The neutralizing effect of heparin on blood-derived antimicrobial compounds: impact on antibacterial activity and inflammatory response.

Acting through a combination of direct and indirect pathogen clearance mechanisms, blood-derived antimicrobial compounds (AMCs) play a pivotal role in innate immunity, safeguarding the host against invading microorganisms. Besides their antimicrobial activity, some AMCs can neutralize endotoxins, preventing their interaction with immune cells and avoiding an excessive inflammatory response. In this study, we aimed to investigate the influence of unfractionated heparin, a polyanionic drug clinically used as anticoagulant, on the endotoxin-neutralizing and antibacterial activity of blood-derived AMCs. Serum samples from healthy donors were pre-incubated with increasing concentrations of heparin for different time periods and tested against pathogenic bacteria (Acinetobacter baumannii, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus) and endotoxins from E. coli, K. pneumoniae, and P. aeruginosa. Heparin dose-dependently decreased the activity of blood-derived AMCs. Consequently, pre-incubation with heparin led to increased activity of LPS and higher values of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Accordingly, higher concentrations of A. baumannii, E. coli, K. pneumoniae, and P. aeruginosa were observed as well. These findings underscore the neutralizing effect of unfractionated heparin on blood-derived AMCs in vitro and may lead to alternative affinity techniques for isolating and characterizing novel AMCs with the potential for clinical translation.

Storage of plasma-derived exosomes: evaluation of anticoagulant use and preserving temperatures.

Exosomes carry large cargo of proteins, lipids, and nucleic acids, serving as versatile biomarkers for disease diagnosis and vehicles for drug delivery. However, up to date, no well recognized standard procedures for exosome storage were available for clinical application. This study aimed to determine the optimal storage conditions and the anticoagulants for plasma-derived exosome isolation. Fresh whole blood samples were collected from healthy participants and preserved in four different anticoagulants including sodium citrate (SC1/4), sodium citrate (SC1/9), lithium heparin (LH), or Ethylenediamine tetraacetic acid (EDTA), respectively. Exosomes were extracted from the plasma by differential ultracentrifugation and stored at three different temperatures, 4°C, -20°C or - 80°C for a duration ranging from one week to six months. All plasma samples for storage conditions comparison were pretreated with LH anticoagulant. Exosome features including morphological characteristics, pariticles size diameter, and surface protein profiles (TSG101, CD63, CD81, CD9, CALNEXIN) were assessed by transmission electron microscopy, Nanoparticle Tracking Analysis, and Western Blotting, respectively. Exosomes preserved in LH and SC1/4 group tended to remain intact microstructure with highly abundant protein biomarkers. Exosomes stored at 4°C for short time were prone to be more stable compared to thos at -80°C. Exosomes stored in plasma were superior in terms of ultrastructure, size diameter and surface protein expression to those stored in PBS. In conclusion, plasma-dervied exosome characteristics strictly depend on the anticoagulants and storage temperature and duration.

What is the context? Effective isolation of exosomes is a prerequisite for subsequent investigation into its involvemnt in disease development as well as potentialtherapeutic applications.Anticoagulants, storage temperature and durations might change the microscopical structure, integrity and also the stability of plasma-derived exosomes. However, no internationally recognized standard of exosome storage procedure was available for clinical use.What is new? Our finding evaluated the effect of anticoagulants and storage on plasma exosome characteristics.Exosomes isolated from plasma preserved with Li-heparin and sodium citrate (1/4) showed better physical properties and surface marker protein expression.Isolated exosomes appeared more stable in a short time for 4°C compared to −80°C. Storage of exosomes in plasma showed better physical properties and surface marker protein expression than in PBS.What is the impact? Our findings inform the significance of standardizing procedure of exosome isolation and preservation.

Unified Methodology for the Primary Preclinical In Vivo Screening of New Anticoagulant Pharmaceutical Agents from Hematophagous Organisms.

The development of novel anticoagulants requires a comprehensive investigational approach that is capable of characterizing different aspects of antithrombotic activity. The necessary experiments include both in vitro assays and studies on animal models. The required in vivo approaches include the assessment of pharmacokinetic and pharmacodynamic profiles and studies of hemorrhagic and antithrombotic effects. Comparison of anticoagulants with different mechanisms of action and administration types requires unification of the experiment scheme and its adaptation to existing laboratory conditions. The rodent thrombosis models in combination with the assessment of hemostasis parameters and hematological analysis are the classic methods for conducting preclinical studies. We report an approach for the comparative study of the activity of different anticoagulants in vivo, including the investigation of pharmacodynamics and the assessment of hemorrhagic effects (tail-cut bleeding model) and pathological thrombus formation (inferior vena cava stenosis model of venous thrombosis). The reproducibility and uniformity of our set of experiments were illustrated on unfractionated heparin and dabigatran etexilate (the most common pharmaceuticals in antithrombic therapy) as comparator drugs and an experimental drug variegin from the tick Amblyomma variegatum. Variegin is notorious since it is a potential analogue of bivalirudin (Angiomax, Novartis AG, Basel, Switzerland), which is now being actively introduced into antithrombotic therapy.

