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Background: Drug shortages are a frequent challenge in current clinical practice. Certain drugs (e.g., protamine) lack alternatives, and inadequate supplies can limit access to services. Conventional protamine dosing uses heparin ratio-based calculations for heparin reversal after cardiopulmonary bypass and may result in excess protamine utilization and potential harm due to its intrinsic anticoagulation. This study hypothesized that a fixed 250-mg protamine dose would be comparable, as measured by the activated clotting time, to a 1:1 (1 mg for every 100 U) protamine-to-heparin ratio-based strategy for heparin reversal and that protamine would be conserved., Methods: In a single-center, double-blinded trial, consenting elective adult cardiac surgical patients without preexisting coagulopathy or ongoing anticoagulation and a calculated initial heparin dose greater than or equal to 27,500 U were randomized to receive, after cardiopulmonary bypass, protamine as a fixed dose (250 mg) or a ratio-based dose (1 mg:100 U heparin). The primary outcome was the activated clotting time after initial protamine administration, assessed by Student's t test. Secondary outcomes included total protamine, the need for additional protamine, and the cumulative 24-h chest tube output., Results: There were 62 and 63 patients in the fixed- and ratio-based dose groups, respectively. The mean postprotamine activated clotting time was not different between groups (-2.0 s; 95% CI, -7.2 to 3.3 s; P = 0.47). Less total protamine per case was administered in the fixed-dose group (-2.1 50-mg vials; 95% CI, -2.4 to -1.8; P < 0.0001). There was no difference in the cumulative 24-h chest tube output (difference, -77 ml; 95% CI, 220 to 65 ml; P = 0.28)., Conclusions: A 1:1 heparin ratio-based protamine dosing strategy compared to a fixed 250-mg dose resulted in the administration of a larger total dose of protamine but no difference in either the initial activated clotting time or the amount postoperative chest-tube bleeding., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Objectives: To determine protamine administration increases pulmonary artery pressures (PAPs) in patients undergoing unifocalization or pulmonary artery reconstruction surgeries., Design: Retrospective database study., Setting: A large pediatric heart center within an academic quaternary care facility., Participants: All patients undergoing pulmonary artery reconstruction or a unifocalization procedure identifiable within the data warehouse., Interventions: We collected data from Stanford University's data repository, formatted it, and analyzed it using RStudio (v 2023.06.1+524)., Measurements and Main Results: Our primary outcome is the change in PAP after the administration of protamine. Secondary outcomes include changes in the mean arterial pressure, the ratio of systolic pulmonary artery to systemic artery pressure, right-sided filling pressure, and left atrial pressure. After a protamine bolus, we found a difference in PAP (Friedman χ 2 = 49.46; p < 0.001). When compared with 2 minutes before its administration, the PAP was higher at 2 minutes (29.00 mmHg versus 25.00 mmHg; p < 0.001), 5 minutes (30.00 mmHg versus 25.00 mmHg; p < 0.001) and 10 minutes (31 mmHg versus 25 mmHg; p < 0.001). When coadministered with calcium, there was also a significant increase in PAP (Friedman χ 2 = 28.11; p < 0.001), with a higher PAP 10 minutes after calcium administration when compared with 2 minutes before (32 mmHg versus 26 mmHg; p < 0.001)., Conclusions: Protamine administration led to a small increase in PAP after separation from cardiopulmonary bypass in patients undergoing pulmonary artery reconstruction or unifocalization surgeries. Calcium coadministration did not lead to a greater increase in PAP., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To retrospectively assess the incidence and severity of perioperative protamine reactions in adult patients with documented history of fish allergy., Design: Retrospective observational study., Setting: Large academic tertiary referral center., Participants: Adults with fish allergies undergoing surgeries involving protamine, between January 1, 2008, and March 1, 2018., Interventions: Perioperative protamine administration in patients with documented fish allergy., Measurements and Main Results: Perioperative protamine and anaphylactic reactions were reviewed. A diagnosis of anaphylaxis or protamine reaction was based on clinical suspicion, perioperative events, and postoperative evaluations. Among 214 patients, 2 cases (<1%) of anaphylaxis or protamine reactions occurred. Cardiac procedures were most common (67%). The median intraoperative heparin dosage was 46,000 IU, and the median protamine dosage was 310 mg. Nearly all patients (99%) were admitted to the intensive care unit postoperatively, with a median hospital stay of 6.5 days (interquartile range, 5.2-14.6 days). There were 3 deaths (1%) within 30 days, and 15 (7%) within 1 year., Conclusions: The study findings suggest that in patients with a history of fish allergy, cross-reactivity with protamine is unlikely, as anaphylaxis and/or protamine reactions were rare in this patient population in the perioperative environment. Based on these findings, this study does not recommend avoiding protamine solely based on a history of fish allergy when heparin reversal is required during surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To assess the impact of post-protamine neutralisation activated clotting time (ACT) values on postoperative outcomes including chest drain output, transfusion requirements, and CICU stay, in patients undergoing cardiac surgery., Study Design: Observational comparative study. Place and Duration of the Study: Department of Anaesthesiology, The Aga Khan University Hospital, Karachi, Pakistan, from February to August 2023., Methodology: Ethical approval was obtained to collect data from elective cardiac surgery patients' charts. A sequential sampling approach analysed the baseline and post-protamine neutralisation ACT values, categorising patients into two groups. Group A maintained ACT within 10% of baseline, while Group B deviated. The outcomes measured included transfusion needs, chest drain output, additional protamine, cardiac intensive care unit (CICU) stay, and postoperative reopening. Statistical analysis included mean, median, frequency, t-test / Mann-Whitney U test, and Chi-square test., Results: The study comprised 101 patients (39 in Group A, 62 in Group B), with similar baseline health. No significant differences were found in tranexamic acid use, CICU stay, chest drain output, or transfusion rates between the groups (p >0.05)., Conclusion: Maintaining ACT within 10% of baseline post-protamine neutralisation results in similar intraoperative and postoperative outcomes, suggesting potential benefits in avoiding the aggressive protamine therapy and ensuring haemostasis in cardiac surgery., Key Words: Coronary Artery bypass grafting, Cardiopulmonary bypass, Activated clotting time (ACT), Heparin, Postoperative bleeding, Blood transfusions.

