Low Molecular Weight Heparin Anticoagulation Research Articles

Regional citrate anticoagulation versus LMWH anticoagulation for CRRT in liver failure patients without increased bleeding risk.

The optimal anticoagulation regimen for continuous renal replacement therapy (CRRT) in liver failure (LF) patients without increased bleeding risk remains controversial. Therefore, we conducted a monocentric retrospective study to evaluate the efficacy and safety of the regional citrate anticoagulation (RCA) versus low molecular weight heparin (LMWH) anticoagulation for CRRT in LF without increased bleeding risk. According to the anticoagulation strategy for CRRT, patients were divided into the RCA and LMWH-anticoagulation groups. The evaluated endpoints were patient survival, filter lifespan, bleeding, citrate accumulation, and totCa/ionCa ratio. Totally 167 and 164 filters were used in the RCA and LMWH group, respectively. The median filter lifespan was significantly longer in the RCA group (34 h (IQR = 24-54) versus 24 h (IQR = 18-45.5) [95%CI, 24.5-33]; p < 0.001). The 4-week mortality rate was significantly higher in the LMWH-anticoagulation group (71 (57.72%) vs 53 (40.46%); p = 0.006). After adjusted the important parameters in the multivariate COX regression model, the mortality risk was significantly reduced in the RCA group (HR = 0.668 [95%CI, 0.468-0.955]; p = 0.027). In the LMWH group, 30 bleeding episodes (24,19%) were observed, whereas only 7 (5.34%) occurred in the RCA group (p < 0.001). Two patients (1.5%) in the RCA group occurred citrate accumulation. In LF patients without increased bleeding risk who underwent CRRT, RCA significantly extended the filter lifespan and improved patient survival rate. There was no significant difference in the rate of adverse events between the two groups.

A study on the prevention of thrombosis after simultaneous pancreas-kidney transplantation.

Renal failure is one of the most common chronic complications of diabetes. Simultaneous pancreas-kidney transplantation (SPK) is considered the preferred treatment for individuals with diabetes and chronic renal failure. This procedure has demonstrated efficacy in enhancing the quality of life for patients and minimizing the complications associated with diabetes. In this study, we analyzed the incidence and safety of complications in different thrombosis prevention techniques post simultaneous pancreas-kidney transplantation (SPK). Patients who underwent SPK between January 2019 and December 2022 were selectively categorized into two groups: the heparin group and the non-heparin group depending on the utilization of low molecular weight heparin. The occurrence of complications and clinical outcomes were subsequently calculated in each group. In this study, we included a total of 58 recipients who underwent SPK, with 36 in the heparin group and 22 in the non-heparin group. Among the 58 participants, there were 3 cases of pancreatic thrombosis complications, with 2 cases (5.6%) in the heparin group and 1 case (4.6%) in the non-heparin group, and the differences were not statistically significant (P> 0.05). Regarding gastrointestinal bleeding, there were 17 cases out of the total 58 patients, with 14 cases (38.9%) in the heparin group and 3 cases (13.6%) in the non-heparin group, and the difference was statistically significant (P< 0.05). After surgery, the use of low molecular weight heparin anticoagulation may increase the likelihood of experiencing gastrointestinal bleeding. Prior to the surgery, a comprehensive evaluation of the coagulation status and medical history of the patient should be performed, enabling stratification of risks involved. Based on this assessment, either low-molecular-weight heparin or aspirin should be selected as a preventive measure against thrombosis.

Mycoplasma pneumoniae pneumonia-associated thromboembolism with plastic bronchitis: a series of five case reports and literature review

BackgroundMycoplasma pneumoniae pneumonia is a common respiratory infection among children. However, the occurrence of thromboembolism with plastic bronchitis in association with Mycoplasma pneumoniae pneumonia is extremely rare. This case series presents five cases of children with Mycoplasma pneumoniae pneumonia who developed thromboembolism and plastic bronchitis. The clinical presentation, diagnostic approach, and management strategies are discussed.MethodsA retrospective analysis was conducted on medical records from a pediatric hospital. Patient demographics, clinical features, laboratory findings, imaging results, treatment modalities, and outcomes were collected.ResultsThe patients in our case series presented with varying degrees of respiratory distress, cough, and fever. Imaging studies revealed evidence of thromboembolism based on pulmonary artery occlusion. Bronchial casts were observed by bronchoscopy. Laboratory tests demonstrated elevated D-dimer levels and fibrinogen degradation products. All patients received a combination of low molecular weight heparin anticoagulation and supportive care.ConclusionThromboembolism with plastic bronchitis associated with Mycoplasma pneumoniae pneumonia is a rare but potentially serious complication in children. Prompt recognition and management are crucial for improving patient outcomes. This case series highlights the diverse clinical presentations, diagnostic challenges, and treatment strategies for this unique clinical entity. Further research is needed to better understand the pathogenesis and optimal management of this condition.

