Low Molecular Weight Heparin Thromboprophylaxis Research Articles

Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin for thromboprophylaxis after cancer surgery: a systematic review and meta-analysis.

Direct oral anticoagulants (DOACs) used as an alternative to low-molecular-weight heparin (LMWH) for thromboprophylaxis after cancer surgery for venous thromboembolic events (VTE) remains unclear. This study aimed to investigate the efficacy and safety of DOACs versus LMWH in these patients. A search of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science was carried out and included all randomized controlled trials (RCTs) and observational studies that directly compared DOACs with LMWH for thromboprophylaxis in patients after cancer surgery through July 25, 2023. The primary efficacy and safety outcomes were VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB) within 30days of surgery. The risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool for RCTs and ROBINS-I tool for non-randomized studies. This study was registered in PROSPERO (CRD42023445386). We retrieved 5149articles, selected 27 for eligibility, and included 10 studies (three RCTs and seven observational studies) encompassing 3054 patients who underwent postoperative thromboprophylaxis with DOACs (41%) or LMWH (59%). Compared to LMWH thromboprophylaxis, DOACs had a comparable risk of VTE (RR:0.69[95% CI:0.46-1.02], I2 = 0%), major bleeding (RR:1.55 [95% CI:0.82-2.93], I2 = 2%), and CRNMB (RR, 0.89 [95% CI, 0.4-1.98], I2 = 31%) during the 30-day postoperative period. Subgroup analysis of VTE and major bleeding suggested no differences according to study type, extended thromboprophylaxis, tumor types, or different types of DOAC. DOACs are potentially effective alternatives to LMWH for thromboprophylaxis in patients undergoing cancer surgery, without increasing the risk of major bleeding events.

Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question

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Non‐severe COVID‐19 is associated with endothelial damage and hypercoagulability despite pharmacological thromboprophylaxis

BackgroundHypercoagulability and endothelial dysfunction are hallmarks of coronavirus disease 2019 (COVID‐19) and appear to predict disease severity. A high incidence of thrombosis despite thromboprophylaxis is reported in patients with moderate to severe COVID‐19. Recent randomized clinical trials suggest that therapeutic‐intensity heparin confers a survival benefit in moderate‐severity COVID‐19 compared to standard‐intensity heparin, potentially by harnessing heparin‐mediated endothelial‐stabilizing and anti‐inflammatory effects. ObjectiveWe hypothesized that patients with moderate‐severity COVID‐19 exhibit enhanced hypercoagulability despite standard‐intensity thromboprophylaxis with low molecular weight heparin (LMWH) compared to non‐COVID‐19 hospitalized patients. MethodsPatients with moderate COVID‐19 and a control group (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]–negative hospitalized patients) receiving LMWH thromboprophylaxis were recruited. Markers of endothelial damage and plasma thrombin generation parameters were assessed. ResultsTissue plasminogen activator levels were significantly increased in the COVID‐19 group (8.3 ± 4.4 vs. 4.9 ± 2.4 ng/ml; P = .02) compared to non‐COVID‐19–hospitalized patients. Despite thromboprophylaxis, mean endogenous thrombin potential was significantly increased among COVID‐19 patients (1929 ± 448 vs. 1528 ± 460.8 nM*min; P = .04) but lag time to thrombin generation was significantly prolonged (8.1 ± 1.8 vs. 6.2 ± 1.8 mins; P = .02). While tissue factor pathway inhibitor (TFPI) levels were similar in both groups, in the presence of an inhibitory anti‐TFPI antibody, the difference in lag time between the groups was abrogated. ConclusionsCollectively, these data demonstrate that COVID‐19 of moderate severity is associated with increased plasma thrombin generation and endothelial damage, and that hypercoagulability persists despite standard LMWH thromboprophylaxis. These findings may be of clinical interest given recent clinical trial data which suggest escalated heparin dosing in non‐severe COVID‐19 may be associated with improved clinical outcomes.

