Effects Of Unfractionated Heparin Research Articles

Comparative Study of Unfractionated Heparins and Low Molecular Weight Heparin on Skin Wound Repair

Aims: Heparin (HP) has aroused interest in the treatment of skin wounds. The HP extraction sources and the chemical diversity of its structural chain result in different clinical responses. In this study, a comparison was made among the effects of unfractionated heparin from bovine (bovHP) and swine (swi.HP) sources and low molecular weight heparin (LMWH) on skin lesions treatment. Study Design: Wounds were induced on the back of Swiss mice using a punch. Then, the wounds were treated with heparins for 3 and 7 days. Place and Duration of Study: Institute of Biomedical Sciences and Animal Breeding Network and Rodents of the Federal University of Uberlândia, between April 2018 and February 2020. Methodology: Wound closure was performed with a digital caliper. The inflammatory infiltrate was assessed by the activity of neutrophils and macrophages. Angiogenesis was measured by quantifying blood vessels and measuring hemoglobin. While fibrogenesis was assessed by picrosirius red staining. Results: None of the heparins had a healing effect. Swi.HP showed delay in wound closure and intensification of the inflammatory process compared to bov.HP. Swine and bovine heparins showed pro-angiogenic activity, although this did not differ between them. Difference between the groups of heparins was observed in relation to the deposition and organization of collagen fibers, with a reduction in fibrogenesis in wounds of the LMWH group compared to the other heparins, especially bov.HP. A better fibrogenic activity was observed for bov.HP. Conclusion: Thus, we conclude that the source of the heparin used should be considered, as its pharmacological response for wound treatment is quite diverse. Although none of the heparins was able to accelerate wound closure, bov.HP had an anti-inflammatory and pro- fibrogenic effect compared to the other heparins and therefore showed the best response in this experimental model.

Pleiotropic Effects of Heparin and its Monitoring in the Clinical Practice.

Unfractionated heparin (UFH) was uncovered in 1916, has been used as an anticoagulant since 1935, and has been listed in the World Health Organization's Model List of Essential Medicines. Despite the availability of many other anticoagulants, the use of heparin (either low molecular weight heparin [LMWH] or UFH) is still substantial. Heparin has pleotropic effects including anticoagulant and several nonanticoagulant properties such as antiproliferative, anti-inflammatory activity, and anticomplement effects. Although UFH has been widely replaced by LMWH, UFH is still the preferred anticoagulant of choice for patients undergoing cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, and patients with high-risk mechanical cardiac valves requiring temporary bridging with a parenteral anticoagulant. UFH is a highly negatively charged molecule and binds many positively charged molecules, hence has unpredictable pharmacokinetics, and variable anticoagulant effect on an individual patient basis. Therefore, anticoagulant effects of UFH may not be proportional to the dose of UFH given to any individual patient. In this review, we discuss the anticoagulant and nonanticoagulant activities of UFH, differences between UFH and LMWH, when to use UFH, different methods of monitoring the anticoagulant effects of UFH (including activated partial thromboplastin time, heparin anti-Xa activity level, and activated clotting time), while discussing pros and cons related to each method and comparison of clinical outcomes in patients treated with UFH monitored with different methods based on available evidence.

Anticoagulation for people receiving long-term haemodialysis.

