117. Hirudin does not affect the abnormally high thromboxane biosynthesis in homozygous homocystinmia

Subjects with homozygous homocystinuria due to cystathionine-β-synthase deficiency (CBSD) are at risk for arterial and venous thrombosis. In CBSD patients we have previously demonstrated an abnormally high biosynthesis of thromboxane A2 as reflected by the urinary excretion of its major metabolite 11-dehydro-thromboxane B2 (TXM), and its partial dependence on a probucol-sensitive mechanism (J. Clin. Invest. 92:1400-1406; 1993). To address the possibility that this abnormality might be due to a hypercoaguable state, we measured a series of variables before and at different time intervals after a bolus infusion of recombinant hirudin in 9 CBSD patients (5 M, 4 F; aged 7-43 yrs) and 6 controls (5 M, IF; aged 24-42 yrs). Protein C antigen and activity were significantly lower in CBSD subjects as compared to controls (81.8±16.6 vs 107.8±13.7 and 85.0±.21.7 vs 121.8±19.7 respectively, p300 sec (0.3 mg/kg over a 90-min period), did not raise the levels of this anticoagulant, nor did they change TXM excretion (1023±181 pg/ml creatinine in preinfusion samples and 929±131 and 973±152 in the samples obtained 4 and 24 hrs after withdrawing the infusion, p always >0.05). Moreover, activated protein C, protein S, F1+2, TAT, thrombomodulin and C4BP, were all normal in this setting, and their levels were not affected by the infusion. Finally protein C levels did not correlate with TXM excretion, and concentrations of probucol (500 mg daily for 3 weeks) that caused a prolonged reduction (p>0.005) of the abnormal TXM excretion, did not affect protein C levels. We conclude that in homozygous homocystinuria abnormal thromboxane biosynthesis is unlikely to reflect a hypercoaguable state. The mechanism(s) responsible for reduced protein C levels remains to be investigated.