In vitro comparison of spatiotemporal fibrin clot formation dynamics in plasma treated with different protamine-heparin ratios.

INTRODUCTION: Our study aim was to explore how different protamine-heparin ratios impacted enzymatic coagulation and acellular fibrin clot growth in plasma using an in vitro model. We hypothesized that a low protamine-heparin ratio would be associated with superior fibrin clot growth dynamics. METHODS: We performed an in vitro study using 15 plasma samples from a commercial supplier. Different protamine-heparin ratios were added to each donor plasma sample: low ratio (0.7-1), traditional ratio (1-1), and high ratio (1.3-1) and clot formation dynamics were evaluated using a Thrombodynamics analyzer. Study outcomes were initial clot growth velocity and clot size at 30 min. RESULTS: Plasma samples treated with a one-to-one protamine-heparin ratio had significantly lower mean initial clot growth velocity compared to samples treated with a low protamine-heparin ratio; mean difference -2.3 µm/min (95% CI = -4.0 to -0.7, p = .004). Plasma samples treated with a one-to-one protamine-heparin ratio also had significantly smaller mean clot size at 30 min compared to samples treated with a low protamine-heparin ratio; mean difference -54.0 µm (95% CI = -107.6 to -0.4, p = .048). There were no significant differences in mean initial clot growth velocity or clot size at 30 min between plasma samples treated with a high protamine-heparin ratio and those treated with a one-to-one or low protamine-heparin ratio (all p > .05). CONCLUSIONS: Plasma samples treated with a low protamine-heparin ratio had superior clot growth velocity and larger clot size at 30 min compared to a one-to-one ratio, supporting the notion that a low protamine-heparin ratio may optimize enzymatic coagulation after cardiopulmonary bypass.

Protamine use in transfemoral carotid artery stenting is not associated with an increased risk of thromboembolic events.

BACKGROUND: Protamine use in carotid endarterectomy has been shown to be associated with fewer perioperative bleeding complications without higher rates of thromboembolic events. However, the effect of protamine use on complications after transfemoral carotid artery stenting (CAS) is unclear, and concerns remain about thromboembolic events. METHODS: A retrospective review was performed for patients undergoing transfemoral CAS in the Vascular Quality Initiative from March 2005 to December 2018. We assessed in-hospital outcomes using propensity score-matched cohorts of patients who did and did not receive protamine. The primary outcome was in-hospital stroke or death. Secondary outcomes included bleeding complications, stroke, death, transient ischemic attack, myocardial infarction, and congestive heart failure exacerbation. Bleeding complications were categorized as bleeding resulting in intervention or blood transfusions. RESULTS: Of the 17,429 patients undergoing transfemoral CAS, 2697 (15%) patients received protamine. We created 2300 propensity score-matched pairs of patients who did and did not receive protamine. There were no statistically significant differences in stroke or death between the two cohorts (protamine, 2.5%; no protamine, 2.9%; relative risk [RR], 0.85; 95% confidence interval [CI], 0.60-1.21; P = .37). Protamine use was not associated with statistically significant differences in perioperative bleeding complications resulting in interventional treatment (0.9% vs 0.5%; RR, 2.10; 95% CI, 0.99-4.46; P = .05) or blood transfusion (1.2% vs 1.2%; RR, 0.92; 95% CI, 0.53-1.61; P = .78). There were also no statistically significant differences for the individual outcomes of stroke (1.8% vs 2.3%; RR, 0.78; 95% CI, 0.52-1.16; P = .22), death (0.9% vs 0.8%; RR, 1.17; 95% CI, 0.62-2.19; P = .63), transient ischemic attack (1.4% vs 1.3%; RR, 1.10; 95% CI, 0.67-1.82; P = .70), myocardial infarction (0.5% vs 0.4%; RR, 1.20; 95% CI, 0.52-2.78; P = .67), or heart failure exacerbation (1.0% vs 0.9%; RR, 1.05; 95% CI, 0.58-1.90; P = .88). Protamine use in patients presenting with symptomatic carotid stenosis was associated with lower risk of stroke or death (3.0% vs 4.3%; RR, 0.69; 95% CI, 0.47-0.998; P = .048), whereas there were no statistically significant differences in stroke or death with protamine use in asymptomatic patients (1.6% vs 1.0%; RR, 1.63; 95% CI, 0.67-3.92; P = .28). CONCLUSIONS: Heparin reversal with protamine after transfemoral CAS is not associated with an increased risk of thromboembolic events, and its use in symptomatic carotid disease is associated with a lower risk of stroke or death.