Equivalence of DOACS and LMWH for thromboprophylaxis after hip fracture surgery: Systematic review and meta-analysis

BackgroundPatients with hip fractures (HF) have an increased risk of venous thromboembolism (VTE). In elective orthopedic surgery direct oral anticoagulants (DOACs) have proven to be similarly or more effective compared to low molecular weight heparin (LMWH), but DOACs are not yet approved for thromboprophylaxis in trauma patients with HF. The aim of this study was to systematically review the literature comparing the effectiveness of DOACs and LMWH for thromboprophylaxis in trauma patients with surgically treated HF. Materials and MethodsWe searched PubMed, the Cochrane Library, Web of Science, and Embase. The primary outcome was the incidence of VTE (symptomatic and asymptomatic combined). Secondary outcomes were symptomatic VTE; a symptomatic VTE, symptomatic deep venous thrombosis (DVT); symptomatic pulmonary embolism (PE); major, clinically relevant non-major (CRNM), and minor bleeding. Meta-analysis was performed to compare the odds of VTE and secondary outcomes between DOACs and LMWH. ResultsThe search resulted in 738 titles. Five studies matched inclusion criteria. In total, 4748 hip fracture patients were analyzed (DOACs: 2276 patients, LMWH: 2472 patients). The pooled odds ratio for the risk of VTE for DOAC use was 0.52 (95% confidence interval 0.25–1.11, p = 0.09) compared to LMWH. No statistically significant differences between DOAC and LMWH were found for asymptomatic VTE, symptomatic DVT, PE, major or CRNM bleeding, and minor bleeding. ConclusionsMeta-analysis of the literature suggests that DOACs are associated with equivalent effectiveness and safety compared to LMWH.

COVID-19 Is Associated with Endothelial Dysfunction and Enhanced Plasma Thrombin Generation Despite Pharmacological Thromboprophylaxis

BackgroundHospitalised patients with severe COVID-19 (requiring critical care level support) appear to be at increased risk of thrombosis despite standard pharmacological thromboprophylaxis. The magnitude of thrombotic risk in patients with COVID-19 of moderate severity (not requiring critical care) is less clear. The optimal approach to thromboprophylaxis (and the role of intensified thromboprophylaxis) remains to be determined.Evidence of endothelial dysfunction has been widely reported in COVID-19 (particularly in severe COVID) and this may contribute to hypercoagulability.AimTo assess differences in patterns of hypercoagulability and endothelial dysfunction between a group of patients with moderate COVID-19 and a group of age-matched hospitalized patients (SARS-CoV-2 PCR negative) receiving low molecular weight heparin (LMWH) thromboprophylaxis.MethodsBlood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care level support) and a group of age-matched patients admitted with infective/inflammatory illness (SARS-CoV-2 PCR negative). All subjects received standard-dose LMWH thromboprophylaxis, with blood drawn at 12 hours post-dose (and with measurement of anti-FXa activity levels). Circulating levels of endothelial & fibrinolytic markers including ICAM, PAI-1, VCAM, soluble thrombomodulin (sTM), and tissue plasminogen activator (tPA) were determined by ELISA. Thrombin generation (TG) in platelet-poor plasma was assessed by calibrated automated thrombography in the presence of tissue factor (Final concentration, 1pM & 5pM), thrombomodulin (TM) (Final concentration, 6.25nM), and an inhibitory anti-tissue factor pathway inhibitor antibody (anti-TFPI; Final concentration 100μg/mL).Results14 COVID-19 positive subjects and 11 hospitalized controls were recruited. There were no differences in mean age (69.7±4.5 vs 61.6±4.7 years; p= 0.2) or mean Body mass index (25.7±1.1 vs 22.7±1.2 Kg/m2; p=0.1) between groups. No COVID-19 patient or control required critical care support. In the COVID group, radiological evidence of pneumonitis [diffuse (n=3) or peripheral infiltrates (n=7)] was present in the majority of cases. None of the COVID-19 cases were requiring supplemental oxygen at the time of recruitment.All controls were admitted with either respiratory or urinary infection [radiological evidence of pneumonia in 4/11; supplemental oxygen requirement in 2/11, (28-36% FiO2 via nasal cannula)].Plasma levels of sTM, ICAM, PAI-1 & VCAM were similar in both groups. Levels of t-PA were significantly higher in the COVID group (8.31±4.35 vs 4.91±2.37 ng/mL; p= 0.005). Despite similar plasma anti-Xa activity in both groups (0.06 vs 0.04 IU/mL; p=0.2), mean endogenous thrombin potential (ETP) was significantly higher in the COVID group (1929±119.7 vs 1528±138.9 nM*min; p=0.02), although peak thrombin was similar (173.6±26 vs 161.5±31nM). ETP-TM ratio was similar between groups (0.3±0.1 vs 0.2±0.1; p=0.3).Despite increased ETP, the lag time to thrombin generation was significantly prolonged in the COVID group (8.3±0.6 vs 5.8±0.5 mins, p= 0.006). This pattern has previously been observed in vascular diseases associated with altered plasma tissue factor pathway inhibitor (TFPI) activity. In the presence of an anti-TFPI antibody, the difference in lagtime between groups was attenuated (4.7±0.2 vs 3.5±0.1 mins; p= 0.002) and the difference in overall thrombin generation (delta TG) between both groups became significantly increased (Fig.1).ConclusionPlasma thrombin generation is enhanced in patients with non-severe COVID-19 despite pharmacological thromboprophylaxis. Endothelial dysfunction is also observed in this group and appears to modulate parameters of plasma thrombin generation. The clinical implications of these observations are not known although clinical studies of intensified thromboprophylaxis in attenuating thrombotic risk and other complications are ongoing.Fig 1. Inhibition of TFPI activity enhances thrombin generation in COVID-19.In the presence of an inhibitory anti-TFPI antibody, peak plasma thrombin generation was enhanced in COVID-19 in contrast to that observed among SARS-CoV-2 PCR negative hospitalised patients (339.6+25.2 vs 247.4+10.1, p=0.01). [Display omitted] DisclosuresMaguire: Actelion: Research Funding; Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Kevane: Leo Pharma: Research Funding.

