Venous thromboembolism (VTE) is the third most common cause of vascular mortality worldwide and comprises deep-vein thrombosis (DVT) and pulmonary embolism (PE). In this review, we discuss how an understanding of VTE epidemiology and the results of thromboprophylaxis trials have shaped the current approach to VTE prevention. We will discuss modern thromboprophylaxis as it pertains to genetic risk factors, exogenous hormonal therapies, pregnancy, surgery, medical hospitalization, cancer, and what is known thus far about VTE in COVID-19 infection.

Cell-free DNA from nuclear, mitochondrial, and bacterial sources have varying proinflammatory effects, although all three have similar procoagulant and platelet-stimulating potential. The pathophysiological effects of CFDNA in sepsis may vary with the source of DNA.

BackgroundDue to a paucity of data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with a body mass index >40 kg/m2 or a weight >120 kg, the use of DOACs in this group is not recommended.ObjectivesTo determine the proportion of obese patients with body weight >120 kg with a peak plasma concentration of DOACs lower than the expected median trough level derived from population pharmacokinetic studies for each DOAC.MethodsPatients with body weight >120 kg taking DOACs for any indication underwent a peak drug concentration measurement at steady state.Results38 patients were included in the analysis. The mean age was 64 ± 11 years, and 30 (79%) were males. The median body weight was 132.5 kg (interquartile range [IQR] 127‐146.5). The median peak concentrations (IQR) were 148 ng/mL (138‐240), 138 ng/mL (123‐156.5), 215 ng/mL (181‐249) for apixaban, dabigatran, and rivaroxaban, respectively. Two patients (5%, 95% confidence interval [CI]: 0.5%‐18%) had a peak plasma concentration lower than the median trough and eight (21%, 95% CI: 11%‐37%) had a peak plasma concentration below the fifth percentile (10th percentile for dabigatran) peak concentration.ConclusionsMost patients in our study had peak plasma concentration higher than the median trough level for each of the three DOACs. However, 21% had a peak plasma concentration that was below the usual on‐therapy range of peak concentration for the corresponding DOAC.

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having>1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

Background In patients with nonvalvular atrial fibrillation (AF), apixaban is given in doses of 5 or 2.5 mg twice daily, according to clinical characteristics. The usual ontreatment range of apixaban drug levels, as determined by apixaban-calibrated antifactor Xa (anti-Xa) activity, has previously been measured in small cohorts; however, the association between anti-Xa activity and clinical outcomes and the predictors of variability in anti-Xa activity have not been well studied in the AF population. Methods and Results Anti-Xa activity was measured before taking the morning dose, 3 months after enrollment in the AVERROES study using a calibrated anti-Xa assay (Rotachrom). Patients with two of the following criteria-age >80; weight <60 kg; or creatinine >133 μg/L-received 2.5 mg twice daily (n ¼ 145), while all others received 5 mg twice daily (n ¼ 2,247). A total of 2,392 patients were included, with median follow-up of 1.1 years. Median apixaban anti-Xa activity was 122 ng/mL (interquartile range [IQR]: 63-198 ng/mL) for the entire group; 99 ng/mL (IQR: 60-146 ng/mL) for the 2.5-mg group; and 125 ng/mL (IQR: 64-202 ng/mL) for the 5-mg group (p ¼ 0.003). A relationship was evident between bleeding and anti-Xa activity (p ¼ 0.01), which was driven by minor bleeding. No relationship was evident between major bleeding or stroke/systemic embolism and anti-Xa activity. In those receiving the 5-mg dose, estimated glomerular filtration rate, sex, and age had the strongest association with anti-Xa activity. Conclusion There is considerable variability in anti-Xa activity among AF patients receiving apixaban. Rates of major bleeding and stroke/systemic embolism were low irrespective of anti-Xa activity. Clinical Trial Registration ClinicalTrials.gov NCT00496769; https://clinicaltrials.gov/ ct2/show/NCT00496769.

Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

Background Systematic reviews reporting time trends in mortality following major orthopaedic surgery are few and have limitations. They reported on only a fraction (< 15%) of the available data and did not investigate potential causes of the reduction in mortality. Methods We searched PubMed for randomized trials and observational studies, published between 1950 and 2016, reporting on mortality within 3 months of elective total hip and knee replacement (THR/TKR). Mortality risks were estimated for each 5-year interval using a Poisson regression model and presented by study design and mode of prophylaxis. To estimate the mortality reduction unrelated to anti-thrombotic use, we performed a pooled analysis of four thromboprophylaxis strategies for which data spanned five decades. Results We identified 255 eligible studies, which documented 31,604 deaths among 6,293,954 patients, and found a consistent decline in mortality irrespective of study design and mode of prophylaxis. Mortality declined from 1.15% pre-1980 to 0.24% post-2000, a 78.7% relative risk reduction (95% confidence interval [CI]: 74.7–82.1%) in randomized and cohort studies. Furthermore, our data showed a 74.4% (95% CI: 68.7–79.0%) relative reduction in mortality independent of the methods of prophylaxis, thereby indicating that improvements in peri-operative care unrelated to anti-thrombotic prophylaxis played a major role in such reduction. Conclusion Mortality following elective THR/TKR has markedly declined over the past 50 years and is now low irrespective of which prophylactic agent is being used. Although anti-thrombotic prophylaxis may have contributed, other improvements in peri-operative care played a major role in the mortality reduction.

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially preventable cause of morbidity and mortality. Unfractionated heparin, low-molecular-weight heparin, and warfarin have been the cornerstone of VTE prevention and treatment but are being replaced by recently approved non-vitamin K antagonist oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, and edoxaban. The NOACs are at least as effective and as safe as heparins and warfarin for VTE prevention and treatment and are more convenient because they have a low propensity for food and drug interactions and are given in fixed doses without routine coagulation monitoring. The remaining limitations of currently available NOACs include their dependence on renal and hepatic function for clearance, and the lack of an approved antidote. Betrixaban is a new NOAC with distinct pharmacological characteristics: minimal renal clearance, minimal hepatic metabolism, and long half-life. It has undergone successful Phase II studies in orthopedic thromboprophylaxis, and in stroke prevention in atrial fibrillation. Currently, it is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX study). In this article, we describe the development of betrixaban, review its pharmacological profile, discuss the results of clinical trials, and examine its potential for VTE prevention and treatment.