Circulating Microparticles in the Pathogenesis and Early Anticoagulation of Thrombosis in COVID-19 With Kidney Injury

Abstract

As more is learned about the pathophysiological mechanisms of COVID-19, systemic thrombosis has been recognized as being associated with more severe clinical manifestations, mortality and sequelae. As many as 40% of patients admitted to the hospital due to COVID-19 have acute kidney injury, with coagulation abnormalities the main cause of impaired function. However, the mechanism of renal thrombosis and the process leading to kidney injury are unclear. Microparticles (MPs) are membrane bubbles released in response to activation, injury or apoptosis of cells. The phosphatidylserine (PS) exposed on the surface of MPs provides binding sites for endogenous and exogenous FXase complexes and prothrombin complexes, thus providing a platform for the coagulation cascade reaction and facilitating clot formation. In the context of COVID-19 infection, viral attack leads immune cells to release cytokines that damage circulating blood cells and vascular endothelial cells, resulting in increased MPs levels. Therefore, MPs can be used as a risk factor to predict renal microthrombosis and kidney injury. In this paper, we have summarized the latest data on the pathophysiological mechanism and treatment of renal thrombosis caused by MPs in COVID-19, revealing that the coagulation abnormality caused by MP and PS storms is a universal progression that aggravates the mortality and sequelae of COVID-19 and potentially other pandemic diseases. This paper also describes the risk factors affecting renal thrombosis in COVID-19 from the perspective of the Virchow's triad: blood hypercoagulability, vascular endothelial injury, and decreased blood flow velocity. In summary, given the serious consequences of thrombosis, current guidelines and clinical studies suggest that early prophylactic anticoagulant therapy reduces mortality and improves clinical outcomes. Early anticoagulation, through inhibition of PS-mediated coagulopathy, allows maintenance of unobstructed blood circulation and oxygen delivery thereby facilitating the removal of inflammatory factors, viruses, MPs, and dead or damaged cells, and expediting patient rehabilitation.

Keywords: COVID-19; early anticoagulation; kidney; microparticle; phosphatidylserine; thrombosis.

FIGURE 1

Role of circulating microparticles in the pathogenesis of thrombosis in COVID-19. (A) This figure shows the mechanism of MPs production in COVID-19. During the invasion and replication of SARS-CoV-2, the body first initiates immune cell recruitment (i.e., monocytes, macrophages, dendritic cells, neutrophils, and T cells) and the release of cytokines. After cell activation and injury, ATP production is reduced and consumption increases. With the resulting increase in intracellular Ca²⁺, two ATP-dependent transposases (flippase and floppase) are blocked, and ATP-independent scramblases are activated. This leads to the exposure of phosphatidylserine (PS) in the outer cell membrane, accompanied by the shedding of microparticles (MPs). SARS-CoV-2 replicates in alveolar epithelial cells, damages the membrane and releases the virus, infecting more adjacent alveolar epithelial II cells and pulmonary capillary endothelial cells (ECs), resulting in vascular endothelial injury. As the main triggering site of clot formation, vascular endothelial function and integrity destruction can lead to endothelial MPs release, up-regulation of TF expression on cell surfaces, platelets activation, increased vWF and FVIII, and thus promote platelet aggregation and thrombosis. The damaged endothelium is shed, weakening the normal endothelial anticoagulation functions and causing fibrinolysis disorder. Finally, alveolar capillary microthrombosis results in insufficient blood perfusion, leading to hypoxemia. In conclusion, increased viral load, hypoxemia, endothelial injury, and inflammatory response jointly promote PS and MP storms which drive the coagulation cascade. (B) Diagram of renal thrombosis in COVID-19 from the perspective of Virchow’s triad. Virchow’s triad composes abnormal blood composition (hypercoagulable blood state), vascular endothelial damage, and decreased blood flow velocity. The three elements of Virchow are themselves mutually influenced and inseparable. Of the three, systemic vascular endothelial injury is the main triggering factor for COVID-19 clot formation. Endothelial dysfunction caused by viruses, hypoxia, immune response and hypercoagulable state, platelet activation, high viscosity and abnormal blood flow lead to thrombosis in COVID-19.

FIGURE 2

Thrombosis from the lung to the kidney in COVID-19 and its influence on the physiological process of renal hemofiltration and initial urine production. Illustration of the link between thrombosis in the lungs and the kidneys in COVID-19. (A) In the lungs, viruses, cytokines, PS⁺ MPs and hypoxia lead to damage and contraction of pulmonary capillary endothelial cells, thickening and narrowing of capillaries, and ultimately causing pulmonary hypertension. As the pressure differential increases, plasma and a small number of erythrocytes in the pulmonary capillaries are pushed into the alveolar space, disrupting air-blood exchange. As plasma is forced into the alveoli, the water is evaporated by respiration, leaving tremelloid proteins. The patients develop progressive dyspnea as the air space in the alveoli decreases. Ultimately, thrombosis can result in increased metabolic toxicants, energy deficiency, massive cell damage and death, and multiple organ failure. As the disease progresses, SARS-CoV-2 can travel through the bloodstream from infected alveolar type II epithelial cells and pulmonary capillaries ECs to distant blood vessels, including the glomerular filtration barrier ECs and podocytes, gradually invading various organs. (B) This part represents the physiological process of kidney hemofiltration and initial urine production. When blood flows into the glomerulus through the afferent arterioles, it is filtered through the glomerular filtration barrier and capillary walls. The filtered water and soluble substances enter the renal capsule, and then the filtrate enters tubules to form initial urine. The capillaries around the renal tubules are connected with the filtrate in the tubules to ensure the reabsorption of water, electrolytes and organic nutrients, and waste products such as creatinine, excess H⁺ and K⁺ are actively excreted in the filtrate. Due to the high pressure in the glomerulus, the blood in the glomerular capillaries is highly concentrated, the hematocrit increases, and the fluidity is significantly reduced. Simultaneously, the blood in the glomerular capillaries is highly concentrated, the hematocrit increases, and the fluidity decreases significantly. Importantly, SARS-CoV-2, cytokines, and hypoxia damage glomerular capillary endothelial cells and podocytes, affect their metabolism, lead to insufficient ATP production, activate scramblase, release PS⁺ MPs, and promote thrombin production, which hinders blood circulation, increasing blood viscosity and kidney thrombosis. In addition, renal tubular epithelial cells are damaged, resulting in renal filtration dysfunction. This further activates the blood coagulation pathway and the accumulation of procoagulant substances, which hinders the flow of concentrated blood, and ultimately causes the glomerular filtration rate, renal tubular reabsorption, secretion and excretion functions to decrease, leading to symptoms such as increased creatinine, hematuria, and proteinuria.