Congenital and Acquired Activated Protein C Resistance

Abstract

Resistance to the anticoagulant action of activated protein C, APC resistance, is a highly prevalent risk factor for venous thrombosis among individuals of Caucasian origin. In most cases, APC resistance is associated with a single missense mutation in the gene for coagulation factor V (FV (Leiden)), which predicts the replacement of Arg (506) with a Gln at one of the cleavage sites for APC in factor V. Factor V is a Janus-faced protein with dual functions, serving as an essential nonenzymatic cofactor in both pro- and anticoagulant pathways. Procoagulant factor Va, generated after proteolysis by thrombin or factor Xa, is a cofactor to factor Xa in the activation of prothrombin, whereas anticoagulant factor V, generated after proteolysis by APC, functions as a cofactor in the APC-mediated degradation of FVIIIa. The FV (Leiden) mutation affects the anticoagulant response to APC at two distinct levels of the coagulation pathway, as it impairs degradation of both activated factor V and activated factor VIII, the latter effect inasmuch as FVLeiden is a poor APC cofactor. Several other genetic traits, some of them quite common, are known to affect the anticoagulant response to APC, but none of them cause the same severe APC-resistance phenotype as FV (Leiden) and their importance as risk factors for thrombosis is unclear. A poor APC response may also result from acquired conditions, some of which are clearly involved in the pathogenesis of venous thrombosis. Venous thrombosis is a typical multifactorial disease, the pathogenesis of which involves multiple gene-gene and gene-environment interactions. In many patients with severe thrombophilia, APC resistance is found as a contributing risk factor.

The effect of aprotinin on activated protein C‐mediated downregulation of endogenous thrombin generation

“…Although the carriers of factor V Leiden mutation that undergo CPB have been reported to have a lower transfusion rate and chest tube drainage compared with non-carrier patients (Sweeney et al, 1997;Donahue et al, 2003), the association between arterial thromboses (e.g. graft occlusion) and factor V mutation is not conclusive (Nicolaes & Dahlback, 2003). The present findings shed light on the generation of thrombin and APC that was not previously appreciated.…”

Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

“…In America, where the population is of mixed ethnic background the prevalence is Ϸ5% in the north and somewhat lower in the south. 69,71 Heterozygous individuals have Ϸ5-fold increased risk of venous thrombosis, whereas homozygotes have Ϸ50-fold increased risk. The mutation is not a risk factor for arterial thrombosis.…”

Value of Protein C and D-Dimer in Predicting Non Hepatocellular Carcinoma Portal Vein Thrombosis in Patients with Liver Cirrhosis

“…Protein C (PC) is a major physiological anticoagulant that is synthesized in the liver, circulates in plasma and is considered a key component of an important natural anticoagulant pathway [5,6]. It is vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC), and the treatment with vitamin K antagonists might further reduce the level of this naturally occurring anticoagulant in patients with liver cirrhosis, increasing the risk of thrombosis [5].…”