Extended thromboprophylaxis following major abdominal/pelvic cancer-related surgery: A systematic review and meta-analysis of the literature

BackgroundPostoperative venous thromboembolism (VTE) is a significant source of morbidity and mortality in cancer patients undergoing major abdominopelvic surgery. Many guidelines recommend the use of extended duration postoperative low molecular weight heparin (LMWH) thromboprophylaxis, although the evidence for its overall safety and efficacy is unclear. AimsWe sought to assess the 30-day postoperative rates of VTE and bleeding complications following major abdominopelvic cancer surgery and to explore the potential risks and benefits of extended duration thromboprophylaxis with LMWH in such setting. MethodsA systematic search of the literature was conducted. Observational studies and RCTs of adult patients that underwent abdominopelvic cancer surgery were included. Pooled proportions for the outcome measures and pooled relative risks for the extended duration thromboprophylaxis analyses were generated. ResultsA total of 68 studies (1,631,118 patients) were included in the analysis. The 30-day postoperative rate of VTE was 1.7% (95%CI: 1.5 to 1.9, I2 = 98%). The postoperative rate of clinically-relevant bleeding complications was 3.5% (95%CI: 1.6 to 6.1, I2 = 99%). Extended duration thromboprophylaxis was associated with a significant reduction in the incidence of clinical VTE (1.0% vs 2.1%; Risk ratio (RR) 0.48, 95%CI: 0.31 to 0.74; I2 = 0), without a significant increase in clinically-relevant bleeding (4.0% vs. 4.9%; RR 1.0, 95%CI: 0.66 to 1.5, I2 = 0). ConclusionsThe overall risk of symptomatic VTE within 30 days of surgery was relatively low. Extended LMWH thromboprophylaxis following major abdominopelvic cancer surgery was associated with a reduced incidence of clinical VTE without an increase in clinically-relevant bleeding.

Monitoring of Low Molecular Weight Heparin Thromboprophylaxis with Alternative Methods to Anti-Factor Xa

Introduction: Initiating low molecular weight heparin (LMWH) thromboprophylaxis too early in patients with traumatic braininjury increases the risk of intracranial bleeding. Therefore, it is important to monitor LMWH and asses when it is safe to initiate.The aim of this research was to study alternative monitoring methods for LMWH than the standard method anti-factor Xa (antiFXa), and to investigate the peak anti-FXa level. We hoped to answer “How do rotational thromboelastometry (ROTEM) andSonoclot change at different LMWH concentrations added in vitro to blood from intensive care patients? How do point of careparameters change after subcutaneous LMWH administration on healthy volunteers with consecutive measurements to catch thepeak effect?”.Methods: Different concentrations of enoxaparin were added in vitro to citrated whole blood from fifteen intensive care patients.The first ten patients’ coagulation was analysed with ROTEM using the INTEM and NATEM assays, and the last five withSonoclot with a kaolin activator and ROTEM INTEM. Previously collected data was used from nine healthy volunteers that hadreceived subcutaneous enoxaparin. Citrated blood samples were collected before and after LMWH initiation and analysed withSonoclot kaolin and a chromogenic anti-FXa-assay. Friedman test, Dunn’s multiple comparison test and Spearman’s correlationtest were performed.Results: ROTEM INTEM CT, CFT, A10 and MCF were significantly affected with increasing in vitro enoxaparin from 0.4anti-FXa concentration. ROTEM NATEM CT was also prolonged at this LMWH concentration. Sonoclot’s parameters didn’tsignificantly change with increasing in vitro enoxaparin. The peak of in vivo LMWH was reached after 2 to 4 hours with avariation of peak anti-FXa between 0.3-0.5 IU/mL.Conclusions: ROTEM INTEM CT performed best and was prolonged at anti-FXa from 0.4-0.6 IU/mL. ROTEM INTEM shouldbe tested in neurointensive care to increase the safety of LMWH thromboprophylaxis and possibly to individualize the dosage. (Less)

