key: cord-1055182-jrb8dgvo
authors: Brandão, Simone Cristina Soares; Godoi, Emmanuelle Tenório Albuquerque Madruga; Ramos, Júlia de Oliveira Xavier; de Melo, Leila Maria Magalhães Pessoa; Sarinho, Emanuel Sávio Cavalcanti
title: Severe COVID-19: understanding the role of immunity, endothelium, and coagulation in clinical practice
date: 2020-11-16
journal: Jornal vascular brasileiro
DOI: 10.1590/1677-5449.200131
sha: 58ed90cf4f9937b3e6167e43f5cae6f863fa3c0e
doc_id: 1055182
cord_uid: jrb8dgvo

SARS-CoV-2 is responsible for the COVID-19 pandemic. The immune system is a determinant factor in defense against viral infections. Thus, when it acts in a balanced and effective manner the disease is self-limited and benign. Nevertheless, in a significant proportion of the population, the immune response is exaggerated. When infected, patients with diabetes, hypertension, obesity, and cardiovascular disease are more likely to progress to severe forms. These diseases are related to chronic inflammation and endothelial dysfunction. Toll-like receptors are expressed on immune cells and play an important role in the physiopathology of cardiovascular and metabolic diseases. When activated, they can induce release of inflammatory cytokines. Hypercoagulability, hyperinflammation, platelet hyperresponsiveness, and endothelial dysfunction occur in immune system hyperactivity caused by viral activity, thereby increasing the risk of arterial and venous thrombosis. We discuss the interactions between COVID-19, immunity, the endothelium, and coagulation, as well as why cardiometabolic diseases have a negative impact on COVID-19 prognosis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for COVID-19 disease (COronaVIrus Disease 2019). Coronaviruses cause outbreaks that threaten health, including the 2002 severe acute respiratory syndrome (SARS) epidemic in China, the 2012 Middle East respiratory syndrome (MERS), and the current COVID-19 pandemic. [1] [2] [3] SARS-CoV-2 was identified in patients with atypical pneumonia, characterized by fever, dry cough, and progressive dyspnea. 1, [4] [5] [6] The initial data from China, showed that 81% of COVID-19 cases exhibited mild to moderate symptoms, including patients with no pneumonia or with mild pneumonia. Fourteen percent of patients developed the severe disease and 5% became critically ill, with respiratory failure and multiple organ failure and an extremely high risk of death. 1, [7] [8] [9] The major question is why some people progress to the severe form of COVID-19. Studies have shown a significant relationship between disease severity and immune system markers. It was suggested that during the response to SARS-CoV-2, immunological dysregulation and elevated levels of proinflammatory cytokines could be the primary cause of tissue damage. More than anything, it is people with cardiovascular diseases (CVD) and metabolic diseases who are at the highest risk of death from COVID-19. 2, [10] [11] [12] Therefore, this pandemic has created many challenges for medicine, since there is an urgent need to save lives. We know that immunresponse, the endothelium, and the coagulation system interact intimately and that chronic inflammatory processes are involved in the pathophysiology of CVD and metabolic diseases. This review discusses the interactions between COVID-19, immunity, the endothelium, and coagulation, and also the possible aspects that induce cardiometabolic diseases to have a negative impact on COVID-19 cases. The objective is to stimulate increased reflection on the influence of these factors on treatment approaches to this new disease.

