High-dose Unfractionated Heparin Research Articles

Lupus anticoagulant and valvular cardiac surgery.

Despite its name, lupus anticoagulant (LAC) neither exclusively occurs in lupus nor induces anticoagulation. It is an antiphospholipid antibody found in 2%-4% of the population that promotes clot formation by targeting phospholipid-protein complexes in cell membranes. However, in vitro, LAC exhibits paradoxical effects, prolonging clotting times in phospholipid-dependent assays such as Activated Partial Thromboplastin Time (APTT). This unpredictability extends to point-of-care tests like Activated Clotting Time (ACT), which are frequently used to monitor anticoagulation during cardiac surgeries involving cardiopulmonary bypass (CPB). High doses of unfractionated heparin (UFH) are administered in these procedures, but the presence of LAC complicates ACT measurements, creating challenges for both anesthesiologists and surgeons. This case report highlights the clinical implications of LAC in perioperative management, underscoring the difficulties in ensuring adequate anticoagulation during CPB.

Prophylactic Unfractionated Heparin in Antepartum Hospitalizations: A Randomized Controlled Trial.

To assess the effect of gestational age-based dosing of unfractionated heparin (UFH) compared with standard dosing of UFH for thromboprophylaxis on an elevated serum activated partial thromboplastin time (aPTT) during prolonged antepartum hospitalizations. This was a randomized trial of pregnant persons who were admitted in the antepartum period for at least 72 hours. Participants were randomly allocated to the standard dose of UFH (5,000 units subcutaneously every 12 hours) or the gestational age-based dose of UFH (first trimester [less than 14 weeks]: 5,000 units subcutaneously every 12 hours; second trimester [14-27 6/7 weeks]: 7,500 units subcutaneously every 12 hours; third trimester (28 weeks or more): 10,000 units subcutaneously every 12 hours). The primary outcome was the proportion of antepartum patients who had an elevated serum aPTT value above the normal range (more than 36.2 seconds) 6 hours after an UFH dose. Secondary outcomes included the development of venous thromboembolism (VTE) and reported side effects of heparin administration. Between December 15, 2020, and April 1, 2022, 97 patients with antepartum hospitalizations were screened and 46 were randomized: 22 allocated to standard dosing and 24 allocated to gestational age-based dosing of UFH. A significantly greater proportion of antepartum patients who received gestational age-based dosing had an abnormal elevation in aPTT compared with those who received standard dosing (33.3% vs 4.8%, P =.02). Gestational age-based dosing resulted in higher maximum [interquartile range] aPTT (30.4 [27.4, 37.5] vs 26.6 [23.0, 29.6], P =.01) and anti-Xa levels (0.09 [0.09, 0.11] vs 0.09 [0.09, 0.09], P =.04). There was no significant difference in VTE between groups ( P =.47). Gestational age-based dosing of UFH for thromboprophylaxis of antepartum hospitalizations was associated with significantly increased rates of elevated coagulation parameters compared with standard fixed dosing. This study suggests a need for close monitoring if higher doses of UFH during pregnancy are used later in gestation. The efficacy of gestational age-based dosing compared with standard dosing for UFH to prevent thromboembolic events remains an area for future investigation. ClinicalTrials.gov , NCT04635839.

Risk for excessive anticoagulation during hemodialysis is associated with type of vascular access and bedside coagulation testing: Results of a cross-sectional study.