Andexanet Alfa, the Possible Alternative to Protamine for Reversal of Unfractionated Heparin.

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.

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice.

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously.

Protamine use in transcarotid artery revascularization is associated with lower risk of bleeding complications without higher risk of thromboembolic events.

OBJECTIVE: Recent studies have found that transcarotid artery revascularization (TCAR) is associated with lower risk of stroke or death compared with transfemoral carotid artery stenting but higher risk of bleeding complications, presumably associated with the need for an incision. Heparin anticoagulation is universally used during TCAR, so protamine use may reduce bleeding complications. However, the safety and effectiveness of protamine use in TCAR are unknown. We therefore evaluated the impact of protamine use on perioperative outcomes after TCAR in the Vascular Quality Initiative TCAR Surveillance Project. METHODS: We performed a retrospective review of patients undergoing TCAR in the Vascular Quality Initiative TCAR Surveillance Project from September 2016 to April 2019. We assessed in-hospital outcomes using propensity score-matched cohorts of patients who did and did not receive protamine. The primary efficacy end point was access site bleeding complications, and the primary safety end point was in-hospital stroke or death. Secondary end points included the individual end points of stroke, death, transient ischemic attack, myocardial infarction, congestive heart failure exacerbation, and hemodynamic instability. RESULTS: Of the 5144 patients undergoing TCAR, all patients received heparin and 4072 (79%) patients received protamine. We identified 944 matched pairs of patients who did and did not receive protamine. Protamine use was associated with a significantly lower risk of bleeding complications (2.8% vs 8.3%; relative risk [RR], 0.33; 95% confidence interval [CI], 0.21-0.52; P < .001), including bleeding that resulted in interventional treatment (1.0% vs 3.6%; RR, 0.26; 95% CI, 0.13-0.54; P < .001) and in blood transfusion (1.2% vs 3.9%; RR, 0.30; 95% CI, 0.15-0.58; P <.001). There were no statistically significant differences in in-hospital stroke or death for patients who received protamine and those who did not (1.6% vs 2.2%; RR, 0.71; 95% CI, 0.37-1.39; P = .32); however, there was a trend toward lower risk of stroke for patients who received protamine (1.1% vs 2.0%; RR, 0.53; 95% CI, 0.24-1.13; P = .09). There were also no statistically significant differences in the rates of transient ischemic attack (0.4% vs 1.1%; RR, 0.40; 95% CI, 0.13-1.28; P = .11), myocardial infarction (0.4% vs 0.8%; RR, 0.50; 95% CI, 0.15-1.66; P = .25), heart failure exacerbation (0.4% vs 0.3%; RR, 1.33; 95% CI, 0.30-5.96; P = .71), or postoperative hypotensive hemodynamic instability (16% vs 15%; RR, 1.06; 95% CI, 0.83-1.35; P = .50) with protamine use. CONCLUSIONS: Protamine can be safely used in TCAR to reduce the risk of perioperative bleeding complications without increasing the risk of thrombotic events.

Editor's Choice - Protamine Reduces Serious Bleeding Complications Associated with Carotid Endarterectomy in Asymptomatic Patients without Increasing the Risk of Stroke, Myocardial Infarction, or Death in a Large National Analysis.

