Activated Clotting Time Research Articles

Emicizumab does not interfere with the activated clotting time.

The activated clotting time (ACT) is a useful marker of unfractionated heparin (UFH) activity during cardiopulmonary bypass (CPB) or cardiac catheterization. Emicizumab, recently approved for bleeding prevention in haemophilia A patients, acts like FVIII but does not need prior activation; it therefore shortens coagulation times in assays using intrinsic pathway activators and so is expected to shorten the ACT. To evaluated emicizumab's impact on heparin-induced ACT (Hemochron®) prolongation. We measured the high-range (HR) ACT in citrated blood samples from healthy donors (HDs) (n=9), CPB patients (n=3) and emicizumab-treated patients (n=5) after spiking with UFH and/or emicizumab. The low range (LR) ACT was also measured in spiked-samples from HDs and emicizumab-treated patients. In HDs, the median [interquartile range] baseline HR-ACTs were similar with and without emicizumab (129 [123-138] and 136 [115-141]s for 50μg/ml, respectively); whatever the concentration of emicizumab (10 to 50μg/ml), increasing the UFH concentration (1-5 UI/ml) prolonged the HR-ACT. In blood from patients undergoing CPB, the HR-ACT prolongation observed during this procedure was not masked by emicizumab at any concentration. Likewise, the addition of increasing concentrations of UFH to blood from emicizumab-treated patients induced a concentration-dependent prolongation of HR-ACT. Baseline LR-ACT were prolonged in emicizumab-treated patients but as for HR-ACT, emicizumab does not prevent heparin-induced prolongation of LR-ACT. Emicizumab does not interfere with UFH-induced ACT prolongation. The hemochron® ACT can be used to monitor UFH in patients receiving emicizumab during CPB or cardiac catheterization.

Risk Factors Associated With Bleeding in Children With Cardiac Disease Receiving Extracorporeal Membrane Oxygenation: A Multi-Center Data Linkage Analysis.

Background: Bleeding is a common complication of extracorporeal membrane oxygenation (ECMO) for pediatric cardiac patients. We aimed to identify anticoagulation practices, cardiac diagnoses, and surgical variables associated with bleeding during pediatric cardiac ECMO by combining two established databases, the Collaborative Pediatric Critical Care Research Network (CPCCRN) Bleeding and Thrombosis in ECMO (BATE) and the Extracorporeal Life Support Organization (ELSO) Registry.Methods: All children (<19 years) with a primary cardiac diagnosis managed on ECMO included in BATE from six centers were analyzed. ELSO Registry criteria for bleeding events included pulmonary or intracranial bleeding, or red blood cell transfusion >80 ml/kg on any ECMO day. Bleeding odds were assessed on ECMO Day 1 and from ECMO Day 2 onwards with multivariable logistic regression.Results: There were 187 children with 114 (61%) bleeding events in the study cohort. Biventricular congenital heart disease (94/187, 50%) and cardiac medical diagnoses (75/187, 40%) were most common, and 48 (26%) patients were cannulated directly from cardiopulmonary bypass (CPB). Bleeding events were not associated with achieving pre-specified therapeutic ranges of activated clotting time (ACT) or platelet levels. In multivariable analysis, elevated INR and fibrinogen were associated with bleeding events (OR 1.1, CI 1.0–1.3, p = 0.02; OR 0.77, CI 0.6–0.9, p = 0.004). Bleeding events were also associated with clinical site (OR 4.8, CI 2.0–11.1, p < 0.001) and central cannulation (OR 1.75, CI 1.0–3.1, p = 0.05) but not with cardiac diagnosis, surgical complexity, or cannulation from CPB. Bleeding odds on ECMO day 1 were increased in patients with central cannulation (OR 2.82, 95% CI 1.15–7.08, p = 0.023) and those cannulated directly from CPB (OR 3.32, 95% CI 1.02–11.61, p = 0.047).Conclusions: Bleeding events in children with cardiac diagnoses supported on ECMO were associated with central cannulation strategy and coagulopathy, but were not modulated by achieving pre-specified therapeutic ranges of monitoring assays.

Different Kinetics of Activated Clotting Time Among Uninterrupted Oral Anticoagulants During Catheter Ablation Procedure.

