TH Open: Companion Journal to Thrombosis and Haemostasis最新文献

Patients with cancer are at a high risk of symptomatic venous thromboembolism (VTE), which is a common cause of morbidity and mortality in this patient population. Increased risk of recurrent VTE and bleeding complications are two major challenges associated with therapeutic anticoagulation in these patients. Long-term therapy with low-molecular-weight heparins (LMWHs) has been the standard of care for the treatment of cancer-associated VTE given its favorable risk-benefit ratio in comparison with vitamin K antagonists. Direct oral anticoagulants (DOACs), which offer the convenience of oral administration and have a rapid onset of action, have recently emerged as a new treatment option for patients with cancer-associated thrombosis (CT). Randomized clinical trial data with head-to-head comparisons between DOACs and LMWHs showed that overall, DOACs have a similar efficacy profile but a higher risk of bleeding was observed in some of these studies. This review aims to identify unmet needs in the treatment of CT. We discuss important considerations for clinicians tailoring anticoagulation (1) drug-drug interactions, (2) risk of bleeding (e.g., gastrointestinal bleeding), (3) thrombocytopenia, hematological malignancies, (4) metastatic or primary brain tumors, and (5) renal impairment. Additional research is warranted in several clinical scenarios to help clinicians on the best therapeutic approach.

Background  Aprotinin is a broad-acting serine protease inhibitor that has been clinically used to prevent blood loss during major surgical procedures including cardiac surgery and liver transplantation. The prohemostatic properties of aprotinin likely are related to its antifibrinolytic effects, but other mechanisms including preservation of platelet function have been proposed. Aim  Here we assessed effects of aprotinin on various hemostatic pathways in vitro, and compared effects to tranexamic acid(TXA), which is an antifibrinolytic but not a serine protease inhibitor. Methods  We used plasma-based clot lysis assays, clotting assays in whole blood, plasma, and using purified proteins, and platelet activation assays to which aprotinin or TXA were added in pharmacological concentrations. Results  Aprotinin and TXA dose-dependently inhibited fibrinolysis in plasma. Aprotinin inhibited clot formation and thrombin generation initiated via the intrinsic pathway, but had no effect on reactions initiated by tissue factor. However, in the presence of thrombomodulin, aprotinin enhanced thrombin generation in reactions started by tissue factor. TXA had no effect on coagulation. Aprotinin did not inhibit thrombin, only weakly inhibited the TF-VIIa complex and had no effect on platelet activation and aggregation by various agonists including thrombin. Aprotinin and TXA inhibited plasmin-induced platelet activation. Conclusion  Pharmacologically relevant concentrations of aprotinin inhibit coagulation initiated via the intrinsic pathway. The antifibrinolytic activity of aprotinin likely explains the prohemostatic effects of aprotinin during surgical procedures. The anticoagulant properties may be beneficial during surgical procedures in which pathological activation of the intrinsic pathway, for example by extracorporeal circuits, occurs.

Introduction  Platelets are increasingly appreciated as key effectors during sepsis, raising the question of the usefulness of antiplatelet drugs to treat patients with sepsis. Objective  Evaluate the potential contribution of the platelet P2Y ₁₂ receptor in the pathogenesis of polymicrobial-induced sepsis and septic shock in mice. Methods  The effects of P2Y ₁₂ inhibition using clopidogrel treatment and of platelet-specific deletion of the P2Y ₁₂ receptor in mice were examined in two severity grades of cecal ligation and puncture (CLP) leading to mild sepsis or septic shock. Results  Twenty hours after induction of the high grade CLP, clopidogrel- and vehicle-treated mice displayed a similar 30% decrease in mean arterial blood pressure (MAP) characteristic of shock. Septic shock-induced thrombocytopenia was not modified by clopidogrel treatment. Plasma concentrations of inflammatory cytokines and myeloperoxidase (MPO) were similarly increased in clopidogrel- and vehicle-treated mice, indicating comparable increase in systemic inflammation. Thrombin-antithrombin (TAT) complexes and the extent of organ damage were also similar. In mild-grade CLP, clopidogrel- and vehicle-treated mice did not display a significant decrease in MAP, while thrombocytopenia and plasma concentrations of TNFα, IL6, IL10, MPO, TAT and organ damage reached similar levels in both groups, although lower than those reached in the high grade CLP. Similarly, mice with platelet-specific deletion of the P2Y ₁₂ receptor were not protected from CLP-induced sepsis or septic shock. Conclusion  The platelet P2Y ₁₂ receptor does not contribute to the pathogenesis of sepsis or septic shock in mice, suggesting that P2Y ₁₂ receptor antagonists may not be beneficial in patients with sepsis or septic shock.