Safety of Preoperative Low-Molecular-Weight Heparin in Patients Who Underwent Hepatectomy

Background: Although international guidelines advocate preoperative venous thromboembolism (VTE) chemoprophylaxis for hepatectomy, there are still safety concerns. Methods: We conducted a medical chart review of patients who underwent hepatectomy from 2016 to 2020 in a tertiary hospital in Thailand. Our center has applied preoperative chemoprophylaxis protocols with low-molecular-weight heparin (LMWH) since 2018. The rates of post-hepatectomy hemorrhage (PHH) were compared between patients receiving and those not receiving preoperative LMWH. Results: Of 204 patients who underwent hepatectomy, 186 were eligible for the analysis. Moreover, 48% were included in the LMWH group. Major hepatectomies accounted for approximately 50% in both LMWH and No-LMWH groups. The overall PHH rate was 3.8% and was not different between the LMWH (4.4%) and No-LMWH groups (3.1%). PHH was significantly associated with intraoperative blood transfusion > 2 units and post-hepatectomy liver failure. Postoperative VTE developed in 0.5% of patients. Conclusion: No association between PHH and preoperative VTE prophylaxis for hepatectomies was found. Although half of patients in this study underwent major hepatectomies, the PPH rate was low. A single dose of preoperative LMWH plus mechanical thromboprophylaxis may be appropriate in populations with low incidence of VTE. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: This study was approved by the Prince of Songkla University Hospital Ethics Committee (approval no. REC. 63443101).

Direct Oral Anticoagulants Are a Potential Alternative to Low-Molecular-Weight Heparin for Thromboprophylaxis in Trauma Patients Sustaining Lower Extremity Fractures

BackgroundTrauma patients are at a significant risk of venous thromboembolism (VTE), with lower extremity fractures (LEF) being independent risk factors. Use of direct oral anticoagusants (DOACs) for VTE prophylaxis is effective in elective orthopedic surgery, but currently not approved for trauma patients. The primary objective of this study was to compare the effectiveness and safety of thromboprophylaxis of DOACs with low-molecular-weight heparin (LMWH) in trauma patients sustaining LEF. Materials and methodsWe included adult trauma patients admitted to trauma quality improvement program participating trauma centers (between 2013 and 2016), who sustained LEF and were started on DOACs or LMWH for thromboprophylaxis after admission. Propensity score matching was performed to compare symptomatic VTE and bleeding control interventions between the groups. ResultsOf 1,009,922 patients in trauma quality improvement program, 167,640 met inclusion criteria (165,009 received LMWH and 2631 received DOACs). After propensity score matching, 2280 predominantly elderly (median age: 67 y) isolated femur fracture patients (median ISS: 10) were included in each group (4560 patients in total). Symptomatic VTE occurred in 1.4% of patients in both matched groups (P = 0.992). Bleeding control interventions occurred less often in the DOAC group, albeit statistically insignificant (5.8% versus 6.0%, P = 0.772). ConclusionsThis study found similar rates of VTE and bleeding control measures for thromboprophylaxis with DOACs or LMWH in matched trauma patients with LEF. Further prospective research is warranted to consolidate the safety of DOAC thromboprophylaxis in trauma patients with LEF. Favorable oral administration and likely increased adherence could benefit this high-risk population.

