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Factor V Quebec revisited
C M Janeway1, G E Rivard, P B Tracy
1Department of Biochemistry, University of Vermont, College of Medicine, Burlington 05404-0068, USA.
Insights
Factor V Quebec disorder, a bleeding condition, involves defective platelet factor V. This study reveals a generalized defect causing degradation of alpha-granule proteins in platelets.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Factor V Quebec is an autosomal dominant bleeding disorder causing severe bleeding post-trauma.
- Previous studies noted mild thrombocytopenia and defective platelet factor V in affected individuals.
- Plasma factor V is near normal and functional, suggesting a platelet-specific issue.
Purpose of the Study:
- To reevaluate patients with Factor V Quebec disorder following reports of multimerin deficiency.
- To investigate the underlying molecular defect causing the bleeding diathesis.
- To determine the integrity of alpha-granule proteins in affected platelets.
Main Methods:
- Western blot analysis of platelet lysates.
- Use of monoclonal antibodies to detect specific proteins.
- Comparative analysis between affected individuals and controls (implied).
Main Results:
- Alpha-granule proteins (fibrinogen, von Willebrand factor, factor V, osteonectin) were decreased and degraded in patient platelets.
- Thrombospondin was decreased but not degraded.
- Platelet factor 4 and beta-thromboglobulin levels were unaffected.
- Platelet alpha-granules appear to be assembled correctly but their contents undergo degradation.
Conclusions:
- Factor V Quebec disorder is associated with a generalized defect leading to the degradation of most alpha-granule proteins.
- The bleeding diathesis likely stems from the absence of functional platelet factor V due to this degradation.
- This defect impacts multiple proteins within platelet alpha-granules, not just factor V.
Abstract:
Factor V Quebec has been described as a bleeding disorder that exhibits an autosomal dominant inheritance pattern and presents severe bleeding after trauma. Two members of a fourth-generation (IV.13 and IV.15) Canadian family have been studied in detail and are the subject of this report. Their clinical presentations and histories have been described previously (Tracy et al: J Clin Invest 74:1221, 1984). Persistent abnormalities include mild thrombocytopenia and defective platelet factor V. Plasma factor V is present at near normal concentration and is fully functional. Thus, the bleeding diathesis appears to reflect the absence of platelet factor V activity. The recent report (Hayward et al: Blood 84:110a, 1994 [suppl, abstr]) of multimerin deficiency in these individuals led us to reevaluate these patients. Western blot analyses of platelet lysates developed with a variety of monoclonal antibodies show that the alpha-granule proteins, fibrinogen, von Willebrand factor, factor V and osteonectin are decreased in concentration and significantly degraded in the platelets of these patients. Thrombospondin, while not degraded, is substantially decreased. In contrast, platelet factor 4 and beta-thromboglobulin do not appear to be affected. These observations suggest that the alpha-granules are correctly assembled but the contents are subsequently subjected to proteolytic degradation. The results indicate that factor V Quebec disorder is probably associated with a generalized defect that leads to degradation of most proteins of the alpha-granules.