A [+18RGD] Protamine Variant for Nontoxic and Effective Reversal of Conventional Heparin and Low-Molecular- Weight Heparin Anticoagulation

Wakefield, Thomas W.; Andrews, Philip C.; Wrobleski, Shirley K.; Kadell, Amy M.; Tejwani, Samir; Hulin, Marc S.; Stanley, James C.

doi:10.1006/jsre.1996.0261

Cited by 28 publications

(19 citation statements)

References 3 publications

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“…Low molecular weight variants of protamine and synthetic variants of protamine have been reported to reverse heparin with lower toxicity than normal protamine [13,14]. However, in the 15 years since the first of these was described there have been no clinical trials of these molecules (clinicaltrials.gov).…”

Section: Discussionmentioning

confidence: 99%

“…Adverse reactions to protamine correlate with increased mortality and approximately 1900 additional deaths per year in the US can be attributed to these adverse events during cardiopulmonary bypass [8,9]. Consequently, there is a compelling scientific and pharmacologic rationale for developing alternative heparin reversal agents, and indeed several research groups have designed and tested new heparin antagonists [3,10–14]. Some of these appear to currently be under development by pharmaceutical companies.…”

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confidence: 99%

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Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Gale

Elias

Averell

et al. 2011

Thrombosis Research

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Heparin is widely used for anticoagulation, often requiring the subsequent administration of a reversal agent. The only approved reversal agent for heparin is protamine sulfate, which induces well described adverse reactions in patients. Previously we reported a novel class of heparin antagonists based on the bacteriophage Qβ platform, displaying polyvalent cationic motifs which bind with high affinity to heparin. Here we report heparin reversal by the most effective of these virus-like particles (VLP) in samples from patients who were administered heparin during cardiac procedures or therapeutically for treatment of various thrombotic conditions. The VLP consistently reversed heparin in these samples, including those from patients that received high doses of heparin, with greater efficiency than a negative control VLP and with significantly less variability than protamine sulfate. These results provide the first step towards validation of heparin antagonist VLPs as viable alternatives to protamine.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Gale

Elias

Averell

et al. 2011

Thrombosis Research

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“…[13][14][15] The Wakefield peptide 13 [ϩ18RGD] contains pairs of arginine interspersed between 1 or 2 alanines. These sequences are very different from the Cardin and Weintraub 3 consensus sequences.…”

Section: Discussionmentioning

confidence: 99%

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Schick

Maslow

Moshinski

et al. 2004

Blood

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Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA) n tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [K d ], Ϸ 50 nM), similar potencies in neutralizing anti-Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA) 3 VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4-to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti-Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans. (Blood.

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“…First, changes in protamine structure may not be sufficient to correct for the loss of affinity towards cationic groups by sulphate‐deficient LMWH chains. This would explain why a number of protamine variants have been shown to have improved but not complete reversibility of LMWH activities (Wakefield et al , 1996; Byun et al , 1999). Second, sensitivity of antifactor Xa (and other) activity towards protamine may be improved by increasing the charge density of LMWH preparations.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms responsible for the failure of protamine  to inactivate low‐molecular‐weight heparin

et al. 2002

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Summary. Protamine is unable to completely reverse the anticoagulant effect of the low-molecular-weight heparins (LMWH), a fact of clinical importance given the rapid increase in use of LMWH in clinical practice. This investigation sought to determine the mechanism by which LMWH were able to resist protamine-mediated inactivation. Af®nity fractionation of LMWH by passage through a protamine column, with subsequent determination of molecular mass and sulphate charge density, demonstrated that the protamine-resistant fraction in LMWH is an ultralow-molecular-weight fraction with low sulphate charge density. This group of molecules was not found in unfractionated heparin, even when species of similar molecular mass were compared. We then determined that different commercially available LMWH varied in their ability to be neutralized by protamine, and that this variability correlated with the total sulphate content of the LMWH. We conclude that reduced sulphate charge, not molecular mass, is the principle reason that protamine is unable to fully inactivate LMWH. Furthermore, different LMWH vary in their ability to be neutralized by protamine, suggesting that product-speci®c recommendations for neutralization might be developed.

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A [+18RGD] Protamine Variant for Nontoxic and Effective Reversal of Conventional Heparin and Low-Molecular- Weight Heparin Anticoagulation

Cited by 28 publications

References 3 publications

Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Mechanisms responsible for the failure of protamine  to inactivate low‐molecular‐weight heparin

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A [+18RGD] Protamine Variant for Nontoxic and Effective Reversal of Conventional Heparin and Low-Molecular- Weight Heparin Anticoagulation

Cited by 28 publications

References 3 publications

Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Mechanisms responsible for the failure of protamine to inactivate low‐molecular‐weight heparin

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Mechanisms responsible for the failure of protamine  to inactivate low‐molecular‐weight heparin