Integral assays of hemostasis in hospitalized patients with COVID-19 on admission and during heparin thromboprophylaxis.

BACKGROUND: Blood coagulation abnormalities play a major role in COVID-19 pathophysiology. However, the specific details of hypercoagulation and anticoagulation treatment require investigation. The aim of this study was to investigate the status of the coagulation system by means of integral and local clotting assays in COVID-19 patients on admission to the hospital and in hospitalized COVID-19 patients receiving heparin thromboprophylaxis. METHODS: Thrombodynamics (TD), thromboelastography (TEG), and standard clotting assays were performed in 153 COVID-19 patients observed in a hospital setting. All patients receiving treatment, except extracorporeal membrane oxygenation (ECMO) patients (n = 108), were administered therapeutic doses of low molecular weight heparin (LMWH) depending on body weight. The ECMO patients (n = 15) were administered unfractionated heparin (UFH). RESULTS: On admission, the patients (n = 30) had extreme hypercoagulation by all integral assays: TD showed hypercoagulation in ~75% of patients, while TEG showed hypercoagulation in ~50% of patients. The patients receiving treatment showed a significant heparin response based on TD; 77% of measurements were in the hypocoagulation range, 15% were normal, and 8% remained in hypercoagulation. TEG showed less of a response to heparin: 24% of measurements were in the hypocoagulation range, 59% were normal and 17% remained in hypercoagulation. While hypocoagulation is likely due to heparin treatment, remaining in significant hypercoagulation may indicate insufficient anticoagulation for some patients, which is in agreement with our clinical findings. There were 3 study patients with registered thrombosis episodes, and all were outside the target range for TD parameters typical for effective thromboprophylaxis (1 patient was in weak hypocoagulation, atypical for the LMWH dose used, and 2 patients remained in the hypercoagulation range despite therapeutic LMWH doses). CONCLUSION: Patients with COVID-19 have severe hypercoagulation, which persists in some patients receiving anticoagulation treatment, while significant hypocoagulation is observed in others. The data suggest critical issues of hemostasis balance in these patients and indicate the potential importance of integral assays in its control.

Early Initiation of Extracorporeal Blood Purification Using the AN69ST (oXiris®) Hemofilter as a Treatment Modality for COVID-19 Patients: a Single-Centre Case Series.

INTRODUCTION: Severe coronavirus disease 2019 (COVID-19) is characterised by hyperinflammatory state, systemic coagulopathies, and multiorgan involvement, especially acute respiratory distress syndrome (ARDS). We here describe our preliminary clinical experience with COVID-19 patients treated via an early initiation of extracorporeal blood purification combined with systemic heparinisation and respiratory support. METHODS: Fifteen patients were included; several biomarkers associated with COVID-19 severity were monitored. Personalised treatment was tailored according to the levels of interleukin (IL)-6, IL-8, tumour necrosis factor alpha, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, thrombocyte counts, D-dimers, and fibrinogen. Treatment consisted of respiratory support, extracorporeal blood purification using the AN69ST (oXiris®) hemofilter, and 300 U/kg heparin to maintain activation clotting time ≥ 180 seconds. RESULTS: Ten patients presented with severe to critical disease (dyspnoea, hypoxia, respiratory rate > 30/min, peripheral oxygen saturation < 90%, or > 50% lung involvement on X-ray imaging). The median intensive care unit length of stay was 9.3 days (interquartile range 5.3-10.1); two patients developed ARDS and died after 5 and 26 days. Clinical improvement was associated with normalisation (increase) of thrombocytes and white blood cells, stable levels of IL-6 (< 50 ng/mL), and a decrease of CRP and fibrinogen. CONCLUSION: Continuous monitoring of COVID-19 severity biomarkers and radiological imaging is crucial to assess disease progression, uncontrolled inflammation, and to avert irreversible multiorgan failure. The combination of systemic heparin anticoagulation regimens and extracorporeal blood purification using cytokine-adsorbing hemofilters may reduce hyperinflammation, prevent coagulopathy, and support clinical recovery.

A practical approach for the treatment of post-COVID symptoms.

For the past 3 years, our daily lives have been largely dictated by the coronavirus disease 2019 (COVID-19) pandemic. In many people, this infectious disease leads to long-lasting symptoms, which can vary greatly in form and intensity between individuals. This report describes the case of a young patient who had no health restrictions until she came into contact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As part of a post-COVID syndrome, she not only temporarily lost her ability to work, but was also no longer able to manage her daily life independently. A crucial therapeutic approach, in this case, was the use of heparin-induced extracorporeal LDL/fibrinogen precipitation (H.E.L.P.) apheresis.

