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Background: Anticoagulants, including warfarin and direct oral anticoagulants (DOACs), are used to prevent and treat venous thromboembolism (VTE) which is common in patients with obesity. Guidance statements regarding use of DOACs for VTE treatment in this patient population have been updated., Objective: Examine DOAC prescribing trends in patients with obesity and VTE., Methods: We performed a retrospective, single-site cross-sequential study of DOAC prescribing trends in adult patients with obesity (BMI ≥30) and objectively confirmed VTE diagnosis between 2014 and 2022. The primary outcome of interest was the proportion of patients with obesity prescribed DOACs., Results: A total of 1826 patients were included in our analysis. Most patients were of White race (85.8 %) and approximately half were female. Pulmonary embolism was the most common VTE type (62.2 %). A total of 1018 patients were prescribed DOAC therapy (55.8 %), 524 warfarin therapy (28.7 %), and 284 enoxaparin (15.6 %). Logistic regression analysis revealed that the utilization of DOACs exhibited a significant upward trend from 2017 to 2022 (odds ratio [OR] 1.85 to 14.08 compared to 2014), but not from 2015 to 2016 (OR 1.30 to 1.52). Patients with BMI ≥ 40 and ≥ 50 were twice and 4-times as likely to be prescribed warfarin than DOACs, respectively., Conclusion: Between 2017 and 2022, the proportion of patients with obesity prescribed DOACs for the treatment of VTE increased significantly. This suggests an increasing likelihood to prescribe DOACs in this patient population despite the lack of safety and efficacy data from randomized controlled trials except for very heavy patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel M. Witt reports a relationship with the Agency for Healthcare Research and Quality that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The purpose of this study was to describe the enoxaparin dose required by preterm neonates and infants to achieve therapeutic anti-Xa levels., Study Design: Retrospective chart review of preterm infants, <12 weeks postnatal age, born before 37 weeks gestation, receiving subcutaneous (SUBQ) enoxaparin every 12 h (q12h) with an anti-Xa goal of 0.5-1 units/mL. The primary endpoint was the enoxaparin dose required to achieve a therapeutic anti-Xa level. Secondary endpoints included initial enoxaparin dose and the frequency of achieving therapeutic anti-Xa levels with the initial dose, index thrombus progression, formation of new thrombi, and suspected or confirmed bleeding., Results: Fifty-six patients were included for analysis. At time of enoxaparin initiation, the median gestational age, post-menstrual age, and weight were 34 weeks and 2 days, 38 weeks and 4 days, and 2.5 kg (kg), respectively. The median dose required to achieve a therapeutic anti-Xa was 2 mg/kg (IQR 1.7-2.6 mg/kg) SUBQ q12h. The median initial enoxaparin dose of 1.7 mg/kg SUBQ q12h aligned with formulary recommendations. Twenty-three patients (41 %) achieved a therapeutic anti-Xa with the initial dose. Follow-up ultrasounds were available for 38 patients, of which 3 (8 %) showed progression of the index thrombus and 5 (13 %) showed formation of a new thrombus. One patient discontinued enoxaparin due to pulmonary hemorrhage, necessitating protamine administration., Conclusions: Preterm neonates appear to require a median enoxaparin dose of 2 mg/kg subcutaneously every 12 h to achieve therapeutic anti-Xa levels., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hilary Whitworth is supported by the National Hemophilia Foundation-Takeda Clinical Fellowship. Christopher Thom is supported by the National Institutes of Health (K99HL156052). All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Anticoagulants have consistently emerged as the leading cause of adverse drug events in both inpatient and outpatient settings. While literature on anticoagulation stewardship programs (ACSP) exists for hospital settings, there is a paucity of data in long-term care and rehabilitation settings., Objective: Assess the feasibility of a pharmacist led ACSP in the ambulatory healthcare settings of long-term care facilities (LTC) and rehabilitation centers (RC)., Methods: We conducted a prospective pilot project in 3 rehabilitation centers and 7 long-term care facilities. Patients were selected over 5 months in 2023. Patient and anticoagulant prescription-related characteristics were collected. The primary feasibility outcome was the proportion of anticoagulant prescription reviews leading to a pharmacist intervention., Results: A total of 411 patients were enrolled. Common indications for anticoagulants were atrial fibrillation (n = 255, 62.0 %), medical thromboprophylaxis (n = 52, 12.7 %) and venous thromboembolism (n = 53, 12.9 %). Direct oral anticoagulants (DOAC) were most frequently prescribed (n = 309, 75.2 %). Of 411 prescription reviews, 93 led to at least one intervention (22.6 %), for a total of 100 interventions. Interventions mainly concerned laboratory ordering (n = 29) and DOAC dose adjustment (n = 24). Baseline anticoagulant characteristics and outcomes varied by healthcare setting., Conclusion: Expanding ACSP into outpatient LTC and RC settings is feasible. ACSP should include both therapeutic and thromboprophylactic anticoagulants. Additional research is warranted to evaluate the viability of ongoing ACSP monitoring, and more extensive prospective studies are required to assess clinical outcomes effectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ryan S. Kerzner reports a relationship with Pfizer Canada Inc. that includes: consulting or advisory. Ryan S. Kerzner reports a relationship with Valeo Pharma Inc. that includes: speaking and lecture fees. Ryan S. Kerzner reports a relationship with LEO Pharma Inc. that includes: speaking and lecture fees. Vincent Dagenais-Beaule reports a relationship with Quebec National Institute of Excellence in Health and Social Services that includes: consulting or advisory. Vincent Dagenais-Beaule reports a relationship with AbbVie Inc. that includes: consulting or advisory and speaking and lecture fees. Vincent Dagenais-Beaule reports a relationship with HLS Therapeutics Inc. that includes: consulting or advisory and speaking and lecture fees. Vincent Dagenais-Beaule reports a relationship with Otsuka Pharmaceutical Co Ltd. that includes: consulting or advisory and speaking and lecture fees. Vincent Dagenais-Beaule reports a relationship with Association des Pharmaciens en Établissement de Santé du Québec that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Guidelines recommend considering percutaneous left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) at moderate to high stroke risk and contraindications to long-term anticoagulation. Discontinuation of anticoagulation in this patient population, without an alternative treatment option, may place patients at unnecessary risk. This study aimed to assess the prevalence of discussions around LAAO as a treatment option following major bleeding adverse events in patients on oral anticoagulation for AF and to identify the proportion of patients stopping anticoagulation without evidence of LAAO discussions., Methods: From a single, large medical center in the United States, patients on an oral anticoagulant for AF and having at least one major bleeding adverse event, defined by the International Society on Thrombosis and Haemostasis, between January 2015 and October 2023 were identified within a quality improvement registry. Information about LAAO discussions, subsequent procedures, and permanent discontinuation of anticoagulation was assessed using the Electronic Medical Record Search Engine and manual electronic medical record reviews., Results: A total of 222 patients experienced major bleeding (54.5 % male, 86.9 % white, median age 77 years, 58.6 % on warfarin). From this group, 283 major bleeds were documented (44.2 % gastrointestinal, 17.7 % intracranial). LAAO discussions were documented in 51 patients (23 %), with LAAO procedures performed in 9 of these patients (17.6 %). After the major bleed, 54 (24.3 %) patients permanently stopped anticoagulation. Of these patients, 18 (33.3 %) had LAAO discussions prior to discontinuation and only 1 (1.9 %) had LAAO implantation., Conclusions: In patients experiencing a major bleed, less than a quarter had documented discussions about LAAO and over a quarter permanently stopped anticoagulation., Competing Interests: Declaration of competing interest Deborah DeCamillo