COVID-19 associated thromboinflammation of renal capillary: potential mechanisms and treatment

Abstract

Coronavirus disease 2019 (COVID-19) infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic disease with high morbidity and mortality. Inflammatory and thrombosis are its main manifestations. As an important organ of hemofiltration metabolism, the kidney is prone to blockage and destruction when filter high inflammatory and high viscous blood of COVID-19, resulting in the loss of a large amount of protein, aggravating blood concentration, and then worsening COVID-19 hypercoagulability, which may explain the phenomenon of erythrocytes aggregation blocking the capillary lumen and the main reason why the kidney has become the second largest involvement organs. Therefore, this review discusses the effects of pathophysiological mechanisms such as inflammatory storm, endothelial injury, phosphatidylserine expression, extracellular traps release on renal capillary thrombosis caused by COVID-19 infection. Meanwhile, in view of the above mechanisms, we put forward the potential targets of antithrombotic therapy, and graded management of patients, reasonable use of drugs according to the severity of the disease and the choice of time. And we support the view of prevention of thrombus before admission, continuous anticoagulation and drug choice after discharge. It is suggested that the symptomatic and supportive treatment of renal disease in critically ill patients should be combined with the concept of antithrombotic therapy. The ultimate goal is to reduce the occurrence and development of kidney disease, provide direction for the current management of COVID-19 with kidney disease, and reduce the mortality of COVID-19.

Keywords: COVID-19; antithrombotic therapy; graded management; inflammation; renal capillary thrombosis.

Figure 1

Cascade activation of capillary thrombosis. Blood viscosity, flow velocity and endothelial cell (EC) integrity play an important role in maintaining capillary blood homeostasis, especially EC integrity. When EC are damaged and subendothelial matrices, such as collagen and VWF, are exposed, they activate endogenous coagulation pathways and promote platelet adhesion and aggregation. Endothelial injury promotes PS exposure and TF expression, the latter activating exogenous coagulation pathway, then forming TF-VIIa complex in circulating blood, together with endogenous pathway promote Xa generation through PS, Ca²⁺ and VIIIa assistance. Xa and Va promotes IIa generation under the presence of II and Ca²⁺ on the PS, which further leads to fibrin deposition, the latter becomes dense fibrin clots under the action of XIIIa. Endothelial cells fall off in the process of injury, resulting in the weakening of their normal anticoagulation and maintenance of fibrinolysis homeostasis. When the blood passes through the damaged endothelium, it is easy to transform to procoagulation and fibrinolysis inhibition. The aggregation of red cells, platelets and fibrin in this process eventually promotes thrombosis.

Figure 2

Possible mechanism and treatment direction of COVID-19-associated renal capillary thrombosis. Inflammatory and thrombus: SARS-CoV-2 binds to ACE2 receptors on the surface of immune cells (T cells, NK cells, macrophages), promoting the release of IL-6, IL-17, TNF-α, IL-8, IL-10, and the formation of particles, then further promotes the expression of CRP, which activates the RAAS system, increases the expression of anticoagulant and antifibrinolytic substances, promotes the expression of TF on the surface of macrophages, acting on endothelial cells and promoting PS exposure and fibrin thrombosis on it. Endothelial injury and thrombus: direct effect of virus leads to endothelial PS exposure and apoptosis; inflammatory factors cause endothelial procoagulation and antifibrinolysis; the activation of the complement system aggravates endothelial injury; hypoxia leads to endothelial ischemia and Hypoxemia. The injured endothelium formed procoagulant particles with PS and TF expression and promoted multi-site thrombosis through circulating blood; expressed E-selectin, P-selectin, enhancing platelet and neutrophil aggregation; decreased expression of TFPI, anti-thrombin, PAI-1, impairing antithrombotic ability; promoted the expression of inflammatory factors. After promoting the injury of renal endothelium, the gap increases, which leads to the leakage of plasma albumin. At the same time, viruses and immune cells also migrate to the epithelium of podocytes and renal tubules through the damaged endothelium. The increase of neutrophils produces NETs, and macrophages also express MET in oxidative stress environment. These extracellular traps lead to endothelial damage, promote the stability of thrombus and the release of inflammatory factors. Hypoxia can also activate the formation of VIIa and promote the production of thrombin, which acts on PAR and aggravates the release of inflammatory factors. The activation of complement system promotes the formation of renal membrane attack complex, aggravating oxidative stress and leads to disease progression. The expression of inflammation, endothelial injury and activation of coagulation factors in the process of thrombosis may be inhibited, which may be new methods to delay the progression of the disease.