Pharmacology of Heparin and Related Drugs: An Update.

Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed mainly to the pentasaccharide sequence, which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been elucidated that heparin exhibits anti-inflammatory effect via interference of the formation of neutrophil extracellular traps and this may also contribute to heparin's antithrombotic activity. This illustrates that heparin interacts with a broad range of biomolecules, exerting both anticoagulant and nonanticoagulant actions. Since our previous review, there has been an increased interest in these nonanticoagulant effects of heparin, with the beneficial role in patients infected with SARS2-coronavirus a highly topical example. This article provides an update on our previous review with more recent developments and observations made for these novel uses of heparin and an overview of the development status of heparin-based drugs. SIGNIFICANCE STATEMENT: This state-of-the-art review covers recent developments in the use of heparin and heparin-like materials as anticoagulant, now including immunothrombosis observations, and as nonanticoagulant including a role in the treatment of SARS-coronavirus and inflammatory conditions.

Membrane oxygenator longevity was higher in argatroban-treated patients undergoing vvECMO.

BACKGROUND: In severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (vvECMO) can be a lifesaver. However, anticoagulation therapy is mandatory because the nonendothelial extracorporeal surface increases the risk of thromboembolic problems. Heparin is still the most common anticoagulant, but argatroban could be an alternative. This work investigates whether argatroban offers a therapeutic advantage over heparin during vvECMO. METHODS: We performed a retrospective cohort study of patients who underwent vvECMO for severe ARDS and received heparin or argatroban as anticoagulation therapy. Demographic variables, intensive care unit (ICU) treatment and outcome parameters were evaluated. The primary outcome parameter was the operating time of the membrane oxygenator normalized to the duration of vvECMO treatment. Secondary outcome parameters were transfusion requirements normalized to the duration of vvECMO therapy. RESULTS: Fifty seven patients from January 2019 to February 2021 underwent vvECMO and were included in this study. Thirty three patients received heparin and 24 patients argatroban as anticoagulatory therapy. The groups did not differ in demographics, ICU scoring systems, or comorbidities. Platelet counts and partial prothrombin time did not differ between the two groups during the first 6 days of vvECMO. The argatroban group had lower requirements for red blood cells, platelets and fresh frozen plasma. The mean runtime of the individual membrane oxygenator increased from 12.3 days (heparin group) to 16.6 days in the argatroban group. CONCLUSIONS: Our findings suggest that argatroban can be considered as anticoagulant during vvECMO.

[Mechanism and clinical treatment strategy of heparin resistance].

Heparin resistance is becoming a hot issue of clinical concern. In critically ill patients, heparin resistance can lead to failure of anticoagulation therapy or increase the risk of major bleeding. Prompt recognition of heparin resistance can help to precisely adjust heparin dosage and avoid deterioration and adverse events. Heparin resistance can be mechanistically classified into the antithrombin-mediated and the non-antithrombin-mediated. Common etiologies include heparin-induced thrombocytopenia, severe infections such as severe COVID-19, treatment with extracorporeal circulation or extracorporeal membrane oxygenation (ECMO), and use of factor Xa reversal agents; heparin resistance is now often identified by the concordance of activated partial thromboplastin time (APTT) ratio with anti-FXa. Common clinical management strategies include antithrombin supplementation and replacement of anticoagulant drugs (e.g., direct thrombin inhibitors), but their safety and efficacy still need to be further validated.

Tinzaparin-a review of its molecular profile, pharmacology, special properties, and clinical uses.

PURPOSE: Low molecular weight heparins (LMWHs) are a group of heterogenous moieties, long used in the prevention and treatment of thrombosis. They derive from heparin and since they are prepared by different methods of depolymerization, they differ in pharmacokinetic properties and anticoagulant profiles, and thus are not clinically interchangeable. METHODS: In this review we provide an overview of tinzaparin's main characteristics and uses. RESULTS: Tinzaparin which is produced by the enzymatic depolymerization of unfractionated heparin (UFH) can be used for the treatment and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE); it has been also used in special populations such as elders, obese, pregnant women, and patients with renal impairment and/or cancer with favorable outcomes in both safety and efficacy, with a once daily dose regimen. Furthermore, LMWHs are extensively used in clinical practice for both thromboprophylaxis and thrombosis treatment of COVID-19 patients. CONCLUSION: Tinzaparin features support the hypothesis for having a role in immunothrombosis treatment (i.e. in the context of cancer ,COVID-19), interfering not only with coagulation cascade but also exhibiting anti-inflammatory potency.