#949 Factor XIIa inhibitory antibody does not provide sufficient anticoagulation in ex vivo hemodialysis

Abstract Background and Aims Unfractionated heparin (UFH) and low molecular-weight heparin (LMWH) are the most commonly used anticoagulants in haemodialysis (HD). While effective in preventing clotting, they are also associated with complications including increased risk of bleeding and heparin induced thrombocytopenia. The contact activation system is commonly assumed to be the main trigger of coagulation during HD, through autoactivation of factor (F)XII upon contact with the dialyser. FXII deficient individuals do not have an increased risk of bleeding which makes activated FXII (FXIIa) an attractive drug target as it has the potential to inhibit clotting without disrupting haemostasis. The aim of the study was to evaluate the efficacy of CSL312, a monoclonal, humanized IgG4 antibody against activated FXII (FXIIa), in preventing intradialytic coagulation. Method An ex vivo haemodialysisis model was used to test the efficacy of CSL312 as an anticoagulant. CSL312 (400 µg/mL) was compared to standard doses of UFH, LMWH and citrate anticoagulation. The antibody was provided by CSL Limited. Anticoagulant-free haemodialysisis was used as control. Whole-blood was collected from 12 healthy adult donors in blood-transfer bags containing citrate to prevent clotting before dialysis. Each donor provided blood for two HD-sessions, using different anticoagulants. The blood was dialyzed for one hour through paediatric polysulfone high-flux dialysers. Right before the start of HD, calcium was added to reverse the anticoagulant effect of citrate, except in the citrate group. Blood was sampled before and at 5, 15, 30 and 60 minutes after HD start. To quantify the activity of the contact system, the concentrations of enzyme-inhibitor complexes of antithrombin (AT) or C1-inhibitor (C1INH) in conjunction with FXIIa, FXIa, kallikrein, MASP-1, MASP-2 and thrombin were measured in plasma using enzyme-linked immunosorbent assays. Results Using CSL312 to inhibit FXIIa protease activity (n = 5), clotting occurred in all tests (at 30, 31, 36, 49 and 50 minutes) with a mean clotting time of 39.2 minutes compared to 17 and 30 minutes using no anticoagulation (n = 2). No clotting was evident with other anticoagulants. Using CSL312, the plasma concentration of FXIIa-C1INH at 15 minutes was significantly higher than at baseline (mean 26.2 (SD 9.08) vs mean 17.6 (SD 10.6) µg/mL, p = 0.011). Conclusion FXIIa inhibition using a monoclonal antibody does not provide sufficient anticoagulation during HD. This suggests that the contact system may not be solely responsible for clotting during HD.

Effectiveness and Safety of Early Versus Routine Switching from Low-Molecular-Weight Heparin to Maintenance Therapy of Rivaroxaban for Acute Iliofemoral Vein Thrombosis: A Retrospective Cohort Study

The anticoagulation strategy of switching to rivaroxaban after 1week of initial low-molecular-weight heparin (LMWH) therapy is recommended by a guideline for the treatment of acute iliofemoral deep vein thrombosis (DVT). However, the initial rivaroxaban dose in the switching strategy, as well as the effectiveness and safety of the early switching (less than 1week) to rivaroxaban, remain inadequately substantiated. We aimed to evaluate the effectiveness and safety of early switching from LMWH to maintenance therapy of rivaroxaban (20mg once daily) for acute iliofemoral DVT. A retrospective cohort study was conducted using data from patients with acute iliofemoral DVT who received initial LMWH anticoagulation followed by rivaroxaban maintenance therapy. The clinical outcomes were compared between early (LMWH course ≤7days) and routine (LMWH course >7days) switching strategies within 3months of initiating anticoagulation. 217 patients were included, 59 (27.2%) receiving early switching and 158 (72.8%) receiving routine switching. Compared with routine switching, patients with early switching had a significantly shorter hospital stay (7days vs. 14days, P<0.001). The length of hospital stay was significantly positively correlated with the duration of LMWH (r=0.762, P<0.001). The incidences of recurrent venous thromboembolism (5.1% vs. 2.5%, P=0.606), major bleeding (0% vs. 1.9%, P=0.564), clinically relevant nonmajor bleeding (1.7% vs. 2.5%, P=1.000) and all-cause mortality (6.8% vs. 2.5%, P=0.283) were not statistically different between the 2 groups. Direct early switching from LMWH to maintenance therapy of rivaroxaban is effective and safe for acute iliofemoral DVT.