COVID-19-Associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults with COVID-19

Background:COVID-19-associated coagulopathy increases mortality in patients with COVID-19 infection. The International Society of Thrombosis and Hemostasis (ISTH) has published a guidance document recommending thromboprophylaxis with low-molecular weight heparin (LMWH) for all hospitalized patients with COVID-19. Despite standard dose LMWH thromboprophylaxis, arterial and venous thrombotic events occur in up to 30-40% of COVID-19 patients admitted to the intensive care unit (ICU). It is not known if patients with coagulopathy from COVID-19 benefit from higher levels of prophylactic anticoagulation therapy. No data exist regarding the comparative safety or efficacy of intermediate dose versus standard prophylactic dose LMWH.Study Design and Methods:This is a multi-center, randomized, open-label study (NCT04360824) comparing standard prophylactic dose enoxaparin (40 mg SC daily if BMI < 30 kg/m2; 30 mg SC twice daily or 40 mg SC twice daily if BMI ≥ 30 kg/m2) versus intermediate-weight adjusted dose enoxaparin (1 mg/kg SC daily if BMI < 30 kg/m2 or 0.5 mg/kg SC twice daily if BMI ≥ 30 kg/m2) in hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are either admitted to an intensive care unit or have a modified ISTH Overt DIC score ≥ 3.Objectives:The primary endpoint is to compare all-cause 30-day mortality of patients treated with standard prophylactic dose versus intermediate-dose enoxaparin. The secondary endpoints are to determine whether the use of standard prophylactic dose versus intermediate dose enoxaparin impacts major bleeding, arterial thrombosis, venous thrombosis, time to intubation or transfusion of blood products. The exploratory endpoints are to determine the effects of SARS-CoV-2 infection on laboratory coagulation parameters to better understand the mechanism of COVID-19 coagulopathy compared to healthy control subjects; parameters include citrullinated histone H3 (H3Cit), a component of neutrophil extracellular traps. The null hypothesis is that intermediate dose enoxaparin (intervention arm) will have a mortality rate that is not less than standard prophylactic dose enoxaparin (standard of care arm). Assuming a true margin of 20%, a sample size of 82 patients in each arm of the study is required to have 80% power when testing for a difference.Baseline Data:Three centers are currently enrolling patients. As of August 1, 2020, we have enrolled 52 patients (28 males and 24 females) with a median age of 61 years (range 24-80). 51% were Caucasian, 36% Hispanic, and 16% other ethnicities. Median BMI was 31 kg/m2 (range 20-52). Baseline D-Dimer was elevated in 95% of participants with a median of 2.23 mg/mL (range 0.39-40.32). The majority of participants had normal baseline PT, PTT, and platelet levels. All patients had fibrinogen levels over 100 mg/dL with a median of 607 mg/dL. Plasma H3Cit was elevated significantly in patients with COVID-19 (n = 21) vs healthy control subjects (n = 10) (6.48 vs 1.09 ng/mL, P = 0.001).Conclusion:Baseline data for the first 52 patients enrolled confirm the presence of multiple risk factors for thrombosis such as elevated BMI, D dimer, and plasma markers of neutrophil extracellular traps. In contrast to initial reports from China, the prevalence of thrombocytopenia and hypofibrinogenemia was very low in our cohort. Hispanics represented 36% of our study population, compared with 19% of overall COVID-19 infections in the region, suggesting a higher severity of illness in this subpopulation. The enrollment of this trial is ongoing with the addition of sites that have larger African American populations. As safety and efficacy data mature, this study will help clarify the optimum dose of prophylactic enoxaparin to prevent COVID-19 associated coagulopathy.DisclosuresNo relevant conflicts of interest to declare.

Prophylaxis with rivaroxaban after laparoscopic sleeve gastrectomy could reduce the frequency of portomesenteric venous thrombosis

Portal and mesenteric venous thrombosis is a rare but potentially serious complication after laparoscopic sleeve gastrectomy. There are no consistent studies that prove the safety and effectiveness of oral anticoagulant thromboprophylaxis with rivaroxaban after laparoscopic sleeve gastrectomy. The objective was to evaluate the effect of rivaroxaban on the frequency of portal and mesenteric venous thrombosis and its safety profile after laparoscopic sleeve gastrectomy. This retrospective analysis of prospectively collected data includes all laparoscopic sleeve gastrectomies performed by a single surgeon at Pontificia Universidad Católica de Chile Hospital between January 2009 and June 2019. All patients received low molecular weight heparin thromboprophylaxis during the whole hospital stay. Between July 2012 and June 2019, patients received additional post-discharge thromboprophylaxis with rivaroxaban. Patient demographics, impaired renal, post-surgical portal and mesenteric venous thrombosis, and bleeding episodes were registered. A total of 516 patients were identified; 95 patients were excluded. Results for 421 patients were analysed: 198 received only intrahospital thromboprophylaxis (group 1) and 223 received additional post-discharge thromboprophylaxis with rivaroxaban (group 2). There was no statistically significant difference between the two groups concerning age, sex and body mass index. In group 1, four cases of portal and mesenteric venous thrombosis were registered and no cases were reported in group 2 (p < 0.05). All cases occurred before 30 days after surgery. No bleeding episodes and no adverse reactions were detected in group 2. Thromboprophylaxis during the whole hospital stay (two to three days), followed by rivaroxaban 10mg once daily for 10 days after discharge (completing in total 13-14 days of prophylaxis), could reduce cases of post-surgical portal and mesenteric venous thrombosis without an increase in bleeding complications.

