In a report published in the journal Metabolites, researchers describe an underappreciated mechanism through which hyperhomocysteinemia (HHcy) contributes to thrombosis, directly and indirectly activating platelets. Excessive platelet activation can lead to exhaustion and impaired contractility, making clots larger and more obstructive.
To study the mechanistic links between homocysteine (Hcy), a metabolic intermediate of methionine, and blood clot kinetics, the investigators evaluated the impact of Hcy levels on clot contraction in human and rat blood samples in vitro and in a rat model of HHcy in vivo.
Human blood with no diseases and rat blood were incubated (1 and 15 minutes) with exogenous Hcy at various concentrations within and exceeding the normal range of Hcy (5, 20, and 50 μM) for both species. Clot formation and kinetics of clot contraction were monitored.
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The 1-minute incubation of blood from either species with Hcy enhanced clot contraction. In contrast, the 15-minute incubation resulted in a dose-dependent suppression of contraction. Further evaluation of human platelet functionality in the absence of thrombin or any other platelet stimulants indicated an increase in fibrinogen-binding capacity and P-selectin expression, suggesting that the time-dependent effects of Hcy incubation appear to be due to direct Hcy-induced platelet activation followed by energetic exhaustion and dysfunction of platelets.
In the rat model of HHcy, blood Hcy levels are continuously elevated. Rats were divided into 3 groups based on their plasma Hcy concentrations: low (3.6 to 9.9 μM), moderate (10 to 50 μM), and high (51 to 122 μM). The clot contraction area under the kinetic curve was higher in the group with moderately elevated Hcy levels (10 to 50 μM) compared with the control and other subgroups. The onset of clot contraction was delayed in the group with highly elevated Hcy levels (>50 μM) compared with the control and other subgroups. The extent and average velocity of clot contraction was enhanced in both the moderately and highly elevated HHcy subgroups compared with the control and low HHcy subgroup. In vivo HHcy level was associated with thrombocytosis, reduced erythrocyte count, and hypofibrinogenemia.
“Taken together, our results suggest that in HHcy, platelets get activated directly and indirectly, leading to enhanced clot contraction that is also facilitated by the reduced content and resilience of fibrin and erythrocytes in the clot. After Hcy-induced activation, some platelets later become partially dysfunctional and less contractile, resulting in reduced extent and rate of clot contraction,” the authors wrote. “The dual effect of Hcy on blood clot contraction may comprise a novel mechanism of hemostatic disorders associated with HHcy.”
Reference
Litvinov RI, Peshkova AD, Le Minh G, et al. Effects of hyperhomocysteinemia on the platelet-driven contraction of blood clots. Metabolites. 2021;11(6):354. doi:10.3390/metabo11060354
