Hemostatic effects of low-dose protamine following cardiopulmonary bypass

Miyashita, Tetsuya; Nakajima, Toshito; Hayashi, Yukio; Kuro, Masakazu

doi:10.1002/(sici)1096-8652(200006)64:2<112::aid-ajh7>3.0.co;2-n

Cited by 19 publications

(10 citation statements)

References 20 publications

(23 reference statements)

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“…However, the parallel HTC testing with heparinase excluded that the slight postoperative increase in ACT in both groups was caused by remaining heparin. Data from this study support previous studies [14][15][16] that advocate a low-dose protamine regime to avoid the possible drawbacks of the drug. Furthermore, both The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists recommend a low-dose protamine regime in their Clinical Practice Guidelines.…”

Section: Discussionsupporting

confidence: 89%

An Adjusted Calculation Model Allows for Reduced Protamine Doses without Increasing Blood Loss in Cardiac Surgery

Kjellberg

Sartipy

Linden

et al. 2015

Thorac cardiovasc Surg

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Background Heparin dosage for anticoagulation during cardiopulmonary bypass (CPB) is commonly calculated based on the patient's body weight. The protamine-heparin ratio used for heparin reversal varies widely among institutions (0.7-1.3 mg protamine/100 IU heparin). Excess protamine may impair coagulation. With an empirically developed algorithm, the HeProCalc program, heparin, and protamine doses are calculated during the procedure. The primary aim was to investigate whether HeProCalc-based dosage of heparin could reduce protamine use compared with traditional dosages. The secondary aim was to investigate whether HeProCalc-based dosage of protamine affected postoperative bleeding. Patients and Methods We consecutively randomized 40 patients into two groups. In the control group, traditional heparin and protamine doses, based on body weight alone, were given. In the treatment group, the HeProCalc program was used, which calculated the initial heparin bolus dose from weight, height, and baseline activated clotting time and the protamine dose at termination of CPB. Results We analyzed the results from 37 patients, after exclusion of three patients. Equal doses of heparin were given in both groups, whereas significantly lower mean doses of protamine were given in the treatment group versus control group (211 ± 56 vs. 330 ± 61 mg, p < 0.001). Postoperative bleeding was less in the HeProCalc group (280 ± 229 mL) as compared with the control group (649 ± 279 mL). However, this difference was not found statistically significant (p = 0.074). Conclusion HeProCalc-based dosage of heparin and protamine allowed for reduced protamine use after CPB compared with when conventional calculations were used. Furthermore, HeProCalc-based regimen for heparin reversal suggested less postoperative bleeding, although the difference between the groups was not statistically significant.

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Section: Discussionsupporting

confidence: 89%

An Adjusted Calculation Model Allows for Reduced Protamine Doses without Increasing Blood Loss in Cardiac Surgery

Kjellberg

Sartipy

Linden

et al. 2015

Thorac cardiovasc Surg

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“…In a small prospective study, randomisation of patients to a 0.8 vs 2.0 protamine-to-heparin dosing ratio revealed that high protamine dosing was associated with changes in platelet count and PF4, whilst post-protamine ACT levels were similar amongst groups. 81 In a randomised controlled trial in coronary artery bypass graft (CABG) patients, we showed that a protamine-to-heparin dosing ratio of 1. .021] when compared with a protamine-toheparin dosing ratio of 0.8, respectively.…”

Section: Ratio-based Dosingmentioning

confidence: 99%

Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review

Boer

Meesters

Veerhoek

et al. 2018

British Journal of Anaesthesia

158

146

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Neutralisation of systemic anticoagulation with heparin in cardiac surgery with cardiopulmonary bypass requires protamine administration. If adequately dosed, protamine neutralises heparin and reduces the risk of postoperative bleeding. However, as its anticoagulant properties are particularly exerted in the absence of heparin, overdosing of protamine may contribute to bleeding and increased transfusion requirements. This narrative review describes the mechanisms underlying the anticoagulant properties and side-effects of protamine, and the impact of protamine dosing on the activated clotting time and point-of-care viscoelastic test results, and explains the distinct protamine dosing strategies in relation to haemostatic activation and postoperative bleeding. The available evidence suggests that protamine dosing should not exceed a protamine-to-heparin ratio of 1:1. In particular, protamine-to-heparin dosing ratios >1 are associated with more postoperative 12 h blood loss. The optimal protamine-to-heparin ratio in cardiac surgery has, however, not yet been elaborated, and may vary between 0.6 and 1.0 based on the initial heparin dose.