Recommendations and practice patterns for heparin dosing during hemodialysis show substantial heterogeneity and are scantly supported by evidence. This study assessed the variability in unfractionated heparin (UFH) dosing during hemodialysis and its clinical and biological anticoagulatory effects, and identified explanatory factors of heparin dosing. Cross-sectional study assessing UFH dosing, coagulation tests - activated partial thromboplastin time (aPTT) and activated clotting time (ACT) before dialysis start, 1 h after start and at treatment end (4 h) - and measurement of residual blood compartment volume of used dialyzers. 101 patients, 58% male, with a median dialysis vintage of 33 (6-71) months received hemodialysis using a total UFH dose of 9,306 ± 4,079 (range 3,000-23,050) IU/session. Use of a dialysis catheter (n = 56, 55%) was associated with a 1.4 times higher UFH dose (p < 0.001) irrespective of prior access function. aPTT increased significantly more than ACT both 1 h and 4 h after dialysis start, independent of the dialysis access used. 53% of patients with catheter access and ACT ratio < 1.5, 1 h after dialysis start had simultaneous aPTT ratios > 2.5. Similar findings were present at 1 h for patients with AVF/AVG and at dialysis end for catheter use. No clinically significant clotting of the extracorporeal circuit was noted during the studied sessions. Dialyzer's blood compartment volume was reduced with a median of 9% (6-20%) without significant effect of UFH dose, aPTT or ACT measurements and vascular access type. UFH dose adaptations based on ACT measurements frequently result in excessive anticoagulation according to aPTT results. Higher doses of UFH are used in patients with hemodialysis catheters without evidence that this reduces dialyzer clotting.

Effects of systemic anticoagulation in a murine model of compensatory lung growth.

Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.

Uninterrupted DOACs Approach for Catheter Ablation of Atrial Fibrillation: Do DOACs Levels Matter?

Most patients present for catheter ablation of atrial fibrillation (CAAF) with residual or full effect of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). In daily practice, it has been observed that the activated clotting time (ACT) was actually poorly sensitive to the effect of DOACs and that patients on DOACs required more unfractionated heparin (UFH) to achieve the ACT target of 300 s during the procedure, leading some authors to worry about potential overdosing. Conversely, we hypothesize that these higher doses of UFH are necessary to achieve adequate hemostasis during CAAF regardless of the residual effect of DOACs. During CAAF, thrombosis is promoted mainly by the presence of thrombogenic sheaths and catheters in the bloodstream. Preclinical data suggest that only high doses of DOACs are able to mitigate catheter-induced thrombin generation, whereas low dose UFH already do so. In addition, the effect of UFH seems to be lower in patients on DOACs, compared to patients on VKAs, explaining part of the differences observed in heparin requirements. Clinical studies could not identify increased bleeding risk in patients on DOACs compared to those on VKAs despite similar efficacy during CAAF procedures. Moreover, targeting a lower ACT was associated with an increased periprocedural thrombotic risk for both DOAC and VKA patients. Therefore, the low sensitivity of the ACT to the residual effect of DOACs should not be a major concern in its use in the interventional cardiology laboratory.

Periprocedural anticoagulation in the uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation (ELIMINATE-AF) trial.

Aims This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy.Methods and results Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0–3.0). Uninterrupted anticoagulation was mandated for 21–28 days’ pre-ablation and 90 days’ post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300–400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1–Q3) time from last dose to ablation procedure was 14.8 (13.3–16.5) vs. 16.5 (14.8–19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU).Conclusion The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.

Safety of High-Dose Unfractionated Heparin for Prophylaxis of Venous Thromboembolism in Hospitalized Obese Patients.

Optimal dosing of unfractionated heparin (UFH) for thromboprophylaxis in the obese patient population is uncertain because of their high-risk, prothrombotic state and a complexity of pharmacokinetic considerations. Literature on the appropriateness of the use of a higher dose UFH regimen remains unclear and inconsistent. To evaluate the safety of the use of 7500 units every 8 hours (high-dose) of subcutaneous UFH compared with the use of 5000 units every 8 hours (standard-dose) of subcutaneous UFH for thromboprophylaxis in obese patients (defined as BMI ≥30 kg/m2). In a retrospective cohort study, 326 adult patients were included, with a BMI ≥30 kg/m2, who were admitted to a large, urban academic medical center between September 1, 2015, and September 1, 2018. Patients received either high-dose or standard-dose UFH for at least 48 hours. The primary end point was the incidence rate of bleeding events, defined as a ≥2-g/dL fall in hemoglobin level or receipt of transfusion of 2 or more units of packed red blood cells (pRBCs) from the start of the UFH order. The incidence rate of bleeding was significantly higher in those who received high-dose UFH (43%) compared with those who received standard-dose UFH (29%; P = 0.008). No significant difference was found between venous thromboembolism event rates. High-dose UFH was associated with an increased bleeding event rate compared with standard-dose UFH in patients with a BMI ≥30 kg/m2. This raises safety concerns about the appropriateness of utilizing this regimen in this population.