Introduction: Individualized heparin and protamine management is increasingly used as a strategy to reduce coagulation activation and bleeding complications. While it is associated with increased heparin requirements during Cardiopulmonary Bypass (CPB), the impact on protamine administration remains controversial. We aim to investigate the effect of heparin level-guided monitoring on protamine dosing during cardiac surgery where low-anticoagulation protocols are implemented., Methods: This is a prospective, randomized, controlled trial. A total of 132 patients undergoing elective full-spectrum cardiac surgery with Minimal Invasive Extracorporeal Circulation (MiECC) were recruited. All patients were managed by the same anaesthetic, surgical and perfusion team. Patients were randomly allocated in two groups; the individualized heparin-protamine titration (IHPT) group and the conventional heparinization and reversal group by using ACT (cACT) with a 0.75:1, protamine: heparin ratio. Titration was accomplished with the Hepcon HMS Plus (Medtronic, Minneapolis, MN) system. The primary outcome of the study was the total protamine dose used. Secondary outcomes comprised of the total heparin dose, the percentage of patients achieving target ACT, 24-h transfusion requirements, postoperative bleeding, duration of mechanical ventilation, major morbidity and length of hospital stay. Patients in each group were divided in two subgroups according to the target ACT; those operated for coronary artery bypass grafting (CABG) using a target ACT >300 s and the rest (non-CABG) patients operated with a target ACT >400 s, respectively., Results: Protamine requirements were significantly reduced when IHPT was implemented; CABG (118 ± 24 mg vs 163 ± 61 mg; p < 0.001) and non-CABG cases (151 ± 46 mg vs 197 ± 45 mg; p < 0.001). Moreover, heparin requirements were significantly higher in the non-CABG subgroup managed with IHPT (34,539 ± 7658 IU vs 29,893 ± 9037 IU; p = 0.02). In overall, no significant differences were detected with respect to postoperative bleeding, transfusion of RBC or other blood products., Conclusions: Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery with MiECC implementing reduced anticoagulation strategy., Trial Registration: clinicaltrials.gov; NCT04215588., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A multidisciplinary Quality Assurance/Performance Improvement study to identify the incidence of "heparin rebound" in our adult cardiac surgical population instead detected a thromboelastometry pattern suggestive of initial protamine overdose in 34% despite Hepcon-guided anticoagulation management. Analysis of our practice led to an intervention that made an additional lower-range Hepcon cartridge available to the perfusionists., Methods: One year later, an IRB-approved retrospective study was conducted in >500 patients to analyze the effects of the intervention, specifically focusing on the impact of the initial protamine dose accuracy and 18-h mediastinal chest tube drainage (MCTd)., Results: No differences were observed between group demographics, surgical procedures, duration of CPB or perioperative blood product transfusion. Both groups were managed using the same perfusion and anesthesia equipment, strategies, and protocols. The median initial protamine dose decreased by 19% ( p < .001) in the intervention group (170 [IQR 140-220] mg; n = 295) versus the control group (210 [180-250] mg; n = 257). Mean 18-h MCTd decreased by 13% ( p < .001) in the intervention group (405.15 ± 231.54 mL; n = 295) versus the control group (466.13 ± 286.73 mL; n = 257). Covariate-adjusted mixed effects model showed a significant reduction of MCTd in the intervention group, starting from hour 11 after surgery (group by time interaction p = .002)., Conclusion: Though previous investigators have associated lower protamine doses with less MCTd, this study demonstrates that more accurately matching the initial protamine dose to the remaining circulating heparin concentration reduces postoperative bleeding., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Vascular complications after transfemoral transcatheter aortic valve implantation (TAVI) remain an important cause of procedure-related morbidity. Routine reversal of anticoagulation with protamine at the conclusion of transfemoral TAVI could reduce complications, but data remain scarce., Objective: To evaluate the efficacy and safety of routine protamine administration after transfemoral TAVI., Design, Setting, and Participants: The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals between December 2021 and June 2023 with a 1-year follow-up period. All patients accepted for transfemoral TAVI by a multidisciplinary heart team were eligible for enrollment., Interventions: Eligible patients were randomized 1:1 between routine protamine administration and placebo., Main Outcomes and Measures: The coprimary outcomes were the rate of hemostasis success and time to hemostasis (TTH), presented as categorical variables and compared with a χ2 test or as continuous variables as mean (SD) or median (IQR), depending on distribution. The major secondary outcome was a composite of all-cause death, major and minor bleeding complications, and major and minor vascular complications after 30 days, reported in odds ratios (ORs) with 95% CIs and P values., Results: The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients [97.9%]) than patients in the placebo group (186 of 203 patients [91.6%]; absolute risk difference, 6.3%; 95% CI, 2.0%-10.6%; P = .006); in addition, patients receiving up-front protamine had a shorter median (IQR) TTH (181 [120-420] seconds vs 279 [122-600] seconds; P = .002). Routine protamine administration resulted in a reduced risk of the composite outcome in the protamine group (10 of 192 [5.2%]) vs the placebo group (26 of 203 [12.8%]; OR, 0.37; 95% CI, 0.1-0.8; P = .01). This difference was predominantly driven by the difference in the prevalence of minor vascular complications. There were no adverse events associated with protamine use., Conclusions and Relevance: In the ACE-PROTAVI randomized clinical trial, routine administration of protamine increased the rate of hemostasis success and decreased TTH. The beneficial effect of protamine was reflected in a reduction in minor vascular complications, procedural time, and postprocedural hospital stay duration in patients receiving routine protamine compared with patients receiving placebo., Trial Registration: anzctr.org.au Identifier: ACTRN12621001261808.