Intestinal obstruction as a result of intra-abdominal hematoma: a complication of low molecular weight heparin in pediatric patients. / Obstrucción intestinal por hematoma intraabdominal: una complicación de la heparina de bajo peso molecular en el paciente pediátrico.

INTRODUCTION: Hematomas are a rare cause of intestinal obstruction. Subcutaneous heparin can bring about direct punctures on small bowel loops, potentially leading to traumatic hematoma and intestinal obstruction. CASE REPORTS: We present three cases of pediatric patients with clinical signs of intestinal obstruction treated with subcutaneous heparin. Two cases had increased acute-phase reactants and radiological signs of intestinal suffering, so surgical treatment was decided upon, with intramural hematoma emerging as an intraoperative finding. The third case was conservatively managed with anticoagulant discontinuation and gut rest, since the patient had an adequate general condition and no findings compatible with ischemia or necrosis were noted in the complementary tests. DISCUSSION: The administration of subcutaneous heparin may cause intestinal wall hematomas due to its anticoagulating effect and to the risk of inadvertent punctures on small bowel loops.

INTRODUCCION: Los hematomas son una causa poco frecuente de obstrucción intestinal. La heparina subcutánea tiene riesgo de producir la punción directa de un asa intestinal, provocando un hematoma traumático que genere una obstrucción intestinal. CASOS CLINICOS: Se describen tres casos de pacientes pediátricos con clínica de obstrucción intestinal en tratamiento con heparina subcutánea. Dos casos presentaron elevación de reactantes de fase aguda y signos radiológicos de sufrimiento intestinal por lo que se optó por tratamiento quirúrgico, con el hallazgo intraoperatorio de hematoma intramural. El tercer caso fue manejado de manera conservadora con supresión de la anticoagulación y reposo intestinal, dado el adecuado estado general y ausencia de hallazgos compatibles con isquemia o necrosis en las pruebas complementarias. COMENTARIOS: La administración de heparina subcutánea puede provocar la aparición de hematomas de pared intestinal, tanto por su efecto anticoagulante, como por el riesgo de punción inadvertida de un asa intestinal.

Unfractionated heparin reverses aspirin inhibition of platelets during coronary artery bypass graft surgery.

Unfractionated heparin (UFH) is an effective antithrombotic during surgery but has known adverse effects, in particular on platelets. A marked increase in platelet responsiveness has previously been observed in patients within minutes of receiving UFH, despite adequate inhibition by aspirin prior to heparin. We studied this phenomenon in patients undergoing cardiac artery bypass grafting (n = 17) to determine whether the effects of heparin were systemic or platelet-specific. All patients' platelets were fully inhibited by aspirin prior to surgery, but within 3 min of receiving heparin spontaneous aggregation and responses to arachidonic acid (AA) and ADP increased significantly (p ≥ 0.0002), and activated platelets were found in the circulation. While there was no rise in thromboxane in the plasma following heparin, levels of the major platelet 12-lipoxygenase product, 12-HETE, rose significantly. Mixing experiments demonstrated that the changes caused by heparin resided primarily in the platelets, while addition of AA pathway inhibitors, and analysis of oxylipins provided evidence that, following heparin, aggregating platelets regained their ability to synthesise thromboxane. These findings highlight potentially unrecognised pro-thrombotic and pro-inflammatory changes during CABG surgery, and provide further evidence of adverse effects associated with UFH.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

BACKGROUND: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. DESIGN: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DISCUSSION: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. CONCLUSION: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Anaesthesiologic Considerations for Intraoperative ECMO Anticoagulation During Lung Transplantation: A Single-Centre, Retrospective, Observational Study.