Continuous intravenous infusion of enoxaparin controls thrombin formation more than standard subcutaneous administration in critically ill patients. A sub-study of the ENOKSI thromboprophylaxis RCT.

Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis. Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h. At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05). Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.

Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial

AbstractHospitalized patients with cancer are at an increased risk of developing venous thromboembolism (VTE). The recommendation for routine pharmacologic thromboprophylaxis in hospitalized patients with cancer to prevent VTE is based on extrapolation of results from noncancer cohorts. There are limited data to support the efficacy and safety of fixed-dose low-molecular-weight heparin (LMWH) regimens in high-risk hospitalized patients with cancer. We conducted a randomized, double-blinded, phase 2 trial in hospitalized patients with active cancer at high risk of developing VTE based on Padua risk score. Patients were randomly assigned to fixed-dose enoxaparin (40 mg daily) vs weight-adjusted enoxaparin (1 mg/kg daily) during hospitalization. The primary objectives were to evaluate the safety of dose-adjusted enoxaparin and evaluate the incidence of VTE with fixed-dose enoxaparin. Blinded clinical assessments were performed at day 14, and patients randomly assigned to fixed-dose enoxaparin subsequently underwent a bilateral lower extremity ultrasound. A total of 50 patients were enrolled and randomized. The median weight of patients enrolled in weight-adjusted enoxaparin arm was 76 kg (range, 60.9-124.5 kg). There were no major hemorrhages or symptomatic VTE in either arm. At time of completion of the blinded clinical assessment, there was only 1 incidentally identified pulmonary embolus that occurred in the weight-adjusted arm. In the group randomly assigned to fixed-dose enoxaparin who subsequently underwent surveillance ultrasound, the cumulative incidence of DVT was 22% (90% binomial confidence interval, 0%-51.3%). This phase 2 trial confirms a high incidence of asymptomatic VTE among high-risk hospitalized patients with cancer and that weight-adjusted LMWH thromboprophylaxis is feasible and well-tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02706249.

Efficacy and safety of direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH) for primary prevention of venous thromboembolism (VTE) in ambulatory cancer patients.

12088 Background: Active malignancy is a well described risk factor for thrombosis. Randomized clinical trials (RCT) have evaluated anticoagulation (AC) with DOACs or LMWH for prevention of VTE in ambulatory cancer patients. This objective of this meta-analysis is to evaluate the efficacy and safety of DOACs and LMWH thromboprophylaxis in adult patients with active solid organ malignancy or lymphoma. Methods: We conducted a search of MEDLINE, EMBASE, and CENTRAL from 10/31/2009-11/31/2019. Data for meta-analysis was extracted from studies that met inclusion criteria (RCT, ambulatory patients age &gt;18 years with active solid organ malignancy or lymphoma, prophylactic AC with DOAC or LMWH). Risk ratio (RR) were calculated for primary (efficacy) end point of VTE occurrence and secondary (safety) end points of major bleeding (MB) and clinically relevant non-major (CRNMB). Subgroup analyses of efficacy and safety endpoints were conducted based on AC and cancer types. Results: Eleven trials met inclusion criteria with total of 7741 participants. Two trials evaluated DOACs and nine trials evaluated LWMH for thromboprophylaxis. Efficacy results are noted in Table. Safety outcomes for MB and CRNMB for AC were RR 1.83 (95% CI 1.26, 2.65), p=0.001 and RR 1.36 (95% CI 1.05, 1.76), p=0.02. Safety outcomes for MB and CRNMB for DOAC were RR 1.95 (95% CI 0.88, 4.30), p=0.10 and RR 1.35 (95% CI 0.80, 2.27), p=0.26. Safety outcomes for MB and CRNMB for LMWH were RR 2.05 (95% CI 1.19, 3.51), p=0.009 and RR 1.44 (95% CI 1.01, 2.05), p=0.04. Conclusions: Both DOACs and LMWH decrease risk for VTE development in ambulatory adult cancer patients. MB and CRNMB were significantly increased in patients taking LMWH but not in patients taking DOACs. A large clinical trial using DOACs for thromboprophylaxis would help elucidate the thrombosis and bleeding event rate in ambulatory cancer patients. [Table: see text]

COVID19 coagulopathy in Caucasian patients.

