Coronavirus Disease 2019-Associated Thrombosis and Coagulopathy: Review of the Pathophysiological Characteristics and Implications for Antithrombotic Management

Abstract

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2, which has posed a significant threat to global health. Although the infection is frequently asymptomatic or associated with mild symptoms, in a small proportion of patients it can produce an intense inflammatory and prothrombotic state that can lead to acute respiratory distress syndrome, multiple organ failure, and death. Angiotensin-converting enzyme 2, highly expressed in the respiratory system, has been identified as a functional receptor for severe acute respiratory syndrome coronavirus-2. Notably, angiotensin-converting enzyme 2 is also expressed in the cardiovascular system, and there are multiple cardiovascular implications of COVID-19. Cardiovascular risk factors and cardiovascular disease have been associated with severe manifestations and poor prognosis in patients with COVID-19. More important, patients with COVID-19 may have thrombotic and coagulation abnormalities, promoting a hypercoagulable state and resulting in an increased rate of thrombotic and thromboembolic events. This review will describe the pathophysiological characteristics of the cardiovascular involvement following infection by severe acute respiratory syndrome coronavirus-2, with a focus on thrombotic and thromboembolic manifestations and implications for antithrombotic management.

Keywords: anticoagulant therapy; antiplatelet therapy; coronavirus disease 2019; endothelium; platelets; severe acute respiratory syndrome coronavirus‐2; thrombosis.

Figure 1. Pathophysiological mechanism related to coronavirus disease 2019 (COVID‐19)–associated thrombosis and coagulopathy.

A, The interaction of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) with endothelial cells (type II pneumocytes, glomerular capillary loops, and small intestine capillaries). Angiotensin‐converting enzyme 2 (ACE2) imbalance may promote susceptibility to the SARS‐CoV‐2 infection of these cell types. Furthermore, cell infection and induced inflammation in pericytes and endothelial cells may promote local apoptosis and potent inflammatory cytokines. B, Inflammatory process in the pulmonary alveoli, leading to pulmonary tissue edema and intravascular coagulopathy. C, Selection of thrombotic complications in COVID‐19 and their approximate frequency. D, Proposed intravascular thrombosis pathways leading to microvascular and macrovascular thrombosis complications. Because of the potent local and systemic cytokine production, the platelets are activated and interact with neutrophils. The neutrophil extracellular trap (NET)osis process may also stimulate thrombin production and fibrin deposition. The excess of fibrin deposition and fibrinolysis shutdown lead to intravascular thrombosis and, finally, to clinical thromboembolic complications. The pointed black and continued black lines denote pathway connections, pointed red lines denote inhibition, and green arrows denote agonism. ACE‐I indicates angiotensin‐converting enzyme inhibitor; anti‐Xa, anti–factor Xa; AT1, angiotensin II receptor type 1; CAHA, COVID‐19–associated hemostatic abnormalities; D‐D, D‐dimer; DTI, direct thrombin inhibitor; IL, interleukin; LMWH, low‐molecular‐weight heparin; PAI‐1, plasminogen activator inhibitor I; PFD, fibrin degradation product; r‐tPA, recombinant tPA; TMPRSS2, transmembrane protease serine 2; tPA, tissue‐type plasminogen activator; TriS, synthesized trisulfated heparin; and UFH, unfractionated heparin. Data derived and visual presentation modeled from Bikdeli et al. ¹⁴

Figure 2. Effects of coronavirus disease 2019 on the cardiovascular and coagulation system.

ACE indicates angiotensin‐converting enzyme; DIC, disseminated intravascular coagulation; IL, interleukin; and SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.

Figure 3. Stages of coronavirus disease 2019 (COVID‐19)–associated hemostatic abnormalities.

^*Laboratory parameters included in the COVID‐19–associated hemostatic abnormality stages described by Thachil et al. ⁴⁶ aPTT indicates activated partial thromboplastin time; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; HDU, high‐dependency unit; ICU, intensive care unit; IMV, invasive mechanical ventilation; LWMH, low‐molecular‐weight heparin; PT, prothrombin time; and URL, upper reference level.

Figure 4. Proposed algorithm for diagnosis and treatment of myocardial injury and acute myocardial infarction in patients with confirmed coronavirus disease 2019 (COVID‐19).

*Signs of myocardial ischemia are needed to meet the criteria for this category. ^†The complete list of very‐high‐risk and high‐risk criteria includes those defined in the corresponding clinical guidelines. ¹²⁰ Immediate transfer for invasive strategy should be done regardless of the COVID‐19 status. ^‡If the COVID‐19 diagnosis is unknown, the management decision can be delayed until the COVID‐19 status is confirmed or ruled out. ARDS indicates acute respiratory distress syndrome; CKD, chronic kidney disease; cTn, cardiac troponin; ESRD, end‐stage renal disease; MI, myocardial infarction; NSTEMI, non–ST‐segment–elevation MI; PCI, percutaneous coronary intervention; PE, pulmonary embolism; pPCI, primary PCI; STEMI, ST‐segment–elevation MI; UDMI, Universal Definition of Myocardial Infarction; and URL, upper reference level.

Figure 5. Summary of drug‐drug interactions between coronavirus disease 2019 investigational treatments and antithrombotic therapies.

GPI indicates glycoprotein IIb to IIIa inhibitor; LWMH, low‐molecular‐weight heparin; NA, not available; rTPA, recombinant tissue‐type plasminogen activator; UFH, unfractionated heparin; and VKA, vitamin K antagonist. Data derived and visual presentation modeled from Bikdeli et al. ¹⁴