Severe pulmonary vasoconstriction induced by protamine is a rare complication. We report a case of a 77-year-old male patient with a history of mitral valve plasty (MVP). He underwent redo MVP via right thoracotomy under the totally endoscopic procedure (MICS redo-MVP). Immediately after weaning cardiopulmonary bypass (CPB), protamine was administrated. 10 min later peak systolic pulmonary arterial pressure (sys PAP) rose to 62 mmHg, and 30 min later to 80 mmHg. Due to the negative impact of protamine administration, nitric oxide inhalation (iNO) therapy was started with a concentration of 20 ppm. 10 min after iNO therapy started, sys PAP decreased to 63 mmHg. After entering the intensive care unit (ICU), sys PAP decreased to 35 mmHg. Here, we present an effective iNO therapy case for pulmonary hypertension due to protamine and the patient had a good postoperative recovery. This study was approved by the Institutional Review Board at Kitaharima Medical Center (IRB-0602) with the waiver of informed consent., (© The Author(s), published by EDP Sciences, 2024.)

Objectives: To optimize protamine titration for heparin antagonization after weaning from cardiopulmonary bypass (CPB)., Design: A prospective, observational trial., Setting: Single-center, non-university teaching hospital., Participants: Forty patients presenting for elective on-pump coronary artery bypass grafting with or without single valve surgery., Interventions: At the end of CPB, the residual amount of heparin in the patient was estimated using a Bull-curve. The total protamine dose was calculated as 1 unit of protamine for 1 unit of heparin. Protamine was administered as 5 aliquots containing 20% of the total protamine dose each, with 2-min intervals., Measurements and Main Results: Activated Clotting Time (ACT) values were measured 2 min after administration of each aliquot. ROTEM(®)-analysis was performed after the full dose of protamine had been administered. After 60% of the total protamine dose had been administered, ACT values were normalized in 86.5% of patients. After the complete dose of protamine had been administered, 61.1% of patients displayed signs of protamine overdose on ROTEM(®)-analysis., Conclusions: In patients who present for on-pump coronary artery bypass grafting with or without single valve surgery, a 0.6-to-1 ratio of protamine-to-heparin to antagonize heparin may be sufficient and beneficial for patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Competing interests: Mark Crowther reports receiving consulting fees from Servier Canada, Asahi Kasei, Precision Biologics and Hemostasis Reference Laboratories; payments or honoraria for educational material or presentations from Bayer, Pfizer, CSL Behring and Diagnostica Stago; and payment for expert testimony for various cases in Canada and the United States. Dr. Crowther also reports holding positions as Treasurer of the American Society of Hematology and The Anticoagulation Forum, and as Vice Chair of the Senior Research Committee, Heart and Stroke Foundation. Dr. Crowther has past and current relationships with a number of not-for-profit and for-profit entities that are not pharmaceutical manufacturers, and holds the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr. Siraj Mithoowani reports receiving support from Leo Pharma for attending a meeting. No other competing interests were declared.

Background: The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio., Methods and Findings: We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C)., Conclusions: Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients., Trial Registration: ClinicalTrials.gov Unique identifier NCT03532594., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FF has received speaking fees and research support from Abbott Laboratories and LivaNova. He is a member of the Scientific Advisory Committees for Abbott Point-of-Care, Werfen and LivaNova. The other authors have declared that no competing interests exist.

Background: Rapid growth of cardiac wall hematoma is a rare but potentially fatal complication of cardiac surgery. However, its pathophysiology and optimal management remain undefined., Case Presentation: Here we present a rare case of a large cardiac wall hematoma in the right ventricle during a thoracic aortic and valvular surgery. The hematoma expanded rapidly with epicardial rupture during cardiopulmonary bypass. We could establish non-surgical hemostasis and prevent further expansion of hematoma by early weaning of the cardiopulmonary bypass, followed by the administration of protamine and manual compression by hemostatic agent application. His postoperative recovery was uneventful and upon computed tomography analysis, the hematoma was observed to have absorbed completely at 1 week postoperatively. The patient is doing well 1 year after the surgery without evidence of recurrent cardiac wall hematoma on follow-up computed tomography., Conclusions: Cardiovascular surgeons should bear in mind this potentially catastrophic complication during cardiac surgery. Because of the vulnerability of the cardiac wall at the area of the hematoma, we believe that a hemostatic approach without sutures may be effective for this lethal complication.

The recent shortage of protamine prompted an investigation of alternatives for reversal of unfractionated heparin. Heparin is an anticoagulant utilized in the hospital setting. Available options for anticoagulation include direct oral anticoagulants, vitamin K antagonists, thrombin inhibitors, low-molecular-weight heparins, and heparin. Protamine is the approved reversal agent for heparin with few alternatives under investigation. Although andexanet was designed as an antidote for apixaban and rivaroxaban, in vitro studies show that in a dose-dependent technique, andexanet had near full reversal of heparin, reversed anti-factor Xa activity, and neutralized anticoagulant effects of activated partial thromboplastin time and thrombin time induced by heparin.

Objectives: While the use of protamine sulfate as a heparin reversal agent has been extensively reviewed in patients undergoing carotid endarterectomy and coronary artery bypass grafting, there is a lack of literature on protamine's effects on lower extremity bypasses. The purpose of this study was to determine the risk of protamine sulfate dosing after tibial bypass on thrombotic or bleeding events, including early bypass failure., Methods: We performed a retrospective review of our institutional database for patients undergoing primary distal peripheral bypass from January 2009 through December 2015 (contralateral bypass was considered to be a new primary bypass). Primary endpoints include composite thrombotic events (myocardial infarction, stroke, amputation at 30 days and patency less than 30 days) and composite bleeding events (bleeding or transfusion)., Results: A total of 152 tibial or peroneal bypasses in 136 patients with critical limb ischemia were identified. Of these, 78 (57.4%) patients received protamine sulfate intraoperatively and 58 (42.6%) did not. There were no differences in composite thrombotic or hemorrhagic outcomes. Protamine use had no effect on the rates of perioperative MI (9.0% versus 3.5%, p  = 0.20), stroke (1.3% versus 1.7%, p  = 0.83), or perioperative mortality (5.1% versus 3.5%, p  = 0.64). There was no significant difference in composite post-operative bleeding events (20.7% versus 14.1%, p  = 0.31) or composite thrombotic events (17.2% versus 18.0%, p  = 0.91). Patients who received protamine undergoing bypass with non-autogenous conduit had significantly higher-recorded median operative blood loss (250 mL versus 150 mL, p  = 0.0097) and median procedure lengths (265 min versus 201 min, p  = 0.0229). No difference in 30-day amputation-free survival was noted (91.0% versus 91.4%, p  = 0.94). Follow-up Kaplan-Meier estimation did not demonstrate a difference in 30-day patency (91.7% versus 88.5%, p  = 0.52)., Conclusions: Heparin reversal with protamine sulfate after tibial or peroneal bypass grafting is not associated with higher cardiovascular morbidity, bypass thrombosis, amputation, or mortality. Additionally, there was no statistically significant difference in post-operative bleeding or thrombosis complications for patients who did not receive protamine, although the findings are suggestive of a potential difference in a more adequately powered study. Our results suggest that protamine sulfate is safe for intraoperative use without increased risk of thrombotic complications or early tibial bypass graft failure.

