Factor V Leiden and the genetics of myocardial infarction: we need to look elsewhere

In the July 1, 2002, issue of Blood, Juul and colleagues (Blood. 2002;100:3-10) convincingly demonstrate Factor V Leiden (FVL) to be a risk factor neither for myocardial infarction (MI) nor for ischemic stroke or non–MI ischemic heart disease. FVL is a point mutation in the gene for factor V, which results in the replacement of single amino acid residue: Arg506 is changed to Gln. As a consequence, the FV molecule becomes less sensitive to cleavage and inhibition by the anticoagulant serine protease activated protein C (APC). The condition is also known as APC resistance. The hypercoagulable state being associated with FVL conveys a lifelong 5- to 10-fold increased risk factor for venous thrombosis, FVL being the most prevalent genetic risk factor for venous thrombosis yet described. It is present in 2%-15% of white populations, whereas it is absent in other populations, this difference contributing an explanation for the low incidence of venous thrombosis in nonwhite populations. FVL is the result of a founder effect, the single mutational event being estimated to have occurred approximately 30 000 years ago. A reason for the high prevalence of FVL in certain populations is believed to be that the associated hypercoagulable state conveys a survival advantage to its carriers due to decreased risk of severe bleeds, for example, after delivery. The results of Juul et al highlight an interesting difference in the pathogenesis of arterial and venous thrombosis. None of the known genetic risk factors of venous thrombosis—that is, FVL, the 20210G>A mutation in the prothrombin gene, and deficiencies of protein C, protein S, and antithrombin—are risk factors for arterial thrombosis. Arterial thrombosis is developing in a high-flow, high-pressure system and is usually associated with atherosclerotic plaque ruptures resulting in the formation of a platelet plug and concomitant activation of blood coagulation through the exposure of plaque-associated tissue factor. In contrast, venous thrombosis develops at low flow rate in a low-pressure system, where the naturally occurring anticoagulant pathways apparently are crucial for inhibition of thrombosis. These anticoagulant pathways are insufficient in preventing thrombosis in the arterial circulation in the event of an atherosclerotic plaque rupture. The search for genetic risk factors of MI will continue and will hopefully provide insights into the pathogenetic mechanisms of arterial thrombosis. The results of Juul et al demonstrate that genetic investigation of the protein C system is less likely to provide the solution to the problem.