IJCS | Volume 33, Nº4, July and August 2020

407 infected with the new coronavirus. 10 The best prognosis for LMWH therapy in severe cases of COVID-19 is attributed to the uncoordinated coexistence of hyperproteolysis and hypercoagulation. The endothelial cell dysfunction induced by coronavirus infection results in increased production of thrombin, which generates a hypercoagulable state. Moreover, hypoxia found in severe COVID-19 may stimulate thrombosis, not only increasing blood viscosity, but also a signaling pathway dependent on the hypoxia-inducible transcription factor. The anti- inflammatory effect of LMWH can also add benefit to its use. In China, a dose considered prophylactic (Table 1) was used, with hemorrhagic complications being uncommon and generallymild. However, it is important to consider whether a higher dose of LMWH could be convenient innon-Asianpatientswith severeCOVID-19. Since the decline in platelet count and the prolongation of prothrombin time correlate with increased mortality and hypofibrinogenemia is not common in sepsis, the criteria for sepsis-induced coagulopathy are important to guide anticoagulant therapy, as well as high levels of D-dimer, which acts as an indirect marker of coagulation activation, even because the activation of coagulation contributes to the compartmentalization of pathogens, reducing their invasion. Anticoagulation in patients without significant coagulopathy is associated with a potential risk. 9 Therefore, anticoagulant therapy performedmainly with LMWH appears to be associated with a better prognosis in severe cases of COVID-19 in patients who clearly meet sepsis-induced coagulopathy criteria or have significantly high levels of D-dimer. 9 Drugs that Modulate the Renin-Angiotensin- Aldosterone System The Renin-Angiotensin-Aldosterone System (RAAS) plays a crucial role in the homeostasis of blood volume, and consequently, of systemic blood pressure. Its actions are mediated by Angiotensin II (Ang II) via the AT1 and AT2 receptors, which in vascular smooth muscle generate vasoconstriction and vasodilation, respectively. The cleavage of Angiotensin I (Ang I) by ACE accounts for the formation of Ang II. On the other hand, the homologous ACE2 enzyme converts Ang I to Ang 1-9, which is an inactive metabolite, and Ang II to Ang 1-7, a peptide that can act via the MAS receptor (MasR) playing an anti-inflammatory, antifibrotic and vasodilator role. ACE2 is expressed in several tissues Table 1 – Therapeutic regimen recommended for the control of ARDS in patients with COVID-19 Drug Dosage Unfractionated heparin 9 10000-15000 U/day Enoxaparin 9 40-60 mg every 24h Acetazolamide 21 250mg every 12h Nifedipine 21 30mg every 12h (prolonged release) Sildenafil 21 20-50mg every 8h Tadalafil 21 10mg every 12h such as heart, lung, kidney, spleen, liver, brain, among others, presenting about 40% homology to ACE (figure 2). The affinity of Ang II for its binding site in the ACE2 enzyme is 400 times greater than the affinity of this same peptide for the binding site in ACE. 13,14 It is known that ACE2 participates in the process of cell invasion by the SARS virus, in which the S protein (Spike) present in the virion binds to this transmembrane enzyme, promoting its internalization via endocytosis with the virus. This interaction configures an important and limiting process in its replication cycle. In addition, with endocytosis and consequent decrease in the density of this enzyme in the tissue membrane, there is a decrease in the degradation of the Ang II substrate by the former and consequently the formation of Ang 1-7 product, which favors the process of pulmonary fibrosis. Studies show that the mechanism adopted by the new coronavirus is similar, corroborating the clinical findings that ARDS is highly prevalent in COVID-19. 14,15 Furthermore, in silico studies have shown that, due to mutations, this virus has a greater affinity for ACE2 than other SARS, which may be related to a greater dynamics of infection by the new coronavirus. 15 Atri et al., 11 also described that the expression of ACE2 is encoded on the X chromosomes, which may explain the sexual differences pointed out in the epidemiology of COVID-19, which seems to affect more males than females. 11 In the pathophysiology of heart failure, changes in the density of ACE2 and the increase of its expression in the heart are also identified, which may reflect a compensatory effect in the face of cardiac remodeling and hypertrophy, favoring the increase in the local concentration of Ang 1-7. Thus, the deleterious effects Pedro et al. Cardiovascular pharmacotherapy and covid-19 Int J Cardiovasc Sci. 2020; 33(4):404-411 Viewpoint