Resistance to unfractionated heparin in the ICU: evaluation and management options.
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ABSTRACT:
SUBMITTER: Levy JH
PROVIDER: S-EPMC10242222 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Resistance to unfractionated heparin in the ICU: evaluation and management options.
Levy Jerrold H JH Frere Corinne C Koster Andreas A
Intensive care medicine 20230606 8
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Project description:Protamine, the only registered antidote of unfractionated heparin (UFH), may produce a number of adverse effects, such as anaphylactic shock or serious hypotension. We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce. As a starting material, we have chosen generally non-toxic, biocompatible, widely available, inexpensive, and easy to functionalize polysaccharides. Our approach was to synthesize, purify and characterize cationic derivatives of dextran, hydroxypropylcellulose, pullulan and γ-cyclodextrin, then to screen them for potential heparin-reversal activity using an in vitro assay and finally examine efficacy and safety of the most active polymers in Wistar rat and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation, activated partial thromboplastin time, bleeding time, and anti-factor Xa activity; safety studies included the measurement of hemodynamic, hematologic and immunologic parameters. Linear, high molecular weight dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3) is the most potent and the safest UFH inhibitor showing activity comparable to that of protamine while possessing lower immunogenicity. Cationic polysaccharides of various structures neutralize UFH. Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine.
| S-EPMC4362941 | biostudies-literature
Project description:BackgroundPatients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full-dose anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID-19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population.ObjectivesThe aim of this study was to assess therapeutic UFH infusions and associated bleeding risk in patients with COVID-19.Patients/methodsThis retrospective cohort study includes patients at Brigham and Women's Hospital, Boston, Massachusetts, receiving weight-based nursing-nomogram titrated UFH infusion during a 10-week surge in COVID-19 hospitalizations. Of 358 patients on therapeutic UFH during this interval, 97 (27.1%) had confirmed COVID-19. Patient characteristics, laboratory values, and information regarding UFH infusion and bleeding events were obtained from the electronic medical record.ResultsPatients who were COVID-19 positive had fewer therapeutic activatrd partial thromboplastin times (aPTTs) compared to COVID-19-negative patients (median rate, 40.0% vs 53.1%; P < .0005). Both major and clinically relevant nonmajor bleeding were increased in COVID-19-positive patients, with major bleeding observed in 10.3% (95% confidence interval [CI], 5.7%-17.9%) of patients who were COVID-19 positive and 3.1% (95% CI, 1.6%-5.9%) of patients who were COVID-19 negative (P < .005). In logistic regression, bleeding events were associated with receiving UFH for longer than 7 days, but not platelet count, coagulation, or inflammatory measurements.ConclusionsOur data indicate a higher incidence of bleeding complications in patients with COVID-19 receiving weight-based nursing-nomogram titrated UFH infusions despite a higher prevalence of subtherapeutic aPTTs in this population. These data underscore the need for prospective studies aimed at improving the quality and safety of therapeutic anticoagulation in patients with COVID-19.
| S-EPMC8114028 | biostudies-literature
Project description: Not available
| S-EPMC6478064 | biostudies-literature
Project description:BackgroundUnfractionated heparin (UFH) is an anticoagulant drug that is considered a high-risk medication because an excessive dose can cause bleeding, whereas an insufficient dose can lead to a recurrent embolic event. Therapeutic response to the initiation of intravenous UFH is monitored using activated partial thromboplastin time (aPTT) as a measure of blood clotting time. Clinicians iteratively adjust the dose of UFH toward a target, indication-defined therapeutic aPTT range using nomograms, but this process can be imprecise and can take ≥36 hours to achieve the target range. Thus, a more efficient approach is required.ObjectiveIn this study, we aimed to develop and validate a machine learning (ML) algorithm to predict aPTT within 12 hours after a specified bolus and maintenance dose of UFH.MethodsThis was a retrospective cohort study of 3019 patient episodes of care from January 2017 to August 2020 using data collected from electronic health records of 5 hospitals in Queensland, Australia. Data from 4 hospitals were used to build and test ensemble models using cross-validation, whereas data from the fifth hospital were used for external validation. We built 2 ML models: a regression model to predict the aPTT value after a UFH bolus dose and a multiclass model to predict the aPTT, classified as subtherapeutic (aPTT <70 seconds), therapeutic (aPTT 70-100 seconds), or supratherapeutic (aPTT >100 seconds). Modeling was performed using Driverless AI (H2O), an automated ML tool, and 17 different experiments were iteratively conducted to optimize model accuracy.ResultsIn predicting aPTT, the best performing model was an ensemble with 4x LightGBM models with a root mean square error of 31.35 (SD 1.37). In predicting the aPTT class using a repurposed data set, the best performing ensemble model achieved an accuracy of 0.599 (SD 0.0289) and an area under the receiver operating characteristic curve of 0.735. External validation yielded similar results: root mean square error of 30.52 (SD 1.29) for the aPTT prediction model, and accuracy of 0.568 (SD 0.0315) and area under the receiver operating characteristic curve of 0.724 for the aPTT multiclassification model.ConclusionsTo the best of our knowledge, this is the first ML model applied to intravenous UFH dosing that has been developed and externally validated in a multisite adult general medical and surgical inpatient setting. We present the processes of data collection, preparation, and feature engineering for replication.
