key: cord-0785559-pr6jlc5c authors: Emert, Roger; Shah, Payal; Zampella, John G. title: COVID-19 and hypercoagulability in the outpatient setting date: 2020-05-23 journal: Thromb Res DOI: 10.1016/j.thromres.2020.05.031 sha: 887804f6ea215518a8e7a95b55795ad049dc56c2 doc_id: 785559 cord_uid: pr6jlc5c nan The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an overwhelming surge in utilization of healthcare resources. The effect on hospitals is incontrovertible but the effect on outpatient services is less well-studied. The most common symptoms at onset of COVID-19 are fever, cough, fatigue, and headache and may mimic other common upper respiratory infections. [1] Patients with these symptoms are likely to present to outpatient providers. In most patients, symptoms will be mild to moderate, where management for mild symptoms does not require hospitalization [2] . These patients are encouraged to remain isolated with frequent follow-up with their healthcare provider to assess their respiratory status, with urgent hospitalization for respiratory distress. Factors predicting poor outcomes include older age, obesity, diabetes mellitus, and hypertension [1] . Among hospitalized patients with COVID-19, venous thromboembolism (VTE), and in particular pulmonary emboli, are commonly diagnosed [3] . Recently, evidence for D-dimer cutoff values that predict high-risk for VTE has been demonstrated and the presence of VTE has been shown to be a poor prognostic indicator in severe COVID-19 patients [4] . The extent to which the risk of hypercoagulability exists in the outpatient setting is unknown but has serious implications for outpatient and primary care providers (PCP). In the inpatient setting, patients with severe SARS-CoV-2 infections leading to pneumonia and hypoxic respiratory failure demonstrate elevated D-dimer and fibrinogen, evidencing a hypercoagulable state [5] . The underlying pathophysiology contributing to the hypercoagulable state may be related to cytokine storm inducing endothelial damage, microvascular thrombosis, and/or to the development of prothrombotic antiphospholipid antibodies. [6] In patients with severe COVID, elevated D-dimer correlated positively with increased 28-day mortality [7] and current guidelines recommend therapeutic anti-Journal Pre-proof J o u r n a l P r e -p r o o f coagulation in the setting of elevated D-dimers, as a high incidence of VTE has been reported on prophylactic dosing [8] . The prognostic value of D-dimers and anti-coagulation benefit in mild disease remains unknown. The pathophysiologic differences between patients with severe and mild disease is currently being worked out, however patients with mild disease demonstrate decreased lymphocyte count with increases in plasma IL-6 concentrations, suggesting the presence of an activated underlying inflammatory cascade [9] . Comparable to hospitalized patients, this proinflammatory state may predispose outpatients to the development of VTE and portend a worse outcome. Prior studies have demonstrated an association between proinflammatory cytokines and onset of VTE [10, 11] . Moreover, studies of outpatients with VTE demonstrated that about 1/5 of patients had a recent infection, suggesting the recent setting of inflammation from infection may contribute to VTE risk. It stands to reason that viral infection from COVID-19, which has demonstrated remarkable elevations in hematological markers of coagulation [12] , would increase this risk further, especially as similar findings were seen in patients with severe acute respiratory syndrome (SARS), a related coronavirus [13] . Patients with acute medical illness are at elevated VTE risk for up to 90 days postdischarge [14] . Specific regimens of extended thromboprophylaxis may include betrixaban J o u r n a l P r e -p r o o f patients to consider stopping pro-thrombotic medications such as selective cyclooxygenase-2 (COX-2) inhibitors or supplements such as vitamin K or vitamin E. Studies evaluating any benefit versus perceived harm from standard NSAIDS are ongoing. With the global burden of COVID-19 mortality, reaching over 300,000 deaths worldwide, little is known about the specific pathogenic viral features and poor outcomes in these patients. A recent prospective study of autopsy findings from consecutive deaths from COVID-19 found thromboembolic events to an important feature of mortality, with only a small proportion of patients characterized from the outpatient setting [18] . In the case of patients with mild symptoms from coronavirus, risk factors should be integrated with laboratory data and emerging guidelines to mitigate the risks of thromboembolism. Further investigations from the outpatient setting of COVID-19 are warranted with high priority, as the global impact of optimizing risk-management in these patients extends far beyond VTE prevention alone. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Mild or Moderate Covid-19 Pulmonary embolism in patients with Covid-19 pneumonia Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Hypercoagulability of COVID-19 patients in Intensive Care Unit. 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