Evaluation of anticoagulant effect and predicted dose of low molecular weight heparin in hemodialysis by anti-Ⅹa factor activity

The purpose of this study was to explore the reasonable dose of low molecular weight heparin (LMWH) in hemodialysis (HD) and the strategy of preventing extracorporeal circuit coagulation (ECC). A retrospective case-control study included patients who used LMWH for anticoagulation during maintenance hemodialysis (MHD) in the Hemodialysis Center of Beijing Hospital from December 2020 to January 2021. Basic data such as weight, height, basic kidney disease, dialysis age and anti-Ⅹa factor activity before, during and after dialysis were collected. A total of 46 patients were enrolled in this study, including 5 patients in coagulation group (10.9%) and 41 patients in non-coagulation group (89.1%). The anti-Ⅹa factor activity reached its peak at 0.5 h after the start of HD. The level of anti-Ⅹa factor was incorporated into the receiver operating characteristic curve (ROC curve). The results showed that the area under the ROC curve (AUC) was 0.802 (95% confidence interval: 0.651-0.54, P=0.029), and the cutoff was 0.31 IU/ml (sensitivity 1, specificity 0.683). It is suggested that the body surface area should be used as the basis to estimate the anticoagulant dose of LMWH in HD, and the activity of HD 4 h anti-Ⅹa factor ≤0.31 IU/ml, which is of diagnostic value for ECC. In addition, the results of binary logistic regression analysis showed that dialysis age was an independent risk factor for ECC (OR value 1.319, 95%CI 1.052-1.654, P=0.017). In summary, this study reveals that dialysis age may be a risk factor for ECC and that the activity of HD 4 h anti-Ⅹa factor ≤0.31 IU/ml can be used as a potential diagnostic cut-off point for ECC in HD patients, which provides a scientific basis for monitoring strategies to prevent blood coagulation in HD filters.

Cancer-associated thrombosis and bleeding.

Development of thrombosis is closely associated with poor prognosis in cancer patients. Cancer patients often fulfill Virchow's triad of hyper-coagulable state, vascular endothelial injury, and venous stasis. Cancer cells aberrantly express a variety of procoagulant factors, including tissue factor and podoplanin. Chemotherapeutic agents and radiation cause vascular endothelial injury, and reduced daily activity and bed rest for chemotherapy lead to venous stasis. Due to these factors, cancer patients are at high risk of developing thrombosis. Cancer patients are also at high risk of bleeding when they have disseminated intravascular coagulation and/or chemotherapy-induced thrombocytopenia as complications. International societies, such as the American Society of Clinical Oncology and the International Initiative on Thrombosis and Cancer (ITAC), have published clinical guidelines to help physicians better manage cancer-associated thrombosis (CAT). These guidelines recommend use of low molecular weight heparin or direct oral anticoagulants for the prevention of CAT, but unfortunately use of these drugs is not approved in Japan. This gap between Japan and other countries needs to be closed.

Anticoagulation for people receiving long-term haemodialysis.

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

Clinical analysis of 11 cases multisystem inflammatory syndrome associated with SARS-CoV-2 Omicron variant infection in children

Objective: To explore the clinical characteristics, diagnosis, treatment, and follow-up of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 Omicron variant infection. Methods: A retrospective analysis was conducted on clinical data of 11 children with MIS-C, who were admitted to the Department of Pediatrics of Peking University First Hospital from December 2022 to January 2023. Clinical characteristics, treatment, and follow-up of MIS-C were summarized in this study. Results: The 11 cases contained 7 boys and 4 girls, with an age of 4.4 (2.0, 5.5) years on admission. All the patients had fever, with a duration of 7(5, 9) days. Other clinical manifestations included rash in 7 cases, conjunctival hyperemia in 5 cases, red lips and raspberry tongue in 3 cases, lymphadenopathy in 3 cases, and swollen fingers and toes in 2 cases. There were 8 cases of digestive symptoms, 8 cases of respiratory symptoms, and 3 cases of nervous system symptoms. Eight patients had multi-system injuries, and one of them had shock presentation. All 11 patients were infected with SARS-CoV-2 Omicron BF.7 variant. The laboratory examination results showed that all cases had elevated inflammatory indicators, abnormal coagulation function and myocardial damage. Six patients had elevated white blood cell counts, 5 cases had liver function abnormalities, 3 cases had kidney function abnormalities, and 8 cases had coronary artery involvement. All 11 patients received anti-infection treatment, of which 3 cases received only 2 g/kg intravenous immunoglobulin (IVIG), while the remaining 8 cases received a combination of IVIG and 2 mg/(kg·d) methylprednisolone. Among the 8 cases with coronary artery disease, 6 cases received low molecular weight heparin anticoagulation therapy. All patients were followed up in 2 weeks after being discharged, and their inflammatory markers had returned to normal by that time. The 8 cases with coronary artery disease and 3 cases with pneumonia showed significant improvement or back to normal at the 4-week follow-up. All patients had no new complications or comorbidities during follow-up of more than 3 months. Conclusions: MIS-C may present with Kawasaki disease-like symptoms, with or without gastrointestinal, neurological, or respiratory symptoms. Elevated inflammatory markers, abnormal coagulation function, and cardiac injury contribute to the diagnosis of MIS-C. IVIG and methylprednisolone were the primary treatments for MIS-C, and a favorable short-term prognosis was observed during a follow-up period of more than 3 months.