Haemodialysis (HD) requires safe and effective anticoagulation to prevent clot formation within the extracorporeal circuit during dialysis treatments to enable adequate dialysis and minimise adverse events, including major bleeding. Low molecular weight heparin (LMWH) may provide a more predictable dose, reliable anticoagulant effects and be simpler to administer than unfractionated heparin (UFH) for HD anticoagulation, but may accumulate in the kidneys and lead to bleeding. To assess the efficacy and safety of anticoagulation strategies (including both heparin and non-heparin drugs) for long-term HD in people with kidney failure. Any intervention preventing clotting within the extracorporeal circuit without establishing anticoagulation within the patient, such as regional citrate, citrate enriched dialysate, heparin-coated dialysers, pre-dilution haemodiafiltration (HDF), and saline flushes were also included. We searched the Cochrane Kidney and Transplant Register of Studies up to November 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials (RCTs) and quasi-randomised controlled studies (quasi-RCTs) evaluating anticoagulant agents administered during HD treatment in adults and children with kidney failure. Two authors independently assessed the risk of bias using the Cochrane tool and extracted data. Treatment effects were estimated using random effects meta-analysis and expressed as relative risk (RR) or mean difference (MD) with 95% confidence intervals (CI). Evidence certainty was assessed using the Grading of Recommendation, Assessment, Development and Evaluation approach (GRADE). We included 113 studies randomising 4535 participants. The risk of bias in each study was adjudicated as high or unclear for most risk domains. Compared to UFH, LMWH had uncertain effects on extracorporeal circuit thrombosis (3 studies, 91 participants: RR 1.58, 95% CI 0.46 to 5.42; I2 = 8%; low certainty evidence), while major bleeding and minor bleeding were not adequately reported. Regional citrate anticoagulation may lower the risk of minor bleeding compared to UFH (2 studies, 82 participants: RR 0.34, 95% CI 0.14 to 0.85; I2 = 0%; low certainty evidence). No studies reported data comparing regional citrate to UFH on risks of extracorporeal circuit thrombosis and major bleeding. The effects of very LMWH, danaparoid, prostacyclin, direct thrombin inhibitors, factor XI inhibitors or heparin-grafted membranes were uncertain due to insufficient data. The effects of different LMWH, different doses of LMWH, and the administration of LMWH anticoagulants using inlet versus outlet bloodline or bolus versus infusion were uncertain. Evidence to compare citrate to another citrate or control was scant. The effects of UFH compared to no anticoagulant therapy or different doses of UFH were uncertain. Death, dialysis vascular access outcomes, blood transfusions, measures of anticoagulation effect, and costs of interventions were rarely reported. No studies evaluated the effects of treatment on non-fatal myocardial infarction, non-fatal stroke and hospital admissions. Adverse events were inconsistently and rarely reported. Anticoagulant strategies, including UFH and LMWH, have uncertain comparative risks on extracorporeal circuit thrombosis, while major bleeding and minor bleeding were not adequately reported. Regional citrate may decrease minor bleeding, but the effects on major bleeding and extracorporeal circuit thrombosis were not reported. Evidence supporting clinical decision-making for different forms of anticoagulant strategies for HD is of low and very low certainty, as available studies have not been designed to measure treatment effects on important clinical outcomes.

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PurposePercutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.Materials and methodsAll patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).ResultsThromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.ConclusionOur retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Novel Coagulation Test Detects Anticoagulation Resistance and Is Associated With Thrombotic Events in Pediatric Patients Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES:Bivalirudin, an IV direct thrombin inhibitor, and unfractionated heparin (UFH) are frequently used anticoagulants in the pediatric critical care setting. An accurate, specific, point-of-care test to quantify and detect anticoagulation resistance is not currently available. This study evaluates the ability of a rapid (< 10 min), micro-volume (< 50 uL) coagulation test to detect and quantify the anticoagulation effect of bivalirudin and UFH using a functional, clot time endpoint in pediatric critical care patients.DESIGN:Single-site retrospective laboratory sample analysis and chart review.SETTING:A 105-bed pediatric and cardiac ICUs delivering extracorporeal membrane oxygenation.SUBJECTS:Forty-one citrated, frozen, biobanked plasma specimens comprising 21 with bivalirudin and 20 with UFH from 15 anticoagulated pediatric patients were analyzed. Thirteen patients were on extracorporeal membrane oxygenation, one had a submassive pulmonary embolism, and one was on a left ventricular assist device.INTERVENTIONS:None.MEASUREMENT AND MAIN RESULTS:A Clotting Time Score (CTS) was derived on each sample. The CTS detected patients that had developed a pathologic clotting event with 100% sensitivity and 82% specificity compared with prothrombin time with 25% sensitivity/76% specificity and activated partial thromboplastin time with 0% sensitivity/0% specificity. Additionally, the CTS detected subtherapeutic anticoagulation in response to UFH in patients that were clinically determined to be UFH resistant requiring alternative anticoagulation with bivalirudin.CONCLUSIONS:The CTS appears to be a clinically valuable indicator of coagulation status in patients treated with either UFH or bivalirudin. Results outside of the therapeutic range due to inadequate dosing or anticoagulation resistance appeared to be associated with clot formation. CTS testing may reduce the risk of anticoagulation-related complications via the rapid identification of patients at high risk for pathologic thrombotic events.