SummaryAlthough the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung‐centric coagulopathy may play an important role. Elevated D‐dimer levels which correlated inversely with overall survival were recently reported in Chinese cohort studies. Critically however, ethnicity has major effects on thrombotic risk, with a 3–4‐fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African‐Americans. In this study, we investigated COVID19 coagulopathy in Caucasian patients. Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity. Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC). In rare COVID19 cases where DIC does develop, it tends to be restricted to late‐stage disease. Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary‐specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC. Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality.

Changes in Coagulation and Fibrinolysis in Post-Cesarean Section Parturients Treated With Low Molecular Weight Heparin.

Background:Cesarean section is an independent risk factor for Venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is extensively used for VTE prophylaxis after cesarean section. In this study, the effects of LMWH on coagulation and fibrinolysis after cesarean section and its clinical value were explored by studying the changes in laboratory indicators.Methods:Antepartum and postpartum peripheral blood of 44 pregnant women who underwent vaginal delivery and 44 pregnant women who underwent cesarean section treated per routine with LMWH thromboprophylaxis on the first day post-operatively were collected for the following tests: D-dimer; thrombotic markers such as thrombomodulin (TM), thrombin-antithrombin complex (TAT), α2-plasmin inhibitor-plasmin complex (PIC), and tissue plasminogen activator inhibitor complex (t-PAIC); thromboelastography.Results:Compared to the antepartum levels, PIC increased, TM, TAT, and t-PAIC decreased significantly in the parturients after a spontaneous vaginal delivery. Compared to the antepartum levels, parturients routinely treated with LMWH after cesarean section had higher PIC levels and lower D-dimer, TAT, and t-PAIC levels. Compared with parturients after vaginal delivery, parturients treated with LMWH after cesarean section had higher levels of TM, R, and MA, while there was no significant differences in the levels of D-dimer, TAT, PIC, t-PAIC, K, angle, LY30, and CI.Conclusion:The coagulation and fibrinolytic systems in gravidas and parturients are in a high level of dynamic equilibrium. The levels of coagulation and fibrinolytic system activation were similar in parturients who were routinely treated with LMWH after cesarean section compared with parturients after a spontaneous vaginal delivery.

Pulmonary embolism in cases of COVID-19.

Emerging reports indicate a high incidence of venous thromboembolism in patients hospitalised for SARS-CoV-2pneumonia during the spring 2020pandemic. The pronounced pulmonary and systemic inflammatory responses observed in these patients may contribute to a transient hypercoagulable state. In this setting, pulmonary embolism may cause further respiratory distress and clinical deterioration. We describe the clinical course of three patients admitted with SARS-CoV-2 infection and respiratory distress, where pulmonary embolism was detected during the course of the hospitalisation. Two of the cases occurred despite early institution of standard dosage of low molecular weight heparin thromboprophylaxis, and in one case, pulmonary embolism was diagnosed during the convalescent phase of an otherwise benign COVID-19 disease course. These cases highlight the importance of awareness of the potentially increased incidence of venous thromboembolism in COVID-19 disease. Further research is required to establish appropriate clinical management guidelines for prevention of thromboembolic complications in COVID-19.

227: Factors associated with women's adherence to postpartum thromboprophylaxis: a prospective cohort study

Postpartum low-molecular-weight heparin (LMWH) thromboprophylaxis is indicated for a substantial proportion of women. We assessed women's adherence to postpartum thromboprophylaxis and the factors associated with adherence. This prospective cohort study was conducted at a university hospital during 2018. Parturients for whom a recommendation for LMWH prophylaxis was given at discharge from the maternity ward were contacted at the end of the recommended post-discharge course of LMWH, and were invited to participate in a telephone survey. The main outcome measures were optimal (>80%) and suboptimal adherence (< 80%) to LMWH administration, reasons for nonadherence, and views regarding LMWH, as assessed by an adapted Beliefs about Medication Questionnaire. Overall, 250 women completed the questionnaire. The median recommended duration of post-discharge LMWH was 7 [5-8] days. Suboptimal adherence was reported by 82 (32.8%); 45 (18.0%) women did not administer any LMWH dose following discharge and only 147 (58.8%) completed the full LMWH course. In multivariate analysis, optimal adherence was positively associated with patients' perceptions of the necessity of LMWH (odds ratio [95% CI]: 3.50 (2.12, 9.53), P=0.002) and of the adequacy of explanation given prior to discharge regarding LMWH technical administration (odds ratio [95% CI]: 5.0 (2.33, 11.11), P< 0.001). Nearly one-third of women prescribed postpartum LMWH thromboprophylaxis reported suboptimal adherence. Patients' perceptions of the necessity of the treatment and their opinion of the adequacy of explanation regarding LMWH technical administration were identified as predictors of treatment compliance, and thus represent potential areas for improvement.