Activated clotting time (ACT) kinetics under uninterrupted oral anticoagulants (OACs) has not been fully evaluated. The present study is sought to validate ACT kinetics including stability under uninterrupted use of OACs during an ablation procedure in daily clinical practice. We prospectively enrolled consecutive 554 patients with atrial fibrillation who underwent catheter ablation procedure under uninterrupted OACs. We evaluated ACT kinetics at an interval of 15 minutes during the procedure and periprocedural complications among 5 OACs (dabigatran [N = 46], rivaroxaban [N = 125], apixaban [N = 129], edoxaban [N = 184], and warfarin [N = 70]). Compared with the dabigatran group, time to achieve target ACT was significantly longer in the rivaroxaban and apixaban groups, but not in the edoxaban and warfarin groups (8.7 vs 11.7 minutes, P < .001; 13.3 minutes, P < .001; 8.8 minutes, P = .64; 10.3 minutes, P = .19, respectively). Heparin dose to achieve target ACT was comparable except for the warfarin group, whereas, compared with the dabigatran group, time in therapeutic range of ACT within the first hour was comparable in the rivaroxaban and apixaban group but significantly lower in the edoxaban and warfarin groups (73.7 % vs 63.0%, P = .06; 67.0 %, P = .16; 59.2 %, P = .001; 58.2%, P = .004, respectively). In multiple regression analysis, low body weight, rivaroxaban, apixaban, and morning session had significant associations with time and heparin dose to achieve target ACT, and there were positive associations of dabigatran and apixaban with time in therapeutic range of ACT within the first hour. The incidence of periprocedural complications did not significantly differ among the 5 groups. Under uninterrupted OAC use in daily clinical practice, dabigatran showed faster achievement of target ACT and higher stability of ACT than other OACs.

Differential Neutralization of Unfractionated Heparin and Enoxaparin by Andexanet Alfa.

IntroductionAndexanet alfa (andexanet) is an approved antidote used to reverse the bleeding effects of Direct Oral Anticoagulant (Direct-Xa agents) agents because it reverses anti-Xa activity. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit anti-Xa activity. The purpose is to investigate the neutralization of UFH and LMWH by andexanet in activated clotting time (ACT), thrombelastography (TEG), and anti-Xa due to the protamine sulfate shortage.MethodsUFH and LMWH were studied with andexanet, PS, or saline as potential reversal agents/controls at varying concentrations in ACT, TEG, and anti-Xa and compared to each other.ResultsAndexanet partially neutralized both drugs several TEG parameters at high andexanet concentrations, but it was not as effective as protamine sulfate in any of the assays used. Most TEG parameters were correlated with andexanet concentration. In ACT, significant neutralization was demonstrated at many andexanet concentrations for UFH, but not LMWH. UFH was completely neutralized by PS in ACT, while LMWH was partially neutralized by PS in ACT. Andexanet alfa was a less effective neutralization agent than the protamine sulfate as it only partially neutralized UFH in ACT and was ineffective at neutralizing LMWH when tested at the same concentration as PS (10 ug/mL).ConclusionAndexanet partially neutralized UFH and LMWH with variability between assays, necessitating investigation into assay-dependent differences.

Higher Doses of Heparin Required to Achieve Target ACT During AF Ablation for Those Treated With Rivaroxaban Than Dabigatran

Heparin dosing of patients anticoagulated with direct oral anticoagulants (DOACs) undergoing atrial fibrillation (AF) ablation can be challenging. Higher doses are required to achieve target activated clotting times (ACT) for those anticoagulated with DOACs than with warfarin. We describe heparin dosing requirements to achieve and maintain ACTs>350 sec.

Contemporary Practice of Heparin Prescription and Its Monitoring via Activated Clotting Time in Percutaneous Coronary Intervention in Victoria, Australia

Adequate anticoagulation during percutaneous coronary intervention (PCI) with unfractionated heparin (UFH) is the standard practice to minimise thrombotic complications. Current international guidelines lack clarity on the use of activated clotting time (ACT) to measure the adequacy of anticoagulation during and post PCI, and the need for UFH supplementation post PCI.

In vitro comparative study of activated clotting time in fresh human whole blood with various levels of coagulability using two devices

In vitro comparative study of activated clotting time in fresh human whole blood with various levels of coagulability using two devices

Investigation of heparin-loaded poly(ethylene glycol)-based hydrogels as anti-thrombogenic surface coatings for extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.

