Effect of Homocysteine and Homocystine on Platelet and Vascular Arachidonic Acid Metabolism

Abstract

Summary: Normal hemostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A₂, measured as its stable end-product thromboxane B₂ (TXB₂), and vascular prostacyclin (PGI₂), which inhibits platelet aggregation and is antithrombotic. Cystathionine-β-synthase deficiency is characterized by a high frequency of thromboembolic disease. We therefore studied, in vitro, the effects of homocysteine and related compounds on platelet TXB₂ and vascular PGI₂ formation. In paired samples of platelet rich plasma, which had been preincubated with L-homocystine (1 mM), mean production of the two platelet cyclooxygenase products, TXB₂ and 12-hydroxy-5,8,10-heptadecatrienoic acid increased significantly from control levels [13.6% ± 1.9 to 19.8% ± 2.1 (P < 0.02) TXB₂ and 29.8% ± 4.2 to 39.4% ± 4.1 (P < 0.01) HHT]. In the presence of D.L-homocysteine (1 mM), mean platelet TXB₂ and 12-hydroxy-5,8,10-heptadecatrienoic acid production was also significantly increased [12.7% ± 1.5 to 16.9% ± 1.5 (P < 0.01) TXB₂ and 27% ± 4 to 31% ± 4.1 (P < 0.02) HHT]. Cystine, cysteine, or methionine (1 mM) did not have similar effects in this test system. Homocysteine and homocystine were without effect on the synthesis of vascular PGI₂ by umbilical artery segments [control, 0.22 ± 0.03 to 0.21 ± 0.03 ng/mg with D.L-homocysteine and 0.20 ± 0.04 control to 0.19 ± 0.04 ng/mg with D.L-homocystine]. A homocyst(e)ine-induced increase in platelet thromboxane production in the absence of an increase in vascular prostacyclin, if present in vivo, may contribute to the vascular thromboses characteristic of human homocystinemias (homocystinurias).