How does low-dose unfractionated heparin (UFH) compare with high-dose UFH for children undergoing cardiac catheterization?

How does low-dose unfractionated heparin (UFH) compare with high-dose UFH for children undergoing cardiac catheterization?

The high dose unfractionated heparin is related to less radial artery occlusion rates after diagnostic cardiac catheterisation: a single centre experience

Background Transradial approach (TRA) has increasingly become the default strategy for cardiac catheterisation. However, TRA can result in several complications; radial artery occlusion (RAO) is the most unwilling complication. Unfractionated heparin (UFH) is an effective therapy in preventing RAO. The goal of this study was to evaluate whether weight-adjusted high dose UFH reduces the rate of RAO after diagnostic cardiac catheterisation compared to weight-adjusted standard dose UFH. Methods A total of 1215 patients screened and after exclusion criteria, 686 consecutive patients were enrolled. 100 IU/kg UFH (high dose UFH group) and 50 IU/kg UFH (standard dose UFH group) were given the patients undergoing diagnostic cardiac catheterisation. RAO was evaluated with vascular Doppler ultrasonography at 10 days after cardiac catheterisation. Results Among 686 patients undergoing diagnostic cardiac catheterisation, RAO was detected in 36 (5.2%) patients. There was no significant difference with respect to baseline characteristics and co-morbid diseases between high dose UFH group and standard dose UFH group. RAO was significantly higher in standard dose UFH group than high dose UFH group (7.9% vs. 3.0%, p = .004). Multivariate logistic regression analysis was demonstrated that age (OR: 0.958, 95% CI: 0.924–0.993, p = .019) and standard dose heparin (OR: 2.811, 95% CI: 1.347–5.866, p = .006) were independent factor for RAO. Conclusions High dose UFH was independently associated with a lower rate of RAO. Given that RAO nearly affects about 10% patient underwent TRA, prefer to high dose UFH may be a reasonable choice for RAO prevention.

Safety and Efficacy of High-Dose Unfractionated Heparin Versus High-Dose Enoxaparin for Venous Thromboembolism Prevention in Morbidly Obese Hospitalized Patients

Venous thromboembolism is a cause of morbidity and mortality in hospitalized patients, and morbid obesity increases this risk. Various prophylaxis dosing strategies have been investigated. However, it is unclear if high-fixed dose enoxaparin or high-fixed dose unfractionated heparin thromboprophylaxis is optimal for minimizing the incidence of major bleeding and reducing hospital-acquired venous thromboembolism. A single-center retrospective observational study was conducted in hospitalized patients who were morbidly obese (body mass index ≥40 kg/m2) and who received either high-fixed dose enoxaparin (40 mg every 12 hours) or unfractionated heparin (7500 units every 8 hours) for venous thromboembolism prophylaxis. Co-primary outcomes included incidence of major bleeding and venous thromboembolism diagnosed during hospitalization. Predictors of major bleeding were evaluated by multivariable regression. In the 305 patients included (n=190 unfractionated heparin, n=115 enoxaparin), the incidence of major bleeding was significantly higher in the unfractionated heparin group (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.07-3.13; P=0.025), with no significant difference in the incidence of venous thromboembolism diagnosed during hospitalization. The only independent predictors of major bleeding were intensive care acuity (OR 3.32, 95% CI 1.91-5.78; P <0.001) and selection of unfractionated heparin rather than enoxaparin for venous thromboembolism prophylaxis (OR 2.16, 95% CI 1.22-3.82; P=0.008). High-fixed dose unfractionated heparin for venous thromboembolism prophylaxis may lead to a higher risk of major bleeding events compared with high-fixed dose enoxaparin in patients who are morbidly obese.