reports financial support was provided by the Blue Cross Blue Shield of Michigan Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The clinical presentation, outcomes, and anticoagulation strategies in patients with lung cancer-associated isolated distal deep vein thrombosis (LC-iDDVT) are not well-defined., Materials and Methods: The study included 593 patients with LC-iDDVT and 260 patients with lung cancer-associated proximal DVT (LC-Proximal DVT). LC-iDDVT was further classified into axial venous thrombosis (AVT; 112 patients) and muscular venous thrombosis (MVT; 481 patients). Cox proportional risk regression models with Fine-Gray tests and competing risk models were employed to evaluate short-term (90-day) and long-term (1-year) outcomes (hazard ratio [HR]; 95 % confidence intervals [CI])., Results: At the 90-day follow-up, patients with MVT had lower adjusted risks of pulmonary embolism (PE; HR = 0.20 [0.07-0.55], p = 0.002) and venous thromboembolism (VTE) recurrence (HR = 0.54 [0.34-0.88], p = 0.013) than those with LC-Proximal DVT. Similar results were observed at the 1-year follow-up. However, adjusted risks for PE (HR = 0.74 [0.29-1.92], p = 0.540; HR = 0.87 [0.42-1.78], p = 0.700) and VTE recurrence (HR = 0.96 (0.54-1.71), p = 0.890; HR = 0.99 [0.63-1.56], p = 0.970) at 90-day and 1-year were not significantly different between patients with AVT and those with LC-Proximal DVT. Among patients with LC-iDDVT, those receiving anticoagulation had reduced risks of VTE recurrence (HR = 0.57 [0.35-0.95], p = 0.030) and DVT deterioration (HR = 0.28 [0.13-0.60], p = 0.001) compared to those without anticoagulation. Moreover, AVT patients on >3 months of anticoagulation had a lower VTE recurrence risk (HR = 0.23 [0.03-0.92], p = 0.038) than those on ≤3 months of anticoagulation., Conclusion: In the context of lung cancer, patients with AVT may have a higher tendency for recurrent thrombosis compared to those with MVT, especially if anticoagulation is refused or given briefly., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Iliac vein stenting is an effective treatment for iliac venous stenosis after percutaneous mechanical thrombectomy. Nevertheless, while some researchers have investigated medical therapy following iliac vein stenting, no consensus has been reached to date., Objectives: To evaluate the effectiveness and safety of anticoagulation plus antiplatelet therapy following iliac vein stent implantation in patients with acute and subacute iliofemoral deep vein thrombosis (DVT)., Materials and Methods: This retrospective study comprised 234 patients: 167 patients in Group 1 with a mean age of 64.3 ± 13.5 years received anticoagulants alone, and 67 patients in Group 2 with a mean age of 60.7 ± 15.4 years received anticoagulation plus antiplatelet therapy. All patients received technically successful percutaneous pharmacomechanical thrombectomy and iliac vein stent implantation, and 61 patients underwent additional catheter-directed thrombolysis. The two groups exhibited comparable demographics, comorbidities, DVT burdens, and procedural details. Through propensity score matching (PSM) analysis, 62 pairs of patients from Group 1 and Group 2 were matched., Results: During a follow-up period of 33.7 ± 16.5 months, the cumulative primary patency rates were 95.1 %, 89.7 % and 88.3 % at one, three and five years in Group 1 compared to 98.8 %, 98.5 % and 98.5 % in Group 2 for the entire cohort (p = 0.042); in the PSM analysis, the rates were 91.9 %, 87.3 % and 87.3 % at one, three and five years in Group 1 versus 98.4 % at one, three and five years in Group 2 (p = 0.039). The cumulative bleeding-free rate was 98.2 % at one, three and five years in Group 1 versus 95.5 %, 93.8 % and 93.8 % at one, three and five years in Group 2 for the entire cohort (p = 0.089), and it was 98.4 % at one, three and five years in Group 1 versus 95.2 %, 93.3 % and 93.3 % (p = 0.156) at one, three and five years in Group 2 in the PSM analysis., Conclusion: Anticoagulation plus antiplatelet therapy significantly improved stent patency, with a non-significant increase in the bleeding rate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Mortality and changes in treatment options for disseminated intravascular coagulation (DIC) are trending downward. This study investigated temporal trends in mortality and treatment preferences of several anticoagulants in Japan., Methods: This retrospective observational study used the Japanese Diagnosis Procedure Combination inpatient database containing data from >1500 acute-care Japanese hospitals. All adult patients diagnosed as having DIC from July 2010 to March 2022 were sorted by predefined underlying conditions: sepsis, solid cancer, leukemia, trauma, or obstetric. We evaluated in-hospital mortality and clinical status of anticoagulant use for DIC treatment., Results: Baseline characteristics of the 443,098 DIC patients showed increased age, worsened comorbid conditions, and higher illness severity over time. Over the 12 years, in-hospital mortality for overall DIC patients declined by 17 % from 42.0 % (95 % CI 41.4-42.5 %) to 34.7 % (95 % CI 34.1-35.3 %) (P trend  < 0.001). This downward decrease was more evident in patients with sepsis (17 %), solid cancer (18 %), and leukemia (22 %) but was not clinically meaningful in trauma and obstetrics patients. The trend in treatment preferences of anticoagulants for DIC patients also changed. Recombinant thrombomodulin administration increased dramatically from 2011 to 2015 and remained high through 2021. Only 7 % of DIC patients were administered antithrombin and recombinant thrombomodulin concomitantly, and its use continues to decline., Conclusions: All-cause in-hospital mortality for DIC patients clearly decrease by 17 % over the study period. Anticoagulant therapy for patients with DIC has been decreasing, possibly due to recent published clinical evidence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kazuma Yamakawa reports a relationship with Asahi Kasei Pharma Corporation that includes: funding grants. Kazuma Yamakawa reports a relationship with Japan Blood Products Organisation that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Patients with cancer have an increased risk of developing venous thromboembolism (VTE) but also have an increased risk of both recurrent VTE and bleeding with anticoagulation compared to anticoagulated patients without cancer. CANVAS, a randomized pragmatic effectiveness trial, compared the direct oral anticoagulants a class to low molecular weight heparin for treatment of a new VTE in patients with cancer. The aim of this prespecified secondary analysis of the CANVAS trial is to identify predictors of both recurrent VTE and major bleeding in patients with cancer and new VTE., Methods: Data from the 671 participants in the analysis population were used to identify predictors of recurrent VTE and bleeding during the 6-month treatment period. Significant predictors identified in the univariable models were carried forward in the multivariable models to identify independent predictors of both risks., Results: Independent predictors of recurrent VTE include ECOG performance status ≥2 (HR, 3.19 [95 % CI, 1.45-7.02]; P < .005), presence of metastatic disease (HR, 2.57 [95 % CI, 1.14-5.80]; P = .023), treatment with bevacizumab (HR, 2.50 [95 % CI, 1.04-5.99]; P = .041), and deep vein thrombosis without pulmonary embolus as index VTE (HR, 1.86 [95 % CI, 1.04-3.33]; P = .037). Independent predictors of major bleeding include serum albumin <3.5 g/dL (HR 1.97 [95 % CI, 1.02-3.79]; P = .044) and metastatic disease (HR 2.80 [95 % CI, 1.08-7.22]; P = .034)., Conclusion: Findings from this pre-specified analysis of the CANVAS trial identified risk factors for recurrent VTE and major bleeding in a population of participants with cancer and new VTE that reflect current oncology clinical practice. Results can be used to identify at risk patients in practice and inform new risk prediction models to improve the care of these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jean Connors reports financial support was provided by Patient-Centered Outcomes Research Institute. Jean Connors reports administrative support was provided by Alliance for Clinical Trials in Oncology Foundation. Jean Connors reports a relationship with Abbott that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Anthos that includes: board membership and consulting or advisory. Jean Connors reports a relationship with BMS that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Janssen that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Pfizer that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Perosphere that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Roche that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Sanofi that includes: board membership and consulting or advisory. Jean Connors reports a relationship with Werfen that includes: board membership and consulting or advisory. Jean Connors reports a relationship with CSL Behring that includes: funding grants. Deborah Schrag reports a relationship with JAMA that includes: consulting or advisory. Deborah Schrag reports a relationship with Swiss Re Management Ltd that includes: consulting or advisory. Deborah Schrag reports a relationship with Merck that includes: equity or stocks. Deborah Schrag reports a relationship with AACR that includes: funding grants. Deborah Schrag reports a relationship with Grail that includes: funding grants. Deborah Schrag has intellectual property. Specifically, the PRISSMM model is trademarked and curation tools are available to academic medical centers and government under creative commons license. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The risk of intracranial bleeding during anticoagulation for venous thromboembolism (VTE) is substantial and persists beyond the initial treatment phase. We aimed to refine risk-assessment through phase-specific prognostic scores., Methods: We identified data from 77,786 VTE patients in the RIETE registry from March 2009 to October 2023 to develop two prognostic scores for intracranial bleeding. Multivariable Cox regression was used to analyze distinct variables for the early (≤90 days) and late (>90 days) phases, with comparative validation against existing scores (modified ACCP, RIETE, VTE-BLEED, and CHAP)., Results: Intracranial bleeding occurred in 411 patients (0.53 %), with 208 cases in the early phase and 203 in the late phase. The 30-day mortality was 45 % and 35 %, respectively. Shared significant predictors for both phases include baseline abnormal mental status, brain cancer, recent intracranial bleeding, and epilepsy. Unique to early-phase bleeding were body weight, non-brain cancer, hypertension, dementia, thrombocytopenia, renal insufficiency, and thrombolytic therapy. Advanced age, pulmonary embolism initially, prior stroke, depression, treatment with direct oral anticoagulants, and use of corticosteroids predicted late-phase bleeding. Both prognostic scores showed a c-statistic of 0.68, outperforming existing scores., Conclusions: The study introduces two temporal prognostic scores for intracranial bleeding during anticoagulation for VTE. By discerning specific risk factors pertinent to each treatment phase, these scores outperform traditional models, offering an advanced tool for clinical decision-making. They hold significant potential for optimizing anticoagulation management and reducing bleeding-related mortality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Randomized controlled trials suggest that prophylactic doses of anticoagulants effectively prevent venous thromboembolism (VTE) in hospitalized medical patients with high thromboembolic risk. However, no prospective studies exist regarding the real-world prevalence of prophylactic anticoagulant use. This prospective study aimed to determine the rate and predictors of thromboprophylaxis in an unselected population of patients hospitalized in medical departments., Methods: We conducted a multicenter prospective observational study (AURELIO - rAte of venous thrombosis in acutely iLl patIents hOspitalized) to assess the rate of deep vein thrombosis (DVT) in unselected acutely ill patients hospitalized in medical wards using compression ultrasound (CUS) at admission and discharge. Additionally, we evaluated the rate of pharmacological thromboprophylaxis administration in this population and analyzed the thrombotic risk by assessing RAMs (Risk Assessment Models) such as the IMPROVE-VTE and PADUA scores following the clinician's decision to administer thromboprophylaxis. Patients with IMPROVE-VTE scores ≥3 and/or PADUA scores ≥4 were classified as high thrombotic risk; those with IMPROVE-VTE scores <3 and/or PADUA scores <4 were classified as low risk., Results: We recruited 2371 patients (1233 males [52 %] and 1138 females [48 %]; mean age 72 ± 16 years). The median length of hospitalization was 13 ± 12 days. Overall, 442/2371 (18.6 %) patients received prophylactic parenteral anticoagulants (subcutaneous low weight molecular heparin or fondaparinux once daily) at admission. Assessing the thrombotic risk of the population recruited 1016 (42.9 %) patients were classified as high risk and 1354 (57.1 %) were low risk. Among high-risk patients, 339/1016 (33.4 %) received anticoagulant prophylaxis compared to 103/1354 (7.6 %) low-risk patients. During hospitalization, 9 patients developed DVT, comprising 7 asymptomatic and 2 symptomatic cases of proximal DVT. Of these, 3 patients were on anticoagulant prophylaxis, while 6 were not. Among the high-risk population, 7 out of 1016 patients (0.7 %) experienced proximal DVT during hospitalization, with 2 out of these 7 (28 %) receiving anticoagulant thromboprophylaxis. In the low-risk population, 2 out of 1354 patients (0.2 %) developed DVT, with 1 out of these 2 (50 %) receiving anticoagulant thromboprophylaxis. Age, heart or respiratory failure, pneumonia, active neoplasia, previous VTE, reduced mobility, and absence of kidney failure were more frequent in patients receiving prophylaxis. Multivariable logistic regression identified age (RR 1.010; CI 95 % 1002-1019; p = 0.015), heart/respiratory failure (RR 1.609; CI 95 % 1248-2075; p < 0.0001), active neoplasia (RR 2.041; CI 95 % 1222-2141; p < 0.0001), pneumonia (RR 1.618; CI 95 % 1557-2676; p < 0.0001), previous VTE (RR 1.954; CI 95 % 1222-3125; p < 0.0001), and reduced mobility (RR 4.674; CI 95 % 3700-5905; p < 0.0001) as independent predictors of thromboprophylaxis., Conclusions: This study, conducted without pre-established thromboembolic risk scores, offers a comprehensive view of venous thromboembolism prophylaxis in medical patients with acute conditions hospitalized in internal medicine departments. It reveals that advanced age, heart or respiratory failure, active cancer, pneumonia, previous VTE, and reduced mobility are predictors that may influence the decision to administer thromboprophylaxis in these patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Anticoagulation was once recommended for patients with pulmonary arterial hypertension (PAH). However, its survival benefit still remained controversial. We performed a meta-analysis to evaluate the effect of anticoagulation on the long-term survival of PAH patients., Methods: The PubMed, EMBASE, Web of Science, and WanFang electronic database were searched for eligible studies. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated for effect estimate regarding anticoagulation on the survival of PAH patients., Results: Fifteen cohort studies involving 4266 PAH patients were included. Approximately 45.8 % patients received anticoagulation. The mean follow-up period ranged from 2.1 to 14 years. Anticoagulation had a tendency to, however, did not significantly reduce mortality of PAH patients (HR: 0.86, 95 % CI: 0.73-1.02). In subgroup analysis, anticoagulation decreased the mortality risk as analyzed from retrospective studies (HR: 0.80, 95 % CI: 0.65-0.98), but not prospective studies (HR: 0.95, 95 % CI: 0.70-1.29). For both idiopathic PAH (IPAH) and connective tissue disease associated PAH (CTD-PAH), anticoagulation therapy did not significantly improve the long-term survival rate (HR: 0.83, 95 % CI: 0.65-1.07, and HR: 1.05, 95 % CI: 0.77-1.42, respectively), and this result remained unchanged when pooling data from either retrospective or prospective studies. Further analysis showed that anticoagulation had no advantage in reducing mortality in patients with systemic sclerosis associated PAH, systemic erythematosus lupus related PAH (free of antiphospholipid syndrome), or CTD-PAH of non-specified etiology., Conclusion: Anticoagulation may not reduce the long-term mortality of PAH patients, including those with IPAH and CTD-PAH. In the management of PAH, anticoagulants should be prescribed with caution before comprehensive risk to benefit evaluation. Larger and more vigorously designed controlled trials are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: SARS-CoV-2 (COVID-19) infection and multisystem inflammatory syndrome