Background: Extracorporeal membrane oxygenation (ECMO) is frequently used during lung transplantation. Unfractionated heparin (UFH) is mainly used as part of ECMO support for anticoagulation. One of the most common perioperative complications is bleeding, which high-dose UFH can aggravate. Methods: We retrospectively analyzed (n = 141) patients who underwent lung transplantation between 2020 and 2022. All subjects (n = 109) underwent central cannulated VA ECMO with successful intraoperative ECMO weaning. Patients on ECMO bridge, postoperative ECMO, heart-lung transplants and transplants without ECMO were excluded. The dose of UFH for the entire surgical procedure, blood loss and consumption of blood derivatives intraoperatively and 48 h after ICU admission were recorded. Surgical revision for postoperative bleeding were analyzed. Thrombotic complications, mortality and long-term survival were evaluated. Results: Lower doses of UFH administered for intraoperative ECMO anticoagulation contribute to a reduction in intraoperative blood derivates consumption and blood loss with no thrombotic complications related to the patient or the ECMO circuit. Lower doses of UFH may lead to a decreased incidence of surgical revision for hemothorax. Conclusion: Lower doses of UFH as part of intraoperative ECMO anticoagulation might reduce the incidence of complications and lead to better postoperative outcomes.

Heparin-free veno-arterial extracorporeal membrane oxygenation in lung transplantation: a retrospective cohort study.

BACKGROUND: In lung transplantation (LTx) surgery, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide mechanical circulatory support to patients with cardiopulmonary failure. However, the use of heparin in the administration of ECMO can increase blood loss during LTx. This study aimed to evaluate the safety of heparin-free V-A ECMO strategies. METHODS: From September 2019 to April 2022, patients who underwent lung transplantation at the First Affiliated Hospital of Guangzhou Medical University were retrospectively reviewed. A total of 229 patients were included, including 117 patients in the ECMO group and 112 in the non-ECMO group. RESULT: There was no significant difference in the incidence of thrombus events and bleeding requiring reoperation between the two groups. The in-hospital survival rate after single lung transplantation (SLTx) was 81.08%in the ECMO group and 85.14% in the Non-ECMO group, (P = 0.585). The in-hospital survival rate after double lung transplantation (DLTx) was 80.00% in the ECMO group and 92.11% in the Non-ECMO groups (P = 0.095). CONCLUSIONS: In conclusion, the findings of this study suggest that the heparin-free V-A ECMO strategy in lung transplantation is a safe approach that does not increase the incidence of perioperative thrombotic events or bleeding requiring reoperation.

Heparin-induced DRESS syndrome in a paediatric patient and successful anaesthetic management in cardiovascular bypass surgery: case report.

BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin. CASE PRESENTATION: We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia. CONCLUSION: The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.

Alpha gal syndrome, a relative not absolute contraindication to the use of bovine pericardium to close an intracardiac septal defect: a case report.

BACKGROUND: Alpha-gal syndrome is an allergic condition in which individuals develop an immune-mediated hypersensitivity response when consuming red meat and its derived products. Its diagnosis is important in individuals undergoing cardiac surgery, as patients frequently require large doses of unfractionated heparin or the insertion of surgical implants, both of which are porcine or bovine in origin. There are currently no guidelines for heparin administration in alpha-gal patients, with even less knowledge regarding the long-term clinical implications of these patients after receiving bioprosthetic valve replacements or other prostheses. CASE PRESENTATION: We present the case of a 31-year-old male who underwent cardiac surgery in the setting of alpha-gal syndrome for a large atrial septal defect (ASD) and mitral valve prolapse (MVP). The patient continues to do well one year after undergoing a mitral valve repair, tricuspid valve repair and an ASD closure using bovine pericardium. He sustained no adverse reaction to the use of heparin products or the presence of a bovine pericardial patch. This rare case was managed by a multidisciplinary team consisting of cardiothoracic surgery, cardiac anesthesiology, and allergy/immunology that led to an optimal outcome despite the patient's pertinent allergic history. CONCLUSIONS: This case highlights that the use of bovine pericardium and porcine heparin to close septal defects in patients with milder forms of alpha-gal allergy can be considered if other options are not available. Further studies are warranted to investigate the long-term outcomes of such potential alpha-gal containing prostheses and heparin exposure and establish the optimal decision making algorithm and prophylactic regimen.

Chlorpromazine-Polypyrrole Drug Delivery System Tailored for Neurological Application.