High-dose heparin is associated with higher bleeding and thrombosis rates in pediatric patients following cardiac surgery

ObjectiveTo determine the association between unfractionated heparin (UFH) dose and the rate of postoperative bleeding and thrombosis events in pediatric cardiac patients. We tested the hypothesis that high-dose UFH is associated with higher rates of bleeding and thrombosis. MethodsThis is a retrospective review of pediatric patients admitted to the cardiac intensive care unit following cardiac surgery between November 2016 and December 2017. Peripheral venous thrombosis was excluded from analysis. Bleeding was defined as spontaneous bleeding remote from procedural manipulation. Postoperative UFH dosing strategy was categorized into 3 groups: no UFH, low-dose UFH (<15 U/kg/h) and high-dose UFH (≥15 U/kg/h). Statistical analysis was performed using multivariable logistic regression. ResultsWe observed 966 consecutive patients (median age, 1.37 years; interquartile range, 0.27-5.50 years) during their stay in the cardiac intensive care unit. There were 94 patients (10%) with bleeding and 52 patients (5%) with thrombosis during follow-up. Patients receiving high-dose UFH experienced significantly more bleeding (odds ratio, 2.35; 95% confidence interval, 1.45-3.95) and thrombosis events (odds ratio, 3.65; 95% confidence interval, 1.81-7.38) compared with patients receiving low-dose UFH. The odds of bleeding (odds ratio, 0.81; 95% confidence interval, 0.45-1.47) and thrombosis (odds ratio, 0.59; 95% confidence interval, 0.26-1.35) were similar in the low-dose UFH and no-UFH groups. ConclusionsBleeding remote from immediate postsurgical bleeding occurs uncommonly in pediatric patients following cardiac surgery. Anticoagulation with high-dose UFH is associated with higher bleeding rates as well as higher thrombosis rates. Indications for high-dose UFH should be carefully considered to reduce the rate of bleeding in this population.

49Patients on novel oral anticoagulants require higher doses of unfractionated heparin than those on warfarin to achieve a target act value during ablation of left atrial tachyarrhythmias

49Patients on novel oral anticoagulants require higher doses of unfractionated heparin than those on warfarin to achieve a target act value during ablation of left atrial tachyarrhythmias

Anti‐activated factor II assay for monitoring unfractionated heparin in children: results of the HEARTCAT study

Background Unfractionated heparin (UFH) is used for the prophylaxis and treatment of thrombosis in children. Laboratory monitoring of UFH is needed to prevent over-anticoagulation or under-anticoagulation. Objectives To investigate the association between UFH dose and UFH effect as monitored with the anti-activated factor II (FIIa) assay, the relationship between anti-FIIa and anti-activated factor X (FXa) effects, and the influence of patient age and other factors on UFH effect. Patients and methods This was a randomized controlled trial in children during cardiac catheterization, comparing high-dose UFH (100 units kg-1 bolus) with low-dose UFH (50 units kg-1 bolus). Blood samples were drawn at baseline, and after 30 min, 60 min, and 90 min. For the purpose of this study, 49 children and 117 blood samples were evaluated. Results The anti-FIIa assay discriminated well between high-dose and low-dose UFH. Multiple regression demonstrated significant influences of UFH dose and age on anti-FIIa levels. Younger children had lower anti-FIIa levels than older children, an effect that was more pronounced with low-dose UFH. Anti-FXa/anti-FIIa ratios were equal with low-dose UFH. However, anti-FXa levels were relatively increased over anti-FIIa levels in infants and after high-dose UFH bolus administration. Conclusion The UFH effect on anti-FIIa levels is lower in infants than in older children. This influence of age appears to be dose-dependent, being more pronounced with low-dose UFH. Anti-FXa and anti-FIIa levels are not equal, particularly in infants and after high-dose UFH. Monitoring UFH solely with anti-FXa assays may not be sufficient in children, and the anti-FIIa assay may provide important complementary information.

