Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

Updated Australian consensus statement on management of inherited bleeding disorders in pregnancy.

INTRODUCTION: There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors' Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion. MAIN RECOMMENDATIONS: During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid.

New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease and, globally, more than an estimated 10 million people have it yearly. It is a chronic and recurrent disease. The symptoms of VTE are non-specific and the diagnosis should actively be sought once considered. The mainstay of VTE treatment is anticoagulation, with few patients requiring additional intervention. A working group of experts in the area recently completed an evidence-based guideline for the diagnosis and management of DVT and PE on behalf of the Thrombosis and Haemostasis Society of Australia and New Zealand (www.thanz.org.au/resources/thanz-guidelines). MAIN RECOMMENDATIONS: The diagnosis of VTE should be established with imaging; it may be excluded by the use of clinical prediction rules combined with D-dimer testing. Proximal DVT or PE caused by a major surgery or trauma that is no longer present should be treated with anticoagulant therapy for 3 months. Proximal DVT or PE that is unprovoked or associated with a transient risk factor (non-surgical) should be treated with anticoagulant therapy for 3-6 months. Proximal DVT or PE that is recurrent (two or more) and provoked by active cancer or antiphospholipid syndrome should receive extended anticoagulation. Distal DVT caused by a major provoking factor that is no longer present should be treated with anticoagulant therapy for 6 weeks. For patients continuing with extended anticoagulant therapy, either therapeutic or low dose direct oral anticoagulants can be prescribed and is preferred over warfarin in the absence of contraindications. Routine thrombophilia testing is not indicated. Thrombolysis or a suitable alternative is indicated for massive (haemodynamically unstable) PE. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Most patients with acute VTE should be treated with a factor Xa inhibitor and be assessed for extended anticoagulation.

Procoagulant Effects of Low-Level Platelet Activation and Its Inhibition by Colchicine.

Platelets play an important role in diseases such as cardiovascular disease and cancer, especially through their release of extracellular vesicles (EVs) and role in thrombosis. The effects of the anti-inflammatory drug colchicine on platelets are not well understood. We investigated the effect of colchicine on the release of pro-coagulant EVs from platelets under low-level activation. Citrated platelet-rich plasma (PRP) from healthy donors was incubated with 2 mM colchicine or vehicle at 37°C for 30 minutes with gentle rotation. The incubation conditions caused mild platelet activation (expression of CD62P and increased surface lactadherin binding) and release of EVs expressing phosphatidylserine (PS, measured by binding of lactadherin), CD61 and CD62P, both of which were attenuated by colchicine. The incubation conditions shortened the delay to fibrin generation and this correlated with elevated levels of PS+/CD61+ EVs. Removal of EVs from plasma abrogated clot formation in the overall haemostatic potential (OHP) assay. Colchicine decreased levels of both PS+/CD61+ and CD62P+ EVs and abrogated the shortened delay to fibrin generation achieved by platelet activation. Similar results were observed after incubation of PRP with 200 µM vinblastine, suggesting a microtubular effect. An alternative method of platelet activation using platelet agonists 20 µM ADP or 10 µM epinephrine also increased CD62P+ EV levels, and this too was attenuated by prior incubation with colchicine. Our novel findings demonstrate procoagulant effects of low-level platelet activation and EV formation which are inhibited by colchicine.

Characterization of the hypercoagulable state following severe orthopedic trauma.

BACKGROUND: Acute traumatic coagulopathy develops in seriously injured patients, which is followed by a paradoxical hypercoagulable state. The hypercoagulable state contributes to venous thromboembolism, and yet, there are no sensitive tests available to detect it. The aim of this study was to characterize the hypercoagulable state caused by major orthopedic trauma using the overall hemostatic potential (OHP) assay. METHODS: Major orthopedic trauma patients admitted during a 7-month period in 2012 were included in the study. Blood samples were drawn 1 hour before surgery, then 1, 7, 24 hours and 3, 5, 10, and 42 days postoperatively. The assay parameters were determined and analyzed according to injury severity (polytrauma or nonpolytrauma), type of surgical intervention, and shock status. Values were compared with 20 healthy controls. RESULTS: Forty-one consecutive patients were enrolled (age, 41.5 ± 2.7 years; 70% male; Injury Severity Score [ISS], 21.5 ± 2.1). Hypercoagulability based on OHP was present in the preoperative sample compared with the controls (OHP, 13.8 ± 1.4 U vs. 8.1 ± 0.5 U; p = 0.020) and then further elevated after surgery (1 hour postoperative, 17.8 ± 2.0 U vs. preoperative, 13.8 ± 1.4 U, p = 0.008). Polytrauma patients were more hypercoagulable than nonpolytrauma at the preoperative sample time (17.7 ± 2.6 U vs. 10.7 ± 1.2 U, p = 0.040) and postoperative period (24.3 ± 3.4 U vs. 11.9 ± 1.4 U, p = 0.006). The OHP for patients undergoing open pelvic surgery (28.3 ± 3.0 U) was higher than both intramedullary nailing (16.2 ± 2.0 U) and percutaneous pelvic surgery (17.0 ± 1.7 U) on Day 5 (p < 0.05). Patients demonstrated a higher OHP than controls did at all time points, except at 6 weeks (patients, 10.8 ± 1.7 U vs. controls, 8.1 ± 0.5 U; p = 0.400). CONCLUSION: The OHP assay detected the hypercoagulable state following major orthopedic trauma and surgical intervention, which was present for 10 days postoperatively. The extent of hypercoagulability could be associated with polytrauma and the type of surgical intervention; however, further studies are needed to confirm this. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Natural history of hypercoagulability in patients undergoing coronary revascularization and effect of preoperative myocardial infarction.

