Phytochemicals as Potential Therapeutics for SARS-CoV-2-Induced Cardiovascular Complications: Thrombosis and Platelet Perspective

Abstract

After gaining entry through ACE2 aided by TMPRSS2, the SARS-CoV-2 causes serious complications of the cardiovascular system leading to myocarditis and other myocardial injuries apart from causing lung, kidney and brain dysfunctions. Here in this review, we are going to divulge the cellular and immunological mechanisms behind the cardiovascular, thrombotic and platelet impairments that are caused in COVID-19. In addition, we also propose the significance of various anti-platelet and anti-thrombotic phytochemicals in the treatment of COVID-19. The virus induces many immune-modulatory cytokines and chemokines which help in the intravascular coagulation and create a pro-thrombotic environment along with pulmonary embolism and thrombocytopenia. Different types of innate and adaptive immune cells and their granular contents regulate the pathophysiology of SARS-CoV-2 induced endothelial and platelet dysfunctions which correlate the involvement of platelets with myocardial injury and intravascular thrombi directly or indirectly. Hence, by exploiting the natural bioactive compounds from medicinal plants and inhibiting the platelet mediated thrombus formation can be beneficial for the treatment of SARS-CoV-2 infection.

Keywords: ACE2; SARS-CoV-2; cytokine storm; myocardial injury; phytochemical; platelet; thrombosis.

FIGURE 1

Phytochemicals targeting platelet function and thrombosis: Platelet function is governed by intracellular Ca²⁺ signaling resulting in platelet adhesion, activation, aggregation, and secretion. SARS-CoV-2 is demonstrated here to cause increased platelet activation, secretion, and aggregation. There are few phytochemicals which are reported to have antiplatelet activity and could be potential therapeutic candidates for the treatment of COVID-19.

FIGURE 2

SARS-CoV-2 structure and routes of entry: SARS-CoV-2 consists of Spike protein (S) membrane protein (M), envelope protein (E), nucleoprotein (N), and the viral genome (+ve ssRNA). Among these, the S protein is most important and is made up of two types of subunits that is, S1 (for binding with host receptor) and S2 (for viral fusion) subunits. During viral attachment, the receptor-binding domain (RBD) of S1 interacts with the peptidase domain (PD) of ACE2. The entry and fusion of this virus is aided by a transmembrane serine protease, TMPRSS2.

FIGURE 3

SARS-CoV-2 life cycle and cardiovascular complications: SARS-CoV-2 infects a host cell through ACE2 and TMPRSS2, and through its intracellular life cycle it produces a number of new virions. The virus activates different innate and adaptive immune cells (APCs and T cells) to release certain pro-inflammatory molecules like IL-6, IFN-γ, TNF-α, and MCP-1 that results in cytokine storm. This surge in immunomodulatory molecules mediates the occurrence myocarditis. Virus itself can induce the host cell to produce pro-inflammatory cytokines through IL-6–mediated JAK/STAT and NF-κB pathways. Few circulating biomarker proteins like TnT, CRP, CK, and BNP can potentially cause myocardial injury.

FIGURE 4

SARS-CoV-2–induced thromboses and platelet dysfunction: SARS-CoV-2 infection caused endothelial dysfunction that releases ROS, IL-6, TF, and vWF. These molecules along with thrombin can activate platelets. The activated platelets adhere, aggregate, and secrete its granular (α and dense granules) contents as well as extracellular vesicles. The aggregated platelets induce high platelet consumption and IFN-I through Toll pathway inhibiting magakaryocyte to produce platelets, thus leading to low platelet production. All these cumulatively results in thrombocytopenia. The fibrinogen degradation produces D-dimer and other thrombogenic molecules that result in venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), and thrombotic microangiopathy (TMA).