Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding often occur in subjects with weak constitutions, multiple risk factors and comorbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (VWF). Central to the activity of these biomarkers are their receptors and signalling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19 and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of VWF, P-selectin and fibrinogen are present, with normal or slightly increased levels of D-dimer (however, D-dimer levels will rapidly increase as the disease progresses). Progression to VWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devices and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients.

Erythrocyte, Platelet, Serum Ferritin, and P-Selectin Pathophysiology Implicated in Severe Hypercoagulation and Vascular Complications in COVID-19

“…Figure 6E-H are micrographs to show how, in some instances, the fibrin(ogen) deposits aggregate to erythrocytes. We previously reported that spontaneous clotlets are present in platelet-poor plasma (PPP) of COVID-19 patients and that these clotlets have an amyloid structure, as shown using the fluorescent stain ThT [14]. Here, we show these deposits with SEM micrographs, where we find these amyloid deposits in a WB smear (without the addition of thrombin).…”

“…Such fusions between membranes can be facilitated by P-selectin when present on the platelet membrane. When on the platelet membrane, P-selectin is known to act as adhesion receptor, where it promotes platelet-platelet, platelet-endothelial cells, or platelet-erythrocyte adhesions [14,39]. Figure 2A,B shows scanning electron micrographs from healthy erythrocytes ( Figure 2A) and platelets ( Figure 2B), while Figure 3A-H show platelets from COVID-19 patients.…”

“…Our TEG ® and viscometry results also showed that our COVID-19 samples were significantly hypercoagulable and more viscous than that of healthy PPP. The various plasma proteins and their effects on blood clotting and viscosity, together with the presence of the noteworthy activated and aggregated platelets-that is, the cause of platelets and erythrocytes to form aggregates in WB may be the direct cause of vascular pathologies noted in the lungs of COVID-19 patients [14,17].…”

Therapeutic Potential of Resveratrol in COVID-19-Associated Hemostatic Disorders

“…Interestingly, levels of vWF and Factor VIII are directly linked to the severity of thrombosis and the ensuing stroke [ 62 , 63 ]. In addition, these appear to be common in COVID-19 patients, where they contribute to VTE [ 64 , 65 ]. Alarmingly, a young and asymptomatic SARS-CoV-2-infected patient who showed increased FVIII and vWF levels without any sign of hyperinflammatory state or blood coagulation activation suffered a stroke [ 66 ].…”

Serum Amyloid P inhibits single stranded RNA-induced lung inflammation, lung damage, and cytokine storm in mice

“…Lung biopsy and autopsy findings indicate that COVID-19 is associated with an accumulation of cell-free protein-rich exudate in the alveoli, alveolar wall thickening, and inflammation (accumulation of immune cells) [8][9][10][11][12][13]. COVID-19 patients are also at risk of disseminated intravascular coagulation and deposition of fibrin clots in the lungs [8,9,[12][13][14]. In both animal models and COVID-19 patients, there is a consistent accumulation of macrophages in the lungs, whereas increased numbers of lung neutrophils appear to be associated with comorbidities such as pneumonia [12,15,16].…”