ABSTRACT
Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia
(HHcy) as an independent vascular risk factor. However, the mechanisms through which
elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote
thrombosis remain elusive. Most findings have been achieved in in vitro studies employing
exceedingly high concentrations of Hcy, whereas only a few studies have been carried
out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the
gene coding for the cystathionine β-synthase enzyme, abnormalities of coagulation
variables reflecting a hypercoagulable state, have been reported. In vitro studies
provide a biochemical background for such a state. In homocystinuric patients, an
in vivo platelet activation has also been reported. The latter abnormality is not
corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting
impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it
appears at least in part lowered by the administration of the antioxidant drug probucol.
During the autooxidation of Hcy in plasma, reactive oxygen species are generated.
The latter initiate lipid peroxidation in cell membranes (potentially responsible
for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density
lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic
abnormalities reported in such patients. Thus the oxidative stress induced by Hcy
may be a key process in the pathogenesis of thrombosis in HHcy.
Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels
of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of
aged or damaged cells. This mechanism has been recently documented in patients with
renal failure and HHcy and provides an additional direction to be followed to understand
the tendency to thrombosis in moderate HHcy.
KEYWORD
Homocysteine - platelets - hypercoagulable state - oxidative stress - endothelial
dysfunction
