New Oral Anticoagulants for Venous Thromboembolism Prophylaxis in Total Hip and Knee Arthroplasty: A Systematic Review and Network Meta-Analysis

Background: There is controversy over whether use of new oral anticoagulants (NOACs) associates with increased hemorrhage risk compared with non-NOAC. Meanwhile, determining which NOAC to use remains unclear. We aimed to summarize the evidence about NOACs in venous thromboembolism (VTE) prevention for patients with total hip and knee arthroplasty (THA and TKA).Methods: We searched RCTs assessing NOACs for VTE prophylaxis in adults undergoing THA and TKA in Medline, Embase, and Cochrane up to May 2021. Primary outcomes were VTE [included deep vein thrombosis (DVT) and pulmonary embolism (PE)], major VTE, and major bleeding. The rank probabilities of each treatment were summarized by the surface under the cumulative ranking curve area (SUCRA).Results: 25 RCTs with 42,994 patients were included. Compared with non-NOAC, NOACs were associated with a decreased risk of VTE (RR 0.68; 95% CI 0.55–0.84) and major VTE (RR = 0.52; 95% CI 0.35–0.76). Additionally, rivaroxaban, apixaban, and edoxaban but not dabigatran and betrixaban, did confer a higher efficacy compared with non-NOAC. None of the individual NOACs increased the risk of bleeding, while apixaban and betrixaban were even associated with a decreased risk of bleeding. In the comparison of different NOACs, rivaroxaban was associated with the greatest benefits in VTE (SUCRA = 79.6), DVT (SUCRA = 88.8), and major VTE (SUCRA = 89.9) prevention. Furthermore, subgroup analysis confirmed that NOACs associated with a higher efficacy tendency in patients with follow-up duration <60 days than follow-up duration ≥60 days.Conclusion: Evidence suggests that NOACs exert more benefits on VTE prophylaxis, and none of the individual NOACs increased hemorrhage compared with non-NOAC. Among various NOACs, rivaroxaban is recommended in patients with lower bleeding risk, and apixaban is recommended in patients with higher bleeding risk.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021266890].

Clinical impact of glycans in platelet and megakaryocyte biology

Humans produce and remove 1011 platelets daily to maintain a steady-state platelet count. The production of platelets by bone marrow megakaryocytes and their removal from the blood circulation are tightly regulated mechanisms, and abnormalities in both processes can result in thrombocytopenia (low platelet count) or thrombocytosis (high platelet count), often associated with the risk of bleeding or overt thrombus formation, respectively. This review focuses on the role of glycans, also known as carbohydrates or oligosaccharides, including N- and O-glycans, proteoglycans, and glycosaminoglycans, in human and mouse platelet and megakaryocyte physiology. Based on recent clinical observations and mouse models, we focused on the pathological aspects of glycan biosynthesis and degradation and its effects on platelet numbers and megakaryocyte function.

Antiplatelet and Antithrombotic Effects of Isaridin E Isolated from the Marine-Derived Fungus via Downregulating the PI3K/Akt Signaling Pathway

Isaridin E, a cyclodepsipeptide isolated from the marine-derived fungus Amphichorda felina (syn. Beauveria felina) SYSU-MS7908, has been demonstrated to possess anti-inflammatory and insecticidal activities. Here, we first found that isaridin E concentration-dependently inhibited ADP-induced platelet aggregation, activation, and secretion in vitro, but did not affect collagen- or thrombin-induced platelet aggregation. Furthermore, isaridin E dose-dependently reduced thrombosis formation in an FeCl3-induced mouse carotid model without increasing the bleeding time. Mechanistically, isaridin E significantly decreased the ADP-mediated phosphorylation of PI3K and Akt. In conclusion, these results suggest that isaridin E exerts potent antithrombotic effects in vivo without increasing the risk of bleeding, which may be due to its important role in inhibiting ADP-induced platelet activation, secretion and aggregation via the PI3K/Akt pathways.

Fatal Adverse Events of Dabigatran Combined With Aspirin in Elderly Patients: An Analysis Using Data From VigiBase