in children (MIS-C) are risk factors for venous thromboembolism (VTE). Guidelines for VTE prophylaxis were established at our institution at the beginning of the pandemic. Patients who had any VTE risk factors in addition to COVID-19 met criteria for anticoagulation prophylaxis. Patients who were diagnosed with MIS-C met criteria regardless of additional risk factors., Materials and Methods: We conducted a retrospective review of patients admitted with COVID-19 or MIS-C to determine compliance with VTE prophylaxis guidelines and to evaluate the incidence of VTE and bleeding events in our population., Results and Conclusions: Among a total of 678 patients admitted with COVID-19 or MIS-C, 519 (76 %) patients met criteria for VTE prophylaxis and 348 (65.6 %) started prophylaxis. Logistic regression analysis identified a personal or family history of thrombosis or thrombophilia, diagnosis of MIS-C, admission to the intensive care unit, and presence of a central venous catheter as significantly associated with starting VTE prophylaxis. There were 18 patients who developed VTE. Minor bleeding events occurred in 19 patients (5 %), patient important bleeding, no intervention occurred in 8 patients (2 %), clinically relevant nonmajor bleeding in 8 patients (2 %), and major bleeding in 10 patients (3 %). The incidence of VTE in our patients with COVID-19 and MIS-C is similar to VTE rates at other institutions. We found that universally recognized VTE risk factors were appropriate to include as risk factors for thrombosis in hospitalized children with COVID-19 and MIS-C., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren Amos reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Lauren Amos reports a relationship with HemaBiologics that includes: consulting or advisory. Lauren Amos reports a relationship with Genentech that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The risk of venous thromboembolism (VTE) is 15 to 35-fold higher in the postpartum period compared to non-pregnant individuals. Clinical practice guidelines recommend the use of postpartum thromboprophylaxis with low molecular weight heparin (LMWH) for 6 weeks in individuals at high risk of developing VTE. However, a marked reduction in the risk of VTE risk occurs beyond the third week of the postpartum period., Objective: We sought to characterize practice patterns of clinicians who manage postpartum individuals at high risk of VTE., Methods: We conducted a cross-sectional study using a self-administered electronic questionnaire. The survey explored the use of postpartum thromboprophylaxis in high-risk individuals. Descriptive statistics were used to summarize survey responses., Results: Of the 113 participants that responded to the initial invitation, 78 completed the survey (Europe (53.9 %); North America (23.2 %); Australia and New Zealand (19.0 %)). For individuals with a prior unprovoked or provoked deep venous thrombosis or pulmonary embolism, cerebral vein thrombosis and splanchnic vein thrombosis, 97.4 %, 93.5 %, 91.0 % and 88.5 % of the respondents recommended six weeks of postpartum thromboprophylaxis using LMWH, respectively. The recommendation for 6 weeks of thromboprophylaxis in patients with sickle cell disease and obstetric APS was comparatively lower (70.5 and 78.2 % respectively). Respondents with higher practice volumes and more years of experience in clinical practice were more likely to recommend a shorter duration of thromboprophylaxis., Conclusion: Our study highlights the variability in clinician recommendations and the acceptability of treatment durations for postpartum thromboprophylaxis in high-risk conditions. Prospective studies are needed to determine optimal duration and establish evidence-based management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many patients with impaired renal function have concurrent indications for anticoagulant therapy, including atrial fibrillation and venous thromboembolism. For mild chronic kidney disease, data from clinical trials and existing guidelines can be applied to clinical management. The benefits and harms of anticoagulation therapy in patients with more advanced renal impairment are nuanced, as both thrombotic and bleeding risk are increased. Until recently, data regarding anticoagulants in severe renal impairment were primarily observational, but emerging evidence includes a few small clinical trials and the emergence of novel agents hypothesized to have improved efficacy and safety in this population. In this review, we summarize existing data on anticoagulation in patients with chronic kidney disease. We suggest a framework for anticoagulation decision-making in the burgeoning worldwide population of patients with chronic kidney disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Portal vein thrombosis in cirrhotic patients presents a significant clinical challenge. This study aims to (1) explore the impact of anticoagulation therapy on patient outcomes; (2) comparative outcomes in portal vein thrombosis treated between direct oral anticoagulant and Vitamin K Antagonist (VKA)., Materials and Methods: We leveraged the TriNetX database to analyze a cohort comprising 4224 patients with liver cirrhosis and PVT who were treated with anticoagulation, alongside a comparison group of 15,300 patients with the same conditions but not receiving anticoagulation therapy., Results: The anticoagulated group showed a significant reduction in mortality (27.9 % vs. 34.2 %, HR = 0.723, 95 % CI: 0.678-0.770, P < 0.001). When comparing direct oral anticoagulant versus. VKA, in compensated liver cirrhosis, the direct oral anticoagulant group exhibited significantly lower mortality rates compared to VKA (17.7 % vs. 26.5 %, HR = 0.655, 95 % CI: 0.452-0.951, P = 0.025), with no significant difference in liver transplantation rates (4.0 % vs. 4.7 %, P = 0.080). In decompensated liver cirrhosis, the direct oral anticoagulant group exhibited lower mortality compared to the VKA group (23.6 % vs. 30.6 %, HR = 0.732, 95 % CI: 0.629-0.851, P < 0.001), and a higher frequency of liver transplantation was observed in the VKA group (10.6 % vs. 16.0 %, HR = 0.622, 95 % CI: 0.494-0.784, P < 0.001). Hospitalization rates were significantly lower in the direct oral anticoagulant group compared to the VKA group in decompensated cirrhosis (33.4 % vs. 38.3 %, HR = 0.830, 95 % CI: 0.695-0.992, P = 1.937)., Conclusions: Our study offers compelling evidence supporting the use of anticoagulation therapy in liver cirrhosis with portal vein thrombosis. The use of DOACs in patients with both compensated and decompensated liver cirrhosis showed a marked mortality benefit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Assess the safety and efficacy of anticoagulants in treating isolated superficial vein thrombosis (iSVT)., Materials and Methods: A systematic review was conducted according to PRISMA 2020 guidelines, for randomized controlled trials (RCTs) investigating anticoagulants in the treatment of iSVT. The primary endpoint of thrombotic complications encompassed any incident of iSVT progression/recurrence and the development of new-onset (deep vein thrombosis) DVT or (pulmonary embolism) PE., Results: Eight RCT's and 4721 patients treated once daily with either fondaparinux 2.5 mg, rivaroxaban 10 mg, therapeutic, intermediate, and prophylactic low molecular weight heparin (LMW) were included. While all anticoagulants displayed a statistically significant risk reduction compared to placebo in terms of thrombotic complications and iSVT progression/recurrence, only fondaparinux reduced the risk for DVT/PE. Additionally, fondaparinux exhibited enhanced efficacy in decreasing DVT/PE events relative to prophylactic and therapeutic LMWH. Furthermore, rivaroxaban and fondaparinux demonstrated superior outcomes in terms of preventing thrombotic complications compared to all three dosing regimens of LMWH without significant differences between the two, risk ratio RR 1.00(95%CI:0.51-1.92). SUCRA identified fondaparinux as the most effective treatment regarding thrombotic complications, (SUCRA,91.6) and DVT/PE, (SUCRA,96) and rivaroxaban in terms of iSVT progression/recurrence (SUCRA,94.68). Ultimately and despite certain model limitations, meta-regression analysis suggested a possible trend towards improved outcomes with longer treatment durations for thrombotic complications β = -0.34(95%CI:-16.39to12.23)., Conclusions: Despite inherent limitations such as variations in treatment durations and follow-up periods, this review displayed the efficacy of