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies.

BACKGROUND: International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. METHODS: A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. RESULTS: We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59-0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was "moderate." CONCLUSION: Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. STUDY REGISTRATION: PROSPERO, review no. CRD42022348993.

Anticoagulant Use During Extracorporeal Membrane Oxygenation Using Heparin and Direct Thrombin Inhibitors in COVID-19 and ARDS Patients.

Coagulopathies develop in patients supported with the use of extracorporeal membrane oxygenation (ECMO) and can be hemorrhagic and/or thrombophilic in spite of the use of systemic anticoagulation. The purpose this study was to examine the use of heparin and direct thrombin inhibitors (DTI) in COVID-19 patients with acute respiratory distress syndrome (ARDS) on ECMO, with a subset analysis by disease state. Following IRB approval, 570 consecutive records were reviewed of adult patients on venovenous ECMO between May 2020 and December 2021. Patients were grouped by anticoagulant use: Heparin Only (n = 373), DTI Only (bivalirudin or argatroban, n = 90), or DTI after Heparin (n = 107). The effect of anticoagulant grouping was assessed using Bayesian mixed-effects logistic regression adjusting for age, body mass index (BMI), gender, days of mechanical ventilation prior to ECMO, indication for ECMO support, hepatic and renal failure, hours on ECMO, hours off anticoagulation, coagulation monitoring target, and hospital. The primary endpoint was circuit failure requiring change-out with secondary endpoints of organ failure and mortality. Regression-adjusted probability of circuit change-outs were as follows: DTI after Heparin patients-32.7%, 95% Credible Interval [16.1-51.9%]; DTI Only patients-23.3% [7.5-40.8%]; and Heparin Only patients-19.8% [8.1-31.3%]. The posterior probability of difference between groups was strongest for DTI after Heparin vs. Heparin Only (97.0%), moderate for DTI after Heparin vs. DTI Only (88.2%), and weak for DTI Only vs. Heparin only (66.6%). The occurrence of both hepatic and renal failure for DTI Only and DTI after Heparin patients was higher than that of Heparin Only patients. Unadjusted mortality was highest for DTI after Heparin (64.5%) followed by DTI Only (56.7%), and Heparin Only (50.1%, p = 0.027). DTI after Heparin was associated with an increased likelihood of circuit change-out. Unadjusted hepatic failure, renal failure, and mortality were more frequent among DTI patients than Heparin Only patients.

Whole-blood Point-of-Care Activated Partial Thromboplastin Time Ratio (APR) is not Accurate Enough to Monitor Heparin Therapy in Patients with Severe Respiratory Failure Secondary to SARS-Cov-2 Infection Supported with Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO).

Support with VV-ECMO requires anticoagulation with unfractionated heparin to prevent thrombotic complications. This must be monitored due to bleeding risk. A point-of-care (POC) method of testing aPTT and APR was evaluated for agreement with laboratory methods. In a prospective observational study, patients supported on VV-ECMO as a result of severe respiratory failure secondary to Covid-19 infection were given heparin as part of standard therapy. The aPTT was measured (i) at the bedside using the Hemochron Signature Elite device and (ii) at the hospital laboratory. Duplicate results were compared. Agreement between the POC and laboratory tests was poor, as assessed using the Bland-Altman method. The maximum difference between POC and laboratory methods was 133% and the minimum was 0%. Overall bias was 7.3% and limits of agreement were between -43.8% and 58.5%. Correlation increased when results were normalised to platelet count and creatinine. This POC test is insufficiently accurate for use as the primary method of heparin monitoring in patients requiring VV-ECMO for Covid-19. Platelets and renal function may influence the result of this whole blood POC test.

HIGH HEPARANASE LEVEL IN SURVIVORS OF COVID-19 - INDICATOR OF VASCULAR AND PULMONARY RECOVERY?