OBJECTIVE: Controversy persists regarding the use of protamine during carotid endarterectomy (CEA), despite real world evidence to support its use. The purpose of this study was to determine the impact of protamine reversal of heparin anticoagulation on the outcome of CEA in the USA. METHODS: A prospective national registry (Society for Vascular Surgery Vascular Quality Initiative) of 72 787 patients undergoing elective asymptomatic CEA by 1879 surgeons from 316 centres in the USA and Canada from 2012 to 2018 was reviewed. Protamine use varied by both surgeon (20% rare use [< 10%], 30% variable use [11%-79%], 50% routine use [> 80% cases]) and geographical region (44% vs. 96%). Temporal trends in protamine use were also determined. End points included post-operative re-operation for bleeding, as well as potential protamine related thrombotic complications, including stroke, death, and myocardial infarction (MI). Predictors of end points were determined by multivariable logistic regression. Propensity matching was additionally used to control for differences between groups. RESULTS: Of the 72 787 patients who underwent CEA, 69% received protamine, while 31% did not. Protamine use increased over time from 60% (2012) to 73% (2018). In total, 378 patients (0.7%) in the protamine treated group underwent re-operation for bleeding vs. 342 patients (1.4%) in the untreated cohort (p < .001). Protamine use did not affect the rate of MI (0.7% vs. 0.8%; p = .023), stroke (1.1% vs. 1.0%; p = .20), or in hospital death (0.2% vs. 0.2%; p = 0.70) between treated and untreated patients, respectively. On multivariable analysis, protamine use was independently associated with reduced risk of re-operation for bleeding (odds ratio 0.5, 95% confidence interval 0.39-0.55; p < .001). Independent of protamine exposure, the consequences of a return to the operating room (RTOR) for bleeding were statistically significant, with a sevenfold increase in MI (RTOR 4.9% vs. no RTOR 0.7%; p < .001), an eightfold increase in stroke (RTOR 7.2% vs. no RTOR 0.9%; p < .001), and a 13 fold increase in death (RTOR 2.4% vs. no RTOR 0.2%; p < .001). CONCLUSION: Protamine reduces serious bleeding complications at the time of CEA without increasing the risk of MI, stroke, or death, in this large North American analysis. Based on this and previous regional work regarding protamine use in CEA, it is believed that there is now sufficient evidence to support its routine use, and it should be considered as a benchmark for quality during CEA.

Mid-term Clinical Outcomes of Immediate Protamine Use Following Elective Percutaneous Coronary Interventions.

Bleeding complication has been considered as a serious problem in current percutaneous coronary interventions (PCI). Fortunately, several groups have already reported the effectiveness of protamine use just after PCI to immediately remove any arterial sheath. However, there is a concern that protamine reversal may increase non-occlusive thrombus and, in turn, lead to mid-term cardiovascular events such as target vessel revascularization (TVR) or stent thrombosis. Thus, the purpose of this study was to evaluate whether protamine use following elective PCI was associated with mid-term clinical outcomes. In total, 472 patients were included in this study; subsequently, they were divided into protamine group (n = 142) and non-protamine group (n = 330). The primary endpoint was the composite of ischemia-driven TVR and stent thrombosis. The median follow-up period was determined to be at 562 days. In total, 32 primary endpoints were observed during the study period, and the incidence of primary endpoints tended to be greater in the protamine group than in the non-protamine group (P = 0.056). However, the lesion length, the degree of calcification, and the prevalence of hemodialysis were significantly determined greater in the protamine group than in the non-protamine group. In the multivariate Cox proportional hazards model, the use of protamine (versus non-protamine: hazard ratio 0.542 and 95% confidence interval 0.217-1.355, P = 0.191) was deemed not to be associated with the primary endpoint after controlling legion length, calcification, and hemodialysis. In conclusion, immediate protamine use following elective PCI did not increase mid-term ischemia-driven TVR or stent thrombosis. However, immediate protamine use after PCI should be discussed further for the safety of the patient.

Heparin reversal with protamine sulfate is not required in atrial fibrillation ablation with suture hemostasis.

BACKGROUND: The utility of protamine sulfate for heparin reversal in catheter-based atrial fibrillation (AF) ablation is unclear when using the suture closure technique for vascular hemostasis. OBJECTIVE: This study sought to address if protamine sulfate use for heparin reversal reduces vascular access complications in AF catheter ablation when suture techniques are used for postprocedural vascular hemostasis. METHODS: This is a retrospective multicenter observational study of 294 consecutive patients who underwent catheter ablation for AF with subsequent vascular access hemostasis by means of a figure-of-eight suture or stopcock technique. A total of 156 patients received protamine for heparin reversal before sheath removal while 138 patients did not receive protamine. The two groups were compared for procedural activated clotting time (ACT), access site complications, and duration of hospital stay. RESULTS: Baseline demographic characteristics were comparable in both groups. Despite higher ACT before venous sheath removal in patients not receiving protamine (288.0 ± 44.3 vs 153.9 ± 32.0 seconds; P < .001), there was no significant difference in groin complications, postoperative thromboembolic events, or duration of hospital stay between the two groups. Suture failure requiring manual compression was rarely observed in this cohort (0.34%). CONCLUSION: With modern vascular access and sheath management techniques, for patients undergoing catheter ablation for AF, simple suture closure techniques can obviate the need for protamine administration to safely achieve hemostasis after removal of vascular sheaths.