Direct Oral Anticoagulants for the Prevention and Treatment of Venous Thromboembolic Events in Cancer Patients: A Meta-analysis of Randomized Controlled Trials

Introduction:: Cancer is associated with a higher risk of venous thromboembolic events compared to the general population. About one-fifth of patients diagnosed with venous thromboembolic events have underlying cancer. The guidelines recommend both low molecular weight heparin and direct oral anticoagulants for the prevention and treatment of venous thromboembolic events. Further evidence is required to adequately characterize the exact role of direct oral anticoagulants. Methods:: A systematic review of the literature was done by searching the databases of Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. The analysis included only randomized controlled trials enrolling adult patients with cancer and venous thromboembolic events comparing low molecular weight heparin versus direct oral anticoagulants. Duration of follow-up of at least 6 months was considered as a minimum. The studies had to assess the risk of thromboembolic recurrence rate, all-cause mortality, and risk of bleeding. Results:: The final search results led to the inclusion of five randomized controlled trials. The analysis showed a similar risk of recurrence of venous thrombotic events (RR 0.71, 95% CI 0.44-1.17; p = 0.18), mortality risk (RR 1.02, 95% CI 0.88-1.17; p = 0.8), and major bleeding (RR 1.05, 95% CI 0.69-1.62; p = 0.81) between the two treatment groups. Conclusion:: The use of direct oral anticoagulants is a feasible and practical option in ambulatory cancer patients with venous thromboembolic events. The efficacy and safety are similar to that of low molecular weight heparin.

Overall Survival of Warfarin Compared to LMWH/Doacs in Cancer-Associated Venous Thromboembolism: VA Cohort Study

Background: Warfarin has been shown in pre-clinical models to have anti-neoplastic activity. In a population-based study using the SEER-Medicare Linked Database warfarin was associated with improved survival compared to low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis (CAT). To assess whether the observed survival advantage is consistent in other large cohorts, we performed a matched cohort study utilizing the Veterans Affairs (VA) database. The VA is a large, integrated health care system with comprehensive data for their patients at the individual level, which provides the optimal observational cohort to confirm the novel hypothesis warfarin confers a mortality benefit over LMWH. Method: Using the retrospective data from the VA health care system from 2000-2021, we identified patients with CAT who were &amp;gt; 18 years, had available prescription data for anticoagulation within 30 days of venous thromboembolism (VTE), and survived &amp;gt; 14 days after the index VTE event. Patients were excluded if they had prior diagnosis of VTE or had any anticoagulation prescription prior to the first coded VTE event. The primary outcome was overall survival (OS). Patients were matched 1:1 using nearest neighbor matching on the propensity score. The matching variables included cancer site, cancer stage, date of cancer diagnosis, date of VTE diagnosis, age at VTE diagnosis, gender, race, BMI, Elixhauser-based weighted comorbidity score, and rurality of residential status. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals. Log-rank test was utilized to estimate the p-value. Subgroup analyses were performed in the largest groups of cancer available in the data set including prostate cancer, lung cancer, gastrointestinal cancer (excluding hepatobiliary cancer), and malignant hematologic neoplasms (including myeloid malignancy, lymphoid malignancy, and multiple myeloma). Finally subgroup analysis was also performed on localized cancer and metastatic disease based on AJCC stage grouping. Result: There were a total of 20,078 patients that met the inclusion and exclusion criteria without missing data. The warfarin cohort consistent of 8383 patients while non-warfarin cohort comprised 11696 patients. Among the non-warfarin cohort, 54% of the patients were prescribed LMWH exclusively and 38% of the patients were prescribed DOAC exclusively within 30days of the VTE diagnosis. The most common malignancies in the cohort included prostate (29.4%), lung (20.9%), gastrointestinal (15.7%) and hematologic malignancies (10.3%). Of patients with solid tumors, 22% had metastatic cancer. Among the VTE events, 33.3% were acute lower extremity deep vein thrombosis, 48.4% were acute pulmonary embolism, and 18.3% were acute upper extremity deep vein thrombosis. After propensity score matching, 8,383 patients were included in the warfarin arm and 8,383 patients in the non-warfarin arm. The median age at VTE diagnosis of the matched cohort was 69 [IQR 63 - 75] and the majority of the patients (96.7%) were male. Warfarin was associated with a significant improvement in OS compared to non-vitamin K antagonists (median OS, 1204 days [95% CI, 1137-1276 days] vs 703 days [95% CI, 665-747 days]; HR 0.79 [95% CI 0.76 - 0.82]; p-value &amp;lt;2x10 -16) (Figure1). The difference was also preserved in gastrointestinal malignancy (HR 0.8 v95% CI 0.73-0.87), lung cancer (HR 0.8, 95% CI 0.79-0.92) and prostate cancer (HR 0.71, 95% CI 0.65-0.77). The survival advantage was preserved in patients with metastatic (HR 0.86, 95% CI 0.78-0.83) and localized cancer (HR 0.80, 95% CI 0.76-0.84) (Figure 2). Conclusion and Relevance: In a population level propensity matched study, warfarin for the treatment of CAT was associated with significantly improved survival over non-vitamin K antagonist anticoagulation in CAT. These provocative finding confirm the previous observation in SEER-Medicare database and have important implications on patient care and health care costs. Further investigation into the biological basis of these findings could potentially lead to biomarker and drug discovery for cancer therapies and prognostication.

