Biochemical Prototype for Familial Thrombosis

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Abstract
Abstract Resistance to activated protein C (APC) is associated with a single amino acid substitution in factor V (Arg 506 →Gln, factor V Leiden) that results in delayed inactivation of the molecule by APC. The mutation is present in 20% of patients with a first episode of deep venous thrombosis. Arterial and venous thromboses are also associated with the type II protein C deficiency (protein C Vermont ). In protein C Vermont , the substitution Glu 20 →Ala alone (rPC γ20A ) is responsible for the defective anticoagulant properties of PC Vermont . It was recently established that a thrombotic episode occurred in 73% of family members who are heterozygous for both a functional protein C gene mutation and the factor V Leiden mutation. We evaluated the molecular defect that would accrue in the combined deficiency state of factor V R506Q /Va R506Q and rAPC γ20A using recombinant APC and natural purified factor V R506Q from patients homozygous for the Arg 506 →Gln substitution. While wild-type recombinant APC (rAPC) slowly cleaves and inactivates factor V R506Q and factor Va R506Q , minimal cleavage of membrane-bound factor V R506Q and Va R506Q by rAPC γ20A at Arg 306 and Arg 679 occurs, and no loss in cofactor activity is observed. Our data demonstrate that rAPC γ20A cannot inactivate either factor V R506Q or factor Va R506Q at biologically relevant rates because of impaired cleavage at Arg 306 and Arg 679 . The result is a stable procofactor and stabilization of an active cofactor in patients possessing both mutations. Our data provide a prototype of familial thrombosis that most likely would be manifested in vivo by the occurrence of massive thrombosis.