The immune system is activated to defend against infectious agents. Initially, this function is mediated by innate immunity reactions and later by adaptive immunity reactions, which are determinant in combating viral infections. In COVID-19, an effective and balanced inflammatory response enables a selflimiting and benign disease course. The severe form occurs in a subset of patients whose immunoresponse to SARS-CoV-2 is exaggerated. 1, [13] [14] [15] SARS-CoV-2 is a member of the betacoronavirus family, it has single-stranded RNA with typical structural proteins, comprising envelope (E protein), membrane (M protein), nucleocapsid (N protein), and spike (S protein) proteins, the last of which is responsible for the virus' infectiousness. 16, 17 The S proteins on the surface of SARS-CoV-2 bind to human ACE2 receptors (angiotensin-converting enzyme 2), transmembrane proteins that, in turn, transfer the genetic material into the cell and initiate the replication process. [16] [17] [18] Human cells infected by the virus are recognized by the immune systems, both innate and adaptive, which triggers cytokine production. Two of the most important cytokines produced are tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). The first is responsible for activation of neutrophils and promotion of coagulation and acts on a centralized level to produce fever; the second induces macrophage activity to destroy the pathogen and amplifies the release of pro-inflammatory, pro-fibrotic, immunoresponseregulating cytokines. 2, 10, 14, [19] [20] [21] Additionally, ACE2 is a carboxypeptidase capable of converting angiotensin 2 into angiotensins 1-7. This enzyme is a homolog of ACE1, but it fulfills the role of a counterweight in the renin-angiotensin-aldosterone system (RAAS). 16, 18, 22 When the virus binds to the ACE2 receptor, production of angiotensins 1-7 is reduced, which can trigger a series of cardiovascular and proinflammatory complications (Figure 1 ). 18 The phases of COVID-19 appear to be linked to the intensity of the immunoresponse. When there is an adequate inflammatory response, patients do not progress beyond phase I and the infection is resolved. In cases in which the immunoresponse is exaggerated, the disease progresses to phases II and III.

The mild form (phase I) is generally characterized by fever, dry cough, and tiredness. Other manifestations include diarrhea, myalgia, headaches, odynophagia, anosmia, ageusia, and coryza. The severe form (phase II) is characterized by dyspnea, tachypnea, low oxygen saturation, and pulmonary infiltrate visible on chest X-rays or computed tomography. Critical cases (phase III) show signs of circulatory shock, respiratory failure, and multiple organ failure. 2, 4, 6, 7, [23] [24] [25] A modulated immunoresponse against SARS-CoV-2 appears to be essential for the resolution of COVID-19. It comprises coordinated production of proinflammatory (IFN-γ and TNF-α) and antiinflammatory cytokines (interleukin-10 [IL-10]), which, together with cellular activity and immunoglobulins (Ig), activate the maximum potential for combating the virus. 14, 19, 20 It is very important for patient management to define the disease phase by careful history taking. 6,7 A syndrome involving pulmonary and extrapulmonary inflammation, known as secondary hemophagocytic lymphohistiocytosis (sHLH), may be present in phase III. It is characterized by immunological hyperactivity due to inadequate elimination of macrophages activated by natural killer (NK) cells and cytotoxic T lymphocytes, resulting in excessive production of proinflammatory cytokines, 2 followed by a cytokine "storm" and exacerbation of the inflammatory mechanisms. This condition can cause death. 2, 25 Therefore, patients with severe COVID-19should be screened for hyperinflammation, using laboratory markers and the HScore. 26 This score was the first score to be validated for the diagnosis of reactive hemophagocytic syndrome. It is based on the largest dataset from adult patients with suspected reactive hemophagocytic syndrome and comprises nine appropriately weighted clinical, biological, and cytological variables. A cutoff of >169 on the HScore has 93% sensitivity and 86% specificity for sHLH. 26 The intensity of the immunoresponse to SARS-CoV-2 interferes negatively with endothelial function and preexisting diseases related to endothelium are factors associated with the severity of COVID-19. This communication network makes it clear that, in the severe form, the immune system/hyperinflammation, the endothelium, and coagulation are involved cyclically. (1) (2) (3) (4) (5) (6) (7) , subproduct of angiotensin 1, and consequences of blocking. Angiotensin-converting enzyme 1 (ACE1) and angiotensin-converting enzyme 2 (ACE2) act on angiotensins 1 and 2. The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) S protein binds to the ACE2 receptor of the human cell, reducing its enzyme activity. AT1R = type 1 angiotensin II receptor; AT2R = type 2 angiotensin II receptor; MASR = angiotensin 1-7 MAS receptor.