An Ovine Model of Awake Veno-Arterial Extracorporeal Membrane Oxygenation.

Background: Large animal models are developed to help understand physiology and explore clinical translational significance in the continuous development of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) technology. The purpose of this study was to investigate the establishment methods and management strategies in an ovine model of VA-ECMO.Methods: Seven sheep underwent VA-ECMO support for 7 days by cannulation via the right jugular vein and artery. The animals were transferred into the monitoring cages after surgery and were kept awake after anesthesia recovery. The hydraulic parameters of ECMO, basic hemodynamics, mental state, and fed state of sheep were observed in real time. Blood gas analysis and activated clotting time (ACT) were tested every 6 h, while the complete blood count, blood chemistry, and coagulation tests were monitored every day. Sheep were euthanized after 7 days. Necropsy was performed and the main organs were removed for histopathological evaluation.Results: Five sheep survived and successfully weaned from ECMO. Two sheep died within 24–48 h of ECMO support. One animal died of fungal pneumonia caused by reflux aspiration, and the other died of hemorrhagic shock caused by bleeding at the left jugular artery cannulation site used for hemodynamic monitoring. During the experiment, the hemodynamics of the five sheep were stable. The animals stayed awake and freely ate hay and feed pellets and drank water. With no need for additional nutrition support or transfusion, the hemoglobin concentration and platelet count were in the normal reference range. The ECMO flow remained stable and the oxygenation performance of the oxygenator was satisfactory. No major adverse pathological injury occurred.Conclusions: The perioperative management strategies and animal care are the key points of the VA-ECMO model in conscious sheep. This model could be a platform for further research of disease animal models, pathophysiology exploration, and new equipment verification.

A Blinded Randomized Trial Comparing Standard Activated Clotting Time Heparin Management to High Target Active Clotting Time and Individualized Hepcon HMS Heparin Management in Cardiopulmonary Bypass Cardiac Surgical Patients.

Purpose: High-dose heparin has been suggested to reduce consumption coagulopathy.Materials and Methods: In a randomized, blinded, prospective trial of patients undergoing elective, complex cardiac surgery with cardiopulmonary bypass, patients were randomized to one of three groups: 1) high-dose heparin (HH) receiving an initial heparin dose of 450 u/kg, 2) heparin concentration monitoring (HC) with Hepcon Hemostasis Management System (HMS; Medtronic, Minneapolis, MN, USA) monitoring, or 3) a control group (C) receiving a standard heparin dose of 300 u/kg. Primary outcome measures were blood loss and transfusion requirements.Results: There were 269 patients block randomized based on primary versus redo sternotomy to one of the three groups from August 2001 to August 2003. There was no difference in operative bleeding between the groups. Chest tube drainage did not differ between treatment groups at 8 hours (median [25th percentile, 75th percentile] for control group was 321 [211, 490] compared to 340 [210, 443] and 327 [250, 545], p = 0.998 and p = 0.540, for HH and HC treatment groups, respectively). The percentage of patients receiving transfusion was not different among the groups.Conclusion: Higher heparin dosing accomplished by either activated clot time or HC monitoring did not reduce 24-hour intensive care unit blood loss or transfusion requirements.

Robust K-PD model for activated clotting time prediction and UFH dose individualisation during cardiopulmonary bypass

Background and objectiveActivated clotting time (ACT) is a point-of-care test used to monitor the effect of unfractionated heparin (UFH) during cardiopulmonary bypass (CPB). This test sometimes returns aberrant values, which can lead to the administration of an inappropriate dosing regimen. The development of a population-robust K-PD model of UFH could allow the individualisation and automation of UFH therapy during CPB. MethodsWe conducted a prospective observational study to collect ACT measurements from patients undergoing surgery using CPB. The ACT data were split into a development and validation cohort. The development cohort was used to estimate a standard and robust population K-PD model characterised by a residual error following a normal distribution and student's t-distribution. The ACT prediction performance using Bayesian estimates of individual K-PD parameters was evaluated by comparing predicted versus observed ACTs. Using estimates of the robust K-PD model, a Bayesian individualisation strategy to automate UFH administration was proposed and evaluated using Monte Carlo simulations. ResultsA total of 295 patients were included in the study, and 1561 ACTs were collected. In patients without outlier values, Bayesian estimates (based on four ACT measurements) from both standard and robust K-PD models had similar performances, with a median prediction bias close to 0 s. In patients with outlier measurements, the use of the robust K-PD model greatly improved the prediction bias and root-mean-square error (RMSE), with a mean prediction bias of 3.25 s, IQR = [-19.9; 46.03] versus -86 s IQR = [-135.7; -63.8] for the standard model. Monte Carlo simulations showed that the robust Bayesian individualisation strategy allowed the ACT to be maintained above the target using only two to three ACT measurements. ConclusionsThe use of a robust K-PD model reduced prediction bias and RMSE in patients with outlier ACT measurements. The Bayesian individualisation strategy using robust estimates of individual parameters may help automate UFH dosing regimens. Proper clinical validation is warranted before its use in daily clinical practice.

