Effect of hyperhomocysteinemia on protein C activation and activity.
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.
Department of Internal Medicine, Veterans Affairs Medical Center, C303 GH, University of Iowa, Iowa City, IA 52242, USA. steven-lentz@uiowa.edu
Steven R
SR
Lentz
Donald J
DJ
Piegors
José A
JA
Fernández
Rochelle A
RA
Erger
Erland
E
Arning
M René
MR
Malinow
John H
JH
Griffin
Teodoro
T
Bottiglieri
William G
WG
Haynes
Donald D
DD
Heistad
D000818:Animals; D003541:Cystathionine beta-Synthase / Q000097:blood / Q000172:deficiency; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005165:Factor V / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000882:Haplorhini; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000201:enzymology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010314:Partial Thromboplastin Time; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism
D011486:Protein C; D005165:Factor V; D008715:Methionine; D013917:Thrombin; D003541:Cystathionine beta-Synthase