Unfractionated Heparin Protects Microcirculation in Endotoxemic Rats by Antagonizing Histones

IntroductionLevels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats. MethodsTwenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells. ResultsUFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro. ConclusionsUFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis.

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.

Complement activation during cardiopulmonary bypass and association with clinical outcomes.

In this prospective, single‐centre observational study of 30 patients undergoing cardiopulmonary bypass (CPB), the effect of unfractionated heparin (UFH), CPB surgery and protamine sulphate on complement and on post‐operative blood loss were assessed. Although C3 and C4 levels decreased significantly immediately following the administration of UFH, C3a, C5a, Bb fragment and SC5b‐9 remained unchanged. During CPB, C3 and C4 continued to fall whilst both alternative and classical pathways activation markers, Bb, C3a, C5a and SC5b‐9 increased significantly. Protamine sulphate had no effect on classical pathway components or activation markers but decreased alternative pathway activation marker Bb. Over the 12–24 h post‐surgery, both classical and alternative pathway activation markers returned to baseline, whilst C3 and C4 levels increased significantly but not to baseline values. Total drain volume 24 h after the surgery showed a moderate inverse correlation with post‐protamine C3 (r = −0.46, p = 0.01) and C4 (r = −0.57, p = 0.0009) levels, whilst a moderate positive correlation was observed with post‐protamine C3a (r = 0.46, p = 0.009), C5a (r = 0.37, p = 0.04) and SC5b‐9 (r = 0.56, p = 0.001) levels but not with Bb fragment (r = 0.25, p = 0.17). Thus, inhibition of complement activation may be a therapeutic intervention to reduce post‐operative blood in patients undergoing CPB.

Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real-World Data: A Pharmacokinetic-Pharmacodynamic Modeling Approach.

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic-pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28L/(h·50kg) and 8.83L/50kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28IU/h/kg for pediatrics <1yearold or 20IU/h/kg for pediatrics >1yearold) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1year, 1-6years, 6-12years, and 12-19years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.

Varying Dosages of Subcutaneous Unfractionated Heparin and Activated Partial Thromboplastin Time in Hospitalized Antepartum Patients: A Retrospective Cohort Analysis.

Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality in the United States. Subcutanous unfractionated heparin (UFH) has been used for decades for VTE prophylaxis and under many obstetric quality of care initiatives, hospitalized antepartum patients now receive doses as high as 10,000 units every 12 hours. This practice increases the likelihood of UFH administration around the time that epidural labor analgesia is requested or neuraxial analgesia for cesarean delivery is needed. To clarify the effect of UFH on coagulation, we reviewed the care of hospitalized antepartum patients receiving VTE prophylaxis with UFH to determine the incidence of concurrent abnormal activated partial thromboplastin time (aPTT) values and associated risk factors. This retrospective cohort study used data from the University of Chicago Pharmacy database to identify hospitalized antepartum patients receiving subcutaneous UFH from June 1, 2016 to July 1, 2019. Our institutional protocol states that all patients hospitalized for antepartum conditions should receive pharmacologic prophylaxis empirically unless contraindicated. For patients receiving UFH, dosing was based on gestational age: 5000 units every 12 hours for first trimester antepartum patients, 7500 units every 12 hours for second trimester patients, and 10,000 units every 12 hours for patients in the third trimester. As per protocol, aPTT values were obtained 2 hours after the third dose of heparin, and platelet counts after 4 days. Data collection included demographics, comorbidities, heparin doses, aPTT values, platelet counts, creatinine if available, and anesthetic type and complications. Logistic regression was performed to determine the association between elevated aPTT >40 seconds and study variables. Of the 321 antepartum patients who received subcutaneous UFH, 33 (10.3%) had an aPTT >40 seconds, 4 of those 33 patients (12.1%) received 5000 units every 12 hours, 14 (42.2%) received 7500 units every 12 hours, and 15 (45.5%) received 10,000 units every 12 hours. The likelihood of a patient having aPTT >40 seconds was 2.8% with 5000 units every 12 hours, 18.9% with 7500 units every 12 hours, and 14.6% with 10,000 units every 12 hours. Elevated aPTT values are likely with total daily doses of 15,000 or 20,000 units subcutaneous UFH in hospitalized antepartum patients.