Aggressive early surgical strategy in patients with intracranial hemorrhage: a new cardiopulmonary bypass option.

We present a novel strategy in cardiac surgery with a cardiopulmonary bypass with low-dose heparin and Nafamostat mesylate as an anticoagulant (NM-CPB), which reduces postoperative neurological complications. 19 patients with a mean age of 63.6 ± 20.2years (range 24-91) and an indication of early cardiac surgery with intracranial complication (ICC) underwent surgery with NM-CPB. The preoperative diagnoses included seven cases of infective endocarditis and six of left atrial appendage thrombosis. ICC were noticed in seven cases with hemorrhages (hemorrhagic infarction: n = 4, subarachnoid hemorrhage: n = 3) and 12 without hemorrhage (large infarction: n = 10, small-multiple infarction at the risk for hemorrhagic transformation: n = 2). The mean interval between a diagnosis and cardiac surgery was 1.1 ± 1.5days in the ICH cases and 1.4 ± 1.4days otherwise. In-hospital mortality was 5.3%. The mean CPB time was 146.7 ± 66.03min, the mean dose of NM, heparin were 2.23 ± 1.59mg/kg/hr and 56.8 ± 20.3IU/kg, respectively. The mean activated clotting time (ACT) was 426.8 ± 112.4s. No further intracranial bleeding and no new hemorrhages were observed after surgery. In early cardiac surgery with ICC, especially with hemorrhage, NM-CPB reduced postoperative neurological complications. We plan to use NM-CPB to expand the indications and to establish an early aggressive treatment.

Managing patients on direct factor Xa inhibitors with rapid thrombelastography

The use of direct factor Xa inhibitors rivaroxaban and apixaban (XABANs) has rapidly increased; however, there is no validated test available to monitor the effect on hemostasis. This study aims to assess how hemostatic management based on the Rapid Thromboelastography (R-TEG) variable activated clotting time (ACT) of XABAN patients with ongoing bleedings or in need for acute surgical intervention, affected patient outcome. A total of 343 XABAN patients were included in the main analysis together with 50 healthy volunteers to validate the reference value for ACT. An ACT >120 s (s) was defined as having XABAN-induced coagulopathy. Sixty-five percent of the XABAN patients presented with R-TEG ACT within the normal reference. Patients with XABAN-induced coagulopathy had a significantly increased risk of severe bleeding. Significantly more patients with extra-cerebral bleeding (ECB) and ACT above 120 s were transfused with five red blood cell (RBC) units or more compared to patients with ACT at 120 s or below (17% vs. 3%, p <.05). Significantly more XABAN-patients with ACT above 120 s received pro-hemostatic intervention with prothrombin complex concentrate (PCC) when compared to those with ACT at 120 s or below (ECB: 2% vs. 8%, p =.03, intracranial hemorrhage: 25% vs. 68%, p <.00). Patients who received PCC had a higher 30- and 90-day mortality compared to the rest of the cohort (16% vs. 6%, p = .02 and 21% vs. 7%, p =.00). Patients with XABAN-induced coagulopathy as evaluated by R-TEG ACT presented with more severe bleeding and higher transfusion requirements when compared to those with ACT in the normal range. This suggests that R-TEG ACT measurement in XABAN patients with active hemorrhage or in need for acute surgery may be of clinical value.