ABSTRACT: Background: Severe progression of coronavirus disease 2019 (COVID-19) causes respiratory failure and critical illness. Recently, COVID-19 has been associated with heparanase (HPSE)-induced endothelial barrier dysfunction and inflammation, so called endothelitis, and therapeutic treatment with heparin or low-molecular-weight heparin (LMWH) targeting HPSE has been postulated. Because, up to this date, clinicians are unable to measure the severity of endothelitis, which can lead to multiorgan failure and concomitant death, we investigated plasma levels of HPSE and heparin-binding protein (HBP) in COVID-19 intensive care patients to render a possible link between endothelitis and these plasma parameters. Therefore, a prospective prolonged cohort study was conducted, including 47 COVID-19 patients from the intensive care unit. Plasma levels of HPSE, and HBP were measured daily by enzyme-linked immunosorbent assay in survivors (n = 35) and nonsurvivors (n = 12) of COVID-19 from admission until discharge or death. All patients were either treated with heparin or LMWH, aiming for an activated partial thromboplastin time of ≥60 seconds or an anti-Xa level of >0.8 IU/mL using enoxaparin, depending on the clinical status of the patient (patients with extracorporeal membrane oxygenation or >0.1 µg/kg/min noradrenaline received heparin, all others enoxaparin). Results: We found significantly higher plasma levels of HPSE and HBP in survivors and nonsurvivors of COVID-19, compared with healthy controls. Still, interestingly, plasma HPSE levels were significantly higher ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. In contrast, plasma HBP levels were significantly reduced ( P < 0.001) in survivors compared with nonsurvivors of COVID-19. Furthermore, when patients received heparin, they had significantly lower HPSE ( P = 2.22 e - 16) and significantly higher HBP ( P = 0.00013) plasma levels as when they received LMWH. Conclusion: Our results demonstrated that patients, who recover from COVID-19-induced vascular and pulmonary damage and were discharged from the intensive care unit, have significantly higher plasma HPSE level than patients who succumb to COVID-19. Therefore, HPSE is not suitable as marker for disease severity in COVID-19 but maybe as marker for patient's recovery. In addition, patients receiving therapeutic heparin treatment displayed significantly lower heparanse plasma level than upon therapeutic treatment with LMWH.

Anticoagulation in hospitalized patients with COVID-19.

Coronavirus disease-19 (COVID-19) includes a thromboinflammatory syndrome that may manifest with microvascular and macrovascular thrombosis. Patients with COVID-19 have a higher incidence of venous thromboembolism than other hospitalized patients. Three randomized control trials suggesting benefit of therapeutic heparin in hospitalized noncritically ill patients with COVID-19 have led to conditional guideline recommendations for this treatment. By contrast, prophylactic-dose heparin is recommended for critically ill patients. Unprecedented collaboration and rapidly funded research have improved care of hospitalized patients with COVID-19.

Viscoelastic Testing in the Management of Adult Patients on Mechanical Circulatory Support Devices with Focus on Extracorporeal Membrane Oxygenation.

Thromboembolic and hemorrhagic complications continue to remain frequent complications that significantly impact the morbidity and mortality of patients implanted with mechanical circulatory support devices (MCSDs). The severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) has resulted in a number of COVID-19 patients being supported by MCSDs, specifically extracorporeal membrane oxygenation (ECMO), which in turn has created a crucial need for rapid assessment of hemostatic status in these patients to avoid bleeding and thrombotic complications. Currently, conventional plasma-based coagulation assays such as prothrombin time and activated partial thromboplastin time (aPTT) are used to assess hemostasis, and the activated clotting time (ACT) and aPTT are the most common tests used to monitor heparin anticoagulation in patients on ECMO. Unfractionated heparin remains the mainstay anticoagulation therapy for patients on ECMO. Extracorporeal Life Support Organization (ELSO) offers little guidance on the subject but does state that each institution should create its internal anticoagulation protocols. Viscoelastic assays (VEAs) are increasingly recognized by ELSO and ECMO community for their potential to assess hemostatic derangements in patients implanted with MCSDs as well as guidance for appropriate hemostatic therapy. This review focuses on the evidence for the use of viscoelastic assays to assess overall hemostasis and to guide the treatment of adult patients connected to an ECMO circuit. Limitations of the use of conventional assays, ACT, and VEA are also discussed.

Predicting the need for mechanical ventilation and mortality in hospitalized COVID-19 patients who received heparin.

