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Effect of hyperhomocysteinemia on protein C activation and activity
Steven R Lentz1, Donald J Piegors, José A Fernández
1Department of Internal Medicine, Veterans Affairs Medical Center, C303 GH, University of Iowa, Iowa City, IA 52242, USA. steven-lentz@uiowa.edu
Insights
Hyperhomocysteinemia does not impair thrombin
Area of Science:
- Biochemistry
- Hematology
- Vascular Biology
Background:
- Hyperhomocysteinemia is linked to thrombosis.
- Proposed mechanisms involve the protein C anticoagulant system.
- Specifically, reduced activated protein C (APC) generation and APC resistance.
Purpose of the Study:
- To investigate if hyperhomocysteinemia impairs APC generation by thrombin.
- To determine if hyperhomocysteinemia causes APC resistance.
- To test these hypotheses in animal models and human subjects.
Main Methods:
- Cynomolgus monkeys were fed control or hyperhomocysteinemic diets.
- Thrombin was infused to measure plasma APC generation.
- APC sensitivity was assessed in hyperhomocysteinemic mice and human volunteers.
Main Results:
- Plasma total homocysteine (tHcy) was elevated in hyperhomocysteinemic monkeys.
- Peak plasma APC levels and thrombin-induced anticoagulation were similar between diet groups.
- No APC resistance was observed in hyperhomocysteinemic mice or humans.
Conclusions:
- Moderate hyperhomocysteinemia does not impair APC generation by thrombin in vivo.
- Hyperhomocysteinemia does not induce resistance to APC.
- The protein C anticoagulant system appears functional in moderate hyperhomocysteinemia.
Abstract:
Hyperhomocysteinemia 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 microM versus 5.6 +/- 1.0 microM; P <.05). After infusion of human thrombin (25 microg/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 beta-synthase (plasma tHcy, 93 +/- 16 microM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 +/- 6 microM). 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.