Although the magnetically levitated centrifugal blood pump (mag-lev pump) is considered superior to other pumps in antithrombogenicity, thrombotic complications are still reported. Research into thrombus detection inside a mag-lev pump is very important for solving this problem. Our research group has already proposed a method to detect a thrombus inside a mag-lev pump in real time without an additional sensor, which is named the impeller vibration method. To efficiently advance our research with reproducibility, a preconditioning method to induce thrombus inside the pump was thought to be necessary. Therefore, this study aimed to develop a preconditioning method that induces thrombus formation. To verify this method, in vitro experiments for thrombus detection were performed. A mag-lev pump developed at Tokyo Institute of Technology was used. A fibrinogen solution was coated on the inner surfaces of the bottom housing to induce thrombus formation at the target point inside the pump. The thrombus is detected by utilizing the phenomenon that the phase difference between the impeller displacement and input current to the magnetic bearing increases when a thrombus is formed inside a pump. Five hundred mL of porcine blood anticoagulated with heparin sodium was circulated in the mock circuit, and protamine sulfate was administered. Flow rate (1 L/min), impeller vibrational frequency (70 Hz), and vibrational amplitude (30 µm) were set to constant. The experiment was terminated when the phase difference increased by over 2° from the minimum value. The experiments were performed in fibrinogen-coated (group F, n = 5) and non-coated pumps (group N, n = 5). In group F, thrombus formation was observed at the fibrinogen-coated point of the housing. In contrast, a relatively small thrombus was observed in varying locations such as the housing or the impeller in group N. Thrombus formation time (the time from when the phase difference takes the minimum value to when the experiment is terminated) was different between the two groups. The mean time was significantly shorter in group F (44 ± 29 minutes) than in group N (143 ± 38 minutes; p = 0.0019). Therefore, a preconditioning method that induced thrombus formation at the target point inside a blood pump was successfully developed., (© 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Objectives: The aim of this study was to evaluate whether protamine administration for heparin reversal after transcatheter aortic valve replacement (TAVR) reduces bleeding complications and affects patient outcomes., Background: Occurrence of major bleeding complications in patients undergoing TAVR is associated with increased morbidity and mortality., Methods: This study included 873 patients undergoing TAVR, of whom 677 received protamine for heparin reversal. Standard access management included the use of pre-closure devices, manual compression, and percutaneous transluminal angioplasty or implantation of a covered stent graft, if necessary. The study complied with Good Clinical Practice guidelines and was approved by the local ethics committee. Written informed consent was obtained from all patients., Results: The primary endpoint, a composite of 30-day all-cause mortality and life-threatening and major bleeding, occurred less frequently in the protamine administration group (3.2%) compared with the control group (8.7%) (p = 0.003). This was driven mainly by lower rates of life-threatening and major bleeding in the protamine group (0.1% vs. 2.6% [p < 0.001] and 1.0% vs. 4.1% [p = 0.008], respectively). Furthermore, protamine administration resulted in a significantly shorter hospital stay (11.1 ± 5.8 days vs. 12.7 ± 7.8 days; p = 0.05). In the overall cohort, stroke was observed in 1.9% and myocardial infarction in 0.2% of patients, with no significant difference between the groups (p > 0.05). Multivariate analysis revealed that only protamine administration (odds ratio: 0.24; 95% confidence interval: 0.10 to 0.58; p = 0.001) and acute kidney injury (odds ratio: 5.82; 95% confidence interval: 2.02 to 16.77; p = 0.001) were independently associated with the primary endpoint., Conclusions: Protamine administration resulted in significantly lower rates of life-threatening and major bleeding complications compared with patients without heparin reversal. Occurrence of stroke and myocardial infarction was not increased by protamine administration., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Protamine reduces platelet aggregation after cardiopulmonary bypass (CPB). We studied the inhibitory effect of a reduced protamine dose, the duration of impaired platelet function and the possible correlation to postoperative bleeding. Design: Platelet function was assessed by impedance aggregometry in 30 patients undergoing cardiac surgery with CPB at baseline, before protamine administration, after 70% and 100% of the calculated protamine dose, after 20 minutes and at arrival to the intensive care unit. Adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used as activators. Blood loss was measured during operation and three hours after surgery. Results are presented as median (25th-75th percentile). Results: Platelet aggregation decreased markedly after the initial dose of protamine (70%) with all activators; ADP 89 (71-110) to 54 (35-78), TRAP 143 (116-167) to 109 (77-136), both p  < .01; AA 25 (16-49) to 17 (12-24) and COL 92 (47-103) to 60 (38-81) U, both p  < .05. No further decrease was seen after 100% protamine. The effect was transient and after twenty minutes platelet aggregation had started to recover; ADP 76 (54-106), TRAP 138 (95-158), AA 20 (10-35), COL 70 (51-93) U. Blood loss during operation correlated to aggregometry measured at baseline and after protaminization. Conclusions: Protamine after CPB induces a marked decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1. The impairment seems to be transient and recovery had started after 20 minutes.