fondaparinux, rivaroxaban and LMWH in treating iSVT. The improved efficacy of fondaparinux over therapeutic LMWH in terms of DVT/PE outcomes necessitates cautious interpretation underscoring the need for further investigation through adequately powered RCTs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Additionally, no funding or grants were received to support this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Advancements in the medical field and increased survival of premature infants have led to a rise of venous thromboembolism (VTE) in neonates. Neonatal hemostasis exists in a delicate balance with a propensity towards pro-coagulation. Current recommendations include careful observation, therapeutic anti-coagulation and in some cases thrombolysis. We hypothesize that a sub-group of neonates may not require anti-coagulation and could be safely observed thus reducing their risk of bleeding complications., Methods: We conducted a retrospective chart review of patients with VTE admitted to the neonatal intensive care unit at the Oklahoma University Children's Hospital from October 2009-October 2019. Patients were selected if they had an ICD-9 or ICD-10 code specific for a VTE or if screening with CPT codes for diagnostic imaging including echocardiogram, venous dopplers and computed topographic/magnetic resonance venogram revealed the word 'thrombus', 'clot' or 'venous thromboembolism'. Data were collected about demographics, medical history, co-morbidities, thrombosis characteristics, treatment and outcome., Results: A total of 211 patients were screened and 119 patients were eligible and included in the study. The majority of patients (85 %) had a central venous catheter (CVC) associated VTE. Two-thirds of patients (n = 81, 68 %) received therapeutic anti-coagulation while one-third (n = 38, 32 %) were observed. The group that received anticoagulation had a significantly older age at diagnosis and had a higher frequency of bacteremia, congenital heart disease and presence of symptoms. There was no difference in the odds of complete resolution between patients who were treated with therapeutic anti-coagulation and those that were observed (OR: 1.37, 95 % CI: 0.59-3.20, p-value: 0.47). Univariate analysis revealed maternal preeclampsia (OR: 0.2, 95 % CI: 0.05-0.82, p-value = 0.025), maternal history of chronic hypertension (OR: 0.17, 95 % CI: 0.04-0.68, p-value = 0.01), and presence of complete occlusion (OR = 0.37, 95 % CI: 0.15-0.91, p-value = 0.03) significantly reduced the odds of complete resolution. Furthermore, having a VTE related to a CVC in an extremity versus an ECMO cannula or cardiac catheterization significantly improved the odds of VTE resolution (OR = 5.94, 95 % CI: 1.30-27.20, p-value = 0.022). Using a stepwise regression model, maternal history of chronic hypertension remained significant for a reduced odds of VTE resolution (OR: 0.14, 95 % CI 0.025-0.73, p-value: 0.02)., Conclusions: The short-term outcome of neonatal VTE does not seem to differ between those that were anticoagulated and those that were observed with serial imaging., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Osman Khan, MD reports a relationship with BioMarin Pharmaceutical Inc., Sanofi, Pfizer, Genentech, Bayer, Novo Nordisk that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc 3S4S -α(1,3)-L-Δ 4,5 GlcA-α(1,3)-{D-GalNAc 4S6S -β(1,4)-[L-Fuc 3S4S -α(1,]3)-D-GlcA-β(1,3)-} 3 -D-GalNAc 4S6S -β(1,4)-[L-Fuc 3S4S -α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %-80.9 % determined by the validated bioanalytical methods. The maximum concentration (C max ) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching C max (T max ) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate., Competing Interests: Declaration of competing interest The authors declare no conflict of competing interest that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) in pediatric patients is an uncommon but serious diagnosis that has an array of therapeutic options and challenges. An assessment of the existing literature on management of pediatric patients with VTE was conducted. The interventions reviewed include anticoagulation, thrombolysis, thrombectomy, inferior vena cava (IVC) filters, and venous stenting. For each intervention, a discussion of mechanism of action, indications, contraindications, and potential complications was performed. While anticoagulants are considered the first-line pediatric VTE treatment, many drugs remain investigational in this patient population and treatment recommendations are extrapolated from adult practice. Thrombolysis may be indicated in cases of acute thrombosis requiring more rapid clot resolution but presents a greater bleeding risk than anticoagulation. Similarly, thrombectomy also provides rapid clot resolution and offers a larger therapeutic window and usage in more mature thrombi than thrombolysis. In select patient groups, IVC filters may be indicated in the prevention of PE but present with inherent thrombogenicity and risk of migration. The data regarding pediatric VTE treatment options, monitoring, and long term outcomes is limited compared to the adult population. The relatively few clinical trials including pediatric patients have a relatively small sample size and are heterogenous with regards to predisposing factors that further exacerbate generalizability. Additional research is needed to help construct and evaluate a robust treatment algorithm for pediatric patients with VTE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Adherence to guideline recommendations for venous thromboembolism prophylaxis (VTE) in hospitalized medical patients is suboptimal despite national policies and institutional interventions. The aim of this quality improvement project was to improve adherence to guidelines and decrease the overuse of VTE prophylaxis in order to reduce the institutional cost for heparins. A multidisciplinary anticoagulation stewardship program (ACSP) using the audit and feedback strategy was implemented on the medicine inpatient units at a teaching hospital in Canada. The primary outcome measure was a comparison, pre and post introduction of the ACSP, of the costs per 6-month period for prophylactic dose enoxaparin and unfractionated heparin on the medicine units. The balancing measures were the 90-day VTE rate and major bleeding rate during the hospitalization. Six months after the implementation of the ACSP, the cost was decreased by >50 % without any observed negative impact on patient safety. This study demonstrates the potential for anticoagulation stewardship programs to optimize the use of VTE prophylaxis and reduce the associated costs and risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Falls are one of the most fearsome events in anticoagulated older adults. The evidence concerning safety of direct oral anticoagulants (DOACs) in falling elderly patients with atrial fibrillation (AF) is still limited., Methods: We prospectively enrolled consecutive anticoagulant-naïve patients aged 65 years and older, starting anticoagulation with DOACs for AF. The study cohort was stratified in fallers vs. non-fallers, according to the occurrence of at least one fall during the 2-year follow-up and bleeding outcomes were evaluated., Results: We enrolled 524 consecutive patients. Mean age was 80.8 years and they were mostly women (54.0%). Among the study cohort, 148 patients (28.2%) presented at least one fall episode during the study period. After the adjustment for potential confounders, no difference was found between fallers and non-fallers for all the study outcomes: major bleeding [HR: 1.04 (95%CI: 0.58-1.85)], intracranial haemorrhage [HR: 1.63 (95%CI: 0.69-3.80)], clinically relevant non-major bleeding [HR: 1.21 (95%CI: 0.83-1.76)], and all-cause death [HR: 1.51 (95%CI: 0.85-2.69)]. The presence of a prior cerebrovascular event [HR: 2.27 (95%CI: 1.12-4.62); p-value: 0.02] and polypharmacy [HR: 1.60 (95%CI: 1.08-2.39); p-value: 0.02] were the main drivers for major and clinically relevant non-major bleedings, respectively., Conclusions: Falls in an anticoagulant-naïve population aged 65 years and over starting a DOAC for AF do not increase the bleeding risk. Thus, the presence of falls should not discourage clinicians from prescribing DOACs also in this subset of patients., Competing Interests: Declaration of competing interest All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial., Material and Methods: This report is the second update of our systematic review with meta-analysis on