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Introduction: The recommended minimum activated clotting time (ACT) level for cardiopulmonary bypass (CPB) of 480 seconds originated from investigations with bubble oxygenators and uncoated extracorporeal circulation (ECC) systems. Modern minimal invasive ECC (MiECC) systems are completely closed circuits containing a membrane oxygenator and a tip-to-tip surface coating. We hypothesized that surface coating and the "closed-loop" design allow the MiECC to safely run with lower ACT levels and that an ACT level of 300 seconds can be safely applied without thromboembolic complications. The aim of this study was to investigate the potential risks during application of reduced heparin levels in patients undergoing coronary surgery., Methods: In this study, 68 patients undergoing coronary artery bypass grafting with MiECC were randomized to either the study group with an ACT target of 300 seconds or the control group with an ACT of 450 seconds. All other factors of MiECC remained unchanged., Results: The study group received significantly less heparin and protamine (heparin [international units] median [min-max], Red&#95;AC: 32,800 [23,000-51,500] vs. Full&#95;AC: 50,000 [35,000-65,000] p  < 0.001; protamine [international units], Red&#95;AC: 18,000 [10,000-35,000] vs. Full&#95;AC: 30,000 [20,000-45,000] p  < 0.001). The ACT in the study group was significantly lower at the start of MiECC (mean ± standard deviation: study group 400 ± 112 vs. control group 633 ± 177; p  < 0.0001). Before termination of CPB the ACT levels were: study group 344 ± 60 versus control group 506 ± 80. In both groups, the values of the endogenous thrombin potential (ETP) decreased simultaneously. None of the study participants experienced thromboembolic complications., Conclusion: Since no evidence of increased thrombin formation (ETP) was found from a laboratory standpoint, we concluded that the use of MiECC with a reduced anticoagulation strategy seems possible. This alternative anticoagulation strategy leads to significant reduction in dosages of both heparin and protamine. We can confidently move forward with investigating this anticoagulation concept. However, to establish clinical safety of ACT below 300 seconds, we need larger clinical studies., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background In patients with autoimmune diseases associated with antiphospholipid antibodies, precise management of anticoagulation during extracorporeal circulation (ECC) is complicated. It was the aim of the present study to determine whether antifactor Xa (aXa) activity is useful in guiding heparin therapy during ECC. Methods In 15 patients undergoing cardiac surgery, anticoagulation with unfractionated heparin (UFH) and its reversal with protamine were guided using activated clotting time (ACT) (>400 second during ECC; ≤100 second for UFH reversal). For each ACT, the corresponding aXa activity levels were measured. Results A total of 144 blood samples were obtained. ACT and aXa activity were significantly correlated (r = 0.771, p< 0.0001, Spearman rank-order correlation). Using receiver operating characteristic curve (ROC) analyses, the cutoffvalues for aXa activity were 1.14 IU/mL (area under the ROC curve [AUC]: 0.89; inaccuracy rate: 9.4%) to predict ACT > 400 seconds and 0.55 IU/mL (AUC: 0.85; inaccuracy rate: 13.3%) for ACT ≤ 100 seconds. Conclusion AXa activity is strongly correlated with ACT, and therefore may be feasible for managing anticoagulation with UFH during ECC., (Georg Thieme Verlag KG Stuttgart · New York.)

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., (Georg Thieme Verlag KG Stuttgart · New York.)

While experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p<0.001), while post-protamine activated clotting times were similar among groups. The high dosing group revealed increased intrinsic clotting times (236 ± 74 vs 196 ± 64 s; p=0.006) and the maximum post-protamine thrombin generation was less suppressed in the low dosing group (38 ± 40 % vs 6 ± 9 %; p=0.001). Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95 % CI 500-830 ml vs 470 ml; 95 % CI 420-530 ml; p=0.021) when compared to the low dosing group, respectively. More patients in the high dosing group received fresh frozen plasma (11 % vs 0 %; p=0.02) and platelet concentrate (21 % vs 6 %; p=0.04) compared to the low dosing group. Our study confirms in vitro data that abundant protamine dosing is associated with increased postoperative blood loss and higher transfusion rates in cardiac surgery.

