key: cord-0981000-3bdz62af authors: Farkouh, Michael E.; Stone, Gregg W.; Lala, Anuradha; Bagiella, Emilia; Moreno, Pedro R.; Nadkarni, Girish N.; Ben-Yehuda, Ori; Granada, Juan F.; Dressler, Ovidiu; Tinuoye, Elizabeth O.; Granada, Carlos; Bustamante, Jessica; Peyra, Carlos; Godoy, Lucas C.; Palacios, Igor F.; Fuster, Valentin title: Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week date: 2022-03-08 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2021.12.023 sha: eb0378bfc2253b0c757c0335541cf4409d6b4d56 doc_id: 981000 cord_uid: 3bdz62af Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079) thromboembolic disease, which has emerged as a common and potentially catastrophic manifestation of COVID-19. [2] [3] [4] [5] More recently, it was observed that COVID-19 may also be associated with chronic physical and mental health consequences, which have been labeled as "long-COVID" or "post-COVID" conditions. 6 Perturbations in laboratory markers of coagulation were noted early on among patients who were hospitalized with COVID- 19, with reports demonstrating an association between elevated D-dimer and an increased risk of mortality. 7, 8 Several pathologic mechanisms have been postulated to account for the laboratory abnormalities and clinical thrombotic associations, collectively described as a "COVID-19-associated coagulopathy." 9 COVID-19 is characterized by mononuclear cell reactivity and pan-endothelialitis that contribute to a high incidence of in situ thrombosis in large and small blood vessels, both arterial and venous, including at the capillary-alveolar interface that may contribute to the high rate of respiratory failure. [10] [11] [12] In this context, many have argued that there might be a role for anticoagulation therapy in patients with severe COVID-19. Early in the pandemic, observational studies suggested that anticoagulation therapy, particularly with heparins, might improve freedom from intubation and survival in hospitalized patients with COVID-19. 13, 14 As a result, prophylactic-dose heparin (at a minimum) has become accepted as the de facto standard of care. 15 Case series initially from China and then from Europe and North America further suggested that therapeutic anticoagulation might be beneficial in these patients. 12, 16 Although no benefit for therapeutic heparin has been found in patients who are receptor. [17] [18] [19] This receptor is expressed in numerous tissues, including type 2 pneumocytes, macrophages, the brain, kidney, heart, and endothelium, all of which are vulnerable to viral infection. Although postulated to mitigate rates and severity of infection, no benefit of pharmacologic modulation of the reninangiotensin-aldosterone system in patients with has been demonstrated. 20 Viral entry through the endothelium may cause inflammation (endothelialitis) and vascular injury and, independently, mononuclear cell activation can trigger cytokine release and a procoagulant state. 21, 22 Mononuclear cell activation also independently contributes to the endothelialitis. 22 Excess release of cytokines is observed in these processes, particularly tumor necrosis factor alpha and interleukins-1 and -6. 23 This cytokine storm may lead to the expression of tissue factor on mononuclear cells, resulting in activation of the coagulation cascade and thrombin formation most prominently. 3 These mechanisms might be involved in the diffuse in situ pulmonary microthrombosis that is seen in advanced COVID-19, as well as more traditional venous and arterial thrombotic events. 24 Other mechanisms may also be associated with In more critically ill COVID-19 cohorts, the prevalence of thrombotic events has been reported to be as high as 35%. 12, 39 A meta-analysis of 49 studies reported the pooled incidences of venous thromboembolism and pulmonary embolism among hospitalized patients with COVID-19 to be 17% and 7.1%, respectively, whereas the incidence of major bleeding was 3.9%. 40 The incidence of thromboembolic events was higher in critically ill patients (27.9% vs 7.1% in ward patients) and bleeding rates were higher among those receiving therapeutic anticoagulation (21.4%). 40 Importantly, the rates of overall thrombotic events in hospitalized patients with COVID-19 seem to be higher than in other critical illness and respiratory viral infections such as influenza. 41 56 The investigators concluded that rivar- The trials listed have reported their results either in a full publication or congress presentation by the time this manuscript was written. A list of ongoing trials is presented in Talasaz et al. 49 All trials had an open-label design, except for HEP-COVID (where patients and most but not all trial personnel were blinded), and ACTIV-4B (double-blinded). a ACTIV-4B also tested aspirin 81 mg once daily with equal patient allocation in the 4 arms (placebo, aspirin, 2.5-mg apixaban, 5-mg apixaban). COVID-19 Map -Johns Hopkins Coronavirus Resource Center. Accessed Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19 COVID-19 and its implications for thrombosis and anticoagulation COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-ofthe-Art Review Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study Clinical characteristics of Coronavirus Disease 2019 in China Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy Proposal of the definition for COVID-19-associated coagulopathy Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study Registry of arterial and venous thromboembolic complications in patients with COVID-19 Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19 Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19 Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2 Reninangiotensin-aldosterone system inhibitors in patients with Covid-19 Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial COVID-19 is, in the end, an endothelial disease COVID-19: staging of a new disease Pathophysiology of coagulopathy in hematological malignancies and in COVID-19 Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review Coagulation abnormalities and thrombosis in patients with COVID-19 A relative ADAMTS13 deficiency supports the presence of a secondary microangiopathy in COVID 19 Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19 A review of pathophysiology, clinical features, and management options of COVID-19 associated coagulopathy Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection Characterization of myocardial injury in patients with COVID-19 Pulmonary, cerebral, and renal thromboembolic disease in a patient with COVID-19 Acute limb ischemia in patients with COVID-19 pneumonia Abdominal imaging findings in COVID-19: preliminary observations Large-vessel stroke as a presenting feature of Covid-19 in the young Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis Incidence of VTE and bleeding among hospitalized patients with Coronavirus Disease 2019: a systematic review and meta-analysis Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis Impact of high-dose prophylactic anticoagulation in critically ill patients with COVID-19 pneumonia Persistent endotheliopathy in the pathogenesis of long COVID syndrome Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry Postdischarge venous thromboembolism following hospital admission with COVID-19 Anticoagulation for patients with COVID-19 being discharged from hospital -recommendation 3 Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC State-ofthe-Art Review Medically ill hospitalized patients for COVID-19 thrombosis extended prophylaxis with rivaroxaban therapy: rationale and design of the MICHELLE Trial Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial ACTIV-4a, and ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19 The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19 Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial Therapeutic anticoagulation in COVID-19 patients KEY WORDS anticoagulation, clinical trial, coagulopathy, COVID-19 APPENDIX For supplemental tables and a figure, please see the online version of this paper.