randomized controlled trials (RCTs) comparing standard thromboprophylaxis, intermediate or therapeutic dose anticoagulation or no anticoagulation in COVID-19 in- and outpatients. We searched eligible studies up to 5 October 2023. Certainty of evidence was assessed using GRADE., Results: For this update we included fourteen new RCTs and a total of 27 RCTs with 16,789 patients. Certainty of evidence ranged from very low to high depending on outcome and comparison. Standard thromboprophylaxis with low dose anticoagulation may have little or no effect for COVID-19 outpatients compared to no anticoagulation. In inpatients with moderate or severe COVID-19, intermediate dose anticoagulation may decrease any thrombotic events or death, but may increase major bleeding compared to standard thromboprophylaxis. Therapeutic dose anticoagulation decreases thrombotic events or deaths in inpatients with moderate COVID-19, but probably has little or no effect in patients with severe COVID-19 compared to standard thromboprophylaxis with low or intermediate dose anticoagulation. With therapeutic dose anticoagulation, the risk of major bleeding probably increases regardless of COVID-19 severity. We are uncertain on the effect of thromboprophylaxis with low dose anticoagulation compared to no anticoagulation in the post-discharge setting., Conclusions: Hospitalized, moderately-ill COVID-19 patients may benefit from intermediate or therapeutic dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Florian Langer reports a relationship with Bayer AG that includes: speaking and lecture fees. Florian Langer reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Florian Langer reports a relationship with Daiichi Sankyo Inc that includes: speaking and lecture fees. Florian Langer reports a relationship with LEO Pharma that includes: speaking and lecture fees. Florian Langer reports a relationship with Pfizer that includes: speaking and lecture fees. Florian Langer reports a relationship with Sanofi that includes: speaking and lecture fees. Florian Langer reports a relationship with Viatris that includes: speaking and lecture fees. Oliver J. Mueller reports a relationship with Bayer AG that includes: speaking and lecture fees. Oliver J. Mueller reports a relationship with Pfizer that includes: speaking and lecture fees. Oliver J. Mueller reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients aged ≥65 years not only account for the majority of patients with atrial fibrillation (AF) and venous thromboembolism (VTE), they are also at a higher risk of morbidity, mortality, and undertreatment than younger patients. Several age-related physiological changes with effects on drug pharmacokinetics/-dynamics and blood vessel fragility as well as the higher prevalence of geriatric conditions such as frailty, multimorbidity, polypharmacy, fall risk, dementia, and malnutrition make older persons more vulnerable to disease- and anticoagulation-related complications. Moreover, because older patients with AF/VTE are underrepresented in oral anticoagulation (OAC) trials, evidence on OAC in older adults with AF/VTE is mainly based on subgroup analyses from clinical trials and observational studies. A growing body of such limited evidence suggests that direct oral anticoagulants (DOACs) may be superior in terms of efficacy and safety compared to vitamin K antagonists in older persons with AF/VTE and that specific DOACs may have a differing risk-benefit profile. In this narrative review, we summarize the evidence on epidemiology of AF/VTE, impact of age-related physiological changes, efficacy/safety of OAC, specifically considering individuals with common geriatric conditions, and review OAC guideline recommendations for older adults with AF/VTE. We also propose a research agenda to improve the evidence basis on OAC older individuals with AF/VTE, including the conduct of advanced age-specific and pragmatic studies using less restrictive eligibility criteria and patient-reported health outcomes, in order to compare the effectiveness and safety of different DOACs, and investigate lower-dose regimens and optimal OAC durations in older patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Acute pulmonary embolism (PE) is a life-threatening situation in cancer patients. In this situation, anticoagulant therapy is complex to administer due to the risk of bleeding. Only few studies have been conducted when these patients are admitted to the intensive care unit (ICU). The aim of this study was to assess the association between anticoagulation strategies as well as other factors with 90-day mortality in patients with cancer and PE admitted to ICU. Major bleeding was also evaluated according to the type of anticoagulation., Methods: Retrospective study carried out in 4 ICUs in France over a 12-year period (2009-2021). All patients with cancer and PE were included. An overlap propensity score weighting analysis was performed in the subgroup of patients treated with either unfractionated heparins (UFH) alone or low-molecular-weight heparins (LMWH) alone on 90-day mortality and major bleeding., Results: A total of 218 consecutive cancer patients admitted to ICU and presenting PE were included. The 90-day mortality rate was 42 % for the global cohort. After propensity score analysis in the subgroup of patients treated with either "UFH alone" (n = 80) or "LMWH alone" (n = 71), the 90-day mortality was similar in patients treated with UFH alone (42.6 %) vs LMWH alone (39.9 %): OR = 1.124, CI 95 % [0.571-2.214], p = 0.750. There was a significant increased toward major bleeding rates in the "UFH alone" group (25.5 %) as compared to "LMWH alone" group (11.5 %), p = 0.04., Conclusion: In 218 patients admitted to ICU and presenting PE, the 90-day mortality rate was 42 %. Treatment with UFH alone was associated with a mortality comparable to treatment with LMWH alone but it appeared to be more prone to major bleeding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

A survey was carried out to assess the state of organization of care (including clinical and laboratory) delivered to patients on vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) followed by clinics affiliated with the Italian Federation of Thrombosis Centers (FCSA), traditionally engaged to assist anticoagulated outpatients within the country. Participants were asked to answer questions concerning (i) proportion of patients on VKA-vs-DOAC and (ii) whether dedicated testing for DOAC is available. The proportion of patients on VKA-vs-DOAC was 60 % vs 40 %. This proportion is in sharp contrast with the real-life distribution where DOAC outweigh VKA prescriptions. Furthermore, the proportion of anticoagulation clinics that provide DOAC testing (even in special situations) is relatively small (i.e., 31 % of the respondents). Furthermore, 25 % of those that declared to follow DOAC patients do not provide any testing at all. The answers to the above questions cause concerns as (i) most patients on DOAC within the country are probably on self-management, or they are managed by general practitioners or specialists outside thrombosis centers. (ii) Most patients on DOAC have no access to testing even in special situations where it would be needed. We feel that there is a (false) perception that the care needed for DOAC treatment can be much less than that required for VKA, as DOAC require prescription and not regular follow-up. A call for action should be urgently made to reassess the role of anticoagulation clinics, which should pay the same attention to patients on DOAC as those on VKA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: There is a scarcity of data on anticoagulation-related nephropathy (ARN) caused by direct-acting oral anticoagulants (DOACs) in recent years., Materials and Methods: We collected literatures on DOACs-induced ARN to October 1, 2022, without language restrictions for retrospective analysis., Results: Twenty events were included with a median onset time of 28 days among which fourteen were caused by dabigatran. Patients accompanied by chronic kidney disease (85 %) seemed more easily to have an ARN. Clinical symptoms associated with ARN were mostly presented as hematuria and acute decline of renal function (100 %), then abnormal coagulation function (75 %) but only one with an INR over 3. Renal biopsies were performed in 14 patients, with thirteen showing occlusive intratubular red blood cell casts and ten showing acute tubular injury of varying intensity or even tubular necrosis. Extensive changes in interstitial compartment like hemorrhage, fibrosis or inflammation were also presented in eight biopsies. IgA nephropathy as a latent or undiagnosed disease was demonstrated in eight biopsies. Treatments of ARN were mainly supportive with all patients discontinuing DOACs and 35 % initiating dialysis for acute deterioration of renal function. Steroids were used in 9 patients with a severe ARN verified by biopsy. 