OBJECTIVES: The balance between hyper- and hypocoagulable states is critical after coronary artery surgery both with (coronary artery bypass grafting [CABG]) and without (off-pump coronary artery bypass [OPCAB]) cardiopulmonary bypass to prevent thrombotic or bleeding complications. We aimed to quantify novel parameters of coagulation, fibrinolysis, and overall hemostasis ≤6 months after CABG and OPCAB and to determine the influences on these parameters. METHODS: A total of 63 patients (30 CABG, 33 OPCAB) had blood collected before and at various points ≤6 months after surgery. Fibrin and fibrinolysis time curves were generated by measuring the absorption of 405 nm each minute for 100 minutes after the addition of tissue factor and tissue plasminogen activator to cell-free plasma. The parameters were compared with those from a group of healthy controls. RESULTS: The patients' preoperative prothrombotic assay parameters were compared with those from healthy controls. Both CABG and OPCAB patients were hypercoagulable until at least day 10 after surgery, with elevation of fibrin generation (CABG, peak day 3, +28.9%; OPCAB, peak day 1, +16.3% vs preoperative baseline) and impairment of fibrinolysis capacity (CABG, day 1, -58.4%; OPCAB, day 1, -22.6%). Surgical revascularization resulted in resolution of preoperative hypercoagulability by 6 months postoperatively. Patients with preoperative myocardial infarction (MI) had prolonged hypercoagulability after surgery that was most exaggerated after CABG (overall hemostatic potential day 5, no MI, +64.1% vs with MI, +128.9% compared with baseline; P = .013). CONCLUSIONS: Patients will be vulnerable to thrombotic events for ≤6 weeks after coronary surgery yet will have resolution of hypercoagulability by 6 months. Preoperative factors, such as MI, could require individualized management of thrombosis prophylaxis in the postoperative period.

Detection of hypofibrinolysis in stable coronary artery disease using the overall haemostatic potential assay.

INTRODUCTION: Patients with stable coronary artery disease (CAD) are at risk of arterial thrombosis causing myocardial infarction. Detection of global haemostatic markers of hypercoagulability and hypofibrinolysis may be important for risk stratification and individualised treatment. We examined overall haemostatic potential (OHP) and thrombin generation in a group of stable CAD patients. We also sought to investigate associations between fibrinolytic inhibitors and abnormal global fibrinolysis in these patients. MATERIALS AND METHODS: Blood samples were collected from 56 patients defined by coronary anatomy as symptomatically stable CAD. Medications were recorded. Samples were analysed using the global coagulation assays OHP and thrombin generation (calibrated automated thrombogram, CAT), platelet aggregometry measured by Multiplate®, and levels of plasminogen activator inhibitor-1 (PAI-1) antigen measured by ELISA. Results were compared with a reference group of healthy controls. RESULTS: Stable CAD patients displayed increased fibrin and thrombin generation and impaired fibrinolysis (decreased overall fibrinolytic potential, OFP, and increased clot lysis time) compared with healthy controls. No effect of antiplatelet agents or other medications on these parameters was observed using platelet-poor plasma. After multivariate adjustment, OFP of healthy individuals was significantly associated with fibrinogen, but in CAD patients PAI-1 became an important determinant. CONCLUSIONS: Hypercoagulability of plasma is observed in stable CAD, with both increased thrombin generation and reduced fibrinolytic potential making a significant contribution. The OHP assay may provide a simple method of identifying hypercoagulability in individual patients.