Un-fractionated heparin counteracts the systemic inflammatory responses and multiple organ damages caused by endotoxaemia in sheep.

BackgroundEndotoxaemia is believed to be a major cause of mortality and there are several therapeutic regimens for the treatment of this situation.ObjectivesThe present experimental study was conducted to evaluate acute phase response, cardiovascular and hepatorenal damages following the treatment of Ovine experimental endotoxaemia model employing unfractionated heparin (UFH).Materials and MethodsTwenty clinically healthy 1‐year‐old fat‐tailed ewes were randomly divided into four equal groups, comprising UFH 200, UFH 400, Ctrl+ and Ctrl‐. Lipopolysaccharide (LPS) from Escherichia coli serotype O55:B5 at 0.4 μg/kg was administered intravenously to the ewes. UFH (at 200 and 400 IU/kg) was administrated to the UFH 200 and UFH 400 groups, respectively. All the ewes were evaluated clinically before and 1.5, 3, 4.5, 6 and 24 hours after LPS injection. Blood samplings were also performed at those hours. We measured serum concentrations of haptoglobin, interferon‐gamma, total antioxidant status, malondialdehyde, cardiac lactate dehydrogenase, cardiac troponin‐I, total bilirubin, alanine transaminase and creatinine. Serum concentrations of acute phase response, cardiovascular, hepatic and renal biomarkers and clinical parameters increased significantly following the induction of endotoxaemia in the groups receiving LPS.ResultsThe significantly lowest concentrations of these parameters at hours 4.5 and 6 among the treatment groups belonged to the UFH 400 sheep.ConclusionsUFH could act as an anti‐inflammatory mediator by decreasing inflammatory cytokines and acute phase proteins, modulating oxidative stress biomarkers and reducing multiple organ dysfunction following endotoxaemia in a dose–dependent manner. Furthermore, the anti‐inflammatory effects of UFH at 400 IU/kg were significantly higher than another dose. This research examined the effect of two doses of UFH and higher doses may have more anti‐inflammatory effects that require further studies.

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.

Unfractionated Heparin Attenuated Histone-Induced Pulmonary Syndecan-1 Degradation in Mice: a Preliminary Study on the Roles of Heparinase Pathway.

Endothelial glycocalyx degradation is thought to facilitate the development of sepsis. Histone is a significant mediator in sepsis. Unfractionated heparin (UFH) possessed beneficial effects on sepsis. Thereby, this study aims to figure out whether histone can disrupt glycocalyx and to investigate the protective effect and mechanism of UFH. Male mice (C57BL/6, 8-10weeks old, weighing 20-25g) were randomly divided into five groups including control group, histone group, histone + UFH group, histone + heparinase (HPA) inhibitor group, and histone + UFH + HPA inhibitor group. The mice were treated with histone (50mg/kg) via tail vein immediately after HPA (20mg/kg) injection. UFH (400 U/kg) was injected 1h after histone administration. The other groups were injected with equal volume of sterile saline accordingly. UFH alleviated histone-induced lung injury and pulmonary edema. UFH inhibited histone-induced lung coagulation activation and inflammatory response. UFH treatment markedly inhibited pulmonary glycocalyx degradation by reducing the histone-induced decrease in the levels of lung syndecan-1 mRNA and protein. UFH downregulated histone-induced expression of HPA mRNA and protein, and thus alleviated glycocalyx degradation. UFH protects against histone-induced pulmonary glycocalyx injury partly by heparinase pathway.

Unfractionated Heparin (UFH) For Prevention of Central Venous Catheter Thrombotic Complications in Children: A systematic review and meta-analysis

