Hypercoagulability and thrombosis in COVID-19: a modifiable cause for mortality?

Abstract

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected >180 million people globally, and the count is still rising. Although most people have mild disease and recover within a few weeks, COVID-19 has disrupted healthcare systems around the world, caused at least 3.9 million deaths, and is associated with long-term health effects, some of which are yet to be fully characterized. The hallmarks of COVID-19 are viraemia, inflammation, hypercoagulability, and organ dysfunction. The most common clinical manifestations of hypercoagulability are venous thrombo-embolism (VTE) followed by stroke, myocardial infarction, and acute peripheral artery occlusion. However, autopsy studies demonstrate small vessel platelet–fibrin thrombi (microvascular thrombosis) in 80% of cases, implicating thrombosis as a major cause of organ dysfunction and death. Mechanisms of hypercoagulability remain incompletely understood, but there is increasing evidence that a dysregulated immune response plays a central role. In the early stages of infection, SARS-CoV-2 is localized to the respiratory tract where it enters epithelial and endothelial cells via the angiotensin-converting enzyme 2 (ACE2) receptor and causes local injury. In more advanced stages, disseminated and unchecked viral replication induces widespread endothelialopathy that is accompanied by a florid maladaptive inflammatory response, increasing hypercoagulability and multiorgan dysfunction. Case series have reported VTE in 4.8–46% of hospitalized patients with COVID-19, with the highest rates in critically ill patients admitted to the intensive care unit, often despite prophylactic anticoagulation. Furthermore, meta-analysis data suggest that COVID-19 patients with VTE have a 2.1-fold higher risk of mortality than those without VTE, prompting calls for routine use of intensified thromboprophylaxis to improve outcomes. However, it is unclear from the published data to what extent hospitalization and the use of thromboprophylaxis contributed to the observed risk of VTE, and whether preventing VTE in patients with COVID-19 improves outcomes remains unresolved. Miró and colleagues took a different approach to many of the earlier studies by focusing their study of VTE in COVID-19 on outpatients. Their study, published in this issue of the European Heart Journal, included patients presenting between 1 March and 30 April 2020 to one of 62 emergency rooms that provide care to about onethird of the Spanish population. Their study has at least three important findings. First, among the 74 814 outpatients with COVID19, a total of 368 were diagnosed with pulmonary embolism (PE), which is 9-fold higher than the rate of PE in those without COVID19 presenting during the same period (i.e. between 1 March and 30 April) in either 2019 or 2020 (standardized incidence: 310.1 vs. 34.7 per 100 000 person-years). Although the overall incidence of PE was low ( 0.5%), their data highlight the importance of COVID-19 as a risk factor for PE. Second, compared with non-COVID-19 patients with PE, patients with COVID-19 and PE were less likely to have a history of VTE or to be receiving chronic oestrogen therapy, more likely to present with fever, diarrhoea or pulmonary infiltrates, and less likely to have accompanying leg pain or swelling, or a D-dimer >1000 ng/mL; and their thrombosis was less likely to involve the main pulmonary arteries, although there was no difference between groups in the proportion of patients with right ventricular dysfunction. These findings provide valuable insights into the manifestations of PE in patients with COVID-19, but it is unclear if this information will help to refine the approach to diagnosis because there was substantial overlap in the clinical presentation of COVID-19 patients with or without PE. Third, although patients diagnosed with PE in the context of COVID-19 had higher in-hospital mortality than those who were diagnosed with PE who did not have COVID-19 (16.0% vs. 6.5%), mortality in COVID-19 patients was similar irrespective of the diagnosis of PE (16.0% vs. 16.6%).