Factor V Leiden Mutation Molecular Basis of Disease

Initial APC cleavage at arginine (R) 506 of F5a is required for optimal exposure and subsequent rapid inactivation of F5a by subsequent APC cleavage at positions R306 (in the presence of phospholipid and protein S) and R679 (Figure 12-8). The discovery of three unrelated patients with idio-pathic VTE, whose plasma was resistant to the anticoagulant effect of exogenously added APC, provided exciting new insights into the etiology of VTE.17 Early epidemio-logical data suggested that activated protein C resistance (APC-R) was familial with an autosomal dominant inheritance pattern. Procoagulant F5 isolated from APC-R patient plasma was resistant to inactivation by APC, triggering an intensive search for the genetic explanation.18 Subsequent work identified a single point mutation, called Factor V Leiden, of guanine (G) to adenine (A) at nucleotide 1691 within exon 10 of the F5 gene on chromosome 1 (1q21-25).19 Factor V Leiden encodes for substitution of a glutamine (Q) for arginine (R) at amino acid position 506 within the heavy chain of F5, at one of three APC cleavage sites (R306,R506,R679). Factor V Leiden promotes thrombosis by impaired downregulation of the generation of thrombin and by inhibition of fibrinolysis.

94 Kd

74 Kd

F5a

A1

A2

Ca2+

A3

C1

C2

Activated protein C

R306

R506 R679

F5i

A3

C1

C2

Figure 12-8. Cleavage sites for inactivation of activated factor V. F5a, activated factor V; F5i, inactivated factor V; Kd, kilodalton; Ca2+, calcium; Arrows, cleavage sites; R, arginine.

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