COVID-19 coagulopathy: an evolving story.

As the coronavirus disease 2019 (COVID-19) exceeds 4 million cases worldwide, spreading across all continents as of May 12, 2020, we can assert both the substantial mortality in at-risk groups and the multiple manifestations of this disease. It is now clear that among hospitalised patients with COVID-19, pneumonia, sepsis, and respiratory failure are frequent complications, with some patients developing severe systemic disease and multiorgan failure. Moreover, since the initial report from Wuhan in January 2020 suggested elevated D-dimers and prolonged prothrombin time were baseline characteristics of patients critically ill with COVID-19, the burden of thrombotic complications in these patients has been confirmed. The latest data suggest the incidence of thrombotic complications is between 16–49% in patients with COVID-19 admitted to intensive care.

Critically ill patients are generally predisposed to thromboembolism; the combination of immobility, systemic inflammation, platelet activation, endothelial dysfunction, and stasis of blood flow can lead to coagulation. COVID-19-associated thrombotic complications seem to resemble other systemic coagulopathies during severe infections, such as sepsis-induced coagulopathy (SIC) or disseminated intravascular coagulation (DIC). Besides elevated D-dimers and fibrinogen, patients with severe COVID-19 have a mild prolongation of prothrombin time and thrombocytopenia is uncommon at admission, while patients with DIC commonly have prolonged prothrombin time and thrombocytopenia. However, as the disease progresses, DIC can develop in patients with severe COVID-19. The first autopsy series reported following COVID-19-related deaths described extensive diffuse alveolar damage and thrombi present within small peripheral vessels in the lungs. This microvascular pulmonary thrombosis could cause obstruction of small vessels and organ failure. Importantly, in line with these clinical and pathological findings, data from Wuhan indicate that clinical markers of coagulopathy in patients severely ill with COVID-19 are associated with a higher risk of death.

In the absence of robust evidence, interim guidance recommends regularly monitoring haemostatic markers—namely D-dimers, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low molecular weight heparin (LMWH) in all hospitalised patients, unless there are contraindications. However, a central question that could inform the prevention, diagnosis, and treatment strategies of COVID-19 coagulopathy remains under debate: are the haemostatic changes a consequence of severe inflammation or are they a specific effect mediated by the virus? In some hospitalised patients with COVID-19, as occurs in sepsis more generally, an overproduction of early response proinflammatory cytokines such as interleukin (IL)-6, IL-1, and TNFα, leads to a cytokine storm. This hyperinflammatory state can cause lung injury, including damage to the microvasculature and endothelial dysfunction, which could trigger haemostatic derangements and generation of pulmonary thrombi. In this scenario, early interventions aimed at reducing inflammation might help prevent thrombosis. The alternative hypothesis is that the virus directly or indirectly interferes with coagulation pathways causing systemic thrombosis. In this case, early thromboprophylaxis might be key to manage the coagulopathy.

Indeed, since antiviral treatments are generally effective early in the disease course, treatment strategies targeting inflammation and coagulation might be more promising for patients with severe COVID-19. Preliminary evidence suggests that LMWH, which has both anticoagulant and anti-inflammatory effects, can improve prognosis in patients with severe COVID-19 meeting SIC criteria or with elevated D-dimers. Other anticoagulants, including different antithrombin III, factor Xa, and complement inhibitors, are being tested. However, many questions remain regarding the efficacy of anticoagulants in severe COVID-19; the timing of intervention in the course of disease is key, and the preferred type, dose, and duration of treatment will need to be established in prospective studies.

In a short time, the global research community has made an impressive effort to report the different characteristics of COVID-19 while taking care of patients. With only preliminary evidence, the haematology community are rising to the challenge of providing guidance to manage COVID-19-associated coagulopathy in the face of uncertainty. There is still much to be learned about this coagulopathy, but the fast and ongoing collaboration worldwide makes for a hopeful outcome.

For more on the incidence of thromboembolism in COVID-19 see Thromb Res 2020; 19: 9–14 and Thromb Res 2020; published online April 30 DOI:10.1016/j.thromres.2020.04.041

For more on the first autopsy series see medRxiv 2020; published online April 10. https://doi.org/10.1101/2020.04.06.20050575 (preprint)

For more on COVID-19 coagulopathy and prognosis see J Thromb Haemost 2020; 18: 844–47

For more on the interim expert guidance see J Thromb Haemost 2020; 18: 1023–26

For more on anticoagulant treatment in patients with COVID-19 see J Thromb Haemost 2020; 18: 1094–99