Bleeding Risk from Anticoagulant Thromboprophylaxis in Patients with Multiple Myeloma

Introduction: Patients with multiple myeloma (MM) have a high risk of venous thromboembolism (VTE) due to unique disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). Thromboprophylaxis is recommended for most patients starting MM therapy. Anticoagulants are preferred over aspirin except in patients at low risk for VTE. However, compliance with prophylaxis guidelines is low. The risk of bleeding from thromboprophylaxis is not well described in these patients so an excessive perceived risk may influence clinicians' practice. We conducted a real-world analysis of bleeding complications from VTE prophylaxis in MM. Methods: The IBM MarketScan Commercial Claims Database was used to identify MM cases between 2013 and 2021. Cases required MM diagnosis from 1 inpatient or 2 outpatient claims, based on ICD-9 or ICD-10 codes, and MM-specific therapy started between 7 days before and 90 days after index diagnosis code, based on HCPCS codes and prescription records. Those with preexisting VTE, atrial fibrillation or stroke were excluded. Thromboprophylaxis was defined as at least 1 prescription for warfarin, low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) within 30 days of diagnosis. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes previously validated (Cunningham algorithm). Patients were followed from end of prophylaxis exposure window (index MM + 30 days) to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2021. Descriptive statistics were used to calculate rates of bleeding. Cox regression was used to assess the risk of bleeding from thromboprophylaxis and define risk factors associated with major bleeding. Results: We included 6,656 patients diagnosed and treated for MM, with mean age 62.7 years and 55.3% males. Although over 50% of the population would have had a high thrombotic risk based on consensus guidelines, concurrent anticoagulant prophylaxis was prescribed in only 6.6% (436). Prophylaxis agent of choice was warfarin in 23% (102), LMWH in 39% (169), and DOAC in 38% (165), respectively. There was a trend over time favoring DOAC over other agents (25% increase in DOAC use vs. other agents per year on average, p&amp;lt;0.01). Patients on prophylaxis had a higher rate of IMiD-based therapy (63.8% vs. 46.7%, p&amp;lt;0.01) and lower concomitant anti-platelet use (2.1% vs. 4.7%, p=0.01) than those not receiving prophylaxis. There were no differences in age/sex distribution, Charlson comorbidity index (CCI) or history of bleeding between groups. With a median 1.3 years follow-up, the incidence of major bleeding among MM patients receiving VTE prophylaxis was 1.4% or 7.8 bleeding events per 1,000 person-years. This was numerically but not statistically lower than the incident bleeding rate in patients not receiving prophylaxis: 1.8% or 10.1 events per 1,000 person-years. Table 1 shows risk factors for bleeding in this MM population, adjusting for age and sex, including higher age (per 10-year increase, HR 1.38), higher CCI (per SD increment, HR 1.18), history of bleeding (HR 1.54), hypertension (HR 1.87), and renal disease (HR 1.56). IMiD-based MM therapy was associated with decreased risk of bleeding (HR 0.69). Table 2 shows the estimated bleeding risk associated with prophylaxis across several models. No statistically significant association was identified between major bleeding and anticoagulant prophylaxis. Discussion: In a real-world analysis of commercial claims data, the risk of major bleeding associated with VTE prophylaxis in patients with MM undergoing cancer therapy is low and no significant increase in bleeding risk was identified for concurrent anticoagulant use. The rate of major bleeding events appears to be comparable between patients who receive VTE prophylaxis and those who do not. Nevertheless, underutilization of VTE prophylaxis is frequent. Higher CCI, bleeding history, hypertension, and renal disease were clinical factors associated bleeding risk, which may be included in models to help clinicians assess individual patient's risk and guide clinical decisions.

Restarting anticoagulation after chronic subdural hematoma neurosurgical evacuation: a prospective observationaL

