Coagulative Disorders in Critically Ill COVID-19 Patients with Acute Distress Respiratory Syndrome: A Critical Review

Abstract

In critically ill patients with acute respiratory distress syndrome (ARDS) coronavirus disease 2019 (COVID-19), a high incidence of thromboembolic and hemorrhagic events is reported. COVID-19 may lead to impairment of the coagulation cascade, with an imbalance in platelet function and the regulatory mechanisms of coagulation and fibrinolysis. Clinical manifestations vary from a rise in laboratory markers and subclinical microthrombi to thromboembolic events, bleeding, and disseminated intravascular coagulation. After an inflammatory trigger, the mechanism for activation of the coagulation cascade in COVID-19 is the tissue factor pathway, which causes endotoxin and tumor necrosis factor-mediated production of interleukins and platelet activation. The consequent massive infiltration of activated platelets may be responsible for inflammatory infiltrates in the endothelial space, as well as thrombocytopenia. The variety of clinical presentations of the coagulopathy confronts the clinician with the difficult questions of whether and how to provide optimal supportive care. In addition to coagulation tests, advanced laboratory tests such as protein C, protein S, antithrombin, tissue factor pathway inhibitors, D-dimers, activated factor Xa, and quantification of specific coagulation factors can be useful, as can thromboelastography or thromboelastometry. Treatment should be tailored, focusing on the estimated risk of bleeding and thrombosis. The aim of this review is to explore the pathophysiology and clinical evidence of coagulation disorders in severe ARDS-related COVID-19 patients.

Keywords: COVID-19; acute distress respiratory syndrome; bleeding; coagulopathy; heparin; platelets; thrombosis.

Figure 1

Coagulation cascade after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Coagulation is initiated by viral binding to angiotensin-converting enzyme 2 receptors (ACE-2Rs) on endothelial cells, resulting in the exposure of tissue factor (TF) and collagen to blood and the release of von Willebrand factor (vWF). Platelets are exposed to TF, collagen, and vWF and activated, thus releasing mediators such as adenosine monophosphate (ADP) and vWF, leading to further platelet recruitment, followed by activation, aggregation, and plug formation. The TF–Factor VII (FVII) interaction activates the extrinsic pathway, while the exposed collagen starts the intrinsic pathway, helped by antithrombin-III (ATIII). Both pathways result in the common coagulation pathway, which ends with the formation of fibrin strands, thus leading to the formation of a stable platelet–fibrin clot. Meanwhile, tissue plasminogen activator (tPA) activates plasminogen to plasmin, which acts on the fibrin strands by degradation. ATIII, antithrombin-III; TF, tissue factor; tPA, tissue plasminogen activator; tPA, tissue plasminogen activator; vWF, von Willebrand factor; ADP, adenosine monophosphate; FDP, fibrin degradation products; ACE-2R, angiotensin-converting enzyme 2 receptors; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Figure 2

Potential beneficial roles of low molecular weight heparin (LMWH) on endothelial glycocalyx dysfunction during coronavirus disease 2019 (COVID-19). Figure Legend: − = inhibition; + = activation; ↑ = increase; ↓ = decrease.

Figure 3

Algorithm of coagulation management in patients with COVID-19. We propose a strict monitoring of the risks/benefits of heparin administration in COVID-19 patients and the importance of coagulation control (risk of hemorrhage) not only in the hospital settings, but also after discharge. Heparin dose and administration during intensive care unit (ICU) stay should be evaluated on the basis of a laboratory test (in particular d-dimer, factor Xa, and thromboelastogram indices), and the occurrence of clinical events (local thrombosis, pulmonary embolism, bleeding, hemorrhagic shock). Prophylactic heparin can be continued after discharge under a strict follow up; in the most severe cases, oral anticoagulation should be taken in consideration after ICU stay. Abbreviations: PE, pulmonary embolism; UHF, unfractioned heparin, DD, D-dimer.

Figure 4

Ultrasound showing iliopsoas muscle bleeding in a patient from our institution.