The coagulopathy caused by SARS-CoV-2 seen in patients hospitalised with COVID-19, especially those with severe or critical illness, is by now well established. Early reports in relatively small studies showing multifold elevated rates of both venous and arterial thromboembolism have given way to more sober estimates from much larger populational studies and systematic reviews or meta-analyses. Overall rates of venous thromboembolism, including in-situ pulmonary thrombosis, are approximately three-times higher than historical matched controls of hospitalised populations, whereas rates of arterial thromboembolism, including acute coronary syndromes and stroke, although still elevated, are lower than previously described. 1 Microvascular thrombotic mechanisms have been implicated in progression to acute respiratory distress syndrome and subsequent need for organ support, and autopsy studies have identified unsuspected pulmonary embolism or in-situ pulmonary arterial thrombosis in nearly 60% of patients, suggesting that thrombosis has an important role in mortality. 2, 3 Proposed mechanisms for these microvessel thrombotic and intravascular coagulopathic mechanisms and classic macrovessel thromboembolism are complex and include patientrelated risk factors seen in medical patients hospitalised with pneumonia and sepsis, as well as more SARS-CoV-2-dependent mechanisms, including endothelial dysfunction, hyperinflammation and cytokine storm, formation of neutrophil-extracellular traps, complementsystem activation, hypofibrinolysis, and platelet-derived and coagulation-derived mechanisms of thrombin generation leading to thromboinflammation. 4 Given this tendency for thrombotic complications with COVID-19, several multicentre randomised trials of antithrombotic therapies were launched globally as a logical next step to test whether the addition or escalated dosing of antithrombotic agents would provide further benefit to existing standards of care, and to understand the risk–benefit in terms of bleeding risk. 5 These trials have included anticoagulants with escalated or therapeutic doses being compared with standard prophylactic doses, anti-platelet agents, and fibrinolytic agents, as well as more novel approaches. 6 Trial designs have included adaptive, multiplatform, and Bayesian design frameworks, and the endpoints have included all-cause mortality, or composites including freedom from organ support or other surrogates of disease severity, and finally thrombosis. 5 For the most part, randomised trials to date have not shown benefits of add-on or escalated antithrombotic therapy over usual standard of care. Published or preprint trials of escalated or treatment dose anticoagulants have not met their primary efficacy outcome in patients who are moderately or critically ill and hospitalised with COVID-19, 7–9 and the results of the large RECOVERY trial10 published in The Lancet by the RECOVERY Collaborative Group showed no benefit of aspirin as an add-on therapy to reduce mortality in patients hospitalised with COVID-19. How do we make sense of the overall negative results seen in antithrombotic trials in COVID-19 to date? The first answer is mechanistic, whereas other answers might pertain to the design of clinical trials themselves. Previous trials might have used suboptimal doses of anticoagulants in a highly thrombotic population, 9 or selected anticoagulants such as direct oral anticoagulants without potential for pleiotropic or anti-inflammatory properties presumed to exist with heparins in the setting of COVID-19-induced hyperinflammation. 2 Alternatively, as suggested by the authors in the RECOVERY trial …