Glycosaminoglycan Neutralization in Coagulation Control.

The glycosaminoglycans (GAGs) heparan sulfate, dermatan sulfate, and heparin are important anticoagulants that inhibit clot formation through interactions with antithrombin and heparin cofactor II. Unfractionated heparin, low-molecular-weight heparin, and heparin-derived drugs are often the main treatments used clinically to handle coagulatory disorders. A wide range of proteins have been reported to bind and neutralize these GAGs to promote clot formation. Such neutralizing proteins are involved in a variety of other physiological processes, including inflammation, transport, and signaling. It is clear that these interactions are important for the control of normal coagulation and influence the efficacy of heparin and heparin-based therapeutics. In addition to neutralization, the anticoagulant activities of GAGs may also be regulated through reduced synthesis or by degradation. In this review, we describe GAG neutralization, the proteins involved, and the molecular processes that contribute to the regulation of anticoagulant GAG activity.

Protamine sulfate for the reversal of enoxaparin associated hemorrhage beyond 12 h.

Clinical practice guidelines recommend protamine sulfate for reversal of enoxaparin associated bleeds dependent on the time from last administration and dose of enoxaparin. We present a case of a hemodynamically unstable patient with an enoxaparin induced abdominal wall hematoma/hemorrhage and the previous enoxaparin administration 21.5 h prior to presentation with a therapeutic anti-Xa assay (0.8 IU/mL) upon assessment in the emergency department. Along with resuscitative efforts, an interdisciplinary team collaborated to administer protamine sulfate 50 mg intravenous once (0.5 mg per 1 mg of enoxaparin) to reverse the therapeutic anticoagulation. Our case demonstrates the importance of monitoring renal function and the potential for accumulation of enoxaparin in patients with renal dysfunction leading to prolonged therapeutic anti-Xa assays. With the availability of anti-Xa assays, future reversal recommendations of enoxaparin associated bleeds using protamine sulfate should include the initial anti-Xa assay as a guide for the dosing regimen.

Neck haematoma after carotid endarterectomy: risks, rescue, and prevention.

OBJECTIVE: This study was performed to identify risk factors for neck haematoma requiring re-exploration after carotid endarterectomy. Neck haematoma is a well-known complication after carotid endarterectomy, but there has been little discussion about intraoperative techniques for its prevention. We also investigated an intraoperative neck flexion technique for prevention of neck haematoma. METHODS: A retrospective study reviewed 384 carotid endarterectomies performed at our institution from 2003 to 2016. The endpoint was neck haematomas requiring re-exploration after carotid endarterectomy. Endpoint predictors (general factors, preoperative medication, and intraoperative factors) were identified by univariate analysis. Our intraoperative neck flexion technique involved changing the neck and head position from extension to flexion during carotid endarterectomy. In patients with neck haematoma, we assessed the interval from carotid endarterectomy to re-exploration, the source of bleeding, and the method of airway rescue. RESULTS: There was one major and three minor perioperative strokes (1.1%). Neck haematoma occurred in 9 patients (2.4%). Univariate analysis (odds ratio [95% confidence interval]) identified preoperative clopidogrel therapy (4.19 [1.03-17.06], P = .04) and not using protamine sulfate after heparin (4.13 [1.02-25.06], P = .04) as risk factors for haematoma. We used the intraoperative neck flexion technique in 87 patients and no neck haematomas occurred. There was no additional morbidity and no mortality in the patients who required re-exploration. The interval between carotid endarterectomy and re-exploration ranged from 0 to 30 hours. Intubation before re-exploration was often difficult. We recommend using a laryngeal mask and performing minor wound re-exploration under local anesthesia before tracheal intubation for general anesthesia. Haematomas were mainly caused by venous bleeding or capillary oozing. CONCLUSIONS: This study showed that neck haematoma is uncommon after carotid endarterectomy, but requires emergency airway rescue and re-exploration.

Thrombolysis Following Heparin Reversal With Protamine Sulfate in Acute Ischemic Stroke: Case Series and Literature Review.