60 % of patients did not recover baseline renal function and some even deteriorated., Conclusions: In conclusion, DOACs-induced ARN is a rare but serious adverse reaction. A prompt diagnosis of ARN and supportive treatments are necessary for patients receiving DOACs concurrent with an acute renal injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Rheumatic heart disease with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires long-life anticoagulation and managing this can be challenging., Methods and Results: We report data of a prospective observational study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum, by Emergency, an Italian Non-Governmental Organization, to evaluate the quality of anticoagulation control and the risk of thrombotic complications., Results: We studied 3647 patients (median age 25.1 years; 53.9 % female). Median Time in Therapeutic Range (TTR) was 53 % (interquartile range 37 % to 67 %) and 70 thrombotic events (rate 1.8 × 100 pt-years [95 % CI 1.38-2.23]) were recorded. Among patients in the first quartile of TTR (≤37 %), we recorded 34/70 (48.6 %) of all thrombotic events (rate 3.7 × 100 pt-years [95 % CI 2.5-5.1]), with a high mortality rate (2.2 × 100 pt-years [95 % CI 1.3-3.3]). In patients with guideline-recommended TTR (≥65 %) the event rate was 0.8 × 100 pt-years for thrombotic events [95 % CI 0.3-1.5] and 0.4 × 100 pt-years for mortality [95 % CI 0.1-0.9]. Multivariable analysis showed that having a TTR in the lowest quartile (≤37 %) and being noncompliant are significantly associated with increased thrombotic risk. Aspirin use or different valve type did not influence the thrombotic risk. Almost 40 % of all thromboembolic complications could have been potentially prevented by further improving VKA management to obtain a TTR > 37 %., Conclusion: The thrombotic risk of MHV patients on VKAs living in a low-income country like Sudan is associated with low quality of anticoagulation control. Efforts should be made to decrease the number of non-compliant patients and to reach a guideline-recommended TTR of ≥65 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented., Objective: This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice., Methods: A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included., Results: A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction., Conclusion: Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events., Competing Interests: Declaration of competing interest No funding was provided for conduction of this study. AL has no conflicts to disclose. ML has no conflicts to disclose. SRV serves as an editorial consultant for UpToDate®, which is a product of Wolters-Kluwer who also produces Lexi-Comp® drug interaction database. She is also a member of the board of directors for the Anticoagulation Forum. MC discloses Data Safety Monitoring board work for Bayer, Advisory Board work for Servier Canada, Asahi Kasei, and Precision Biologicals and preparation of educational materials and/or presentations for Pfizer, CSL Behring and Diagnostica Stago. Doctor Crowther holds individual stocks in Alnylam. Doctor Crowther has ongoing relationships with a number of for profit, and not for profit agencies and has worked on medicolegal cases involving anticoagulant therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bivalirudin is a reversible direct thrombin inhibitor that inhibits both bound and free thrombin and binds to the active (catalytic) and fibrinogen-binding sites of thrombin, with high affinity and specificity. Off-label use of bivalirudin in the paediatric population has increased, as an alternative to heparin, particularly in the setting of anticoagulation for patients undergoing coronary bypass surgery (CPB), extracorporeal life support (ECLS) and those on ventricular assist devices (VAD). This study aimed to determine the age-specific in vitro effect of bivalirudin in children compared to adults. Age-specific pools (neonates, ≤2 years, >2 to 5 years, 6 to 10 years, 11 to 17 years and Adults) were prepared using platelet poor plasma samples from 20 individuals per age group. Pooled plasma was spiked with increasing concentrations of Bivalirudin (from 0 g/mL to 10μg/mL), and thrombin inhibition was measured using standard coagulation assays. There was a significantly increased response to bivalirudin across all paediatric age groups as compared to adults. The age-specific difference in response to bivalirudin was specifically evident in neonates, where the potential to generate thrombin was decreased 2-fold compared to adults (p < 0.001). Our findings support the concept of age-specific pharmaco-dynamic responses to Bivalirudin and support the need for further ex vivo studies in hospitalised children to determine accurate clinical dosing recommendations., Competing Interests: Declaration of competing interest The authors have nothing to declare in relation to this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Fontan procedure has transformed the lives of children born with single-ventricle physiology, previously deemed inoperable. Worldwide, there are an increasing number of children with Fontan circulation, with the potential for survival into adulthood. Due to the abnormal circulation, Fontan patients have an increased risk of thromboembolic (TE) events, with up to 25% of events leading to death. Despite the importance of preventing TE events in this patient population, there is currently no clinical consensus on the optimal monitoring, thromboprophylaxis therapies, and treatment of these events. This paper reviews the available literature regarding anticoagulation in the pediatric and adult Fontan population, including the mechanisms for thrombosis and current antithrombotic therapies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Placenta-mediated pregnancy complications, such as pre-eclampsia, placental abruption, birth of a small-for-gestational age infant and late pregnancy loss, are common and carry significant morbidity and mortality. The etiology of placenta-mediated pregnancy complications is likely multifactorial and may include abnormal coagulation activation of the maternal-fetal interface. The use of antepartum low-molecular-weight heparin (LMWH) prophylaxis to prevent recurrent placenta-mediated pregnancy complications has become common practice despite limited and conflicting evidence to support its use. This paper reviews the evidence, including recently published data from an individual patient level meta-analysis, which challenges the role of LMWH in preventing recurrent placenta-mediated pregnancy complications. Incorporating this recent evidence, we recommend against the use of LMWH to prevent recurrent placenta-mediated pregnancy complications in women with and without inherited thrombophilia., (© 2017 Elsevier Ltd. All rights reserved.)

Whilst the term cancer associated thrombosis (CAT) offers an overarching term for all thrombotic events encountered during the cancer journey, the reality is that this is a far too simplistic reflection of a complex multifactorial process occurring within a heterogeneous population. The management of CAT needs to consider factors beyond the thrombus itself: patients must be treated as individuals within the context of their own cancer journey and their preferences for different treatment options. The breath of pathological, pharmacological and psychosocial variants means it is highly unlikely that one treatment regime will be appropriate for all patients. It is inevitable that regimes may need to be modified and anticoagulant agents changed according to clinical and patient preference needs. There is strong evidence supporting the use of low molecular weight heparin first line in the treatment of acute CAT. The evidence for warfarin and the direct acting oral anticoagulants is not as strong but, as oral agents, may be preferred by some patients. This paper shall identify the various treatment options available, factors which will influence the decision making process and when it is justifiable to treat patients differently to the established protocol., (© 2016 Elsevier Ltd. All rights reserved.)