Abstract Introduction Management of anticoagulation (AC) in patients with chronic subdural hematoma (cSDH) lacks evidences, with uncertainties regarding outcomes after neurosurgical intervention. In patients with atrial fibrillation the interruption of an anticoagulant therapy can be a risk of thromboembolic event within the first 90 days. Purpose We aimed to define safety and effectiveness of AC resumption in a single center cohort undergoing neurosurgical intervention for cSDH. Methods Consecutive patients undergoing neurosurgical intervention for evacuation of cSDH and taking anticoagulants due to atrial fibrillation were included and followed-up over time (3 to 30 months) to define evolution of cSDH thickness depending on AC restart. Secondary outcomes included: (i)ischemic stroke and major bleeding (including intracerebral hemorrhage, ICH), assessed at each visit, and (ii) recurrent cSDH needing neurosurgical re-intervention. Results Overall, we included 47 consecutive patients, mean age 82.5±7.8 years. Previous trauma emerged in 68% of cases. Patients received warfarin (n=30, 64%), low molecular weight heparin (LMWH, n=6, 13%) or direct oral anticoagulants (DOAC, n=11, 23%). Oral AC was stopped before neurosurgery (7.9±16.7 days before intervention), and 42 (89%) underwent AC reversal. Mean cSDH thickness was 2.3±0.6 cm, midline shift was detected in 94% of patients. All patients survived surgical procedure and completed a minimum of 3-month follow-up. Over a mean 8-month follow-up (range 3-29), cSDH thickness substantially decreased (baseline 2.3±0.6 cm vs follow-up 0.7±0.6 cm, p&amp;lt;0.001). Restarting anticoagulation after chronic subdural hematoma neurosurgical evacuation: a prospective observational. Overall, 26 patients (55.3%) restarted AC, 15 with DOAC, 8 with warfarin, 3 with LMWH. Compared to no AC, AC resumption was not associated with changes in cSDH thickness (0.7±0.7 cm vs 0.9±0.6 cm, p=0.4) or modified Rankin scale at follow-up (2.6±1 vs 2±1.3, p=0.3). Four patients restarting AC had cSDH recurrence requiring re-intervention vs 0 in those avoiding AC (p=0.11); 3 of 4 were post-traumatic. No peri-interventional complications occurred. No ischemic stroke or major bleeding was detected during AC withdrawal. Conclusions The study has obviously limitations due to its preliminary nature. Even though, resumption of anticoagulation after neurosurgical intervention for cSDH seems safe, with no significant increase in recurrence rate and cSDH width over time. Longitudinal data from prospectively collected larger cohorts are needed to guide management.

Venous Thromboembolism Prophylaxis in Foot and Ankle Surgery: A Worldwide Survey

Current recommendations on thromboprophylaxis for foot and ankle (FA) surgery are often inconsistent and generally based on weak evidence. The aim of this survey study was to evaluate the current practice among orthopedic surgeons regarding venous thromboembolism (VTE) prophylaxis following FA surgery. From February 2019 to March 2020, an online questionnaire was sent by e-mail to orthopedic societies across the world. The questionnaire was hosted by the International Society of Thrombosis and Haemostais RedCAP platform. Topics of interest were VTE rates following FA surgery, duration and type of thromboprophylaxis, bleeding complications, VTE risk factors for prophylaxis and use of risk assessment. A total of 693 FA orthopedic surgeons from all continents completed the survey of whom 392 (57%) performed more than 200 FA procedures per year. A total of 669/693 (97%) respondents stated that thromboprophylaxis is necessary in FA surgeries. When thromboprophylaxis was prescribed, half of surgeons prescribed it for the duration of immobilization. Acetylsalicylic acid, low molecular weight heparin and direct-oral anticoagulants were, in this order, the preferred choice. Acetylsalicylic acid and low molecular weight heparin were predominantly prescribed in North America and Europe, respectively. Previous deep vein thrombosis, immobility, obesity and inherited thrombophilia were considered the main risk factors indicative of thromboprophylaxis use. In this survey, most surgeons agree that thromboprophylaxis is indicated for FA surgery, but the prescription, type and duration of prophylaxis differs greatly with a large intercontinental discrepancy. These survey results could be a foundation for developing uniform guidelines to optimize thromboprophylactic strategies in FA procedures around the world.

Moderate LMWH Anticoagulation Improves Success Rate of Hind Limb Allotransplantation in Mice.

The mouse hind limb model represents a powerful research tool in vascularized composite tissue allotransplantation, but its applicability is limited due to poor graft survival (62%-83%). Vascular thrombosis and massive hemorrhage are the major causes for these drop-outs. We hypothesize that because of better anticoagulation effect and lower risk of thrombocytopenia, application of low molecular weight heparin (LMWH) will minimize vascular complications and enhance graft and animal survival. Fifty allogeneic hind limb transplantations were performed (C57BL/6 to DBA/2 mice) using five different anticoagulation protocols. Bleeding and thromboembolic events were recorded macroscopically by postoperative hemorrhage and livid discoloration of the graft, respectively. Graft perfusion and survival were monitored daily by capillary-refill-time of graft toes within 2-3 seconds. Vascular congestion and tissue necrosis were examined by histological evaluation of hematoxylin-eosin-stained tissue sections. All transplantations were technically successful. Increase in thromboembolic events and a concomitant decrease in bleeding events were observed with the decreasing concentration of heparin in the perfusion solution. Although treatment of donor and recipient with low dose of LMWH could not reduce thromboembolic events, moderate dose effectively reduced these events. Compared with the poor outcome of graft perfusion with heparin alone, additional treatment of donor and recipient with low dose of LMWH improved graft and animal survival by 18%. Interestingly, animals treated with moderate dose of LMWH demonstrated 100% graft and animal survival. Treatment of donor and recipient mice with a moderate dose of LMWH prevents vascular complications and improves the outcome of murine hind limb transplants.