The endothelium is an active organ with endocrine, paracrine, and autocrine functions, and is indispensable for the regulation of tonus and maintenance of vascular homeostasis. 5, 27 In COVID-19, regardless of whether recruitment of immune cells it is immunomediated or in response to direct viral aggression of the endothelium, it can cause generalized endothelial dysfunction associated with apoptosis. 5, 8, [28] [29] [30] In cases of greatest severity, death is caused by multiple organ failure. Post mortem histological studies have revealed a picture of lymphocytic endotheliitis in the lungs, heart, kidneys, and liver, and also cellular necrosis and presence of microthrombi, which, in the lungs, worsens respiratory failure. 2, 10, [31] [32] [33] [34] [35] The endothelium has been studied previously in relation to other viral diseases, such as the human immunodeficiency virus (HIV). As with HIV, SARS-CoV-2 appears to have a direct endothelial aggression effect. 36 Autopsy studies 33, 34 found evidence of direct infection by SARS-CoV-2 of the endothelial cell and diffuse inflammation. 35 In addition to the impact of immunity, the endothelial dysfunction caused by SARS-CoV-2 would explain why patients with comorbidities of the blood vessels are at greater risk of developing severe COVID-19 and vice-versa. 4, 28 

Elderly patients, males, and those with CVD and/or metabolic diseases are at greater risk of unfavorable progression of COVID-19. Cytokine "storms", elevated acute phase proteins, and biomarkers of cardiac damage are characteristics of the severe form and predictors of death. 24, 28, 37 The idea that inflammatory states are responsible for the onset or exacerbation of diseases is well-established. The association of inflammatory cells and their products with the pathophysiology of atherosclerosis is widely recognized and so is their relationship with the components of the metabolic syndrome (obesity, diabetes mellitus, and hypertension). 27, 28, 36, 38, 39 Richardson et al. 40 evaluated 5,700 electronic patient records from patients hospitalized with COVID-19 in six hospitals in New York and observed that 57% were hypertensive, 41% were obese, and 34% were diabetic. The most recent data in the global literature report greater mortality from COVID-19 in patients with these comorbidities. Also of note in this study from New York was that no deaths were reported among people under the age of 18 years. Although cardiometabolic diseases can have onset in childhood, they are considerably more prevalent in adults and the elderly.

The challenge is to understand why certain people can successfully recover their immunological homeostasis after suffering an insult and others do not. 2, 10, 12, 14, 19, 20 Possibly, some people are genetically susceptible to an imbalanced inflammatory response and, in these people, a single stimulus can have disastrous consequences, such as severe COVID-19, for example. 29, 30 SARS-CoV-2 activates the production of interleukin 12 (IL-12) and IFN-γ by dendritic cells, macrophages, and NK cells. These cytokines stimulate immature CD4+ T cells to differentiate into T H 1 cells. The primary function of the T H 1 phenotype is the production of IFN-γ and TNF-α. In addition to stimulating the T H 1 response, IFN-γ plays a crucial role in the antiviral response as a macrophage activator and inducer of IgG production by B lymphocytes. 41 Of the many chemokines and cytokines that exist, five (IL-1, IL-6, TNF-α, IL-8, and CCL2/ MCP-1) are involved in diseases such as psoriasis, rheumatoid arthritis, and atherosclerosis. Some of the roles of these cytokines are well-established: increased cellular expression of adhesion molecules, chemotaxis of inflammatory cells, stimulation of cell differentiation and production of acute phase proteins, and proliferation of smooth muscle cells. All of these processes amplify the local and systemic inflammatory response, involving platelets and the fibrinolysis and coagulation systems. 2, 14, 22, 38, 42 Just as in COVID-19, atherosclerosis involves a predominance of T H 1 response, involving IFN-γ, TNF-α, and TNF-β, which amplify the inflammatory response. IFN-γ is considered one of the principal proatherogenic cytokines, promoting the participation of these cells in the inflammatory response by activating macrophages. 2, 10, 14, 38, 43 Additionally, studies have demonstrated the production of IL-12 by monocytes in response to oxidized low density lipoprotein. These results prove that IL-12 expressed in atherosclerotic lesions can amplify responses of T H 1 CD4+ T lymphocytes, considerably contributing to the immunopathology of atherosclerosis. Notwithstanding, this process can be highly regulated by the action of anti-inflammatory cytokines, such as IL-10. 2, 5, 10, 14, 22, 38, 44 In view of the above, it is clear that amplification of the atherosclerotic process is triggered by a specific immunoresponse, which generates T H 1 pathway cytokines, such as IL-12 and IFN-γ. 27, 38, 39, 43 In addition to the cytokines, positive acute phase proteins, particularly C-reactive protein, have also been targeted in several different studies of the pathogenesis of atherosclerosis. In addition to their classic role of opsonization of antigens, other interesting aspects have been investigated, such as their elevation in conditions of obesity, inflammation, metabolic syndrome, diabetes, and arterial hypertension, making them a predictive marker of risk of CVD. 10, 22, 44 Cardiovascular diseases and metabolic syndrome are also consequences of immune system imbalances. People who have these diseases, even the youngest among them who have incipient atherosclerosis or metabolic syndrome, are more susceptible to the severe form of COVID-19, since they already have a hyperactive and dysregulated immune "territory".