Introduction: The elderly are vulnerable to cardiovascular diseases and the incidence of atrial fibrillation (AF) and venous thromboembolism (VTE) increases significantly with age. Dabigatran is a commonly used new oral anticoagulant approved by the FDA for stroke prevention in patients with non-valvular AF and VTE treatment and prevention. Aspirin is commonly used as a preventive drug for cardiovascular diseases. AF and coronary heart disease share many risk factors, so these two diseases often coexist and thus dabigatran and aspirin are often combined in those people. The aim of this study was to analyze the clinical characteristics of fatal adverse events of dabigatran combined with aspirin in elderly patients, and to provide references for clinical rational use of drugs.Materials and Methods: Fatal adverse events related to the combined use of dabigatran and aspirin in elderly patients aged over 75 were extracted from the WHO global database of individual case safety reports (VigiBase). Well-documented reports, vigiGrade completeness score ≥0.80, or with an informative narrative, were analyzed with a focus on the clinical features of the cases.Results: From 1968 up to January 19, 2020, there were 112 eligible reports in VigiBase from 13 countries, of which 33 were identified as well-documented. Of these 33, 19 were male (58%) and 14 were female (42%), the average age of the patients was 84 (75–95 years), with five cases of extreme weights (>100 kg in one case, <50 kg in four cases). There were 31 cases of death by internal bleeding (mainly 15 of gastrointestinal hemorrhage and 12 of intracranial hemorrhage) and two cases of the sudden death of unknown cause. Medication errors existed in 15 patients. The times to onset (TTO) was provided in 24 cases, ranging from 2 days to 4 years, and in 12 patients occurred within a month. Of the 31 patients with fatal bleeding events, 29 were associated with other factors that increase the risk of bleeding, such as diseases (hypertension, renal impairment, stroke, gastrointestinal related diseases, hypothyroidism, and cancer), drugs (antiplatelets, anticoagulants, thrombolytics, P glycoprotein substrates, non-steroidal anti-inflammatory drugs, hormones, selective serotonin reuptake inhibitors, and acetaminophen) and other factors (low body weights and alcohol consumption), and 21 of these contained two or more risk factors.Conclusion: The fatal adverse events associated with the combined use of dabigatran and aspirin in elderly patients were mainly serious bleeding events, which often occurred within 1 month. Most of these cases had medication errors and most of the patients had multiple diseases, medications, or other conditions at the same time that increase the risk of bleeding. It is suggested that prescription of dabigatran and aspirin in elderly patients should go along with alertness for medication errors, care for correct dose or control of other bleeding risk factors, and the combined medication time should be as short as possible to minimise serious adverse events.

Management of Vascular Thrombosis in Patients with Thrombocytopenia

Platelets play critical roles in hemostasis and thrombosis. While low platelet counts increase the risk of bleeding, antithrombotic drugs, including anticoagulants and antiplatelet agents, are used to treat thromboembolic events. Thus, the management of thrombosis in patients with low platelet counts is challenging with hardly any evidence available to guide treatment. Recognition of the underlying cause of thrombocytopenia is essential for assessing the bleeding risk and tailoring therapeutic options. A typical clinical scenario is the occurrence of venous thromboembolism (VTE) in cancer patients experiencing transient thrombocytopenia during myelosuppressive chemotherapy. In such patients, the severity of thrombocytopenia, thrombus burden, clinical symptoms, and the timing of VTE relative to thrombocytopenia must be considered. In clinical practice, distinct hematological disorders characterized by low platelet counts and a thrombogenic state require specific diagnostics and treatment. These include the antiphospholipid syndrome, heparin-induced thrombocytopenia (HIT) and (spontaneous) HIT syndromes, disseminated intravascular coagulation, and paroxysmal nocturnal hemoglobinuria.

Respiratory tract infection and risk of bleeding in oral anticoagulant users: self-controlled case series

Objective To estimate the association between untreated, community acquired, respiratory tract infections and bleeding in oral anticoagulant users. Design Self-controlled case series. Setting General practices in England contributing data to the Clinical Practice Research Datalink GOLD. Participants 1208 adult users of warfarin or direct oral anticoagulants with a general practice or hospital admission record of a bleeding event between January 2010 and December 2019, and a general practice record of a consultation for a community acquired respiratory tract infection for which immediate antibiotics were not prescribed (that is, untreated). Main outcome measures Relative incidence of major bleeding and clinically relevant non-major bleeding in the 0-14 days after an untreated respiratory tract infection, compared to unexposed time periods. Results Of 1208 study participants, 58% (n=701) were male, median age at time of first bleed was 79 years (interquartile range 72-85), with a median observation period of 2.4 years (interquartile range 1.3-3.8). 292 major bleeds occurred during unexposed time periods and 41 in the 0-14 days after consultation for a respiratory tract infection. 1003 clinically relevant non-major bleeds occurred during unexposed time periods and 81 in the 0-14 days after consultation for a respiratory tract infection. After adjustment for age, season, and calendar year, the relative incidence of major bleeding (incidence rate ratio 2.68, 95% confidence interval 1.83 to 3.93) and clinically relevant non-major bleeding (2.32, 1.82 to 2.94) increased in the 0-14 days after an untreated respiratory tract infection. Findings were robust to several sensitivity analyses and did not differ by sex or type of oral anticoagulant. Conclusions This study observed a greater than twofold increase in the risk of bleeding during the 0-14 days after an untreated respiratory tract infection. These findings have potential implications for how patients and clinicians manage oral anticoagulant use during an acute intercurrent illness and warrant further investigation into the potential risks and how they might be mitigated.