|
|
Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-03-0727.
Submitted March 7, 2002
Accepted May 12, 2002
Effect of hyperhomocysteinemia on protein C activation and activity
Steven R Lentz*, Donald J Piegors, Jose A Fernandez, Rochelle A Erger, Erland Arning, M R Malinow, John H Griffin, Teodoro Bottiglieri, William G Haynes, and Donald D Heistad
Veterans Affairs Medical Center, Iowa City, IA, USA; Department of Internal Medicine, The University of Iowa, Iowa City, IA, USA
Department of Internal Medicine, The University of Iowa, Iowa City, IA, USA
Department of Pharmacology, The University of Iowa, Iowa City, IA, USA
Veterans Affairs Medical Center, Iowa City, IA, USA
Baylor Institute of Metabolic Disease, Dallas, TX, USA
Oregon Regional Primate Research Center, Beaverton, OR, USA
Veterans Affairs Medical Center, Iowa City, IA, USA; Department of Internal Medicine, The University of Iowa, Iowa City, IA, USA; Department of Pharmacology, The University of Iowa, Iowa City, IA, USA
* Corresponding author; email: steven-lentz{at}uiowa.edu.
Hyperhomocysteinemia has been proposed to inhibit the protein C anticoagulant system through two mechanisms: 1) decreased generation of activated protein C (APC) by thrombin, and 2) resistance to APC caused by decreased inactivation of factor Va. We tested the hypotheses that generation of APC by thrombin is impaired during hyperhomocysteinemia in monkeys and that hyperhomocysteinemia produces resistance to APC in monkeys, mice, and human subjects. 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 on the hyperhomocysteinemic diet compared with the control diet (9.8±2.0 vs. 5.6±1.0 µM; p<0.05). After infusion of human thrombin (25 µg/kg), the peak level of plasma APC was 136±16 U/mL in monkeys fed control diet and 127±13 U/mL in monkeys fed hyperhomocysteinemic diet (p>0.05). The activated partial thromboplastin time was prolonged to a similar extent by infusion of thrombin when monkeys were fed the control or hyperhomocysteinemic diets. The sensitivity of plasma factor V to human APC was identical in monkeys fed control or hyperhomocysteinemic diets. We also failed to detect resistance of plasma factor V to APC in hyperhomocysteinemic cystathionine ß-synthase-deficient mice (plasma tHcy 93±16 µM) or in human subjects with acute hyperhomocysteinemia (plasma tHcy 45±6 µM). Our findings indicate that activation of protein C by thrombin and inactivation of plasma factor V by APC are not impaired during moderate hyperhomocysteinemia in vivo.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Letter in Blood Online:
-
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.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
S. Dayal and S. R. Lentz
Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes
Arterioscler Thromb Vasc Biol,
September 1, 2008;
28(9):
1596 - 1605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dayal, K. M. Wilson, L. Leo, E. Arning, T. Bottiglieri, and S. R. Lentz
Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia
Blood,
October 1, 2006;
108(7):
2237 - 2243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Aso, K.-i. Okumura, K. Takebayashi, S. Wakabayashi, and T. Inukai
Relationships of Plasma Interleukin-18 Concentrations to Hyperhomocysteinemia and Carotid Intimal-Media Wall Thickness in Patients With Type 2 Diabetes
Diabetes Care,
September 1, 2003;
26(9):
2622 - 2627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wang, X. Jiang, F. Yang, J. W. Gaubatz, L. Ma, M. J. Magera, X. Yang, P. B. Berger, W. Durante, H. J. Pownall, et al.
Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta -synthase and apolipoprotein E double knock-out mice with and without dietary perturbation
Blood,
May 15, 2003;
101(10):
3901 - 3907.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Podda, E. M. Faioni, M. L. Zighetti, and M. Cattaneo
No effect of fasting plasma total homocysteine on protein C activity in vitro
Blood,
March 15, 2003;
101(6):
2446 - 2446.
[Full Text]
[PDF]
|
|
|
|
|