Considering that chronic inflammatory processes of the endothelium with a secondary autoimmune component and with specific immune responses against self-antigens are involved in the pathophysiology of atherosclerosis and the cardiometabolic diseases, we postulated that these individuals could have a more active expression of innate immune system cells ready to recognized SARS-CoV-2. 10, 43 After recognition, these cells would stimulate the production of IFN-γ by NK cells which, in turn, would induce macrophages to present viral antigens to T and B lymphocytes in an exaggerated and uncontrolled manner when compared to the cells of healthy individuals.

COVID-19 immunopathology is characterized by the elevation of IL-6 and TNF-α. These cytokines are products of activation of Toll 4 receptors (TLR4), which are components of innate immunity. 16, 42, 45 A study conducted by computer simulation 16 concluded that the SARS-CoV-2 spike protein (the same protein that binds to the ACE2 receptors) interacts with TLR4, thereby suggesting that this is the receptor responsible for recognition of SARS-CoV-2 by the immune system.

That TLR4 is involved in the pathogenesis of atherosclerosis is already well known. Several different types of cells present in atherosclerotic plaques express TLR4 and several proatherogenic ligands appear to activate TLR4. These receptors also participate in the pathophysiology of cardiometabolic diseases such as obesity and diabetes; TLR4 is involved in lipotoxicity and pancreatic beta cell dysfunction. 16, 42, 45 Hyperexpression of TLR4 may even be genetically coded. 16, 42 Another mechanism probably responsible for worse progression in COVID-19 involves the ACE2 receptor. The reduction in ACE2 activity caused by SARS-CoV-2 has implications for CVD because they amplify dysregulation of the RAAS and immune system ( Figure 1 ). 18, 43 Additionally, ACE2 receptors and dipeptidyl peptidase are enzymes that break down bradykinin, a vasoactive peptide. After SARS-CoV-2 binds to ACE2, the viral complex undergoes endocytosis, and the surface ACE2 is inhibited. As a result, the potential for breakdown of bradykinins is reduced. 18, 43 It has been speculated that excess bradykinin can complicate SARS-CoV-2 infection because of vasodilation effects, increased vascular permeability, and exacerbation of the coughing reflex.

ACE1 also breaks down bradykinin, and drugs that inhibit this enzyme (angiotensin-converting enzyme inhibitors [ACEi]) cause an increase in tissue bradykinin and can provoke coughing and angioedema in hypersensitive individuals. However, published studies have shown that the use of medications that block RAAS, such as ACEi and angiotensin receptor blockers (ARB), did not increase COVID-19 mortality and may even be a protective factor. 18 The elderly population is at increased risk of death from COVID-19. Aging is a condition associated with inflammation, whereas the neonatal period is linked to an immature and anti-inflammatory immunoresponse. 25 Men appear to be more susceptible than women to the severe form of COVID-19. Sexual differences (genetic, environmental, and hormonal) are reflected in differences in the immune system, resulting in variable responses to infection. 9 A series of cases with immunodeficiencies also yielded interesting evidence. COVID-19 followed a mild clinical course in patients with agammaglobulinemia without B lymphocytes but progressed aggressively in common variable immunodeficiency. These results suggest mechanisms for possible therapeutic targets. 12, 14, 20 