Comparative effectiveness of aspirin for symptomatic venous thromboembolism prophylaxis in patients undergoing total joint arthroplasty, a cohort study

BackgroundThis study compares the symptomatic 90-day venous thromboembolism (VTE) rates in patients receiving aspirin to patients receiving low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), after total hip (THA) and total knee arthroplasty (TKA).MethodsData were collected from a multi-centre cohort study, including demographics, confounders and prophylaxis type (aspirin alone, LMWH alone, aspirin and LMWH, and DOACs). The primary outcome was symptomatic 90-day VTE. Secondary outcomes were major bleeding, joint related reoperation and mortality within 90 days. Data were analysed using logistic regression, the Student’s t and Fisher’s exact tests (unadjusted) and multivariable regression (adjusted).ResultsThere were 1867 eligible patients; 365 (20%) received aspirin alone, 762 (41%) LMWH alone, 482 (26%) LMWH and aspirin and 170 (9%) DOAC. The 90-day VTE rate was 2.7%; lowest in the aspirin group (1.6%), compared to 3.6% for LMWH, 2.3% for LMWH and aspirin and 2.4% for DOACs. After adjusted analysis, predictors of VTE were prophylaxis duration < 14 days (OR = 6.7, 95% CI 3.5–13.1, p < 0.001) and history of previous VTE (OR = 2.4, 95% CI 1.1–5.8, p = 0.05). There were no significant differences in the primary or secondary outcomes between prophylaxis groups.ConclusionsAspirin may be suitable for VTE prophylaxis following THA and TKA. The comparatively low unadjusted 90-day VTE rate in the aspirin group may have been due to selective use in lower-risk patients.Trial RegistrationThis study was registered at ClinicalTrials.gov, trial number NCT01899443 (15/07/2013).

Intravenous enoxaparin as alternative ECMO anticoagulation over a period of 94 days: a case report

BackgroundUnfractionated heparin is used worldwide as a standard anticoagulation therapy for extracorporeal membrane oxygenation (ECMO) machines. However, its use brings about significant bleeding and thrombotic complications for critically ill patients. This case report shows that low molecular weight heparin together with ECMO-produced primary haemostasis pathology can be used as an alternative way of ECMO anticoagulation.Case presentationThis paper presents the case of a patient with respiratory failure who subsequently suffered from cardiac failure and spent 94 days on combined V-V and V-A ECMO devices (two ECMO devices running simultaneously on one patient) with intravenous enoxaparin used instead of unfractionated heparin anticoagulation. No life-threatening bleeding/thrombotic events happened during this period, nor did any technical problems with ECMO occur.ConclusionsIn this case report, continuous intravenous low molecular weight heparin anticoagulation was used as a safe alternative to ECMO anticoagulation.

The Saudi Consensus for the Management of Cancer-Associated Thromboembolism: A Modified Delphi-Based Study.

Background Cancer is a well-known risk factor of preventable thromboembolic disease. This study aims to provide guidance on the prevention and management of cancer-associated thrombosis (CT) that tailors prophylactic and therapeutic options for medical and surgical oncology patients presenting to health care settings in Saudi Arabia. Methods The present consensus was developed in concordance with the modified Delphi-based approach, which incorporates a face-to-face meeting between two voting rounds to gain experts' feedback on the proposed statements. All experts were either oncologists, hematologists, or hemato-oncologist with an active clinical and research profile in hemato-oncology. Results The experts highlighted that the comparatively high incidence of inherited thrombophilia among the Saudi population may account for a higher CT burden in the Kingdom than in other parts of the world. However, due to the lack of literature that assesses CT in Saudi Arabia, primary venous thromboembolism prophylaxis should be tailored according to a valid risk assessment of cancer patients and should be implemented in routine practice. For hospitalized medical oncology patients, the experts agreed that prophylaxis with low-molecular-weight heparin (LMWH) should be offered, regardless of the presence of acute illness. For ambulatory medical oncology patients, LMWH or direct oral anticoagulants (DOACs) prophylaxis should be offered for high-risk patients. Concerning surgical patients, they agreed that all oncology patients undergoing surgery should be offered thromboprophylaxis. In terms of secondary prophylaxis, the experts recommended continuing a prophylactic dose of anticoagulant (LMWH or DOAC), for an appropriate period depending on the cancer type and stage. Finally, they also provided a set of statements on management of CT in Saudi Arabia. Conclusion The present modified Delphi-based study combined the best available evidence and clinical experience with the current health care policies and settings in Saudi Arabia to build a consensus statement on the epidemiology, prevention, and management of CT.

