Coagulopathy and Thrombosis as a Result of Severe COVID-19 Infection: A Microvascular Focus

Abstract

Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral, or fungal infections are well recognized to activate the coagulation system, COVID-19-associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. von Willebrand factor (VWF) and its protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS-13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS-13 has been reported. Also, an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS-13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment, and improve clinical prognosis.

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

“…We also show that most patients had decreased circulating levels of ADAMTS13 protein and ADAMTS13 proteolytic activity in most cases to between 30% to 70% of normal levels and resulting in a substantially abnormal VWF/ADAMTS13 ratio. These data confirm other recent observations from COVID-19 case series of reduced ADAMTS13 activity [ 10 , [13] , [14] , [15] ] or markedly increased VWF/ADAMTS13 ratio [ 12 , 32 , 33 ]. Although in a further small case series in which comprehensive hemostasis testing was performed longitudinally in COVID-19 patients for the duration of hospital admission, reduced ADAMTS13 was an inconsistent finding [ 34 ].…”

Neutrophil extracellular traps and von Willebrand factor are allies that negatively influence COVID‐19 outcomes

“…Proposed time-course phenomena favoring COVID-19 progression related to the synergistic effect between NET formation and VWF/ADAMTS13 imbalance CRS, and VWF/ADAMTS13: (i) α-defensins, released from neutrophils, bind to A2 domain of VWF inhibiting its proteolytic cleavage by ADAMTS13; (ii) VWF directly binds to leukocytes and NETs; (iii) IL-6 inhibits VWF cleavage by ADAMTS13 in vitro; (iv) CRS is exacerbated in inflammatory diseases when abnormal NET levels are generated; and finally (v) histones from NETs induce VWF release from endothelial cells in vitro and in vivo. 10 In conclusion, our results support that the increase of IL-6 due to the CRS synchronizes a feedback mechanism between NETosis and VWF/ADAMTS13 axis, reflected by the correlation dynamics between plasma levels of NETs and VWF that, in turn, may perpetuate endothelium damage, amplifying immunothrombosis and worsening the course of the disease (Figure 3). Additional studies are warranted to confirm the potential use of VWF and ADAMTS13 activity as predictive markers of clinical outcomes.…”

“…Taken together, these results suggest that cytokine storm is the triggering event in COVID‐19, which is followed by NETosis and endothelial cell activation together with the hemostatic imbalance that correlate with clinical outcomes. Different studies have provided evidences of the connection between neutrophils/NETs, CRS, and VWF/ADAMTS13: (i) α‐defensins, released from neutrophils, bind to A2 domain of VWF inhibiting its proteolytic cleavage by ADAMTS13; (ii) VWF directly binds to leukocytes and NETs; (iii) IL‐6 inhibits VWF cleavage by ADAMTS13 in vitro; (iv) CRS is exacerbated in inflammatory diseases when abnormal NET levels are generated; and finally (v) histones from NETs induce VWF release from endothelial cells in vitro and in vivo 10 …”

Cardiovascular impact of COVID-19 with a focus on children: A systematic review

“…Hence, biologic therapy blocking IL-1 (anakinra) and IL-6 (tocilizumab) receptors have been used in up to 14.5% of PMIS cases. COVID-19 prothrombotic effects are concerning in adults[ 107 - 110 ], increased use of anticoagulation (33.2%; mainly low weighted enoxaparin) and antiplatelet agents (12.5%; primarily aspirin) have been observed in these patients. Children with PMIS are at risk of thrombotic complications from multiple causes, including hypercoagulable state, possible endothelial injury, stasis from immobilization, ventricular dysfunction, and coronary artery aneurysms[ 111 ].…”