Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

JACC State-of-the-Art Review

Azita H. Talasaz, PHARMD; Parham Sadeghipour, MD; Hessam Kakavand, PHARMD; Maryam Aghakouchakzadeh, PHARMD; Elaheh Kordzadeh-Kermani, PHARMD; Benjamin W. Van Tassell, PHARMD; Azin Gheymati, PHARMD; Hamid Ariannejad, MD; Seyed Hossein Hosseini, PHARMD; Sepehr Jamalkhani; Michelle Sholzberg, MDCM, MSC; Manuel Monreal, MD, PHD; David Jimenez, MD, PHD; Gregory Piazza, MD, MS; Sahil A. Parikh, MD; Ajay J. Kirtane, MD, SM; John W. Eikelboom, MBBS; Jean M. Connors, MD; Beverley J. Hunt, MD; Stavros V. Konstantinides, MD, PHD; Mary Cushman, MD, MSC; Jeffrey I. Weitz, MD; Gregg W. Stone, MD; Harlan M. Krumholz, MD, SM; Gregory Y.H. Lip, MD; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS

Disclosures

J Am Coll Cardiol. 2021;77(15):1903-1921. 

In This Article

Pathophysiology of Thromboembolism in COVID-19: Virchow's Triad in Action

COVID-19 can potentiate all 3 components of Virchow's triad and increases the risk of thrombosis (Figure 1). First, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection may trigger endothelial dysfunction. Using the angiotensin-converting enzyme 2, which is expressed on the surface of many cells, SARS-CoV-2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis equilibrium and promote endothelial activation.[10–12] This induction of a procoagulant state along with the reduction in plasminogen activators further results in increased platelet reactivity.[13–15] Inflammatory cytokines and endothelial activation can lead to downregulation of antithrombin and protein C expression. They can also lead to an increase in the levels of plasminogen activator inhibitor; fibrinogen; factors V, VII, VIII, and X; and von Willebrand factor.[16] Increased platelet reactivity, NETosis, and alterations in the aforementioned hemostatic factors result in a hypercoagulable state.[17–22]

Figure 1.

Virchow's Triad and COVID-19 Associated Coagulopathy
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can potentiate all 3 sides of Virchow's triad, including endothelial dysfunction, blood flow stasis, and hypercoagulability. Angiotensin-converting enzyme-2 (ACE-2)–dependent viral entry and the virus-induced inflammatory response can lead to endothelial dysfunction. Bedridden status may lead to stasis; inflammation, viremia, and cytokine storm can produce a hypercoagulable state. Factor Xa may play a role in spike protein cleavage and endocytosis of the virus. COVID-19 = coronavirus disease-2019; DIC = disseminated intravascular coagulopathy; FDP = fibrin degradation products; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; LV = left ventricular; PAI = plasminogen activator inhibitor; RNA = ribonucleic acid; SIC = sepsis-induced coagulopathy; TF = tissue factor; TNF = tumor necrosis factor; tPA = tissue type plasminogen activators; uPA = urokinase plasminogen activators; vWF = von Willebrand factor.

Particularly in COVID-19, it is believed that the excessive inflammatory response plays an important role in the pathogenesis of thrombosis (thromboinflammation), including pulmonary microthrombosis and pulmonary intravascular coagulopathy.[7,8] Antiphospholipid antibodies have been identified in some patients,[23] but their clinical significance is uncertain.[24] Finally, COVID-19 may predispose patients to venous stasis and increase the risk of (venous) thrombosis. Fatigue, hypoxemia, being connected to medical devices (for hospitalized patients), or acute illness (including pulmonary involvement, myocarditis with associated heart failure, or other forms of severe disease) can all lead to limited mobility and venous stasis.[25,26] All the aforementioned mechanisms may increase the risk of arterial and venous thrombosis, thereby affecting the severity of illness.

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