Nowadays, drug delivery systems (DDSs) are gaining more and more attention. Conducting polymers (CPs) are efficiently used for DDS construction as such systems can be used in therapy. In this research, a well-known CP, polypyrrole (PPy), was synthesized in the presence of the polysaccharide heparin (HEP) and chlorpromazine (CPZ) using sodium dodecyl sulfate (SDS) as electrolyte on a steel substrate. The obtained results demonstrate the successful incorporation of CPZ and HEP into the polymer matrix, with the deposited films maintaining stable electrochemical parameters across multiple doping/dedoping cycles. Surface roughness, estimated via AFM analysis, revealed a correlation with layer thickness-decreasing for thinner layers and increasing for thicker ones. Moreover, SEM images revealed a change in the morphology of PPy films when PPy is electropolymerized in the presence of CPZ and HEP, while FTIR confirmed the presence of CPZ and HEP within PPy. Due to its lower molecular mass compared to HEP, CPZ was readily integrated into the thin polymer matrix during deposition, with diffusion being unimpeded, as opposed to films with greater thickness. Finally, the resulting system exhibited the ability to release CPZ, enabling a dosing range of 10 mg to 20 mg per day, effectively covering the therapeutic concentration range.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

A Case Report of Pulmonary Embolectomy Under Cardiopulmonary Bypass in a Patient with Intracranial Hemorrhage and History of Heparin-Induced Thrombocytopenia.

Pulmonary embolism is a common complication after intracranial hemorrhage. As thrombolysis is contraindicated in this situation, surgical pulmonary embolectomy may be indicated in case of high-risk pulmonary embolism but requires transient anticoagulation with heparin during cardiopulmonary bypass. We report the case of a patient with a history of heparin-induced thrombocytopenia who presented with a high-risk pulmonary embolism 10 days after the spontaneous onset of a voluminous intracerebral hematoma. Despite high doses of heparin required to run the cardiopulmonary bypass and subsequent anticoagulation by danaparoid sodium, the brain hematoma remained stable and the patient was discharged without complications 30 days after surgery.

Antiplatelets versus anticoagulants in the treatment of blunt cerebrovascular injury (BCVI) - A systematic review and meta-analysis.

INTRODUCTION: Blunt cerebrovascular injury (BCVI) occurs in 1-3% of blunt traumas and is associated with stroke, disability, and mortality if unrecognized and untreated. Early detection and treatment are imperative to reduce the risk of stroke, however, there is significant variation amongst centers and trauma care providers in the specific medical management strategy used. This study compares antiplatelets vs. anticoagulants to determine BCVI-related stroke risk and bleeding complications to better understand the efficacy and safety of various treatment strategies. METHODS: A systematic review of MEDLINE, Embase, and Cochrane CENTRAL databases was conducted with the assistance of a medical librarian. The search was supplemented with manual review of the literature. Included studies reported treatment-stratified risk of stroke following BCVI. All studies were screened independently by two reviewers, and data was extracted in duplicate. Meta-analysis was conducted using pooled estimates of odds ratios (OR) with a random-effects model using Mantel-Haenszel methods. RESULTS: A total of 3315 studies screened yielded 39 studies for inclusion, evaluating 6552 patients (range 8 - 920 per study) with a total of 7643 BCVI. Stroke rates ranged from 0% to 32.8%. Amongst studies included in the meta-analysis, there were a total of 405 strokes, with 144 (35.5%) occurring on therapy, for a total stroke rate of 4.5 %. Meta-analysis showed that stroke rate after BCVI was lower for patients treated with antiplatelets vs. anticoagulants (OR 0.57; 95% CI 0.33-0.96, p = 0.04); when evaluating only the 9 studies specifically comparing ASA to heparin, the stroke rate was similar between groups (OR 0.43; 95% CI 0.15-1.20, p = 0.11). Eleven studies evaluated bleeding complications and demonstrated lower risk of bleeding with antiplatelets vs. anticoagulants (OR 0.29; 95% CI 0.13-0.63, p = 0.002); 5 studies evaluating risk of bleeding complications with ASA vs. heparin showed lower rates of bleeding complications with ASA (OR 0.16; 95% CI 0.04-0.58, p = 0.005). CONCLUSIONS: Treatment of patients with BCVI with antiplatelets is associated with lower risks of stroke and bleeding complications compared to treatment with anticoagulants. Use of ASA vs. heparin specifically was not associated with differences in stroke risk, however, patients treated with ASA had fewer bleeding complications. Based on this evidence, antiplatelets should be the preferred treatment strategy for patients with BCVI.

Anticoagulation with argatroban using hemoclot™ targets is safe and effective in CARDS patients receiving venovenous extracorporeal membrane oxygenation: An exploratory bi-centric cohort study.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH). METHODS: This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 µg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range). RESULTS: From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45). CONCLUSION: Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 µg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.