Unfractionated heparin after TBI reduces in vivo cerebrovascular inflammation, brain edema and accelerates cognitive recovery.

Severe traumatic brain injury (TBI) may increase the risk of venous thromboembolic complications; however, early prevention with heparinoids is often withheld for its anticoagulant effect. New evidence suggests low molecular weight heparin reduces cerebral edema and improves neurological recovery after stroke and TBI, through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post-TBI. We hypothesized that UFH after TBI reduces cerebral edema by reducing LEU-mediated inflammation and improves neurological recovery. CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. UFH (75 U/kg or 225 U/kg) or vehicle (VEH, 0.9% saline) was administered 2, 11, 20, 27, and 34 hours after TBI. At 48 hours, pial intravital microscopy through a craniotomy was used to visualize live brain LEUs interacting with endothelium and microvascular fluorescein isothiocyanate-albumin leakage. Neurologic function (Garcia Neurological Test, GNT) and body weight loss ratios were evaluated 24 and 48 hours after TBI. Cerebral and lung wet-to-dry ratios were evaluated post mortem. ANOVA with Bonferroni correction was used to determine significance (p < 0.05). Compared to positive controls (CCI), both UFH doses reduced post-TBI in vivo LEU rolling on endothelium, concurrent cerebrovascular albumin leakage, and ipsilateral cerebral water content after TBI. Additionally, only low dose UFH (75 U/kg) improved GNT at both 24 and 48 hours after TBI. High dose UFH (225 U/kg) significantly increased body weight loss above sham at 48 hours. Differences in lung water content and blood pressure between groups were not significant. UFH after TBI reduces LEU recruitment, microvascular permeability, and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery whereas higher UFH may worsen functional recovery. Further study is needed to determine if this is caused by increased bleeding from injured brain with higher UFH doses.

Increased unfractionated heparin requirements with decreasing body mass index in pregnancy.

Pregnant women receiving low-molecular-weight heparin for therapeutic anticoagulation are often converted to unfractionated heparin in anticipation of labor. We aim to characterize the impact of maternal body mass index on attainment of target anticoagulation during the conversion process. We conducted a five-year retrospective study of a pregnancy cohort converted from low-molecular-weight heparin to unfractionated heparin in the third trimester. Patient demographics, anticoagulation regimens, and clinical outcomes were extracted from the medical record. Nonparametric statistical methods were used for analysis by body mass index (<30, 30-35, and >35). Thirty-one subjects were evenly distributed by body mass index (p = 0.97). Linear regression revealed an inverse correlation between patient body mass index and unfractionated heparin dose needed to achieve therapeutic anticoagulation (p = 0.04). Subjects with body mass index > 35 attained therapeutic activated partial thromboplastin time levels at 18 U (Units)/kg/h, while subjects with body mass index < 30 required 25 U/kg/h (p = 0.02). Higher doses of unfractionated heparin are needed to achieve anticoagulation in patients with body mass index < 30 during pregnancy. This paradoxical relationship may be explained by physiologic characteristics that increase unfractionated heparin elimination, including diminished adiposity and increased renal clearance.

Safety and Efficacy of High-Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients.