Epidural Hematoma Following Low Molecular-weight Heparin Prophylaxis and Spinal Anesthesia for Cesarean Delivery

(Int J Obstet Anesth. 2019;37:118–121) Epidural hematoma is a rare complication of spinal anesthesia while cesarean delivery (CD) is a risk factor for maternal venous thromboembolism. The more frequent use of pharmacologic prophylaxis with unfractionated or low–molecular-weight heparin (LMWH) in higher risk women has been recommended as a strategy to decrease venous thromboembolism. This case report described the development of a spinal-epidural hematoma in a parturient who received spinal anesthesia for a planned, repeat CD after receiving LMWH thromboprophylaxis.

Apixaban Versus Dalteparin for Thromboprophylaxis in Patients with Acute Spinal Cord Injury: A Pilot Study

Background: Patients with acute spinal cord injury (SCI) have a high risk of venous thromboembolism despite thromboprophylaxis. Low molecular weight heparin (LMWH), the current standard of care, is inconvenient for long term thromboprophylaxis, costly, and partially effective. Direct oral anticoagulants (DOACs) have been shown to be at least as effective and as safe as LMWH in other thromboprophylaxis settings but there is no randomized evaluation of DOACs in this population. Aim: By conducting a feasibility randomized trial, we aimed to determine the likely recruitment rate of eligible patients into an RCT in which patients with acute SCI were randomized to a prophylactic dose of LMWH or apixaban. Methods: A pilot study was performed at Hamilton General Hospital (HGH). Adult patients with an acute traumatic SCI presenting to the hospital within 1 week of SCI and at least 36 h after the injury were included. Exclusion criteria were the need for therapeutic oral anticoagulation prior to enrolment; active bleeding, intracranial or peri-spinal hematoma, or a bleeding disorder; pregnancy or breastfeeding; severe renal failure (creatinine clearance ≤30 ml/min); severe cirrhosis (Child-Pugh class C); severe thrombocytopenia (platelets &lt;50), unsuitability as determined by the attending physician; geographic inaccessibility; failure to obtain written consent; previous hypersensitivity to study drugs; or expected short hospital admission (≤7 days) due to a minor injury. Eligible patients were randomized to apixaban 2.5 mg twice daily or dalteparin 5000 units once daily for 90 days or until fully mobilized, whatever came first. The primary feasibility outcome was recruitment rate per year. We expected a recruitment rate of 20 patients per year based on an estimated admission rate in a retrospective study at HGH. The primary efficacy outcome was a composite of symptomatic, objectively verified, venous thromboembolism (upper or lower limb deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) or sudden death where PE cannot be excluded. This outcome did not include a catheter-associated DVT. The primary safety end-point was major bleeding. Results: A total of 26 eligible patients were screened and 8 patients were enrolled per year resulting in a recruitment yield of 30.8% (95% confidence interval: 16-50%). The reasons for exclusion included: presence of an epidural hemorrhage (n=8), failure to obtain consent (n=2), not suitable for the study (n=2), &gt;1 week from SCI (n=2), indication for therapeutic anticoagulation (n=2), active bleeding (n=1), and minor injury with an expected short hospital admission (n=1). Four patients were randomized to each drug. Median age was 61 (range 51 to 70) and 7 (87.5%) were males. There were no symptomatic VTE or sudden deaths. One patient randomized to apixaban had major bleeding. There were no serious adverse events. Conclusions: Our pilot study is the first randomized trial to examine the role of a DOAC compared with LMWH for thromboprophylaxis in this high-risk group. The primary feasibility outcome was not met, and therefore a multicenter RCT is unlikely to be feasible. The efficacy and safety of DOACs on this indication should be evaluated in registry- or health care database studies. Disclosures Eikelboom: Heart and Stroke Foundation: Research Funding; Sanofi Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.