INTRODUCTION: Administering intravenous IV tissue plasminogen activator (tPA) is the recommended standard of care in acute ischemic stroke (AIS), although it is not recommended to administer intravenous thrombolysis with tPA following heparin reversal with protamine sulfate in patients with AIS. METHODS: We describe a case series of three patients and the most comprehensive literature review published to date in this specific subset of AIS patients undergoing thrombolysis following heparin reversal with protamine sulfate. The literature review was based on a scoping review methodology performed on four databases; PubMed, CINAHL, Web of Science, and Cochrane Library. All sources were searched from the inauguration of the database until February 2019. A total of six articles involving eight patients were identified. RESULTS: The primary safety outcome of no symptomatic intracranial hemorrhage (sICH) was met in all eleven patients, although only seven cases had a good functional outcome at 3 months. CONCLUSIONS: In appropriately selected AIS patients, coagulopathy correction appears to be safe from an sICH standpoint and may be beneficial. However, given the potential for bias with observational databases, case reports and case series, extreme caution is warranted in applying these results to routine clinical practice.

The effect of protamine dosing variation on bleeding and transfusion after heparinisation for cardiopulmonary bypass.

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.

Safety of Reversing Anticoagulation by Protamine Following Elective Transfemoral Percutaneous Coronary Intervention in the Drug-Eluting Stent Era.

Bleeding complications following percutaneous coronary interventions (PCI) have been closely associated with morbidity and mortality. Although radial arteries have been widely used in current PCI, including primary PCI, transfemoral PCI remains necessary for complex PCI. The purpose of this study was to compare the incidence of complications following elective transfemoral PCI between manual compression with and without protamine. We identified 249 consecutive patients who underwent elective transfemoral PCI from hospital records, and divided them into two groups: patients who used protamine for manual compression (the protamine group; n = 205) and patients who did not (the non-protamine group, n = 44). Complications including acute thrombosis, bleeding requiring blood transfusion, transient hypotension, skin rash, and death within 30 days were compared between groups. The baseline clinical and procedural characteristics were comparable between the protamine and non-protamine groups. The incidences of all complications were not different between the protamine (5.9%) and the non-protamine groups (9.1%) (P = 0.43). While more than 90% of the patients received drug-eluting stent implantation, there was no acute thrombus in either group. The incidence of bleeding requiring blood transfusion was significantly lower in the protamine group (0.5%) than in the non-protamine group (6.8%) (P = 0.002). Multivariate logistic regression analysis revealed the inverse association between protamine use and bleeding requiring blood transfusion (odds ratio 0.08, 95% confidence interval 0.01-0.84, P = 0.04). In conclusion, the use of protamine for manual compression following elective transfemoral PCI was safe and was associated with less bleeding complications.

Advances in Heparins and Related Research. An Epilogue.

The discovery of heparin in 1916 by Jay McLean, a medical student at Johns Hopkins University, not only provided a universal anticoagulant, but also laid the foundation for the discipline of hemostasis and thrombosis[...].

Antifungal activity in vitro and in vivo of a salmon protamine peptide and its derived cyclic peptide against Candida albicans.

Protamine peptide (PP) derived from salmon is a 14-mer with 10 arginine residues. We investigated the in vitro and in vivo antifungal activity of PP against Candida albicans PP showed a concentration-dependent dual mode of action, with fungicidal activity and inhibitory activity for hyphal development in vitro. At lethal concentrations of PP, intracellular accumulation of PP was energy-dependent but independent of endocytosis, and resulted in ATP efflux and the generation of reactive oxygen species in the cells. PP at sublethal concentrations inhibited hyphal development in C. albicans by binding to the cell surface. Though antifungal activity of PP was inactivated by high concentrations of NaCl, the antifungal activity of the synthetic cyclic (via a disulfide bond) form of PP (cyclic PP) was not. Cyclic PP also showed the concentration-dependent dual mode of action, and had five-fold greater antifungal activity than PP. The advantage of antifungal activity of cyclic PP compared with PP in vitro resulted in a high in vivo efficacy in a murine oral candidiasis model. Oral treatment with cyclic PP inhibited hyphal development of C. albicans on mouse tongues and protected against the development of severe candidiasis. This study shows the therapeutic potential of cyclic PP as an antifungal peptide against C. albicans.