Although several studies have utilized AI (artificial intelligence)-based solutions to enhance the decision making for mechanical ventilation, as well as, for mortality in COVID-19, the extraction of explainable predictors regarding heparin's effect in intensive care and mortality has been left unresolved. In the present study, we developed an explainable AI (XAI) workflow to shed light into predictors for admission in the intensive care unit (ICU), as well as, for mortality across those hospitalized COVID-19 patients who received heparin. AI empowered classifiers, such as, the hybrid Extreme gradient boosting (HXGBoost) with customized loss functions were trained on time-series curated clinical data to develop robust AI models. Shapley additive explanation analysis (SHAP) was conducted to determine the positive or negative impact of the predictors in the model's output. The HXGBoost predicted the risk for intensive care and mortality with 0.84 and 0.85 accuracy, respectively. SHAP analysis indicated that the low percentage of lymphocytes at day 7 along with increased FiO2 at days 1 and 5, low SatO2 at days 3 and 7 increase the probability for mortality and highlight the positive effect of heparin administration at the early days of hospitalization for reducing mortality.

Venous Thromboembolic Disease in COVID-19, Pathophysiology, Therapy and Prophylaxis.

For over two years, the world has been facing the epidemiological and health challenge of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Growing problems are also complications after the development of COVID-19 in the form of post and long- COVID syndromes, posing a challenge for the medical community, both for clinicians and the scientific world. SARS-CoV-2 infection is associated with an increased risk of cardiovascular complications, especially thromboembolic complications, which are associated with both thrombosis of small and very small vessels due to immunothrombosis, and the development of venous thromboembolism. Low molecular wight heparin (LMHW) are the basic agents used in the prevention and treatment of thromboembolic complications in COVID-19. There is still a great deal of controversy regarding both the prevention and treatment of thromboembolic complications, including the prophylaxis dose or the optimal duration of anticoagulant treatment in patients with an episode of venous thromboembolism.

Interventions for treating catheter-related bloodstream infections in people receiving maintenance haemodialysis.

BACKGROUND: Patients with kidney failure require vascular access to receive maintenance haemodialysis (HD), which can be achieved by an arteriovenous fistula or a central venous catheter (CVC). CVC use is related to frequent complications such as venous stenosis and infection. Venous stenosis occurs mainly due to trauma caused by the entrance of the catheter into the venous lumen and repeated contact with the vein wall.  A biofilm, a colony of irreversible adherent and self-sufficient micro-organisms embedded in a self-produced matrix of exopolysaccharides, is associated with the development of infections in patients with indwelling catheters. Despite its clinical relevance, the treatment of catheter-related bloodstream infections (CRBSIs) in patients receiving maintenance HD remains controversial, especially regarding catheter management. Antibiotic lock solutions may sterilise the catheter, treat the infection and prevent unnecessary catheter procedures. However, such treatment may also lead to antibiotic resistance or even clinical worsening in certain more virulent pathogens. Catheter removal and delayed replacement may remove the source of infection, improving infectious outcomes, but this approach may also increase vascular access stenosis, thrombosis or both, or even central vein access failure. Catheter guidewire exchange attempts to remove the source of infection while maintaining access to the same vein and, therefore, may improve clinical outcomes and preserve central veins for future access. OBJECTIVES: To assess the benefits and harms of different interventions for CRBSI treatment in patients receiving maintenance HD through a permanent CVC, such as systemic antibiotics alone or systemic antibiotics combined with either lock solutions or catheter guidewire exchange or catheter replacement. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 21 December 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs evaluating the management of CRBSI in permanent CVCs in people receiving maintenance HD. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, assessed their risk of bias, and performed data extraction. Results were expressed as risk ratios (RR) or hazard ratios (HR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, with their 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified two RCTs and one quasi-RCT that enrolled 760 participants addressing the treatment of CRBSIs in people (children and adults) receiving maintenance HD through CVC. No two studies compared the same interventions. The quasi-RCT compared two different lock solutions (tissue plasminogen activator (TPA) and heparin) with concurrent systemic antibiotics. One RCT compared systemic antibiotics alone and in association with an ethanol lock solution, and the other compared systemic antibiotics with different catheter management strategies (guidewire exchange versus removal and replacement). The overall certainty of the evidence was downgraded due to the small number of participants, high risk of bias in many domains, especially randomisation, allocation, and other sources of bias, and missing outcome data. It is uncertain whether an ethanol lock solution used with concurrent systemic antibiotics improved CRBSI eradication compared to systemic antibiotics alone (RR 1.61, 95% CI 1.16 to 2.23) because the certainty of this evidence is very low. There were no reported differences between the effects of TPA and heparin lock solutions on cure rates (RR 0.92, 95% CI 0.74 to 1.15) or between catheter guidewire exchange versus catheter removal with delayed replacement, expressed as catheter infection-free survival (HR 0.88, 95% CI 0.43 to 1.79). To date, no results are available comparing other interventions. Outcomes such as venous stenosis and/or thrombosis, antibiotic resistance, death, and adverse events were not reported. AUTHORS' CONCLUSIONS: Currently, there is no available high certainty evidence to support one treatment over another for CRBSIs. The benefit of using ethanol lock treatment in combination with systemic antibiotics compared to systemic antibiotics alone for CRBSIs in patients receiving maintenance HD remains uncertain due to the very low certainty of the evidence. Hence, further RCTs to identify the benefits and harms of CRBSI treatment options are needed. Future studies should unify CRBSI and cure definitions and improve methodological design.

