1126 AN IMBALANCE IN PLATELET-VASCULAR PROSTAGLANDIN SYNTHESIS INDUCED BY HOMOCYSTEINE (HC) AND HOMOCYSTEIC ACID (HCA)

Abstract

Homocystinuria is characterized by serious vascular thromboses and elevated plasma levels of HC and HCA. The etiology of the thromboses is unknown. Platelets (plts) produce proaggregatory and prothrombotic Thromboxane A₂ (TXA₂) while vascular endothelium produces antiaggregatory and antithrombotic PGI₂. An imbalance in production of TXA₂ and/or PGI₂ can lead to bleeding or thrombosis. We investigated production of plt TXB₂ (the end product of TXA₂) and vascular 6-Keto-PGF_1α (the end product of PGI₂) in plts and vascular endothelium exposed in vitro to HC and HCA, 0.4 to 2.0 mM. Conversion of ¹⁴C arachidonic acid (AA) to plt TXB₂ was increased in the presence of HC or HCA. In 8 paired experiments, mean pit TXB₂ increased to 19.4±3.5% (1SE) in the presence of HCA, compared to control values of 14.6±3.6% (p<0.01). Similarly, in 4 paired experiments pit TXB₂ was increased (18.7±2.3%) in the presence of H.C., when compared to a mean value of 7.8±1.1% (p<0.05) in the control pits. No differences in 6-Keto-PGF_1α production were observed in 6 paired experiments when vessels were incubated with either buffer, HC or HCA (0.73±.07; 0.7±.05; 0.76±.07%). These studies demonstrate that HC and HCA alter plt and vascular AA metabolism by increasing production of prothrombotic plt TXA₂ without a compensatory increase in antithrombotic vascular PGI₂. Such an imbalance may explain the marked thrombotic tendency in Homocystinuria.

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