Pilot validation of an individualised pharmacokinetic algorithm for protamine dosing after systemic heparinisation for cardiopulmonary bypass.

INTRODUCTION: This manuscript represents a pilot study assessing the feasibility of a single-compartment, individualised, pharmacokinetic algorithm for protamine dosing after cardiopulmonary bypass. METHODS: A pilot cohort study in a specialist NHS cardiothoracic hospital targeting patients undergoing elective cardiac surgery using cardiopulmonary bypass. Patients received protamine doses according to a pharmacokinetic algorithm (n = 30) or using an empirical, fixed-dose model (n = 30). Categorical differences between the groups were evaluated using the Chi-squared test or Fisher's exact test. Continuous data was analysed using a paired Student's t-test for parametric data and the paired samples Wilcoxon test for non-parametric data. RESULTS: Patients who had protamine dosing according to the algorithm demonstrated a lower protamine requirement post-bypass relative to empirical management as measured by absolute dose (243 ± 49mg vs. 305 ± 34.7mg; p<0.001) and the heparin to protamine ratio (0.79 ± 0.12 vs. 1.1 ± 0.15; p<0.001). There was no difference in the pre- to post-bypass activated clotting time (ACT) ratio (1.05 ± 0.12 vs. 1.02 ± 0.15; p=0.9). Patients who received protamine according to the algorithm had no significant difference in transfusion requirement (13.3% vs. 30.0%; p=0.21). CONCLUSIONS: This study showed that an individualized pharmacokinetic algorithm for the reversal of heparin after cardiopulmonary bypass is feasible in comparison with a fixed dosing strategy and may reduce the protamine requirement following on-pump cardiac surgery.

Protamine Reduces Bleeding Complications without Increasing the Risk of Stroke after Carotid Endarterectomy: A Meta-analysis.

OBJECTIVES: The aim was to evaluate the safety and efficacy of heparin reversal with protamine after completion of carotid endarterectomy (CEA), summarising the available data from both randomised and non-randomised studies. METHODS: The study was a meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated for the outcomes of stroke and wound haematoma among patients receiving or not receiving protamine after CEA. Meta-regression analysis was performed to examine whether the documented differences were modified by potentially meaningful patient related or procedure related predictors, namely publication year, general anesthesia used, number of patients treated, mean age (years), males, neurological symptoms, use of patch, and use of shunt. RESULTS: Seven studies were included in the meta-analysis reporting on 3,817 patients receiving protamine after CEA and 6,070 patients not receiving protamine for heparin reversal. Only one study was randomised. A statistically significant reduction in wound haematoma requiring re-operation was recorded after heparin reversal with protamine in patients undergoing CEA (OR, 0.42, 95% CI, 0.22-0.80, p = .008). In contrast, no significant difference was observed in stroke rates between groups of patients that received and did not receive protamine (OR, 0.71, 95% CI, 0.49-1.03, p = .07). Meta-regression analysis did not reveal any significant effect mediated by the modifiers examined. CONCLUSION: On the basis of the available data, heparin reversal with protamine seems to reduce the risk of wound haematoma, without increasing the risk of procedural stroke. However, taking into account the limitations of the analysis, further studies are needed to increase the level of evidence provided by the current meta-analysis.

Validation of a point-of-care prothrombin time test after cardiopulmonary bypass in cardiac surgery.

Point-of-care coagulation monitoring can be used for the guidance of haemostasis management. However, the influence of time on point-of-care prothrombin time testing following protamine administration after cardiopulmonary bypass has not been investigated. Bland-Altman and error grid analysis were used to analyse the level of agreement between prothrombin time measurements from point-of-care and laboratory tests before cardiopulmonary bypass, and then 3 min, 6 min and 10 min after protamine administration. Prothrombin times were expressed as International Normalised Ratios. While the point-of-care and laboratory prothrombin time measurements showed a high level of agreement before bypass, this agreement deteriorated following protamine administration to a mean (SD) bias of -0.22 (0.13) [limits of agreement 0.48-0.04]. Error grid analysis revealed that 35 (70%) of the paired values showed a clinically relevant discrepancy in international normalised ratio. At 3 min, 6 min and 10 min after cardiopulmonary bypass there is a clinical unacceptable discrepancy between the point-of-care and laboratory measurement of prothrombin time.