Background  Unprovoked pulmonary embolism (uPE) is a severe and frequent condition. Identification of new risk factors is mandatory to identify patients that would benefit from a long-term treatment. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations that drive clonal expansion in the absence of cytopenia. Its prevalence is estimated of 5% in the population above 65 years. Since inflammation and endothelial dysfunction may share a pathophysiological pathway(1), we hypothesized that CHIP, may be a risk factor for uPE. Methods  We conducted a pilot retrospective observational study. Patients with iPE between 18 to 65 years old were included. PE was considered as unprovoked, when no transient nor persistant risk factor was present and when thrombophilia testing was negative. We excluded documented atherosclerosis, personal or familial history of VTE and presence of cytopenias. CHIP proportion in uPE patients were analyzed using next generation sequencing of the coding sequence of a custom panel composed by DNMT3A, ASXL1, SF3B1, TET2 and TP 53 . Results  Upon 61 patients with uPE consecutively included, a total of 19 somatic mutations were found in 12 patients (20%) IC95% [10 - 20]. 15 mutations were found in DNMT3A gene, 3 in ASXL1 and one in TET2 . There was no diference in terms of age, PE location, DVT presence and risk stratification in CHIP carriers and non carriers. Conclusion  We report for the first time, the presence of high rates of CHIP in patients presenting with uPE. Thus, CHIP may be a new risk factor for VTE. These results need to be confirmed in an ongoing prospective case-control study including more patients and using a more diverse gene panel to better determine CHIP incidence in uPE.

An 84 year old male with a previous history of immune thrombotic thrombocytopenic purpura (iTTP) received the first dose of COVID19 mRNA vaccine (Pfizer-Biontech). Seven days later he was diagnosed with iTTP relapse. He received in-patient treatment with therapeutic plasma exchange, high dose steroids and rituximab and subsequently recovered. This case report highlights the need to monitor patients with iTTP following vaccination.

Background  Since December 2019, an emerging outbreak of novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The aim of the present report is to describe a population with elevated levels of high-sensitive cardiac troponin T (hs-cTnT) and report on their management during the pandemic of COVID-19. Methods  In this retrospective cohort, we collected data from all patients with hs-cTnT levels of >50 ng/mL admitted to Fribourg Hospital between February 15, 2020, and April 15, 2020. The primary diagnosis for troponin elevation was recorded. Echocardiographic, electrocardiographic, and coronary angiographic data were analyzed for signs of myocardial ischemia, infarction, or other cardiomyopathies. In-hospital follow-up was performed for deaths from all causes and for cardiac deaths. Propensity score matching was used in a subgroup analysis to match COVID-19 and non-COVID-19 patients ( n  = 21 per group). Results  Overall, 215 patients with high hs-cTnT levels were enrolled. The median age was 75 [65-83] years and 30% were women. 21 patients (10%) were diagnosed with COVID-19. Of these, acute myocardial injury related to COVID-19 was the most commonly described cardiovascular manifestation during the pandemic peak. Median troponin values were not different between COVID-19 patients and non-COVID-19 patients (94 vs. 137, p  = 0.14). The number of cardiological examinations was globally low (echocardiography 51% and coronary angiography 52%) in the context of the pandemic. Patients in the COVID-19 group underwent significantly less echocardiographic examinations (19 vs. 55%, p ≤ 0.01) and coronary angiographies (5 vs. 58%, p ≤ 0.01) than non-COVID-19 patients. Overall mortality in patient with COVID-19 and elevated troponins was very high, as 38% of patients died during hospitalization including 14% for cardiac death. This trend was confirmed in the propensity score-matched analysis. Conclusion  Interpretation of troponins during the COVID-19 pandemic was complicated due to the low number of cardiovascular investigations in this context. Follow-up of patients with COVID-19 and cardiovascular events is important to assess their prognosis and to improve their care.

The performance of validated bleeding risk scores in patients with venous thromboembolism (VTE) could be different depending on the time after index event or the site of bleeding. In this study we compared the "classic" Registro Informatizado de Enfermedad TromboEmbólica (RIETE) score and the more recently developed VTE-BLEED score for the prediction of major bleeding in patients under anticoagulant therapy in different time intervals after VTE diagnosis. Out of 82,239 patients with acute VTE, the proportion of high-risk patients according to the RIETE and VTE-BLEED scores was 7.1 and 62.3%, respectively. The performance of both scores across the different study periods (first 30 days after VTE diagnosis, days 31-90, days 91-180, and days 181-360) was similar, with areas under the receiving operating characteristics (ROC) curve (AUC) ranging between 0.69 and 0.72. However, the positive predictive values were low, ranging between 0.6 and 3.9 (better for early major bleeding than for later periods). A sensitivity analysis limited to patients with unprovoked VTE showed comparable results. Both scores showed a trend toward a better prediction of extracranial than intracranial major bleeding, the RIETE score resulting more useful for early extracranial bleeding and the VTE-BLEED for late intracranial hemorrhages. Our study reveals that the usefulness of available bleeding scores may vary depending on the characteristics of the patient population and the time frame evaluated. Dynamic scores could be more useful for this purpose.