Reversal of Low-Molecular-Weight Heparin Anticoagulation by Synthetic Protamine Analogues
dc.contributor.author | Wakefield, Thomas W. | en_US |
dc.contributor.author | Andrews, Philip C. | en_US |
dc.contributor.author | Wrobleski, Shirley K. | en_US |
dc.contributor.author | Kadell, Amy M. | en_US |
dc.contributor.author | Fazzalari, Antonio | en_US |
dc.contributor.author | Nichol, Brad J. | en_US |
dc.contributor.author | Vanderkooi, Ted | en_US |
dc.contributor.author | Stanley, James C. | en_US |
dc.date.accessioned | 2006-04-10T18:07:29Z | |
dc.date.available | 2006-04-10T18:07:29Z | |
dc.date.issued | 1994-06 | en_US |
dc.identifier.citation | Wakefield, Thomas W., Andrews, Philip C., Wrobleski, Shirley K., Kadell, Amy M., Fazzalari, Antonio, Nichol, Brad J., Vanderkooi, Ted, Stanley, James C. (1994/06)."Reversal of Low-Molecular-Weight Heparin Anticoagulation by Synthetic Protamine Analogues." Journal of Surgical Research 56(6): 586-593. <http://hdl.handle.net/2027.42/31553> | en_US |
dc.identifier.uri | http://www.sciencedirect.com/science/article/B6WM6-45P0G5R-2R/2/c4a0d235722febd0f8d516407d2f8942 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/31553 | |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=8015315&dopt=citation | en_US |
dc.description.abstract | Protamine reversal of unfractionated and low-molecular-weight heparin (LMWH) causes hypotension, bradycardia, pulmonary artery hypertension, and declines in oxygen consumption. Furthermore, protamine incompletely reverses the anti-Xa activity of LMWH. The present study assesses the efficacy and toxicity of three protamine variants having +16 and +18 charges in reversal of LMWH (Logiparin, LHN-1): [+16] P(AK2A2K2)4, [+18] PK(K2A2K2A)3K2AK3, and [+18B] acetyl-PA(K2A2K2A)4K2-amide. The [+18B] compound was made by acetylating and amidating the [+18] to decrease in vivo degradation and to increase the [alpha]-helix forming propensity. Variants were examined in a canine model (n = 7, each variant) and compared to controls (n = 7) reversed with standard protamine with a +21 charge. Animals were anesthetized, anticoagulated with LMWH (150 IU factor Xa activity/kg), and reversed with protamine variants (1.5 mg/kg with 100 IU/mg). Blood pressure (BP), heart rate (HR), cardiac output (CO), pulmonary artery pressures, oxygen saturations, and oxygen consumption (VO2) were continuously monitored. Comparisons were undertaken at baseline, after heparin, before variant administration, and for 30 min thereafter. A total toxicity score (TTS) was calculated for each variant, accounting for maximal declines in BP, HR, CO, and VO2 during the first 5 min after reversal. Protamine [+21] was most toxic, TTS -7.6, with the variants being less toxic (P < 0.01, ANOVA): TTS = [+16] -2.8, [+18] -1.3, and [+18B] -4.1. Percentage reversal of LMWH 3 min after reversal for activated clotting time, anti-factor Xa activity, TCT, and anti-factor Ha activity, respectively, were: [+16] 26, 25, 66, 43%; [+18] 49, 21, 91, 36%; [+18B] 87, 64, 99, 96%; and protamine [+21] 99, 63, 100, 99%. These data document synthetic protamine variant reversal of LMWH anticoagulation. Preventing variant degradation improved efficacy to a level equaling standard protamine, although with some increased toxicity. Nonetheless, all variants were less toxic than protamine. | en_US |
dc.format.extent | 468916 bytes | |
dc.format.extent | 3118 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | |
dc.publisher | Elsevier | en_US |
dc.title | Reversal of Low-Molecular-Weight Heparin Anticoagulation by Synthetic Protamine Analogues | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Surgery and Anesthesiology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.contributor.affiliationum | Jobst Vascular Laboratory, Section of Vascular Surgery, Department of Surgery, and the Department of Biochemistry, University of Michigan and the Ann Arbor Veterans Administration Medical Center, Ann Arbor, Michigan 48109-0329 | en_US |
dc.identifier.pmid | 8015315 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/31553/1/0000478.pdf | en_US |
dc.identifier.doi | http://dx.doi.org/10.1006/jsre.1994.1093 | en_US |
dc.identifier.source | Journal of Surgical Research | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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