Oral anticoagulant (OAC) intervention trials have typically included clinical event outcomes. However, there is no standard list of outcomes to be used in OAC research. This study aimed to describe and classify the outcomes used in recent prospective clinical studies involving OACs. We searched MEDLINE, EMBASE, and CINAHL databases from January 2009 to July 2019 for prospective studies with an intervention or control group that included one or more oral anticoagulants. We abstracted details about each included study and the outcomes used from the study report and its accompanying protocol. Using the Core Outcome Measures in Effectiveness Trials (COMET) Initiative recommendations, we categorised each outcome into one of five domains (mortality/survival, physiological/clinical, life impact, resource use, and adverse events). Our primary outcome was the prevalence of use of an outcome domain across studies. We included 70 prospective studies, including 52 randomized controlled trials and 18 prospective cohort studies. A total of 121 different outcomes were reported. The COMET domains were represented in the 70 studies as follows: mortality (63/70, 90.0%); physiological/clinical domain (70/70, 100%), life impact domain (43/70, 61.4%), resource use domain (26/70, 37.1%), and adverse events domain (55/70, 78.6%). Outcome reporting in prospective studies of OACs more frequently concentrates on mortality, physiological/clinical domains, and adverse events compared to life impact and resource utilization domains, the latter uncommonly used. A priority for future research includes developing a core outcome set (COS) for OAC research that represents all domains. • No standard list of outcomes to be used in oral anticoagulants research • Most papers having mortality, physiological/clinical, and adverse events domains • Fewer outcomes measured in the life impact and resource use domains • Provide information useful for developing COS for oral anticoagulants research [ABSTRACT FROM AUTHOR]

With the availability of efficient and safe clotting factor replacement therapy, elective total joint arthroplasty is increasingly performed in subjects with haemophilia suffering from chronic haemophilic arthropathy. Little has been published addressing the prevalence and the specific risk factors of thromboembolic complications and the role of thromboembolic prophylaxis in this specific population. While the risk of thrombosis in hemophilic patients following hip or knee arthroplasty is considered to be low and probably mitigated by the clotting factor deficiency, cases have been reported of pulmonary embolism and deep vein thrombosis in hemophilic patients. Although most guidelines advocate thromboembolic prophylaxis in the general population undergoing major orthopaedic surgery, no such standard of care is in place for hemophilic patients. This paper discusses the scope of the problem of venous thromboembolism in patients with haemophilia undergoing major orthopaedic surgery and reviews the published approaches to the use of prophylactic anticoagulation in this setting., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cancer-associated thrombosis is a major cause of morbidity and mortality. Although anticoagulation remains the mainstay for prevention and treatment of thrombosis, current anticoagulants are problematic in cancer patients. Parenteral anticoagulants, such as heparin or low-molecular heparin, require daily subcutaneous injection, whereas warfarin requires coagulation monitoring and frequent dose adjustments. Idrabiotaparinux, a reversible long-acting pentasaccharide, and new oral anticoagulants, such as dabigatran etexilate, rivaroxaban and apixaban, have been designed to replace warfarin for extended prevention or treatment of VTE. Clinical trials with these agents have yielded promising results, and dabigatran etexilate and rivaroxaban are already licensed in many countries for thromboprophylaxis after elective hip or knee replacement surgery. In the coming years, these drugs are likely to replace warfarin for most indications. This paper addresses their potential role for prevention and treatment of cancer-related thrombosis.

Background: This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard "Clinical laboratory testing and in vitro medical devices - Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy". The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin., Methods: The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard., Results: Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias -0.19 to 0.18 INR; >97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity., Conclusion: The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007.

Bleeding is the most common complication of anticoagulant therapy. Despite the frequency of its occurrence, little evidence is available to guide the care of anticoagulated patients with, or at high risk of, bleeding. This article attempts, using a case based format, to describe common clinical scenarios encountered by clinicians who manage anticoagulated patients and who are bleeding. The paper is "case based" and narrative since there is little evidence to guide practice in this area.

In principle, the answer to this question is obvious: "as long as the risk of continued therapy is outweighed by the benefit." In practice, determining an individual patient's risk of recurrent venous thromboembolism (VTE) without warfarin or other vitamin K antagonists is difficult. However, there are many factors (both intrinsic and environmental) that can alter the risk of VTE recurrence. This paper will discuss evidence and considerations (including the issue of bleeding risk) that may be relevant to decisions about duration of anticoagulant therapy for patients with VTE.

Introduction: Enoxaparin is the current anticoagulant of choice for neonatal thrombosis. Present neonatal treatment guidelines of 1.5 mg/kg every 12 hours (q12 h) are extrapolated primarily from an earlier study with 9 infants less than 2 months of age. More recent studies indicate an increased dose requirement for neonates., Materials and Methods: Relevant data from articles and abstracts were identified by searching MEDLINE and pediatric and hematology conference proceedings., Results: Publications between 1996 and 2007 included 8 papers, 4 abstracts and 1 review article with primary research documenting enoxaparin use in 240 neonates. The mean maintenance dose of enoxaparin ranged from 1.48 to 2.27 mg/kg q12 h for all infants, but was higher for preterm neonates at 1.9-2.27 mg/kg q12 h. The efficacy of enoxaparin, causing either complete or partial resolution was between 59 and 100%. Minor side effects were common and adverse events (major bleeding) occurred in 12 patients (0-19%)., Conclusions: Increased experience with enoxaparin use in neonates in the past decade has indicated higher doses to achieve accepted target anti-factor Xa values. The long-term use of indwelling catheters (Insuflon catheter) for enoxaparin administration may need to be reevaluated in ELBW infants. Suggested starting doses of enoxaparin are 1.7 mg/kg q12 h for term neonates and 2.0 mg/kg q12 h for preterm neonates if there is no considerable bleeding risk. However, further prospective studies are needed to validate an increased initial dose of enoxaparin.

Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to "usual intensity" anticoagulation; recent evidence suggests that most such patients are adequately treated with "usual therapy". After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most "experts" recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.

Abstract: Introduction: The use of oral anticoagulant therapy is increasing in children. Managing anticoagulant therapy in children presents unique challenges, including poor venous access. The advent of point-of-care (POC) monitoring of anticoagulant therapy offers a potential solution to this challenge. This paper reviews the published literature relating to POC monitoring of oral anticoagulant therapy in children. Materials and methods: A Medline search was conducted and identified key publications. Papers were reviewed with respect to their objectives, populations and POC device investigated. Study limitations were identified. Results: Five publications and one abstract were identified, reporting studies using five different POC monitors. Three studies had a strong clinical management focus. Outcome measures assessed included target therapeutic range achievement and frequency of adverse events. Correlation between POC and laboratory-based results ranged from 0.83 to 0.96. Home monitoring and self-management using POC monitors were both reported to be preferred compared to standard laboratory testing. Conclusions: POC monitoring of oral anticoagulant therapy in children offers considerable advantages. The reviewed literature would suggest such monitoring can be performed accurately and reliably. The impact of quality control issues, such as calibration of thromboplastin ISI in POC devices, has not been explored in a paediatric population. Further studies are needed to clarify such issues and confirm the safety, reliability and efficacy of POC monitoring of oral anticoagulant therapy in children, including its home monitoring and self-management programs. [Copyright &y& Elsevier]

This paper describes the first human study with aprosulate, a new chemically synthesized anticoagulant with a defined molecular structure and a molecular weight of 2388. Twelve healthy male volunteers received subcutaneous injections of placebo on the first day followed by ascending doses of aprosulate in the range of 0.25 mg/kg to 2.0 mg/kg body weight on alternate days. Anticoagulant, pharmacokinetic and safety parameters were assessed for 48 hours after each injection. The activated partial thromboplastin time and the Heptest showed a dose-dependent increase for up to ten hours after each application. A trend towards prolongation of the bleeding time was indicated with higher doses. In general, the tolerance was good. Plasma transaminase concentrations were raised in some volunteers but returned spontaneously to normal during or after the study.

In previous papers, we have described the preparation and heparin-like properties of insoluble modified polystyrene resins. We now report results about the interactions of several coagulation factors with some of these materials. Most of the non-activated factors are neither adsorbed nor modified, except factor V and prekallikrein. In contrast thrombin, antithrombin III and factor Xa adsorb on the surface of such insoluble polymers. Thrombin can be desorbed by addition of a polycationic compound. The inactivation of thrombin or factor Xa by antithrombin is catalysed by the presence in the mixture of these insoluble materials as it is with soluble heparin. The initial velocity of these reactions is second order for both types of catalysis-homogeneous or heterogeneous - as previously reported for soluble heparin. In the case of these insoluble materials, the inhibition of protease by antiprotease seems to be accelerated when complexes are formed between the polymer and the proteins.