Protamine sulfate (PS) is a polycationic protein drug obtained from the sperm of fish, and is used to reverse the anticoagulant effect of unfractionated heparin (UFH). However, the interactions between PS, UFH, and platelets are still not clear. We measured the platelet numbers and collagen-induced aggregation, P-selectin, platelet factor 4, β-thromboglobulin, prostacyclin metabolite, D-dimers, activated partial thromboplastin time, prothrombin time, anti-factor Xa, fibrinogen, thrombus weight and megakaryocytopoiesis in blood collected from mice and rats in different time points.. All of the groups were treated intravenously with vehicle, UFH, PS, or UFH with PS. We found a short-term antiplatelet activity of PS in mice and rats, and long-term platelet-independent antithrombotic activity in rats with electrically-induced thrombosis. The antiplatelet and antithrombotic potential of PS may contribute to bleeding risk in PS-overdosed patients. The inhibitory effect of PS on the platelets was attenuated by UFH without inducing thrombocytopenia. Treatment with UFH and PS did not affect the formation, number, or activation of platelets, or the thrombosis development in rodents.

Cognitive workload data of members of the cardiac surgery team can be measured intraoperatively and stored for later analysis. We present a case of a near-miss (medication error) that underwent root cause analysis using workload data. Heart rate variability data, representing workload levels, were collected from the attending surgeon, attending anesthesiologist, and lead perfusionist using wireless heart rate monitors. An episode of cognitive overload of the anesthesiologist due to a distractor was associated with the preventable error. Additional studies are needed to better understand the role of psychophysiological data in enhancing surgical patient safety., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.)

Objectives: The aim of the study was to investigate whether the HeProCalc algorithm affects heparin and protamine dosage, postoperative blood loss, and transfusion rate., Design: Randomized controlled trial., Setting: University hospital., Participants: The study comprised 210 cardiac surgery patients undergoing cardiac surgery with cardiopulmonary bypass. Twenty patients were excluded because of re-exploration for localized surgical bleeding (n = 9), violation of protocol (n = 2), aprotinin use (n = 3 and nadir body temperature <32°C (n = 6)., Interventions: Study participants were randomly assigned to either traditional heparin and protamine dosage based on body weight only (control group) or dosage based on the HeProCalc algorithm (intervention group)., Measurements and Main Results: The initial median heparin dose was 32,500 IU (interquartile range [IQR] 30,000-35,000) in the intervention group compared with 35,000 IU (IQR 30,000-37,500) (p = 0.025) in the control group. The total heparin dose in the intervention group was 40,000 IU (IQR 32,500-47,500) compared with 42,500 IU (IQR 35,000-50,000) in the control group (p = 0.685). The total protamine dose was 210 mg (IQR 190-240) in the intervention group compared with 350 mg (IQR 300-380) (p < 0.001) in the control group. The ratio of total protamine to initial dose of heparin in the intervention group was 0.62 compared with 1.0 (p < 0.001). The amount of chest tube bleeding after 12 postoperative hours was 320 mL (IQR 250-460) in the intervention group compared with 350 mL (IQR 250-450) (p = 0.754) in the control group. Neither the transfusion rate nor postoperative blood loss differed significantly between the 2 groups., Conclusion: Use of the HeProCalc algorithm reduced protamine dosage and the protamine/heparin ratio after cardiopulmonary bypass compared with conventional dosage based on weight without significant effect on postoperative blood loss or the transfusion rate., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Four-factor PCC is the recommended standard of care for acute warfarin reversal but optimal dosing is unknown. We aim to show that a low-dose strategy is often adequate and may reduce the risk of thromboembolic events when compared to manufacturer-recommended dosing., Methods: A weight-based dosing strategy of 15-25 units/kg was established as the institutional standard of care in May 2015. This retrospective, before-and-after cohort analysis included patients receiving 4F-PCC according to a manufacturer-recommended (n = 122) or a low-dose (n = 83) strategy. The primary efficacy outcome was a combination of INR reversal on first check and hemostatic efficacy at 24 h., Results: Demographics, indications for warfarin, and presenting INR values were similar between the two groups. Patients in the manufacturer-recommended dose group received significantly more 4F-PCC than the low dose group (2110 units vs. 1530 units). More patients in the manufacturer-recommended dose group achieved the primary endpoint (75.4% vs. 61.4%), with more patients achieving the target INR on recheck in the manufacturer-recommended dose group (95.9% vs. 84.3%) and no difference in hemostatic efficacy between groups (79.5% vs. 74.7%). There was no difference in thromboembolic events at 72 h (4.1% vs. 1.2%) or at 30 days (8.2% vs. 4.8%). Significantly more patients in the manufacturer-recommended dose group died or were transferred to hospice care during hospitalization (21.3% vs. 9.6%)., Conclusion: Utilization of a low-dose 4F-PCC strategy resulted in fewer patients achieving target INR reversal, but no difference in hemostatic efficacy, thromboembolic events, or survival.

Enoxaparin is a low molecular weight heparin used in the neonatal period. It requires less monitoring than standard or unfractionated heparin, although current knowledge about its dose and therapeutic levels in neonates is scarce. In addition, there is very limited information about the management of overdose in this age group. We present the first case published in Spanish of a neonate who accidentally received a dose of enoxaparin ten times higher than the therapeutic one and an isolated dose of protamine to reverse its effect., (Sociedad Argentina de Pediatría.)