Abstract 11378: Reference Intervals of Activated Clotting Time in Pediatric Patients Undergoing Cardiac Surgery

Introduction: Monitoring the anticoagulant effect of heparin is critical to prevent thrombosis and/or bleeding during cardiac surgery. This evaluation is usually performed by assessing the activated clotting time (ACT) with a POC device. Despite the relevance and widespread use of ACT, there are currently limited reference values to use as a target. Furthermore, compared to the adult population, infants have been described with a longer ACT, reinforcing the need to establish a separate reference interval for this segment of the population. Aim: The present work aims to propose reference intervals of ACT in pediatric patients. Methods: We collected data on 155 consecutive patients, ranging in age from 1 day to 18 years, undergoing cardiac surgery from 01-2019 to 01-2021 at Sainte-Justine hospital. Prior to surgery, patients were given UFH as a bolus of 3 mg/kg, and Hemochron Signature Elite ACT+ (Accriva Diagnostics, Inc.) was used to measure ACT before and promptly after heparin injection. Data were subsequently analyzed by using a parametric method. Lower and upper reference limits are the values at the 2.5 and 97.5 percentile, respectively. Results: The ACT before heparin injection followed a normal distribution with a lower reference limit at 85 seconds and an upper limit at 147 seconds compared to the range of 70-120 seconds proposed for the general population. Interestingly, the ACT after heparin bolus exhibited a non-gaussian distribution. Since neonates have been previously described with a greater heparin resistance compared to older infants; patients were separated into two age groups: patients &lt; 1-month of age (Group A; n=31) and patients &gt; 1-month (group B; n=124). Afterward, we performed a log transformation of the ACT values after heparin injection to approximate a Gaussian distribution, yielding mean ACT value of 392 seconds (limits 291-529 seconds) for Group A and 473 seconds (limits 314-996 seconds) for Group B (Welch test p value = 4.4 10 -6 ). No significant difference in ACT values prior to heparin bolus was found between the two groups. Conclusion: Overall, our results provide reference values of ACT measured using an Hemochron device, in a pediatric context, paving the way for improved patient care during cardiac surgery.

Abstract 12394: Development of a Heparin Dosing Algorithm to Maintain Therapeutic Anticoagulation During Atrial Fibrillation Ablation

Introduction: Therapeutic anticoagulation during atrial fibrillation (AF) ablation reduces the risk of cerebral thromboembolism during ablation. Heparin dosing strategies vary and can result in sub-therapeutic anticoagulation. Hypothesis: We hypothesize that a heparin dosing algorithm will improve maintenance of guideline-based therapeutic activated clotting times (ACT) during AF ablation. Methods: Starting from published guidance on heparin dosing during AF ablation, an artificial intelligence algorithm based on a decision tree and other mathematical considerations was developed. The algorithm launches directly from the electronic medical record and captures deidentified data for future improvements. The rules were modified over several months to establish the tested algorithm. The strategy utilized heparin boluses and an infusion. Dosing was adapted based on an individual patient’s response to the first heparin bolus. Goal ACT was 300-350 s. Outcomes from a month prior to algorithm introduction were compared to those from one month using the developed algorithm. The measured outcomes included time from first bolus to therapeutic ACT (&gt;300 s), number of heparin boluses to achieve goal ACT, time in left atrium below therapeutic ACT, and ACT value when below goal in left atrium. Results: Data from seventeen pre-algorithm procedures were compared to fourteen procedures completed using the dosing algorithm. Compared to procedures using typical dosing, procedures using the dosing algorithm reached goal ACT faster (16.1 ± 5.3 min compared to 26.2 ± 14.5 min, p = 0.02) with fewer heparin boluses (1.1 ± 0.3 boluses compared to 1.6 ± 0.9 boluses, p = 0.04). The ACT did drift below goal in some cases (n = 4 using algorithm and n = 5 using typical dosing). The time below goal was not different between dosing strategies (16.5 ± 8.7 min for algorithm compared to 22.4 ± 7.9 min for typical dosing). However, when the ACT drifted below goal with the dosing algorithm, it was significantly closer to goal than with typical dosing (295 ± 3 s compared to 268 ± 21 s, p = 0.02). Conclusion: An artificial intelligence algorithm based on a decision tree and adaptation to individual patient kinetics may improve maintenance of guideline based therapeutic ACT during AF ablation.