Abstract Objective To determine the efficacy of unfractionated heparin in reducing central venous catheter-related deep venous thrombosis and/or catheter thrombotic occlusion in children by systematically searching the literature and conducting a meta-analysis study. Methods Four electronic databases (PubMed, Google Scholar, Elsevier’s thrombosis journal, and the Cochrane Central Register for Controlled Trials) were searched for journal peer-reviewed articles published in the period from Jan 2000 to Dec 2018. The search criteria included observational studies, and randomized controlled trials on patients aged 0–18 years with central venous catheters (CVC), which compare between the effect of UFH (flushes, lock solutions, continuous infusion, and heparin bonded catheter) and no prophylaxis (Normal saline flush or no treatment) for the prevention of CVC thrombotic complications (CVC-related deep venous thrombosis (DVT) and/or catheter thrombotic occlusion). Two authors independently reviewed and identified the eligible studies, which were assessed for study methodology including bias, and extraction of unadjusted data whenever available. To pool data from eligible studies, the meta-analysis was performed on RevMan version 5.3. Odds ratios were generated with the corresponding 95% CI through the random-effect model. Results Of the 413 articles identified, only eight studies were eligible with 1380 patients. Our results revealed that UFH was significantly superior on control group in reducing thrombotic occlusion and/or CVC-related DVT (odds ratio 0.39, 95% CI: 0.19:0.8) (p 0.01). Conclusion The published data support the hypothesis that using UFH as a thromboprophylaxis may significantly reduce catheter thrombotic complication in pediatric patients with CVC.

In vitro and invivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin.

Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization. Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension, and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in‐depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement, and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH–R15 complex. Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement, and cause anticoagulation in a concentration‐dependent manner. However, those influences weakened in whole blood or in live animals and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH–PS complexes, and a slight increase in those involving UFH–R15 complexes. Within 2 h, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U·kg−1, body weight), suggesting possible abnormal renal function. The UFH–PS complex, but not the UFH–R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is nonimmunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH.

Effects of Bivalirudin and Unfractionated Heparin on Liver and Renal Function in Chinese Patients with Coronary Artery Disease Undergoing Coronary Angiography with/without Percutaneous Coronary Intervention.

Background and AimsUnfractionated heparin (UFH) and bivalirudin are widely used as anticoagulants in cardiovascular medicine, including for thrombosis prevention during coronary angiography (CAG) and percutaneous coronary intervention (PCI). Little is known of the effects of UFH and bivalirudin on liver and kidney function in patients subjected to these procedures. This study compared the effects of bivalirudin and UFH on liver/renal function in patients with coronary artery disease who underwent CAG, with or without PCI.MethodsThe study comprised 134 consecutive patients (40–89 years-old), who underwent CAG (or CAG and PCI); among them, 66 and 68 patients were subject to, respectively, bivalirudin or UFH. The following indicators of liver/renal function were measured before and after the procedures: plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, estimated glomerular filtration rate (eGFR), creatinine clearance, and serum creatinine. Patients were further stratified by severity of chronic kidney disease (CKD), based on original eGFR.ResultsRelative to baseline, in the bivalirudin group, ALT and AST were higher after CAG (p=0.005, 0.025), while blood urea nitrogen and serum creatinine were lower (p=0.049, <0.001). In the UFH group, ALT, AST, eGFR, and creatinine clearance were lower after CAG (p≤0.001, all). Patients given bivalirudin with moderate or severe CKD, but not those with mild CKD, gained significant improvement in kidney function.ConclusionsRelative to UFH, bivalirudin may better safeguard the renal function of patients with coronary artery disease who undergo CAG, especially patients with moderate-to-severe renal insufficiency. UFH may cause less liver damage than bivalirudin.

Effect of unfractionated heparin and low molecular weight heparin on the clotting of platelet-reduced whole blood: an in-vitro study utilizing thromboelastography.

Treatment of venous thromboembolism with concomitant thrombocytopenia is challenging. The platelet threshold for safe administration of anticoagulants is under debate, with minimum platelet count of 50 × 109/l being recommended as the safe cutoff. However, some evidence suggests administration of anticoagulants may still be safe at platelet levels of 30 × 109/l. Therefore, we developed an in-vitro thromboelastography (TEG) study to examine the effect of therapeutic or prophylactic levels of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) on the clotting profile of platelet-reduced whole blood. Using magnetic bead-based antibody chromatography, platelets were removed to achieve platelet-depleted blood (<10 × 109/l of platelets). Platelet-depleted blood was then mixed with whole blood to produce blood samples with platelet counts of 30 × 109, 50 × 109 and 150 × 109/l. These blood samples were incubated with therapeutic or prophylactic levels of UFH or LMWH in disposable TEG cups. Clotting was initiated with 10 mmol/l calcium and optimized tissue factor levels for each anticoagulant used (2.25 pmol/l for UFH and 2.05 pmol/l for LMWH). Clotting was monitored by TEG at 37 °C for 180 min. The following TEG parameters were evaluated: R (time to clot), maximum amplitude (strength of clot) and area under the curve in 15 min (overall speed and strength of the clot at 15 min of clotting). No statistically significant differences were observed between platelet counts of 30 × 109 and 50 × 109/l for R, maximum amplitude or area under the curve in 15 min for most of the therapeutic and prophylactic doses of UFH and LMWH tested in this study. Use of anticoagulants compromised all of the TEG parameters relative to a normal platelet count of 150 × 109/l, in a dose dependent manner. The current study demonstrates that in-vitro clotting is impaired with use and increasing doses of anticoagulants. Despite this observation, we did not observe a significant difference in clotting between platelet levels of 30 × 109 and 50 × 109/l. Overall, this work provides further insight in the debated use of anticoagulants in patients with venous thromboembolism and concomitant thrombocytopenia, and provides support for possible use of anticoagulants at lower platelet thresholds.

