COVID-19: imbalance of multiple systems during infection and importance of therapeutic choice and dosing of cardiac and anti-coagulant therapies

Abstract

The renin-angiotensin-aldosterone system and its metabolites play an important role in homeostasis of body, especially the cardiovascular system. In this study, we discuss the imbalance of multiple systems during the infection and the importance of therapeutic choice, dosing, and laboratory monitoring of cardiac and anti-coagulant therapies in COVID-19 patients. The crosstalk between angiotensin, kinin-kallikrein system, as well as inflammatory and coagulation systems plays an essential role in COVID-19. Cardiac complications and coagulopathies imply the crosstalks between the mentioned systems. We believe that the blockage of bradykinin can be a good option in the management of COVID-19 and CVD in patients and that supportive treatment of respiratory and cardiologic complications is needed in COVID-19 patients. Ninety-one percent of COVID-19 patients who were admitted to hospital with a prolonged aPTT were positive for lupus anticoagulant, which increases the risk of thrombosis and prolonged aPTT. Therefore, the question that is posed at this juncture is whether it is safe to use the prophylactic dose of heparin particularly in those with elevated D-dimer levels. It should be noted that timing is of high importance in anti-coagulant therapy; therefore, we should consider the level of D-dimer, fibrinogen, drug-drug interactions, and risk factors during thromboprophylaxis administration. Fibrinogen is an independent predictor of resistance to heparin and should be considered before thromboprophylaxis. Alteplase and Futhan might be a good choice to assess the condition of heparin resistance. Finally, the treatment option, dosing, and laboratory monitoring of anticoagulant therapy are critical decisions in COVID-19 patients.

Keywords: Bradykinin; Cardiac complications; Coagulation; Cytokine storm; SARS-CoV-2.

Fig. 1

Importantly, overactivation of ACE/Ang II/AT1R axis is associated with the pathogenesis of proliferation, oxidative stress, inflammation and fibrosis leading to the onset of pathological disorders including lung, renal and cardiovascular diseases. Increased level of bradykinin and its metabolites enhances inflammation, coagulation and the complement system, and these three systems play an important role in angioedema, cardiovascular dysfunction and sepsis which occur in COVID‐19 patients. Excessive vasodilation happens as a result of Ang (1–7) activation, synthesis of nitric oxide and agonism of AT2, B2, MAS receptors as well as accumulated bradykinin. Ang (1–7) and Ang (1–9) increase bradykinin levels. Bradykinin stimulates renal Na+ and K+ excretion via inhibiting the K+ channel (Kir4.1) in kidney and leads to hypokalemia. Based on recent studies, the accumulation of bradykinin is as important as Ang-II, and it should be balanced in the body to control the harmful effects in COVID-19 patients. Bradykinin is the inflammatory product of coagulation system consisting of factor XII (FXII), plasma prekallikrein (PPK) and high molecular weight kininogen (HK). Bradykinin Receptor B1 (BDKRB1) plays a major role in the outbreak and maintenance of the inflammatory response. Although kinin-kallikrein system crosstalks to RAS, coagulation system and finally the thrombosis leads to organ failure

Fig. 2

COVID-19 patients face multiple-system imbalances. The main imbalances were detected in RAAS, Kallikrein, inflammatory and coagulation systems. These imbalances lead to several cardiac complications such as: Heart palpitation, arrhythmic events, ventricular arrhythmias (VA), myocardial damage (MD) and myocardial infraction (MI). NLRP3 inflammasome might be the major reason of cytokine storm and multi-organ damage in COVID-19 infection; therefore, targeting NLRP3 inflammasome can be a good approach in COVID-19 treatment protocols. Activation of NLRP3 inflammasome provokes an immune response via intracellular caspase, which leads to imbalanced proinflammatory cytokines release, humoral response, and the complement cascade. NLRP3 inflammasome is a good drug target in SARS-CoV-2 treatment so Statin can be one of our best choices in COVID-19 treatment because it affects NLRP3, Cardiac complications and cytokine storm. Additionally, Tocilizumab and Selinexor are strong choices in managing cytokine storm