4ĭespite the widespread use of protamine in clinical practice, the molecular mechanism(s) underlying its associated intrinsic anticoagulant effect is not clearly defined. 12, 13 Therefore, the clinical efficacy of protamine for reversing LMWH-induced anticoagulation remains unclear. 10, 11 Animal studies have shown that although protamine fully neutralizes the thrombin-inhibitory activity of low molecular weight heparins (LMWH), it can only partially neutralize their anti–factor Xa (FXa) activities. 3, 4 However, pharmacokinetic studies have demonstrated that protamine is cleared rapidly from human plasma (half life 7.4 minutes), so that repeated doses may be necessary to prevent rebound heparin anticoagulant effects. 9 Due to concerns regarding the inherent anticoagulant potential of protamine, current consensus guidelines recommend that the dose of protamine is limited to 1 mg protamine per 100 IU heparin. 6-8 Administration of excess protamine in the neutralization of UFH has been associated with increased bleeding in clinical settings, particularly after cardiothoracic surgery. 1 Paradoxically, in vitro studies have also suggested that protamine may possess intrinsic anticoagulant properties. Protamine mediates its anticoagulant activity in plasma by down-regulation of thrombin generation via a novel mechanism, specifically inhibition of factor V activation.Ĭlinical use of protamine is, however, associated with several important adverse side effects, including potentially life-threatening systemic arterial hypotension and pulmonary artery hypertension. Protamine was found to significantly reduce the rate of factor V activation by both thrombin and factor Xa. To assess the mechanism by which protamine mediates down-regulation of thrombin generation, the effect of protamine on factor V activation was assessed. However, elevated protamine concentrations were associated with progressive dose-dependent reduction in thrombin generation. As expected, low-dose protamine effectively reversed the anticoagulant activity of unfractionated heparin in plasma. Protamine also markedly attenuated tissue factor-initiated thrombin generation in human plasma, causing a significant decrease in endogenous thrombin potential (41% ± 7%). Similarly, in pooled normal human plasma, protamine caused significant dose-dependent prolongations of both prothrombin time and activated partial thromboplastin time. In vivo administration of pharmacologic doses of protamine to BALB/c mice significantly reduced plasma thrombin generation and prolonged tail-bleeding time (from 120 to 199 seconds). The molecular mechanism(s) through which protamine mediates this anticoagulant effect has not been defined. Paradoxically, prospective randomized trials have shown that protamine administration for heparin neutralization is associated with increased bleeding, particularly after cardiothoracic surgery with cardiopulmonary bypass. Protamine sulfate is a positively charged polypeptide widely used to reverse heparin-induced anticoagulation.
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