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Homocysteine, coagulation, platelet function, and thrombosis
A Coppola1, G Davi, V De Stefano
1Department of Clinical and Experimental Medicine, University of Naples Federico II, Italy.
Insights
High homocysteine (HHcy) is a vascular risk factor. Oxidative stress from homocysteine (Hcy) may cause vascular injury and thrombosis, impacting cell repair and promoting clotting.
Area of Science:
- Vascular Biology
- Thrombosis
- Biochemistry
Background:
- Hyperhomocysteinemia (HHcy) is an established independent vascular risk factor.
- Mechanisms linking elevated homocysteine (Hcy) to vascular injury and thrombosis are not fully understood.
- Previous studies often used high in vitro Hcy concentrations, with limited in vivo human data.
Purpose of the Study:
- To elucidate the mechanisms by which elevated homocysteine contributes to vascular injury and thrombosis.
- To investigate the role of oxidative stress and impaired cell repair in HHcy-associated thrombosis.
- To explore potential therapeutic interventions targeting Hcy-induced vascular pathology.
Main Methods:
- Review of existing literature on hyperhomocysteinemia and vascular disease.
- Analysis of in vitro and in vivo studies in homocystinuric patients and healthy individuals.
- Examination of biochemical pathways involving homocysteine autooxidation, reactive oxygen species, and methyltransferase inhibition.
Main Results:
- Homocystinuric patients exhibit coagulation abnormalities and in vivo platelet activation.
- Antioxidant drug probucol partially corrects platelet activation, suggesting a role for oxidative stress.
- Homocysteine autooxidation generates reactive oxygen species, leading to lipid peroxidation and potential endothelial dysfunction.
- Accumulation of adenosylhomocysteine inhibits methyltransferases, impairing cellular repair.
Conclusions:
- Oxidative stress induced by homocysteine is a key factor in the pathogenesis of thrombosis in HHcy.
- Impaired cellular repair due to methyltransferase inhibition offers another pathway contributing to thrombosis risk.
- These findings highlight the critical role of homocysteine metabolism and oxidative stress in vascular health.
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 beta-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.