Document Detail


Heparin rescues factor V Leiden-associated placental failure independent of anticoagulation in a murine high-risk pregnancy model.
MedLine Citation:
PMID:  23325830     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Low molecular weight heparin (LMWH) is being tested as an experimental drug for improving pregnancy outcome in women with inherited thrombophilia and placenta-mediated pregnancy complications, such as recurrent pregnancy loss. The role of thrombotic processes in these disorders remains unproven, and the issue of antithrombotic prophylaxis is intensely debated. Using a murine model of factor V Leiden-associated placental failure, we show that treatment of the mother with LMWH allows placental development to proceed and affords significant protection from fetal loss. Nonetheless, the therapeutic effect of LMWH is not replicated by anticoagulation; fondaparinux and a direct Xa inhibitor, C921-78, achieve anticoagulation similar to LMWH but produce little or no improvement in pregnancy outcome. Genetic attenuation of maternal platelet aggregation is similarly ineffective. In contrast, even a partial loss of thrombin sensitivity of maternal platelets protects pregnancies. Neonates born from these pregnancies are growth retarded, suggesting that placental function is only partially restored. The placentae are smaller but do not reveal any evidence of thrombosis. Our data demonstrate an anticoagulation-independent role of LMWH in protecting pregnancies and provide evidence against the involvement of thrombotic processes in thrombophilia-associated placental failure. Importantly, thrombin-mediated maternal platelet activation remains central in the mechanism of placental failure.
Authors:
Jianzhong An; Magarya S Waitara; Michelle Bordas; Vidhyalakshmi Arumugam; Raymond G Hoffmann; Brian G Petrich; Uma Sinha; Paula E North; Rashmi Sood
Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-16
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-13     Revised Date:  2014-04-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2127-34     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticoagulants / pharmacology,  therapeutic use
Blood Coagulation / drug effects*,  genetics
Disease Models, Animal*
Embryo, Mammalian
Factor V / genetics,  physiology*
Female
Heparin / pharmacology,  therapeutic use*
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout*
Placenta Diseases / drug therapy*,  etiology*,  genetics
Pregnancy
Pregnancy Complications, Hematologic / drug therapy,  etiology,  genetics
Pregnancy, High-Risk* / blood
Grant Support
ID/Acronym/Agency:
P01 HL078784/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anticoagulants; 0/factor V Leiden; 9001-24-5/Factor V; 9005-49-6/Heparin
Comments/Corrections
Comment In:
Blood. 2013 Mar 14;121(11):1932-3   [PMID:  23493771 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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