Thrombotic risk determined by protein C receptor (PROCR) variants among middle-aged and older adults: a population-based cohort study

Background: The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the protein C receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives: This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequencies (MAF) < 0.1%. Results: Resequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2584 VTE exomes), 11 synonymous, 22 missense and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio of 1.5 (95%CI 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF=0.004) showed an increased VTE risk (HR=1.3; 95%CI 1.0-1.9). Conclusions: Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.

All that clots is not blood: Bone cement implantation syndrome presenting as an intracardiac mass and pulmonary embolism

Bone cement implantation syndrome (BCIS) is a rare and potentially fatal perioperative complication of cemented orthopaedics surgery. A CT-pulmonary angiogram and echocardiogram images were acquired from an 88-year-old patient who had a perioperative collapse while undergoing a revision operation for a peri-implant fracture of the right femoral neck. Findings were suggestive of an intracardiac clot connected to a saddle pulmonary artery embolus. Patient also developed disseminated intravascular coagulation. Overall findings were suggestive of bone cement implantation syndrome.

NETs in the infarct-related coronary artery – a marker or mediator of adverse outcome?

No Abstract

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population (n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Plasma Homocysteine in Behcet's Disease: A Systematic Review and Meta-Analysis

Aim To evaluate the relevance of plasma homocysteine (HC) in Behcet's disease (BD) and its clinical manifestations. Methods Systematic review of EMBASE and PubMed databases according to PRISMA guidelines from inception to July 2021; random-effects meta-analyses for continuous outcomes. Results The search strategy retrieved 48 case–control (2,669 BD and 2,245 control participants) and 5 cohort studies (708 BD participants). Plasma HC was higher in BD than in controls (p < 0.0001) with wide heterogeneity (I2 = 89.7%) that remained unchanged after sensitivity analysis according to year of article publication, age of BD participants, study size, study quality, method of HC determination, and male/female ratio >1.5; some pooled ethnicities explained a small part of the heterogeneity (I2 = 16.3%). Active BD participants had higher HC than inactive ones (p < 0.0001), with moderate heterogeneity (I2 = 49.2%) that disappeared after removal of an outlier study with very high disease activity. BD participants with any vascular involvement had higher HC than those without (p < 0.0001) with wide heterogeneity (I2 = 89.7%); subgroup analysis on venous thrombosis only changed neither effect size (p < 0.0001) nor heterogeneity (I2 = 72.7%). BD participants with ocular involvement had higher HC than those without (p < 0.0001) with moderate heterogeneity (I2 = 40.3%). Conclusion Although causality cannot be inferred, the consistency of the elevation of plasma HC in BD, particularly in patients with active disease, with vascular and ocular involvement suggests an intrinsic involvement of HC in these clinical manifestations.

Effectiveness and safety of oral anticoagulants in the treatment of acute venous thromboembolism: A nationwide comparative cohort study in France

Introduction: Data from clinical trials indicate that direct oral anticoagulants (DOACs) are non-inferior and safer than conventional therapy (low-molecular weight heparin followed by a vitamin K antagonist [VKA]) for treating venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism (PE). This study compared the effectiveness and safety of DOACs and conventional therapy in a real-world setting. Materials and Methods: This observational study used French national claims data of adult, treatment-naïve patients diagnosed with VTE (majority PE) who were hospitalized and treated for VTE with a DOAC (apixaban or rivaroxaban) or VKAs during 2013–2018. Patients with active cancer were excluded. After propensity score matching for each DOAC-VKA comparison, risks of bleeding, recurrent VTE, and all-cause mortality were compared at 6 months. Cox proportional-hazards regression was used to estimate adjusted hazard ratios of the endpoints. Results: 58137 patients were included (10775 VKAs, 10440 apixaban, 36922 rivaroxaban). Propensity score-matched cohort sizes were 7503 for apixaban and 9179 for rivaroxaban. The hazard ratio (95% confidence interval) was significantly lower for apixaban than VKAs for bleeding requiring hospitalization (0.43 [0.32-0.59]), all-cause death (0.61 [0.51-0.74]), and first-recurrent VTE (0.67 [0.52-0.85]). The hazard ratio was also significantly lower for rivaroxaban than VKAs for all-cause death (0.63 [0.53-0.74]) but not for bleeding requiring hospitalization (0.86 [0.69-1.07]) or first-recurrent VTE (0.91 [0.74-1.13]). Conclusions: Apixaban was associated with superior safety and effectiveness than VKAs. All-cause mortality was lower in both DOACs than VKAs. Our results support recommendations to use DOACs over VKAs for the treatment of VTE.

Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel vs dual antiplatelet therapy in patients with atherosclerotic disease

Aim: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy. Methods and Results: This investigation was conducted in selected cohorts of patients (n=40) with stable atherosclerotic disease enrolled within a larger prospective PD study who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI) or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays assessing of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF [collagen‐related peptide +adenosine diphosphate (ADP) +tissue factor (TF)], markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and TRAP), thrombin generation and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend towards reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP‐induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase‐1 mediated activity. Conclusions: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations support that modulating thrombin generation by means of factor Xa inhibition in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of DPI observed in clinical

Do Patients with a Family or Personal History of Venous Thromboembolism have an Increased Risk of Recurrence?

Background A family (FH) and personal history (PH) of venous thromboembolism (VTE) are commonly evaluated risk factors for recurrence. We examined the association between FH/PH of VTE and the risk of recurrence and whether a stronger history status (i.e., both FH/PH vs. no FH/PH) carries an increased recurrence risk. Methods We prospectively followed 813 patients aged ≥ 65 years with acute VTE from 9 Swiss hospitals. We classified patients into four groups: no FH/PH, FH only, PH only, and both FH/PH. The primary outcome was recurrent VTE during the full observation period. We examined the association between FH/PH status and the time to VTE recurrence using competing risk regression, adjusting for confounders and periods of anticoagulation. Results Of 813 patients with VTE, 59% had no FH/PH, 11% a FH only, 24% a PH only, and 7% had both a FH and PH of VTE. Overall, 105 patients had recurrent VTE during the full observation period. After adjustment, patients with a FH only (subhazard ratio [SHR] 0.8, 95% confidence interval [CI] 0.4–1.7), PH only (SHR 1.5, 95% CI 0.9–2.5), and both FH/PH (SHR 1.4, 95% CI 0.6–3.1) did not have an increased risk of recurrent VTE compared with those without FH/PH. When we considered the period after the completion of initial anticoagulation only, the results were similar. Conclusion Our findings indicate that in patients with acute VTE, a FH and/or PH of VTE does not convey an increased risk of recurrent VTE. In particular, we did not find a “dose–effect” relationship between FH/PH status and VTE recurrence.