| S-EPMC9531006 | biostudies-literature
Project description:We aimed to identify attributing factors to the interindividual variabilities of the infusion rates in unfractionated heparin therapy. We included patients who required unfractionated heparin therapy to achieve the target APTT after cardiac surgery between May 2014 and February 2018. Fifty-nine patients were included, of whom 8 underwent Blalock-Taussig shunt; 27, Glenn procedure; 19, Fontan procedure; 3, mechanical valve replacement; and 2, Rastelli procedure. Previously reported variables that influenced the response to unfractionated heparin treatment were initially compared, which included age; weight; sex; type of surgery; platelet count; fibrinogen, antithrombin III, total protein, albumin, alanine transaminase, and creatinine levels; and use of fresh frozen plasma. The type of surgical procedure was found to be significantly associated with the differences in heparin infusion rate (P = 0.00073). Subsequently, the variance explained by these factors was estimated through a selection based on the minimum Akaike information criterion value; models constructed by various combinations of the surgery types were compared. The model including the Blalock-Taussig shunt, Glenn procedure, and mechanical valve replacement showed the highest summed variance explained (29.1%). More than 70% of the interindividual variability in initial heparin maintenance dosing was unexplained.
| S-EPMC7655810 | biostudies-literature
Project description:BackgroundThe high concentrated thrombin time (hcTT), a thrombin time modified by increasing the thrombin concentration, is a possible alternative assay to activated partial thromboplastin time (aPTT) in unfractionated heparin (UFH) monitoring. This study aimed to determine the optimal thrombin concentration used in the hcTT assay for UFH monitoring.MethodsA total of 30 blood samples obtained from healthy volunteers were included in this study. Thrombin concentrations of 10.0, 15.0, 20.0, and 25.0 IU/ml were used in the hcTT assay. The consistency between the hcTT and anti-FXa assays was evaluated. To validate the hcTT assay, linearity, repeatability, reproducibility, and diagnostic performance of the assay were assessed.ResultsThe hcTT assay using thrombin concentration of 15.0 IU/ml showed a strong correlation to the anti-FXa assay with R2 of 0.72 and the Spearman's correlation coefficient (rs ) of 0.97 (95% CI, 0.96-0.98). Within-run and day-to-day run variabilities of the assay were satisfactory (all coefficients of variation <10%). We found an excellent correlation between the results which were measured using different reagents with intra- or inter-laboratory instruments. Notably, as compared to the aPTT assay, the hcTT assay showed a significantly better performance in identifying the samples which contain UFH at the supratherapeutic level, with an AUC of 0.97 vs. 0.91, p = 0.049.ConclusionThe hcTT assay can be used as an alternative assay for UFH therapy monitoring. A further study using clinical samples is recommended to confirm the appropriateness of the hcTT assay for clinical application.
| S-EPMC9550976 | biostudies-literature
Project description:BackgroundClinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients.ObjectiveTo compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice.MethodsUsing a large, multi-hospital, US database, we identified persons aged > or =40 years hospitalized for > or =6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs.Results479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups.ConclusionWe observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.
| S-EPMC1624807 | biostudies-literature
Project description:Thromboembolism is a known phenomenon in patients with Coronavirus disease 2019 (COVID-19). Recent investigations have revealed that a significant proportion of those hospitalized with severe COVID-19 demonstrate clinical and laboratory markers compatible with hypercoagulability, which is differentiated from disseminated intravascular coagulation (DIC), termed COVID-associated coagulopathy. Additionally, there is increasing concern for development of acute ischemic stroke because of this hypercoagulable state. We present a patient with COVID-19 pneumonia who was managed with unfractionated heparin (UFH) infusion and developed a large ischemic infarct shortly after cessation of the infusion. In retrospect, the patient's coagulation parameters were consistent with overt DIC, although some of these parameters are easily masked by the effects of UFH. These findings emphasize the importance of anticoagulation as well as its careful discontinuation, as failure to do so may result in a significant thromboembolic event.
| S-EPMC7545009 | biostudies-literature
Project description:Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk.This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis.A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70-1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68-1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31-0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30-0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings.This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis.clinicaltrials.gov Identifier: NCT00182143.
| S-EPMC4616653 | biostudies-literature
Project description:Unfractionated heparin (UFH) is commonly used as an anticoagulant in sepsis treatment and has recently been found to have non-anticoagulant effects, but underlying mechanisms remain unclear. This retrospective clinical data showed that UFH has significant protective effects in sepsis compared to low-molecular-weight heparin and enoxaparin, indicating potential benefits of its non-anticoagulant properties. Recombinant protein chip screening, surface plasmon resonance, and molecular docking data demonstrated that UFH specifically bound to the cytoplasmic Drp1 protein through its zone 2 non-anticoagulant segment. In-vitro experiments verified that UFH's specific binding to Drp1 suppressed Drp1 translocation to mitochondria following "sepsis" challenge, thereby improving mitochondrial morphology, function and metabolism in vascular endothelial cells. Consequently, UHF comprehensively protected mitochondrial quality, thus reducing vascular leakage and improving prognosis in a sepsis rat model. These findings highlight the potential of UFH as a sepsis treatment strategy targeting non-anticoagulation mechanism.
| S-EPMC11633531 | biostudies-literature