The Influence of Haemostatic System Maturation on the Dose-Response Relationship of Unfractionated Heparin.

Unfractionated heparin (UFH) dosing and monitoring guidelines for children are often extrapolated from adult data. This practice is suboptimal given the inherent differences in haemostatic maturation and drug handling in children compared with adults. The aim of this work was to investigate the impact of haemostatic system maturation on the dose-response relationship of UFH in children. A quantitative model for haemostasis in adults was adapted to account for maturation in UFH pharmacokinetic (PK) parameters with and without age-related changes in coagulation factor concentrations. The adult and adapted models were used to predict the time courses of anti-factor Xa activity (aXa) and activated partial thromboplastin time (aPTT) in patients receiving UFH infusion. Predictions from both models were compared with observed aXa and aPTT measurements from 31 paediatric patients receiving UFH during extracorporeal membrane oxygenation (ECMO). The model with maturation for both UFH PK and the haemostatic system had an improved aXa and aPTT predictive performance compared with maturation in UFH PK only and the original adult model. Despite the minor effect of haemostatic system maturation on baseline aPTT, it led to substantial changes in the time course of aPTT sensitivity to UFH. This finding suggests that between-subject variability in clotting factors concentrations is potentially a major contributor to the overall variability of aPTT response to UFH. In addition, time-varying clotting factors concentrations may explain within-subject changes in aPTT sensitivity to UFH. We developed the first quantitative systems pharmacology (QSP) model that provides a mechanistic and quantitative basis for linking physiological and pharmacological maturation to UFH effect and response biomarkers. After appropriate clinical validation, the model could be useful for the development of paediatric-specific individualised UFH dosing recommendations.

Impact of pre-angioplasty antithrombotic therapy administration on coronary reperfusion in ST-segment elevation myocardial infarction: Does time matter?

BackgroundOptimal timing of antithrombotic therapy for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) is unclear. We analyzed the impact of pre-angioplasty administration of unfractionated heparin (UFH) on infarct-related artery (IRA) patency and mortality. MethodMulticenter prospective observational study of 3520 STEMI patients treated with PPCI from 2016 to 2018. Subjects were divided into four groups according to the elapsed time from heparin administration to PPCI: Group 1: Upon arrival at catheterization laboratory or ≤ 30 min (n = 800; 22.7%); Group 2: 31 to 60 min (n = 994; 28.2%); Group 3: 61 to 90 min (n = 1091; 31%); Group 4: >90 min (n = 635; 18%). IRA patency was defined as thrombolysis in myocardial infarction (TIMI) flow grade 2–3. Multivariate analyses assessed factors associated with IRA patency and both 30-day and 1-year mortality. ResultsUFH administration at STEMI diagnosis was an independent predictor of IRA patency especially when administered more than 60 min before the PPCI (OR 1.43; 95% CI 1.14–1.81), either an independent predictor of 30-day (HR 0.63; 95% CI 0.42–0.94) and 1-year (HR 0.57; 95% CI 0.41–0.80) mortality. The effect of UFH on IRA patency was higher when administered earlier from the symptom onset. ConclusionUFH administration at STEMI diagnosis improves coronary reperfusion prior to PPCI and this benefit seems associated with superior clinical outcomes. The presented results highlight a time-dependent effectiveness of UFH, since its reported effect is greater the sooner UFH is administered after symptom onset.