Abstract 14187: Differential Neutralization of Unfractionated and Low Molecular Weight Heparin by Andexanet Alfa

Introduction: Andexanet Alfa is an antidote for the neutralization of the bleeding effects of Direct Oral Anticoagulant (Direct Xa) agents such as Rivaroxaban and Apixaban. It represents a molecularly modified factor Xa decoy protein with high specificity for factor Xa inhibitors. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit both anti-Xa and anti-IIa activities. The purpose of this study is to investigate the relative neutralization of the anti-coagulant effects UFH and enoxaparin by andexanet alfa in whole blood assays such as activated clotting time (ACT) and thromelastography (TEG). Methods: The neutralization profiles of UFH and enoxaparin were studied by Andexanet at various concentrations. The final concentration of UFH used for activated clotting time (ACT) was 10 μg/ml, and for enoxaparin was 25 μg/ml. Andexanet was used in a concentration range of 12.5 ug/ml. For the thromboelastographic (TEG) analysis the concentration of all drugs were proportionately reduced. The results were analyzed using R open source statistical software. In order to compare the means of the groups, analysis of variance (ANOVA) tests were performed. If the ANOVA test yielded a significant result, a Tukey post-hoc analysis was performed. A pearson correlation was run for each parameter with respect to the dose of the drug. Results: Andexanet at 200 ug/ml moderately neutralized UFH (302 s vs 198). Andexanet minimally neutralized enoxaparin (200 s vs 190 s). There was no concentration dependent change in the neutralization profiles of UFH and enoxaparin at a concentration range of 12.5 ug/ml - 200 ug/ml. In the TEG assays, Andexanet alfa at 10 ug/ml partially neutralized the anticoagulant effects of UFH at 1 ug/ml as measured by various TEG parameters. At 20 ug/ml, stronger inhibition of all parameters were noted. Discussion: These studies suggest that Andexanet Alfa may be an effective neutralizing agent for UFH, however, it is ineffective in neutralizing LMWH at the concentrations studied. It is interesting to note that LMWHs have a higher anti-Xa to IIa ratio in comparison to heparin, however, their neutralization is lesser with Andexanet. These studies suggest that andexanet can be used in combination with protamine sulfate to neutralize UFH.

Anticoagulation Practices Using Activated Clotting Time in Veno-Venous Extracorporeal Membrane Oxygenation for Patients with Respiratory Failure: A Systematic Review and Met-Analysis

BackgroundVeno-Venous Extracorporeal Membrane Oxygenation (ECMO) technology provides as a alternative approach in the intensive care of patients with respiratory failure due to varied causes who are not responsive to conventional treatment. As per the 2014 Extracorporeal Life Support Organization (ELSO) guidelines, in order to to maintain circuit patency and minimize thromboembolic complications, anticoagulation is used, but the optimal strategy remains to be defined. Activated clotting time (ACT) is the most utilized bedside test to adjust anticoagulation. Therefore, we performed an extended analysis of all published studies on the incidence of thromboembolic and bleeding events in patients with acute respiratory distress syndrome who were put on ECMO.MethodsA comprehensive search of several databases from inception to November 25, 2020, limited to English language and excluding animal studies, was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The studies were classified into low anticoagulation target (ACT<180) or high anticoagulation target (ACT>180). A meta-analysis was performed of all eligible studies with the data on the incidences of thromboembolic and bleeding complications in patients with ARDS on VV-ECMO during different intensities of anticoagulation.ResultsA total of 6 eligible studies (4 retrospective and 2 case series) were identified, including in total 190 patients for 100 patient years. Our study showed that there is two times higher chances of bleeding when ACT goal is >180 versus a lower ACT range of <180 (Risk ratio 2.07, 95% CI 1.23-3.46, P 0.0056). The incidence of thrombosis did not change in the two group (Risk ratio 1.17, 95% CI 0.45-3, P 0.7516).ConclusionsCurrently there is a lack of data for anticoagulation strategies during VV-ECMO for patients in respiratory failure. Our study aimed to find an appropriate anticoagulation target for this patient group. The results show that although anticoagulation is required for circuit patency, there is an increased risk of bleeding when higher anticoagulation targets are set. DisclosuresNo relevant conflicts of interest to declare.

In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients.

Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII mimetic on ACT, and tissue factor (TF)-based coagulation assays. Whole blood from 18 patients undergoing cardiopulmonary bypass (CPB) were mixed in vitro with pooled normal plasma, FVIII-deficient or FVIII-inhibitor plasma to affect functional FVIII levels. ACTs and heparin concentration by protamine titration were measured in whole blood mixture with/without emicizumab (50-100μg/ml). Thrombin generation and plasmin generation were measured in the patient's plasma mixed with normal plasma or FVIII-inhibitor plasma to assess the impact of emicizumab under low TF activation. FVIII inhibitors prolonged ACTs by 2.2-fold compared to those in normal plasma mixture at baseline. During CPB, ACTs in normal plasma mixture, and FVIII-deficient mixture were in 400s, but ACTs reached 900s in FVIII-inhibitor mixture. Emicizumab shortened ACTs by up to 100s in normal plasma mixture, and FVIII-deficient mixtures. ACTs remained over 600s in FVIII-inhibitor mixture, despite adding emicizumab at 100μg/ml. Heparin concentration measured by TF-based protamine titration was unaffected. Emicizumab enhanced thrombin peak in the presence of FVIII inhibitors, whereas plasmin generation was mainly affected by thrombin generation, and systemic use of ɛ-aminocaproic acid. FVIII inhibitors extensively prolong ACTs in heparinized whole blood, and clinical levels of emicizumab partially reverse ACT values. Protamine titration should be considered for optimal heparin monitoring in emicizumab-treated patients with FVIII inhibitors.

An ex vivo comparison of partial thromboplastin time and activated clotting time for heparin anticoagulation in an ovine model.

Sheep are a primary model of mechanical circulatory support (MCS) with heparin anticoagulation therapy frequently being monitored by activated clotting time (ACT) due to ease and cost. In patients undergoing long-term heparin therapy, other anticoagulation monitoring strategies, such as activated partial thromboplastin time (aPTT), have proven to be more reliable indicators for the adequacy of anticoagulation, frequently determined by heparin concentration. As there is a paucity of similar studies in sheep, we sought to investigate the correlation between heparin concentration and ACT and aPTT using whole sheep blood in an ex vivo model. Fresh whole blood was serially drawn from an adult female Dorset-hybrid sheep and aliquots were placed into tubes containing heparin saline solutions with concentrations ranging from 0 to 7.81 U heparin per mL of whole blood. ACT and aPTT values were measured on each of the samples. The experiment was performed four times with the same animal. A simple linear regression was performed to determine correlation, and subgroup analysis was performed on low versus high heparin concentrations typically seen in human patients on long-term MCS, such as extracorporeal membrane oxygenation (ECMO), versus cardiopulmonary bypass, respectively. aPTT measurements versus the heparin concentration had an R2 =0.7295. ACT measurements versus the heparin concentration had a R2 =0.4628. aPTT measurements versus the ACT measurements had a R2 =0.2974. The strength of the correlation between aPTT and heparin concentration increased at low heparin concentrations (R2 =0.8392). aPTT had a more reliable correlation to heparin concentration and thus anticoagulation level than ACT. This was particularly true at lower heparin concentrations, similar to ranges seen for patients on ECMO. The correlation between aPTT and ACT values was poor. Further in vivo studies should be performed to confirm our results.

Efficacy of the hemostatic device VasoSTAT and the study of hemostatic factor

Recently, trans-radial intervention has gained popularity as a common procedure to reduce hemorrhagic complications. However, the cuff-type hemostatic device (TR Band) previously used at our institution required 6 h to achieve hemostasis. Since July 2016, we have been using the VasoSTAT, a new hemostatic device that could achieve hemostasis in 4 h. In a verification study, we found that prolonged activated clotting time (ACT) was related to transient hemorrhage occurrence after the hemostatic procedure. Therefore, we designed a hemostatic protocol based on ACT and evaluated its efficacy. In this retrospective and observational study, 78 and 111 patients used the VasoSTAT and TR Band, respectively, from July 2015 to May 2017. In the VasoSTAT group, the ACTs were significantly lower in the hemostasis success (246 ± 46 s) than in the failure group patients (327 ± 59 s) (P < 0.01). Therefore, we applied the hemostatic protocol to 271 patients from May 2017 to March 2020. The hemostasis success rate was 96% in the post-protocol applied group patients, which was significantly higher than the 82% success rate in the pre-protocol applied group patients (P < 0.01). VasoSTAT resulted in adequate hemostasis in 4 h. Further, ACT was predictive of adequate hemostasis.