The Central Role of Extracellular Vesicles in the Mechanisms of Thrombosis in COVID-19 Patients With Cancer and Therapeutic Strategies

Abstract

Cancer patients have increased SARS-CoV-2 susceptibility and are prone to developing severe COVID-19 infections. The incidence of venous thrombosis is approximately 20% in COVID-19 patients with cancer. It has been suggested that thrombus formation has been suggested to correlate with severe clinical manifestations, mortality, and sequelae. In this review, we primarily elaborate on the pathophysiological mechanisms of thrombosis in COVID-19 patients with cancer, emphasize the role of microparticles (MPs) and phosphatidylserine (PS) in coagulation, and propose an antithrombotic strategy. The coagulation mechanisms of COVID-19 and cancer synergistically amplify the coagulation cascade, and collectively promotes pulmonary microvascular occlusion. During systemic coagulation, the virus activates immune cells to release abundant proinflammatory cytokines, referred to as cytokine storm, resulting in the apoptosis of tumor and blood cells and subsequent MPs release. Additionally, we highlight that tumor cells contribute to MPs and coagulation by apoptosis owing to insufficient blood supply. A positive feedback loop of cytokines storm and MPs storm promotes microvascular coagulation storm, leading to microthrombi formation and inadequate blood perfusion. Microthrombi-damaged endothelial cells (ECs), tumor, and blood cells further aggravate the apoptosis of the cells and facilitate MPs storm. PS, especially on MPs, plays a pivotal role in the blood coagulation process, contributing to clot initiation, amplification, and propagation. Since coagulation is a common pathway of COVID-19 and cancer, and associated with mortality, patients would benefit from antithrombotic therapy. The above results lead us to assert that early stage antithrombotic therapy is optimal. This strategy is likely to maintain blood flow patency contributing to viral clearance, attenuating the formation of cytokines and MPs storm, maintaining oxygen saturation, and avoiding the progress of the disease.

Keywords: COVID-19; cancer; microparticles; phosphatidylserine; thrombosis; treatment strategy.

FIGURE 1

The pathophysiological mechanisms of pulmonary coagulation in COVID-19 patients with cancer. (A) SARS-CoV-2 infects the epithelial cells of the upper respiratory tract and the conducting airways via ACE2 and TMRPSS2 receptors. The virus enters into the host cell and is then freed from the capsid for transcription and translation. (B) Illustration of the mechanisms of thrombi formation in COVID-19 patients with cancer, combining a cancer-induced hypercoagulable state and procoagulant factors of COVID-19. Extensive microthrombi induce elevated pulmonary capillary pressure, eventually leading to PH. Virus infection promotes the damage to alveolar epithelial cells and ECs, causing substances within the blood vessel to extrude into alveolar lumens under the conditions of PH, which impedes the gas-exchange. NETs and activated immune cells extruding into the alveolar lumens are collectively responsible for interstitial inflammatory infiltration, diffuse alveolar damage, and ARDS. Mechanical ventilation can exacerbate the problem by drying the alveolar. The highly concentrated plasma and jelly-like proteins form a hyaline membrane in the alveolar space, and leading to ventilation-perfusion mismatch and serious hypoxia. (C) Massive activation of immune cells produces sustained inflammatory cytokines, which ultimately leads to cytokine storm. Cytokine storm further induces PS-positive MPs to be released from various cells, including blood and cancer cells, ultimately resulting in systemic thrombosis inside the vascular. ACE2: angiotensin-converting enzyme 2; TMPRSS2: type II transmembrane serine protease; PH: pulmonary hypertension; ECs: endothelial cells; ARDS: acute respiratory distress syndrome; RBCs: red blood cells; PLTs: platelets; Neu: neutrophil; NK cells: natural killer cells; DCs: dendritic Cells; Mø: macrophages; IL: interleukin; TNF Tumor necrosis factor-α: Tumor necrosis factor-α; IFN-γ; Interferon-γ; MPs: Microparticles; NETs: neutrophil extracellular traps.

FIGURE 2

The mechanism of PS externalization involved in coagulation. (A) Extracellular vesicles can be classified into two types according to size: MPs (approximately 100–1000 nm) and exosomes (approximately 40–100 nm). GSDMD forms a pore, which leads to calcium influx, TMEM16F activation, and PS exposure, further enhancing the procoagulant activity of TF, and facilitating thrombosis (B) Owning to various stimuli, the caspase-dependent flippases ATP11A and ATP11C are inactivated while the calcium-dependent scramblase Xkr8 is activated, resulting in PS exposure on the outer membrane. FVIIa: Activated factor VII; TF: Tissue factor; FX: Factor X; PS: Phosphatidylserine; TMEM16F: Transmembrane protein 16F; ECs: Endothelial cells; PLTs: Platelets; AP: Activated platelets; RBCs: Red blood cells.; MPs: Microparticles; GSDMD: gasdermin D.

FIGURE 3

The mechanisms of PS involved in coagulation. During the initiation step of the coagulation cascade, PS exposure mediates TF decryption initiating the extrinsic coagulation pathway. TF/FVIIa complex can then activate FIX and FX. Subsequently, FXa assembles with FVa on the surface of monocytes, and the prothrombinase complex generates thrombin by cleavage of prothrombin in blood plasma. During the amplification phase, thrombin activates circulating FV and FVIII, causing its release from vWF. Subsequently, FVIIIa and FVa combine with PS-rich phospholipids on the activated PLTs surface. Following ECs activation, increased P-selectin and vWF expression initiate PLTs adhesion to the endothelium through binding with PLTs PSGL-1 and glycoprotein GP Ib/IX/V complex, respectively. ICAM-1 promotes PLTs adhesion via binding of fibrinogen with GPIIb/IIIa on the PLTs membrane. Moreover, exposed subendothelial collagen promotes PLTs adhesion and activation by binding to GPVI, eventually leading to PLTs aggregation. Activated PLTs release mediators, especially ADP and TXA2, which attract circulating platelets to the growing thrombus. PLTs activate FXII by MPs formation and poly P release, and increase the generation of fibrin. In the propagation phase, exposed PS facilitates the assembly of the tenase and prothrombinase complexes of the coagulation cascade. Thrombin cleaves soluble fibrinogen into fibrin and activates FXIII, which forms cross-linked and stable fibrin. The above coagulation processes ultimately lead to platelet activation and thrombus formation. ECs: Endothelial cells; PS: Phosphatidylserine; TF: Tissue factor; VIIa: Activated factor VII; Xa: Activated factor X; Va: Activated factor V; VIIIa: Activated factor VIII; PT: Prothrombin; TXA2: Thromboxane A2; ICAM-1: Intercellular adhesion molecule 1, PLTs: Platelets; AP: Activated platelets; vWF: von Willebrand factor; GP: Glycoprotein; Poly-P: polyphosphate; FXII: Factor XII; FXIII: Factor XIII; TB: Thrombin; PC: Protein C; APC: Activated protein C; TM: Thrombomodulin; ERCP: endothelial protein C receptor.