Document Detail


Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine.
MedLine Citation:
PMID:  7769743     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: This investigation assessed protamine reversal of heparin anticoagulation by formation of a protamine-heparin alpha-helix by use of a new designer-variant protamine [+18BE] that was made from an existing protamine variant [+18B] whose non-alpha-helix-forming amino acid proline (P) was replaced by an alpha-helix-forming glutamic acid (E). The rate of administration of the new [+18BE] variant protamine on efficacy and toxicity in comparison to that of [+21] standard protamine and [+18B] was also studied.
METHODS: Acetyl-EAA(K2A2K2A)4K2-Amide [+18BE] was administered intravenously in a 1:1 dose to low-molecular-weight heparin (LMWH)-anticoagulated (intravenous 150 IU antifactor Xa/kg) dogs over 10 seconds or 3 minutes (n = 7, each group). Reversal efficacy was documented by measuring activated clotting time, thrombin clotting time, antifactor Xa, and antifactor IIa. Toxicity was defined by measuring systemic blood pressure, heart rate, cardiac output, pulmonary artery pressure, and oxygen consumption. Measurements were made at baseline, after administration of LMWH, before its reversal, and for 30 minutes thereafter. Results were compared with those after LMWH reversal with [+21] standard protamine and the [+18B] variant. A total toxicity score (TTS) was calculated for each compound from maximal declines in blood pressure, heart rate, cardiac output, and oxygen consumption.
RESULTS: LMWH anticoagulation reversal was significantly (p < 0.01) less toxic over 10 seconds and 3 minutes with the [+18BE] designer variant (TTS -2.3, -2.2) compared with the [+21] standard protamine (TTS -6.4, -7.2). Percent LMWH reversal at 3 minutes revealed [+18BE] to have antifactor Xa activity as high as 91%, compared with 68% for protamine [+21], when given over 3 minutes (p < 0.05).
CONCLUSIONS: This investigation documents that a new designer variant of protamine [+18BE] has superior efficacy compared with [+21] standard protamine for reversal of LMWH anticoagulation and that this occurs with a highly favorable toxicity profile.
Authors:
T W Wakefield; P C Andrews; S K Wrobleski; A M Kadell; R Schmidt; S Tejwani; J C Stanley
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of vascular surgery     Volume:  21     ISSN:  0741-5214     ISO Abbreviation:  J. Vasc. Surg.     Publication Date:  1995 May 
Date Detail:
Created Date:  1995-06-30     Completed Date:  1995-06-30     Revised Date:  2012-10-03    
Medline Journal Info:
Nlm Unique ID:  8407742     Medline TA:  J Vasc Surg     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  839-49; discussion 849-50     Citation Subset:  IM    
Affiliation:
Jobst Vascular Laboratory, Department of Surgery, University of Michigan, Ann Arbor, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Blood Coagulation / drug effects
Blood Pressure / drug effects
Cardiac Output / drug effects
Dogs
Drug Design
Drug Interactions
Female
Heart Rate / drug effects
Heparin, Low-Molecular-Weight / metabolism,  pharmacology*
Injections, Intravenous
Molecular Sequence Data
Molecular Weight
Oxygen Consumption / drug effects
Protamines / chemical synthesis,  metabolism,  pharmacology*
Protein Binding
Time Factors
Whole Blood Coagulation Time
Chemical
Reg. No./Substance:
0/Heparin, Low-Molecular-Weight; 0/Logiparin; 0/Protamines

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


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