Background: There are no randomized controlled studies of the efficacy and safety of protamine to reverse anticoagulant effects of heparin after catheter ablation (CA) of atrial fibrillation (AF)., Objective: The purpose of this study was to determine the efficacy and safety of protamine to expedite vascular hemostasis and ambulation after CA of AF., Methods: CA to eliminate AF (n = 139) or left atrial flutter (n = 11) was performed in 150 patients using radiofrequency catheter ablation (n = 112) or cryoballoon ablation (n = 38). CA was performed under uninterrupted anticoagulation with warfarin in 28 patients or after skipping a single dose of a novel oral anticoagulant in 122 patients who were randomized to receive protamine (n = 77) or to the control group (n = 73). Baseline and procedural characteristics were similar between the 2 groups. Hemostasis was achieved manually once the activated clotting time returned to preprocedural values., Results: The maximum activated clotting time during CA was 359 ± 31 and 359 ± 29 seconds in the protamine and control groups, respectively (P = .91). The time to hemostasis was 123 ± 95 minutes in the protamine group and 260 ± 70 minutes in the control group (P < .001). The time to ambulation was 316 ± 80 and 480 ± 92 minutes in the protamine and control groups, respectively (P < .001). There were no differences in the rates of major or minor vascular access complications or thromboembolic events (P > .05)., Conclusion: Protamine expedites vascular hemostasis and time to ambulation by ∼3 hours after CA of AF without an increase in the risk of vascular or thromboembolic complications., (Copyright © 2018 Heart Rhythm Society. All rights reserved.)

Essentials Heparin-protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB). HPB was examined in 44 neonates undergoing CPB. Post-operative bleeding occurred in 36% and heparin rebound in 73%. Thrombin-initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB., Summary: Background Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin. Objectives To evaluate heparin-protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding. Patients/Methods Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin-protamine balance was assessed with calibrated automated thrombography, thrombin-initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti-FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade. Results and Conclusions Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti-FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long-established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population., (© 2018 International Society on Thrombosis and Haemostasis.)

Introduction: Accurate dosing of protamine reversal following on-pump cardiac surgical procedures is challenging, with both excessive and inadequate administration recognised to increase bleeding risk. We aimed to examine the relationship between three ratios for heparin reversal and markers of haemostasis., Methods: A retrospective analysis of a prospectively collected database was undertaken at a single tertiary cardiac unit, reviewing all cases of on-pump coronary artery bypass grafts and single valve replacements from 01/01/2011 to 31/12/2015. The ratio between total intra-operative heparin and protamine was stratified to three groups (low: ≤0.6 mg per 100 IU of heparin, moderate: 0.6-1.0 and high: >1.0) and related to the primary outcome of red blood cell (RBC) transfusion, with secondary outcomes being the number of units transfused, the haemoglobin differential and mediastinal drain output at 4 hours., Results: Of the 803 patients identified, 338 received a blood transfusion, with 1035 units being used. Eighteen percent of individuals (145) received a low ratio, 50% (404) received a moderate ratio and 32% (254) a high ratio. Using the moderate group as a reference, the low dose group was 56.5% less likely to have received a RBC transfusion (OR 0.435; 95% CI 0.270:0.703 p=0.001) while the high dose group carried a 241% increased association with transfusion (OR 3.412; 95% CI 2.399:4.853 p<0.001). For those transfused, a lower protamine:heparin ratio was associated with a lower number of units transfused, lesser haemoglobin differential and less mediastinal drain output., Conclusion: Higher doses of intra-operative protamine relative to heparin are associated with greater risk of transfusion and post-operative bleeding.

The potential applications for nanomaterials continue to grow as new materials are developed and environmental and safety concerns are more adequately addressed. In particular, virus-like particles (VLPs) have myriad applications in medicine and biology, exploiting both the reliable, symmetric self-assembly mechanism and the ability to take advantage of surface functionalities that may be appropriately modified through mutation or bioconjugation. Herein we describe the design and application of hybrid VLPs for use as potent heparin antagonists, providing an alternative to the toxic heparin antidote protamine. A two-plasmid system was utilized to generate VLPs that contain both the wild-type coat protein and a second coat protein with either a C- or N-terminal cationic peptide extension (4-28 amino acids). Incorporation of the modified coat proteins varied from 8 to 31%, while activated partial thromboplastin time (APTT) assays revealed a range of the heparin antagonist activity. Notably, when examined on the basis of the quantity of peptide delivered due to the varied incorporation rates, it appeared that the VLPs largely followed a similar trend, with the quantity of peptide delivered more closely correlating with heparin antagonist activity. The particle with the highest incorporation rate and best antiheparin activity displayed the C-terminal peptide ARK 2 A 2 KA, which corresponds to the Cardin-Weintraub consensus sequence for binding to glycosaminoglycans. Analysis of this particle using heparin affinity chromatography with fraction collection revealed that particles eluting at higher salt concentration had a greater proportion of peptide incorporation. Preliminary dual polarization interferometry experiments further support a strong interaction between this particle and heparin.

Since there were a few articles to report the treatment of severe pulmonary vasoconstriction induced by protamine in cardiac surgery, we described the use of epoprostenol to reverse this condition.A total of 5 cases of severe pulmonary vasoconstriction induced by protamine in cardiac surgery were reviewed. The demographic, clinical data and treatment process were obtained. All the patients were followed up.Severe pulmonary vasoconstriction was occurred 4 to 10 minutes after protamine infusion. The primary sign was sudden hypotension, the pulmonary artery pressure was increased gradually, the arterial oxygen partial pressure was decreased in all the patients. Epoprostenol was infused via pulmonary artery catheter at dosage of 20 to 40 ng/kg·min in all the patients, 2 patients were underwent re-cardiac pulmonary bypass assistance. The hemodynamic instability status lasted 40 to 65 minutes respectively. All the patients were recovered uneventfully.All physicians should alert to the incidence of severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Use epoprostenol through pulmonary artery catheter could treat pulmonary artery vasoconstriction effectively and safely.