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Heparin therapy in COVID-19: Call for randomized controlled trials (RCTs).

Coronavirus disease 2019 (COVID-19) is associated with increases in abnormal coagulation, and particularly D-dimer (D-D) levels. Heparin therapy has been recommended as pharmacologic thromboprophylaxis in patients hospitalized with COVID-19; however, data on its efficacy are lacking. The current study retrospectively analyzed changes in blood coagulation and the impact of heparin therapy. Medical records of 593 patients with confirmed COVID-19 were collected. On admission, elevated fibrinogen (Fg) levels were noted in with 42.2% (250/593) of patients, followed by increases in D-D (28.5%) and a prolonged prothrombin time (PT) (23.9%). Patients with severe/critical COVID-19 had a higher proportion of abnormal coagulation parameters than patients with mild/ordinary COVID-19. Dynamic changes in coagulation parameters were plotted on timeline charts for 97 patients with COVID-19 after heparin treatment. These changes, when combined with Fg, PT, D-D, and other indicators, may provide a relatively comprehensive description of coagulation abnormalities. Heparin seems to be important in the treatment of patients with COVID-19 based on the current findings. The efficacy of heparin in the treatment of COVID-19 should be confirmed by randomized controlled trials (RCTs) as soon as possible.

Comparison of Bivalirudin Versus Unfractionated Heparin for Anticoagulation in Adult Patients on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) contributes to coagulopathy, necessitating systemic anticoagulation to prevent thrombosis. Traditionally, unfractionated heparin (UFH) has been the anticoagulant of choice, however, due to many inadequacies new evidence suggests benefit with the use of direct thrombin inhibitors. This retrospective cohort sought to evaluate the safety and efficacy of bivalirudin compared to UFH in ECMO patients. Primary endpoints included incidence of bleeding and thrombosis. Percent time in therapeutic range (TR), time to achieve TR and number of dose titrations required to maintain TR were calculated to assess efficacy of institutional protocols. Overall incidence of thrombosis was low, with one event in the bivalirudin group and no events in the UFH group. No difference was found in rates of bleeding between groups (6% vs . 10%, P = 0.44). Bivalirudin yielded higher percent time in TR (86% vs. 33%, P < 0.001), faster time to TR (2 vs . 18 hr, P < 0.001) and required fewer dose adjustments to maintain TR (2 vs . 11, P < 0.001) compared to UFH. These results suggest bivalirudin and UFH are associated with similar rates of bleeding and thrombosis in patients requiring ECMO support. Our results demonstrate the favorable pharmacokinetic profile of bivalirudin, and its ability to consistently maintain TR when compared to UFH.

Retroperitoneal Hemorrhage in Patients with COVID-19 Undergoing Hemodialysis: Three Case Reports.

A 73-year-old man receiving hemodialysis and antiplatelets was admitted with a mild case of COVID-19. Heparin was added, and iliopsoas hemorrhage developed. He was successfully treated by interventional radiology. A 76-year-old man receiving hemodialysis and antiplatelets was admitted with mild COVID-19. Heparin was added, and iliacus hemorrhage developed. Despite heparin discontinuation, he died of worsening pneumonia. A 74-year-old man undergoing hemodialysis was admitted with severe COVID-19. Gastrointestinal bleeding developed during continuous hemodiafiltration with heparin. Upon switching to nafamostat and increasing the dose, iliopsoas hemorrhage developed. Despite interventional radiology, he died of infectious complications. Attention to hemorrhagic complications is therefore needed in patients with COVID-19.