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 Blood, 1 November 2008, Vol. 112, No. 9, pp. 3615-3623.
Prepublished online as a Blood First Edition Paper on August 11, 2008; DOI 10.1182/blood-2008-06-162453.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency

Connie Duckers1, Paolo Simioni2, Luca Spiezia2, Claudia Radu2, Sabrina Gavasso2, Jan Rosing1, and Elisabetta Castoldi1

1 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands; and 2 Department of Medical and Surgical Sciences, University of Padua Medical School, Padua, Italy

Severe factor V (FV) deficiency is associated with mild to severe bleeding diathesis, but many patients with FV levels lower than 1% bleed less than anticipated. We used calibrated automated thrombography to screen patients with severe FV deficiency for protective procoagulant defects. Thrombin generation in FV-deficient plasma was only measurable at high tissue factor concentrations. Upon reconstitution of FV-deficient plasma with purified FV, thrombin generation increased steeply with FV concentration, reaching a plateau at approximately 10% FV. FV-deficient plasma reconstituted with 100% FV generated severalfold more thrombin than normal plasma, especially at low tissue factor concentrations (1.36 pM) or in the presence of activated protein C, suggesting reduced tissue factor pathway inhibitor (TFPI) levels in FV-deficient plasma. Plasma TFPI antigen and activity levels were indeed lower (P < .001) in FV-deficient patients (n = 11; 4.0 ± 1.0 ng/mL free TFPI) than in controls (n = 20; 11.5 ± 4.8 ng/mL), while persons with partial FV deficiency had inter-mediate levels (n = 16; 7.9 ± 2.5 ng/mL). FV immunodepletion experiments in normal plasma and surface plasmon resonance analysis provided evidence for the existence of a FV/TFPI complex, possibly affecting TFPI stability/clearance in vivo. Low TFPI levels decreased the FV requirement for minimal thrombin generation in FV-deficient plasma to less than 1% and might therefore protect FV-deficient patients from severe bleeding.


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