Objectives: Pulmonary endarterectomy (PEA) is the only curative treatment option for patients with chronic thromboembolic pulmonary hypertension. Massive endobronchial bleeding that precludes weaning from cardiopulmonary bypass is an often-fatal complication of PEA. The aim of this study was to determine whether short-term extracorporeal membrane oxygenation (ECMO) is a safe and feasible procedure in patients with severe endobronchial bleeding., Methods: From January 2014 to December 2016, 396 patients (mean age 60 ± 18 years, 54.5% male) underwent PEA in our department. Patients with severe endobronchial hemorrhage at the time of weaning from cardiopulmonary bypass (CPB) were switched to a heparin-coated venoarterial ECMO circuit. After full-dose protamine administration to restore normal coagulation, weaning from ECMO was attempted in the operating room., Results: In-hospital mortality was 2.3% (9/396 patients). Eight patients (2.0%) developed severe endobronchial bleeding classified as diffuse (n = 6) or localized (n = 2) by bronchoscopy. After reinstitution of CPB and subsequent switch to ECMO, the mean duration of ECMO support was 49 ± 13 minutes, and all 8 patients were weaned successfully from ECMO in the operating theater without further signs of endobronchial bleeding. One patient needed venovenous ECMO support for poor oxygenation 6 hours after surgery. Seven patients were discharged after a prolonged postoperative stay of 17.6 ± 4.1 days. One patient died. This new concept significantly reduced mortality compared with previous (2009-2013) ECMO support (P = .0406)., Conclusions: For patients with massive endobronchial bleeding after PEA, the intraoperative switch from CPB to venoarterial ECMO support with full-dose protamine administration is a new and potentially life-saving treatment concept., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Few patients presenting with acute ischemic stroke (AIS) are eligible for alteplase, especially those receiving ongoing anticoagulation. We describe the first reported case of a patient receiving full-dose intravenous (IV) alteplase for AIS after heparin reversal with protamine. A 73-year-old man presented with AIS. He was treated with IV heparin, tirofiban, loading-dose prasugrel, and aspirin before percutaneous coronary intervention (PCI) for placement of a right coronary artery stent. One hour following PCI, he abruptly developed left hemiparesis and dysphagia. The National Institutes of Health Stroke Scale was 12, and activated partial thromboplastin time (aPTT) was longer than 150 seconds. Head computed tomography (CT) showed no acute pathology, and CT angiogram showed no large-vessel occlusion amenable to mechanical thrombectomy. Repeat aPTT, obtained 45 minutes later, was 110 seconds, at which time protamine 40 mg IV was administered. At 144 minutes from last known well time, full-dose IV alteplase (0.9 mg/kg) was administered. Follow-up head imaging at 25 hours showed right pontine and cerebellar AIS with no evidence of hemorrhage. The patient was discharged to inpatient rehabilitation 2 days later. Modified Rankin Scale at 3 months was 3, improved from 5 at discharge. Given the lack of adverse events associated with IV alteplase in our patient, we advocate cautious evaluation for potential reversal of acutely administered anticoagulation to facilitate alteplase administration in severely disabled patients who are not eligible for mechanical intervention and would have been excluded from definitive AIS treatment., (© 2017 Pharmacotherapy Publications, Inc.)

The primary focus of cardiopulmonary bypass management in Jehovah's Witness patients is the need to conserve blood. A consequence of these strategies inevitably results in hemodilution that is frequently extreme enough to dilute clotting factors and potentially impair coagulation. The purpose of this case report is to demonstrate that a hemodiluted patient requires less heparin to sustain anticoagulation and less protamine to reverse heparin at cardiopulmonary bypass termination. Patient harm may ensue unless the effects of extreme hemodilution are recognized.

Objectives: To implement a statistical model for protamine titration., Design: Prospective randomized trial., Setting: University hospital., Participants: Sixty (n = 30+30) patients scheduled for elective coronary artery bypass surgery were randomly assigned to 2 groups., Interventions: Protamine dose calculated according to an algorithm established from a statistical model or to a fixed protamine-heparin dose ratio (1:1)., Measurements and Main Results: Both groups demonstrated comparable patient demographics and intraoperative data. Coagulation effects were evaluated using rotational thromboelastometry. Using the statistical model reduced (p<0.01) the protamine dose from 426±43 mg to 251±66 mg, followed by significantly (p<0.01) shorter intrinsic clotting time (208±29 seconds versus 244±52 seconds) and stronger clot firmness (p = 0.01), and effects on indices of extrinsic or fibrinogen coagulation pathways were insignificant. Test of residual heparin was negative in all patients after protamine administration, aligned with insignificant (p = 0.27) intergroup heparinase-verified clotting time differences., Conclusions: The statistical model for protamine titration is clinically feasible and protects the patient from exposure to excessive doses of protamine, with advantageous effects on coagulation as measured using rotational thromboelastometry. Significance regarding clinical outcome is yet to be defined., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.)

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.)

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.

Objective: To examine if methylene blue (MB) can counteract or prevent protamine (P) cardiovascular effects., Methods: The protocol included five heparinized pig groups: Group Sham -without any drug; Group MB - MB 3 mg/kg infusion; Group P - protamine; Group P/MB - MB after protamine; Group MB/P - MB before protamine. Nitric oxide levels were obtained by the nitric oxide/ozone chemiluminescence method, performed using the Nitric Oxide Analizer 280i (Sievers, Boulder, CO, USA). Malondialdehyde plasma levels were estimated using the thiobarbiturate technique., Results: 1) Groups Sham and MB presented unchanged parameters; 2) Group P - a) Intravenous protamine infusion caused mean arterial pressure decrease and recovery trend after 25-30 minutes, b) Cardiac output decreased and remained stable until the end of protamine injection, and c) Sustained systemic vascular resistance increased until the end of protamine injection; 3) Methylene blue infusion after protamine (Group P/MB) - a) Marked mean arterial pressure decreased after protamine, but recovery after methylene blue injection, b) Cardiac output decreased after protamine infusion, recovering after methylene blue infusion, and c) Sustained systemic vascular resistance increased after protamine infusion and methylene blue injections; 4) Methylene blue infusion before protamine (Group MB/P) - a) Mean arterial pressure decrease was less severe with rapid recovery, b) After methylene blue, there was a progressive cardiac output increase up to protamine injection, when cardiac output decreased, and c) Sustained systemic vascular resistance decreased after protamine, followed by immediate Sustained systemic vascular resistance increase; 5) Plasma nitrite/nitrate and malondialdehyde values did not differ among the experimental groups., Conclusion: Reviewing these experimental results and our clinical experience, we suggest methylene blue safely prevents and treats hemodynamic protamine complications, from the endothelium function point of view., Competing Interests: No conflict of interest.

