Abstract
AbstractHyperhomocysteinemia has been proposed to inhibit the protein C anticoagulant system through 2 mechanisms: decreased generation of activated protein C (APC) by thrombin, and resistance to APC caused by decreased inactivation of factor Va (FVa). We tested the hypotheses that generation of APC by thrombin is impaired in hyperhomocysteinemia in monkeys and that hyperhomocysteinemia produces resistance to APC in monkeys, mice, and humans. In a randomized crossover study, cynomolgus monkeys were fed either a control diet or a hyperhomocysteinemic diet for 4 weeks. Plasma total homocysteine (tHcy) was approximately 2-fold higher when monkeys were on the hyperhomocysteinemic diet than when they were on the control diet (9.8 ± 2.0 μM versus 5.6 ± 1.0 μM; P < .05). After infusion of human thrombin (25 μg/kg of body weight), the peak level of plasma APC was 136 ± 16 U/mL in monkeys fed the control diet and 127 ± 13 U/mL in monkeys fed the hyperhomocysteinemic diet (P > .05). The activated partial thromboplastin time was prolonged to a similar extent by infusion of thrombin in monkeys fed the control diet and in those fed the hyperhomocysteinemic diet. The sensitivity of plasma FV to human APC was identical in monkeys on control diet and those on hyperhomocysteinemic diet. We also did not detect resistance of plasma FV to APC in hyperhomocysteinemic mice deficient in cystathionine β-synthase (plasma tHcy, 93 ± 16 μM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 ± 6 μM). Our findings indicate that activation of protein C by thrombin and inactivation of plasma FVa by APC are not impaired during moderate hyperhomocysteinemia in vivo.
Highlights
Like other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction, which can be detected on the basis of impaired responses to endothelium-dependent vasodilators.[5]
Infusion of thrombin produces activation of protein C and APCdependent prolongation of Activated partial thromboplastin time (APTT) in monkeys.[15,26]. To determine whether these anticoagulant responses are impaired in hyperhomocysteinemia, we measured plasma activated protein C (APC) and APTT in response to infusion of human thrombin (25 g/kg given intravenously over 10 minutes) in monkeys after they had been on each diet for 4 weeks
These findings indicate that the hyperhomocysteinemic diet did not produce significant impairment of thrombininduced activation of protein C in vivo, but do not exclude a possible effect
Summary
Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, peripheral arterial disease, and venous thrombosis.[1,2] An association between moderate hyperhomocysteinemia and clinical cardiovascular events has been observed in more than 35 case-control and observational epidemiologic studies, as well as several prospective studies.[3] Because elevated levels of plasma total homocysteine (tHcy) can often be lowered by oral administration of folic acid or combinations of B vitamins, treatment of hyperhomocysteinemia has been proposed as a strategy for preventing cardiovascular disease and its complications This approach is currently being evaluated in several prospective randomized intervention trials.[4]. We tested the hypothesis that hyperhomocysteinemia alters the APC sensitivity of plasma FV in cynomolgus monkeys, mice deficient in cystathionine– -synthase (CBS), and humans
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