Background: In open heart surgery, heparinization is commonly neutralized using an empirical heparin:protamine ratio ranging between 1:1 and 1:1.5. However, these ratios may result in protamine overdose that should be avoided for its negative side effects on the coagulation system. This study aimed to indicate the appropriate treatment for prolonged activated clotting time (ACT) after protamine administration following cardiopulmonary bypass (CPB) in pediatric open heart surgery by investigating the underlying reasons for it., Methods: Twenty-seven children (<10 kg) undergoing open heart surgery were included. Heparin was administered only before CPB (400 IU/kg) and in the pump priming volume for CPB (2,000 IU) and was neutralized by 1:1 protamine after CPB. The blood heparin concentration was measured using anti-Xa assay. ACT and blood concentrations of heparin, coagulation factors, thrombin-antithrombin complex, and prothrombin fragment 1 + 2 were assessed. A rotational thromboelastometry (ROTEM; Tem International GmbH, München, Bayern, Germany) was used to confirm the coagulation status and residual heparin after protamine administration., Results: Anti-Xa assay showed that there is no residual heparin in the blood after 1:1 protamine administration. Nevertheless, ACT (128.89 ± 3.09 seconds before heparin administration) remained prolonged (177.14 ± 5.43 seconds at 10 minutes after protamine, 182.00 ± 5.90 seconds at 30 minutes after protamine). The blood concentrations of coagulation factors were significantly lower than those before heparin administration (p < 0.01). The low FIBTEM MCF of ROTEM (4.43 ± 0.32 mm) at 10 minutes after protamine indicated low fibrinogen concentration., Conclusion: Prolonged ACT after heparin neutralization by 1:1 protamine administration does not necessarily indicate residual heparin, but low blood concentrations of coagulation factors should be considered as a reason as well. Accordingly, supply of coagulation factors instead of additional protamine should be considered., (Georg Thieme Verlag KG Stuttgart · New York.)

Patients undergoing anticoagulation with unfractionated heparin, low molecular weight heparin, or danaparoid may experience excess bleeding which requires reversal of the anticoagulant agent. Protamine is at present the only agent available for reversal of unfractionated heparin. Protamine is not effective in patients who have received low molecular weight heparin or danaparoid. We have developed a series of peptides based on consensus heparin binding sequences (Verrecchio et al., J Biol Chem 2000; 275: 7701-7707) that are capable of neutralizing the anti-thrombin activity of unfractionated heparin in vitro, the antifactor Xa activity of unfractionated heparin, Enoxaparin (Lovenox) and danaparoid (Orgaran) in vitro and the anti-Factor Xa activity of Enoxaparin in vivo in rats. These peptides may serve as alternatives for Protamine reversal of UFH and may be useful for neutralization of enoxaparin and danaparoid in humans.

The administration of protamine to patients undergoing cardiopulmonary bypass (CPB) to neutralize heparin and to reduce the risk of bleeding, induces activation of the classical complement pathway mainly by heparin-protamine complexes. We investigated whether C-reactive protein (CRP) contributes to protamine-induced complement activation. In 24 patients during myocardial revascularization, we measured complement, CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo. We also incubated plasma from healthy volunteers and patients with heparin and protamine in vitro to study CRP-mediated complement activation. During CPB, CRP levels remained unchanged while C3 activation products increased. C4 activation occurred after protamine administration. CRP-complement complexes increased at the end of CPB and upon protamine administration. Incubation of plasma with heparin and protamine in vitro generated complement-CRP complexes, which was blocked by phosphorylcholine and stimulated by exogenous CRP. C4d-CRP complex formation after protamine administration correlated clinically with the incidence of postoperative arrhythmia. Protamine administration during cardiac surgery induces complement activation which in part is CRP-dependent, and correlates with postoperative arrhythmia.

Thromboelastography (TEG) has been used after cardiopulmonary bypass (CPB) to diagnose excessive postoperative hemorrhage. Conventional TEG during CPB is not possible due to the sensitivity of the TEG to even small amounts of heparin, which produces a nondiagnostic tracing. The purpose of this study was to compare heparin neutralization using heparinase or protamine in TEG blood samples obtained during CPB. TEG testing was performed on 48 patients before, during and after CPB. Tissue plasminogen activator activity and antigen were measured on a subset of 32 patients. We found: 1) heparinase neutralized at least 10 IU/ml heparin while 1.6 ug/ml protamine neutralized up to 7 IU/ml heparin, 2) in samples with complete heparin neutralization by both methods, there was no significant difference in the R values, 3) while there was good correlation for other TEG parameters between heparinase and protamine treated samples, heparinase treatment produced shorter K values and higher angle, MA and A60, 4) while fibrinolysis was detected using both methods, heparinase treatment suppressed fibrinolysis in the TEG in both samples from patients and after in vitro addition of tissue plasminogen activator, 5) TEG was not a sensitive indicator of t-PA activity, detecting only 21% of samples with increased t-PA activity during bypass, and 5) heparinase was at least 100 times more expensive than protamine. We conclude that while both heparinase and protamine can be used to neutralize heparin in TEG samples obtained during CPB, protamine neutralization is more sensitive to fibrinolysis and less expensive, but the protamine dose must be carefully selected to match the heparin level used at individual institutions.