Warfarin is widely used to perform catheter ablation for atrial fibrillation (AF). Heparin is usually administered during this procedure to prevent thromboembolic events, while protamine is used to reduce the incidence of bleeding complications. The purpose of this study was to investigate the influence of heparin and protamine administration on the effects of warfarin and its safety. The subjects included 226 AF patients (206 males, 54.9 ± 9.1 years, paroxysmal/persistent AF: 118/108) undergoing AF ablation with the discontinuation of warfarin administration over 2 days. Heparin was administered to achieve an activated clotting time (ACT) above 300 s during the procedure. Several parameters of the coagulation status, including the prothrombin time international normalized ratio (PT-INR) and ACT values, measured immediately before and after protamine infusion were compared. The mean value of PT-INR prior to ablation was 1.9 ± 0.6. At the end of the procedure, the mean ACT and PT-INR values were 348.0 ± 52.9 and 2.9 ± 0.7, respectively. Following the infusion of 30 mg of protamine, both the ACT and PT-INR values significantly decreased, to 159.6 ± 31.0 (p < 0.0001) and 1.6 ± 0.3 (p < 0.0001), respectively. No cases of symptomatic cerebral infarction were observed, although femoral hematomas developed in 17 (7.5 %) of the patients without further consequence. The concomitant use of heparin augments the effect of warfarin. Meanwhile, protamine administration immediately reverses both the ACT and PT-INR, indicating the applicability of protamine for AF ablation in patients under the mixed administration of heparin and warfarin.

Objectives: Platelet dysfunction is an important cause of postoperative bleeding after cardiac surgery. Protamine is routinely used for reversal of heparin after cardiopulmonary bypass (CBP), but may affect platelet aggregation. We assessed changes in platelet function in relation to protamine administration., Design: Platelet aggregation was analyzed by impedance aggregometry before and after protamine administration in 25 adult cardiac surgery patients. Aggregation was also studied after in vitro addition of heparin and protamine. The activators adenosine diphosphate (ADP), thrombin receptor activating peptide-6 (TRAP), arachidonic acid (AA) and collagen (COL) were used., Results: Platelet aggregation was reduced by approximately 50% after in vivo protamine administration; ADP 640 ± 230 (AU*min, mean ± SD) to 250 ± 160, TRAP 939 ± 293 to 472 ± 260, AA 307 ± 238 to 159 ± 143 and COL 1022 ± 350 to 506 ± 238 (all p < 0.001). Aggregation was also reduced after in vitro addition of protamine alone with activators ADP from 518 ± 173 to 384 ± 157 AU*min p < 0.001, and AA 449 ± 311 to 340 ± 285 (p < 0.01) and protamine combined with heparin (1:1 ratio) with activators ADP to 349 ± 160 and AA to 308 ± 260 (both p < 0.001); and COL from 586 ± 180 to 455 ± 172 (p < 0.05)., Conclusions: Protamine given after CPB markedly reduces platelet aggregation. Protamine added in vitro also reduces platelet aggregation, by itself or in combination with heparin.

Coronary artery perforation is a highly feared complication of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) and can lead to pericardial effusion, tamponade, and, rarely, emergent cardiac surgery. Perforation of epicardial collaterals during retrograde CTO-PCI may be particularly challenging to treat, as embolization from both sides of the perforation may be required to control the bleeding. However, conservative measures can occasionally be effective. We present a case of epicardial collateral vessel perforation that was managed conservatively with anticoagulation reversal.

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.)

Purpose: Anticoagulation with heparin is required during catheter ablation of atrial fibrillation (AF) to reduce systemic thromboembolism. In this study, we aim to compare safety and efficacy outcomes between patients who receive protamine administration for reversal of heparin and those who do not, following cryoballoon-based pulmonary vein isolation (PVI) for AF., Methods: Patients with symptomatic paroxysmal or persistent AF despite ≥1 antiarrhythmic drug(s) were scheduled for PVI per the recent consensus recommendations. Some patients were administered protamine at the end of the procedure depending on the operator's choice., Results: Among 380 patients [48.2% male, 56 (20-86) years] that were enrolled, 188 patients received protamine at the end of the procedure. Baseline characteristics did not differ between groups (p > 0.05). Mean protamine dose was 39.1 ± 6.4 mg. Only 1 patient developed rash following protamine infusion. Hospital stay was significantly shorter in patients who were administered protamine (1 [1-5] vs. 2 [1-7] days, p < 0.001). Hematoma/pseudoaneurysm or femoral AV fistula requiring surgical or interventional repair in the femoral access site occurred in 2 (1.1 %) patients who received protamine and 12 (6.3%) patients who did not (p = 0.011). Deep vein thrombosis was seen in 1 patient in whom protamine was not administered (p = 0.499)., Conclusion: To the best of our knowledge, this is one of the largest series showing that protamine administration for heparin reversal in patients undergoing cryoballoon-based PVI allows quicker sheath removal and minimizes the risk of potential vascular complications without causing an increase in thrombotic events.

A new molecular entity, PER977 (di-arginine piperazine), is in clinical development as an anticoagulant reversal agent for new oral anticoagulants and heparins. The good laboratory practices (GLP)-compliant studies were conducted to evaluate the toxicity of PER977 and its primary metabolite, 1,4-bis(3-aminopropyl)piperazine (BAP). PER977 and BAP were negative for systemic toxicity in dogs and rats. PER977 was rapidly eliminated from the blood with little to no accumulation. PER977 was negative for genotoxicity and did not alter neurological, respiratory, or cardiovascular function. Maximum tolerated doses for PER977 were 40 (rat) and 35 mg/kg (dog), and greater than 80 mg/kg (rat) for BAP. The no observable adverse effect level (NOAEL) for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/d. For BAP, the NOAELs for 14-day intravenous exposure to rats and dogs were 5 and 20 mg/kg, respectively. Based on these results, a safe and conservative dose level of 19.4 mg/d was used for the PER977 first in human study., (© The Author(s) 2015.)