| Effect of hyperhomocysteinemia on protein C activation and activity. | |
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MedLine Citation:
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PMID: 12200374 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Donald D Heistad |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Blood Volume: 100 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2002 Sep |
Date Detail:
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Created Date: 2002-08-29 Completed Date: 2002-10-24 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 2108-12 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine, Veterans Affairs Medical Center, C303 GH, University of Iowa, Iowa City, IA 52242, USA. steven-lentz@uiowa.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cystathionine beta-Synthase / blood, deficiency Disease Models, Animal Enzyme Activation Factor V / drug effects, metabolism Female Haplorhini Humans Hyperhomocysteinemia / blood, enzymology* Male Methionine / administration & dosage, pharmacology Mice Mice, Inbred C57BL Partial Thromboplastin Time Protein C / metabolism*, pharmacology Thrombin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK 25295/DK/NIDDK NIH HHS; HL 52246/HL/NHLBI NIH HHS; HL 58972/HL/NHLBI NIH HHS; HL 62984/HL/NHLBI NIH HHS; HL 63943/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Protein C; 63-68-3/Methionine; 9001-24-5/Factor V; EC 3.4.21.5/Thrombin; EC 4.2.1.22/Cystathionine beta-Synthase |
| Comments/Corrections | |
Comment In:
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Blood. 2003 Mar 15;101(6):2446-7
[PMID:
12609965
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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