Bleeding risk in patients with multiple myeloma treated for venous thromboembolism: a MarketScan analysis

BackgroundMultiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Thromboprophylaxis is thoroughly studied in MM. Contrarily, studies assessing the risk of bleeding in people with MM on anticoagulation are lacking. ObjectivesTo determine the rate of serious bleeding in patients with MM receiving anticoagulation for VTE and the clinical factors associated with bleeding risk. MethodsUsing the MarketScan commercial database, we identified 1298 people with MM treated with anticoagulation for incident VTE events between 2011 and 2019. Hospitalized bleeding was identified using the Cunningham algorithm. Rates of bleeding were calculated and Cox regression identified risk factors for bleeding. ResultsBleeding occurred in 51 (3.9%) cases during median follow-up of 1.13 years. Rate of bleeding among patients with MM on anticoagulation was 24.0 per 1000 person-years. In adjusted regression, factors associated with increased bleeding included age (HR, 1.31 per 10-year increase; 95% CI, 1.03-1.65), Charlson comorbidity index (HR, 1.29 per SD increase; 95% CI, 1.02-1.58), use of antiplatelet agents (HR, 2.4; 95% CI, 1.03-5.68), diabetes (HR, 1.85; 95% CI, 1.06-3.26), and renal disease (HR, 1.80; 95% CI, 1.05-3.16). Cumulative incidence of bleeding was 4.7%, 3.2%, and 3.4% for warfarin, low molecular weight heparin, and direct oral anticoagulants, respectively. ConclusionIn this real-world analysis, the rate of bleeding in people with MM on anticoagulation was comparable to those in other subsets of cancer-related VTE. Bleeding rate was lower with low molecular weight heparin and direct oral anticoagulants than warfarin. Higher comorbidity index, diabetes, antiplatelet agent use, and renal disease were risk factors for serious bleeding.

The Risk of Bleeding in Pregnant Women with Acute Venous Thromboembolism Treated with Anticoagulants

Introduction Women are at an increased risk of venous thromboembolism (VTE) during pregnancy and the postpartum period. VTE, which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), complicates 1 to 2 of 1000 pregnancies and is an important cause of maternal morbidity and mortality. The risk of VTE during pregnancy is increased five to ten-fold compared to the non-pregnant woman of comparable age. During pregnancy, subcutaneous weight-adjusted low-molecular-weight-heparin (LMWH) is the standard anticoagulation therapy for acute VTE. Women receive a minimum of 3 months of LMWH with treatment generally extended throughout pregnancy and for at least 6 weeks following delivery given the additional increased VTE risk during the postpartum period. Variable estimates are reported in the literature pertaining to the risk of bleeding in pregnant patients treated with therapeutic anticoagulation. The risk of major bleeding, as defined by the study, ranges between 2.9 and 30.0% according to a recent systematic review of the literature. The ability to make inference is limited by the small number of patients included in the studies and the substantial heterogeneity of bleeding definitions used. The paucity of data doesn't allow healthcare providers to accurately estimate the risk of bleeding in this population and prevents adequate patient counselling. As such, we conducted a population-based cohort study to evaluate the risk of bleeding events among pregnant women with acute VTE treated with LMWH anticoagulants. Methods We conducted a retrospective cohort study using data from electronic healthcare databases from the province of Quebec, Canada, including the Régie de l'assurance maladie du Québec (RAMQ), the Maintenance et Exploitation des Données pour l'Étude de la Clientèle Hospitalière (Med-Echo) and the Institut de la statistique du Québec (ISQ). From an inception cohort of Quebec residents with a diagnosis of incident VTE between January 1, 1998, and December 31, 2015, we created a study cohort of pregnant women diagnosed with VTE during pregnancy who received a prescription for LMWH within 15 days of the incident event. When the gestational age of pregnant women was not available in the database, a previously described algorithm was used to extrapolate the date of conception according to the delivery outcome. Women were followed until an inpatient diagnosis of bleeding within 30 days of delivery or censoring due to discontinuation of LMWH use, cessation of medication coverage eligibility, death, or the end of the study period. Major bleeding was defined as a hospitalization for bleeding within the study period. Results Of the 325,560 patients included in the inception VTE cohort, 259 pregnant patients remained after the exclusion criteria were applied. The mean age of patients was 29 years-old, 80.9% of patients had a DVT and 19.5% had a PE. 72.6% of patients received Dalteparin, while the other patients received Tinzaparin or Enoxaparin. In total, 20 patients (7.7%) experienced bleeding requiring hospitalization during the study period, 5 of which were antepartum bleeding events (1.9%). The incidence rate of major bleeding was 310.5 per 1,000 person-years (95% CI 189.6-479.5). There was no bleeding-related or all-cause related mortality in this cohort. Conclusion This study provides a population-derived estimate of bleeding in pregnant women treated with therapeutic anticoagulation for VTE during pregnancy. This study has some limitations. First, data is not available for women who do not use medical services during pregnancy, those who give birth outside a hospital setting. However, given the free universal healthcare system in the province of Quebec, the effect of this on our result is expected to be minimal. Second, the RAMQ database provides information on individuals adherent to the RAMQ drug plan and welfare recipients, but not on individuals who are covered by private insurance. This may affect the generalizability of our study findings if socioeconomic status is an effect modifier. Our results show that Dalteparin is the most used LMWH in pregnancy. This study provides an estimate of bleeding events that are clinically significant and require hospitalization. Further studies are needed to evaluate the factors associated with increased bleeding in this patient population.