Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms.
Coagulation factor V (FV), present in plasma and platelets, is indispensable to thrombin formation, yet patients with undetectable plasma FV seldom experience major bleeding. We used thrombin generation assays to explore the role of platelet FV in 4 patients with severe congenital FV deficiency (3 with plasma FV clotting activity [FV:C] < 1%). When triggered with tissue factor (TF) concentrations up to 50pM, platelet-poor plasma (PPP) from the patients with undetectable plasma FV showed no thrombin generation, whereas platelet-rich plasma (PRP) formed thrombin already at 1 to 5pM of TF. Thrombin generation in PRP from the FV-deficient patients was enhanced to near-normal levels by platelet activators (collagen or Ca(2+)-ionophore) and could be completely suppressed by specific FV inhibitors, suggesting FV dependence. Accordingly, platelet FV antigen and activity were measurable in all FV-deficient patients and platelet FVa could be visualized by Western blotting. Normalization of the tissue factor pathway inhibitor (TFPI) level, which is physiologically low in FV-deficient plasma, almost completely abolished thrombin generation in PRP from the FV-deficient patients. In conclusion, patients with undetectable plasma FV may contain functional FV in their platelets. In combination with low TFPI level, residual platelet FV allows sufficient thrombin generation to rescue these patients from fatal bleeding.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Connie
C
Duckers
Paolo
P
Simioni
Luca
L
Spiezia
Claudia
C
Radu
Paolo
P
Dabrilli
Sabrina
S
Gavasso
Jan
J
Rosing
Elisabetta
E
Castoldi
D000328:Adult; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D005166:Factor V Deficiency / Q000097:blood* / Q000235:genetics; D005260:Female; D006474:Hemorrhagic Disorders / Q000097:blood* / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008074:Lipoproteins / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense; D015539:Platelet Activation; D012720:Severity of Illness Index; D013917:Thrombin / Q000096:biosynthesis*; D055815:Young Adult
D001779:Blood Coagulation Factors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; C037685:platelet factor V; D013917:Thrombin