance of normal hemostasis, when compared with that of plasma-derived FVa, has been demonstrated in several clinical studies. Individuals expressing substantially decreased levels of FV in their platelets exhibit a life-threatening bleeding diathesis despite their expression of relatively normal levels of plasma-derived FV (4). An individual with an antibody that neutralized greater than 99% of the plasmaderived FV pool endured surgical challenge as the antibody was without effect on platelet-derived FV/Va, indicating that the platelet stores of FV/Va were sufficient to maintain normal hemostasis (11).…”