The mystery of COVID-19-associated arterial thrombosis

Abstract

I read with interest the article by Indes et al 1 regarding the arterial complications in patients with severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Their study has added to the growing body of data on this unique viral complication. Coronavirus disease 2019 (COVID-19)-associated coagulopathy is associated with elevated fibrinogen, D-dimer, and C-reactive protein. Some centers have described higher-than-expected rates of venous thromboembolism. 2 Markedly elevated D-dimer levels have also been reported in association with severe COVID-19 infections and mortality. 2,3 The proposed hypotheses to explain the presence of venous thrombosis in COVID-19 have centered on a dysregulated inflammatory response manifesting as a cytokine storm, complement activation, and endothelial injury. 4,5 The observation of an increased risk of venous thrombosis in association with severe illness due to viral infections in itself is not novel. However, whether (and to what degree) severe COVID-19 infection is associated with a uniquely prothrombotic phenotype remains uncertain.Although venous thromboembolism has been reported in previous outbreaks of coronaviruses, including SARS-CoV-1 and Middle Eastern respiratory syndrome, and influenza A H1N1 acute respiratory distress syndrome, 6,7 the association between SARS-CoV-2 infection and arterial thrombosis has not been reported with other viral infections. The coagulopathy observed in patients with COVID-19 differs from the disseminated intravascular coagulopathy typically seen in sepsis. Specifically, the associated thrombocytopenia and prolonged activated partial thromboplastin time and/or prothrombin time have been mild. 4 This observation led to speculation that the arterial thrombosis is a direct result of SARS-CoV-2 infection of endothelial cells through the angiotensinconverting enzyme 2 receptor and subsequent endotheliitis. 5,8 Also intriguing is the unpredictable nature of this arterial thrombosis among patients infected with COVID-19. Indes et al, 1 and others, observed no correlation between COVID-19 disease severity and the degree of arterial thrombosis, although others have observed arterial

Acute limb ischemia in a COVID-19 patient

“…Evidence from early experience suggests that pathogenesis of arterial thrombosis in COVID-19 patients differs from that of classical arterial thrombosis [ [10] , [11] , [12] ]. In-situ arterial thrombosis mainly occurs due to plaque breakdown or reduced perfusion through an atherosclerotic lesion, or stent or graft [ 13 ].…”

“…Various mechanisms have been proposed to explain this phenomenon. A dysregulated hyperinflammatory response is thought to be responsible for arterial and venous thromboembolic events seen in patients with COVID-19 [ 11 , 12 ]. Increased levels of D-dimer, fibrinogen, coagulation factors, acquired antiphospholipid antibodies, and decreased levels of protein C, protein S, antithrombin, and hyperactivation of platelets and neutrophils are observed [ 10 ].…”

“…However, thrombotic component is more predominant than hemorrhagic component when compared with DIC [ 11 , 12 ]. It has been also speculated that direct viral infection of endothelial cells through the angiotensin-converting enzyme 2 receptor may be the cause of arterial thrombosis in patients with COVID-19 [ 9 , 10 , 12 ]. It is possible that a combination of these mechanisms, but not one, is responsible for increased rate of arterial thromboembolic events in COVID-19 patients.…”

A review of acute limb ischemia in COVID-positive patients

“…In patients with COVID-19 that have diffuse coagulopathy, there are few bleeding complications [9] . Markers usually elevated in patients with COVID-19–related arterial thrombosis are d -dimer, fibrinogen, and C-reactive protein [10] .…”

Acute limb ischemia in COVID-19 patients: an overview

“…Furthermore, angiotensin-converting enzyme 2, the SARS-CoV-2 receptor, is expressed on the membrane of vascular muscle and endothelial cells, and infection of these cells can cause an inflammatory response in the blood vessel walls, predisposing to clot developing. 7 Acute limb ischemia (ALI) is a vascular emergency known as a dramatic drop in arterial perfusion of a limb that poses a challenge to the limb's viability. 8 The most frequent causes involve embolism from cardiac chambers, and is most often combined with atrial fibrillation or acute myocardial infarction, embolism from arterial aneurysms, thrombosis of native limb arteries or artery grafts, iatrogenic thromboembolism after vascular procedures, aortic dissection, and traumatic vascular injury.…”