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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-03-0727.
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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2108-2112
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Effect of hyperhomocysteinemia on protein C activation and
activity
Steven R. Lentz,
Donald J. Piegors,
José A. Fernández,
Rochelle A. Erger,
Erland Arning,
M. René Malinow,
John
H. Griffin,
Teodoro Bottiglieri,
William G. Haynes, and
Donald D. Heistad
From the Veterans Affairs Medical Center, Iowa City,
IA; Departments of Internal Medicine and Pharmacology, University of
Iowa College of Medicine, Iowa City; Scripps Research Institute, La
Jolla, CA; Oregon Regional Primate Research Center, Beaverton; and
Baylor Institute of Metabolic Disease, Dallas, TX.
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 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
 -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.
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Related Letter in Blood Online:
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No effect of fasting plasma total homocysteine on protein C activity in vitro
- GianMarco Podda, Elena M. Faioni, Maddalena L. Zighetti, and Marco Cattaneo
Blood 2003 101: 2446.
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