To determine the safety and efficacy of high-dose subcutaneous unfractionated heparin (UFH) for prevention of venous thromboembolism (VTE) in overweight and obese patients. Single-center retrospective observational cohort study. Large academic tertiary care medical center. A total of 1335 adults who weighed more than 100 kg on admission and received either subcutaneous UFH 7500 units every 8 hours (751 patients [high-dose group]) or 5000 units every 8 hours (584 patients [low-dose group]) for VTE prophylaxis during their hospitalization between January 1, 2013, and August 31, 2014. The incidences of VTE and bleeding complications were assessed in each group. Each group was further divided into four groups based on their body mass index (BMI): overweight (BMI 25-29.9 kg/m(2) ), obese class I (BMI 30-34.9 kg/m(2) ), obese class II (BMI 35-39.9 kg/m(2) ), and obese class III (BMI ≥ 40 kg/m(2) ). The incidence of VTE was similar for patients in the high-dose group versus those in the low-dose group for all BMI categories. Bleeding complications were significantly higher for patients in the high-dose group. The proportion of patients with at least a 2-g/dl hemoglobin drop from admission was higher in patients in the high-dose groups in obese classes II and III: obese class II, 46 (30%) of 152 patients in the high-dose group versus 30 (18%) of 171 patients in the low-dose group (p<0.01); obese class III, 109 (25%) of 432 patients in the high-dose group versus 31 (12%) of 249 patients in the low-dose group (p<0.01). In addition, the proportion of patients who received at least 2 units of packed red blood cell transfusion was significantly higher in patients in the high-dose group who were in obese class III: 47 (11%) of 432 in the high-dose group versus 13 (5%) of 249 in the low-dose group (p<0.01). Administering a higher dose of heparin to patients weighing more than 100 kg may not impart additional efficacy in reducing the incidence of VTE. However, it may increase the risk for bleeding.

Bivalirudin versus unfractionated heparin for percutaneous coronary intervention with radial access: A meta-analysis of randomized trials

BackgroundRadial access for percutaneous coronary intervention (PCI) has been shown to be associated with better outcomes compared with femoral access. However, it is unknown whether bivalirudin would offer any further benefit when compared with unfractionated heparin for PCI with radial access. MethodsA systematic search of electronic databases was conducted for randomized trials comparing bivalirudin with unfractionated heparin in patients undergoing PCI with a radial access. The primary safety outcome was major bleeding, while the primary efficacy outcome was major adverse cardiac events (MACE). Random effects overall risk ratios (RR) were calculated using DerSimonian and Laird model. ResultsA total of 8044 patients from 5 trials were included in the final analysis. The incidence of major bleeding was 1.8% in the bivalirudin group versus 2.2% in the unfractionated heparin group (RR 0.72, 95% CI 0.44–1.17, p=0.18). Meta-regression analysis demonstrated that the risk of major bleeding was lower with bivalirudin when higher doses of unfractionated heparin were used in the control arm (p=0.02). The incidence of MACE was 8.5% in the bivalirudin group versus 7.5% in the unfractionated heparin group (RR 1.15, 95% CI 0.81–1.64, p=0.44). There were no significant differences in the incidence of all-cause mortality, and net adverse clinical events between both groups (RR 0.98, 95% CI 0.70–1.36, p=0.89; and RR 0.79, 95% C I0.60–1.03, p=0.08, respectively). ConclusionsBivalirudin might not be associated with better outcomes, when compared with unfractionated heparin in patients undergoing PCI with radial access.

Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction

BackgroundThe beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. However, the mechanisms underlying the therapeutic benefits of heparin in these conditions have not yet been clearly elucidated. The purpose of this study was to confirm the effect of heparin of neutralizing histone toxicity.MethodsRat models of histone H3-induced organ dysfunction were administered in a low or high dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or argatroban, and the therapeutic effects of each anticoagulant were examined. In another series, the survival of the histone H3-administered animals was evaluated. Furthermore, the effect of each of the aforementioned anticoagulants on cell death induced by histone H3 was examined in cultured vascular endothelial cells and leukocytes.ResultsAlthough UFH, LMWH, and argatroban significantly suppressed the histone-induced decrease of the WBC and platelet counts in the animal models of organ dysfunction, only UFH and LMWH attenuated hepatic and renal dysfunction. In addition, the mortality was significantly reduced only by high-dose UFH and LMWH. The in vitro study revealed that both vascular endothelial cell death and leukocyte cell death were significantly attenuated by UFH and LMWH but not by argatroban.ConclusionsThe histone-neutralizing effect of heparin may contribute to the beneficial effects of heparins observed in the animal study. The results of the in vitro study further confirmed the above contention and suggested that heparin binds to histones to attenuate the cytotoxic actions of the latter. Since heparin has been demonstrated to protect animals from the organ damage induced by histones and consequently reduce the mortality, administration of heparin could become a treatment of choice for patients suffering from severe sepsis.

Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols

AbstractMonitoring unfractionated heparin (UFH) is crucial to prevent over- or under-anticoagulation. However, the optimal parameters for monitoring UFH in children are not well established. The study objectives were to investigate (1) the relationship between UFH dose and its anticoagulant effect as assessed by anti-Xa, activated partial thromboplastin time (aPTT) and activated clotting time (ACT); (2) other factors influencing UFH effect; (3) the agreement between the assays; and (4) the association between UFH effect and clinical outcome. HEARTCAT was a parallel-cohort randomized controlled trial comparing high-dose (100 U/kg bolus followed by age-based continuous infusion in randomized children) vs low-dose UFH (50 U/kg bolus) during cardiac catheterization in children. Blood samples were drawn before and after UFH administration at 30, 60, and 90 minutes. Four-hundred and two samples of 149 patients were evaluable. Anti-Xa, aPTT, and ACT all showed good discrimination between UFH doses. Regression models demonstrated the following determinants of UFH effect: UFH dose, age, baseline antithrombin (for anti-Xa), and baseline levels of aPTT and ACT, respectively. UFH effects were lower in infants compared with older children, which was more pronounced at low-dose than at high-dose UFH. Agreement between the 3 assays was poor. Most aPTT values were above therapeutic range or beyond measuring limit and thus of limited value for UFH monitoring. No association of UFH dose or effect with clinical outcome could be observed. In conclusion, all assays reflected a significant UFH dose-effect relationship, however, with poor agreement between the respective tests. The age-dependency of UFH effect was confirmed. Notably, the influence of age on UFH effect was dose-dependent.

High dose subcutaneous unfractionated heparin for prevention of venous thromboembolism in overweight neurocritical care patients.

Timing and dosing of chemical venous thromboembolism (VTE) prophylaxis in brain injury is controversial. Risk of bleeding while using high dose unfractionated heparin (UFH) in overweight patients to prevent VTE is also unknown. The purpose of this study was to describe the use of subcutaneous heparin 7500 units for VTE prophylaxis in overweight patients. This was a retrospective study comparing patients over 100 kg who received either 7500 units Q8 h (n = 141) (high dose group, HDG), or 5000 units Q8 h (n = 257) (traditional dose group, TDG), of UFH subcutaneously. Both groups had similar rates of bleeding complications. The incidence of drop in hemoglobin by two points in any 24 h was 14 % (20/141) HDG versus 11 % (28/257) TDG; P = 0.33. Hemoglobin drop by two points from baseline was 57 % (81/141) HDG versus 51 % (132/257) TDG; P = 0.24. The need for pRBC transfusion was 26 % (36/141) HDG versus 20 % (52/257) TDG; P = 0.22. An increase in aPTT from baseline by two times was 4 % (5/141) HDG versus 4 % (9/257) TDG, P = 0.59. Discontinuation of heparin therapy for association with progressive bleeding was not documented in any patients. No differences in minor bleeding complications were observed. There was no difference in the incidence of VTE: 5.7 % (8/141) HDG versus 9.3 % (24/257) TDG; P = 0.2. In univariate and multivariable logistic regression analysis, only the time of the initiation of heparin after admission was associated with the occurrence of VTE (median, IQR) 46 h (17-86) HDG versus 105 h (56-167) TDG; OR 1.2 (1.1-1.3); P < 0.001. High dose subcutaneous UFH was not associated with an increased risk of bleeding, nor did it decrease the incidence of VTE in overweight patients.