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“…6,7,24,25 To determine the relative importance of protamine inhibition of FV activation in mediating the anticoagulant effect of protamine in plasma, increasing concentrations of either FV or FVa (0-20 nM) were titrated into FV-deficient plasma in the presence or absence of protamine (30 g/mL; Figure 7). In a TF-initiated thrombin generation assay, addition of FV or FVa resulted in a significant increase in thrombin generation ( Figure 7A-B).…”

Section: Preactivation Of Fv Eliminates Protamine Anticoagulant Effecmentioning

confidence: 99%

Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation

Áinle¹,

Preston²,

Jenkins³

et al. 2009

Blood

111

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Protamine sulfate is a positively charged polypeptide widely used to reverse heparininduced anticoagulation. Paradoxically, prospective randomized trials have shown that protamine administration for heparin neutralization is associated with increased bleeding, particularly after cardiothoracic surgery with cardiopulmonary bypass. The molecular mechanism(s) through which protamine mediates this anticoagulant effect has not been defined. 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). Similarly, in pooled normal human plasma, protamine caused significant dose-dependent prolongations of both prothrombin time and activated partial thromboplastin time. Protamine also markedly attenuated tissue factor-initiated thrombin generation in human plasma, causing a significant decrease in endogenous thrombin potential (41% ؎ 7%). As expected, low-dose protamine effectively reversed the anticoagulant activity of unfractionated heparin in plasma. However, elevated protamine concentrations were associated with progressive dose-dependent reduction in thrombin generation. To assess the mechanism by which protamine mediates down-regulation of thrombin generation, the effect of protamine on factor V activation was assessed. Protamine was found to significantly reduce the rate of factor V activation by both thrombin and factor Xa. Protamine mediates its anticoagulant activity in plasma by downregulation of thrombin generation via a novel mechanism, specifically inhibition of factor V activation. (Blood. 2009;114: 1658-1665) IntroductionProtamine sulfate is a 5-kDa cationic polypeptide derived from salmon sperm that can bind negatively charged unfractionated heparin (UFH). 1 Although the mechanisms of the molecular interaction between protamine and heparin are not well defined, this binding serves to neutralize the antithrombin-mediated anticoagulant properties of heparin. Moreover, the resultant protamineheparin complex is rapidly cleared by the reticuloendothelial system. 2 Consequently, for more than 30 years, protamine has been widely used to reverse the anticoagulant effects of UFH. Protamine is considered the treatment of choice for patients who develop significant bleeding complications while on UFH. 3,4 Furthermore, protamine is routinely administered postoperatively to reverse the high concentrations of UFH required for patients undergoing cardiac surgery and cardiopulmonary bypass (CPB). 5 As a result, estimates suggest that more than 2 million heparinized patients are managed with protamine each year. 2 Clinical use of protamine is, however, associated with several important adverse side effects, including potentially life-threatening systemic arterial hypotension and pulmonary artery hypertension. 1 Paradoxically, in vitro studies have also suggested that protamine may possess intrinsic anticoagulant properties. [6][7][8] Administration of excess protamine in the neutralization of UFH has b...

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Hemostatic effects of low-dose protamine following cardiopulmonary bypass

Cited by 19 publications

References 20 publications

An Adjusted Calculation Model Allows for Reduced Protamine Doses without Increasing Blood Loss in Cardiac Surgery

An Adjusted Calculation Model Allows for Reduced Protamine Doses without Increasing Blood Loss in Cardiac Surgery

Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review

Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation

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