Blood, 1 August 2002, Vol. 100, No. 3, pp. 742-742
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 antithrombinare 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.
Björn Dahlbäck
University of Lund