Hyperinflammatory states cause platelet activation, endothelial dysfunction, and blood stasis, conditions that are directly related to venous and arterial thrombosis. [46] [47] [48] Coagulopathy in severe COVID-19 infection is similar to sepsis-induced coagulopathy (SIC), characterized by disseminated intravascular coagulation (DIVC) and thrombotic microangiopathy. Furthermore, since the lungs are the organ most affected in COVID-19, hypoxemia is a risk factor for thrombosis. 31 Adequate pulmonary function is totally dependent on an intact alveolar-capillary membrane. The SARS-CoV-2 virus provokes SARS. This syndrome is the body's response to severe pulmonary aggression that triggers a series of physiological defense mechanisms, culminating in a form of autoaggression. This amplifies the inflammatory response, which can progress to Systemic Inflammatory Response Syndrome and multiple organ failure. 5, 10, 21, 34, 44 Authors have also observed a build-up of insoluble fibrin in the alveolar space in SARS, due to incomplete fibrinolysis. One hypothesis is that the fibrinogen leaks from plasma because of diffuse alveolar damage and is not completely eliminated due to hypofibrinolysis. This insoluble fibrin will then contribute to pulmonary fibrosis and its negative outcomes. [49] [50] [51] It should be understood that alveolar thrombotic microangiopathy is a primary thrombosis triggered by COVID-19 and differs from pulmonary arterial thrombosis secondary to classic venous thromboembolism (VTE). In classic pulmonary embolism (PE), the thrombus is actually an embolus that migrates, primarily from the deep veins of the lower limbs, whereas in COVID-19 the primary thromboses apparently predominantly originate in pulmonary capillaries. 34 To date, there are no conclusive studies of the incidence of VTE in COVID-19.

Thrombotic complications appear to emerge as an important issue in patients infected by COVID-19. A retrospective French study suggested that systematic investigation of VTE and early therapeutic anticoagulation are warranted in patients with severe COVID-19 in the intensive care unit (ICU). Eight of a total of 26 patients were given prophylactic anticoagulation and 18 were given full anticoagulation, depending on their level of VTE risk. Of these patients, 69% exhibited VTE; 100% in the group given prophylactic anticoagulation and 56% in the group given full anticoagulation (p = 0.03). Surprisingly, we realized that the incidence of VTE was still high even in those given full anticoagulation. Moreover, there were six cases of PE among these patients. 49 According to the experience accumulated over the 6 months since the disease emerged, the most important coagulation abnormalities observed were: increased generation of thrombin, D-dimers, and fibrinogen (initially), and prolongation of the prothrombin time (PT); with reduced fibrinolysis and platelet counts. 3, 8, 31, 48, 49 These abnormal coagulation parameters have been observed in COVID-19 since the initial reports from China. Among the first 99 patients hospitalized in Wuhan, it was observed that 6% exhibited prolonged activated partial thromboplastin time (TTPa), 5% had elevated PT, and 36% had high D-dimers, in addition to increases in biomarkers of inflammation, including IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein. Thrombocytopenia occurred in 12% of cases, five patients had other coinfections (one bacterial and four fungal) and four patients had septic shock. 9, 52, 53 D-dimer levels can help with early recognition of patients at greater risk of death, warning of the need for increased care. Preliminary data show that, in patients with severe COVID-19, the anticoagulant treatment appears to be associated with lower mortality in the subset that fulfills the criteria for SIC or has extremely elevated D-dimer levels. 31, 51 Thrombocytopenia is relatively common among patients with COVID-19 and is associated with an increased risk of hospital mortality. The lower the platelet count, the higher the mortality. However, many patients with severe COVID- 19 do not yet exhibit this finding when admitted to the ICU. 25, 46, 47, 51 Prolongation of the PT is also an important marker of severity. In situations with thrombocytopenia and a prolonged PT, it may be useful to assay fibrinogen, as recommended by the International Society of Thrombosis and Haemostasis (SITH), to evaluate the possibility of DIVC. 51 The SITH has produced diagnostic criteria for DIVC and has developed and validated criteria for SIC. The coagulation abnormalities associated with SIC are less severe and occur later than those associated with DIVC. 51 Tang et al. found that 71% of patients who died from COVID-19 fulfilled the SITH criteria for DIVC, whereas only 0.6% of the survivors had DIVC. These researchers also observed a statistically significant increase in D-dimer levels and PT and a reduction in fibrinogen levels from days 10 to 14 of the disease among those who did not survive. 52 A retrospective study from China suggests that the endothelial dysfunction induced by COVID-19 is responsible for the excessive thrombin production and fibrinolysis deficiency, which indicates a hypercoagulable state. 9,15 A total of 449 individuals were studied, the majority were men (59.7%), with a mean age of 65.1±12.0 years and one or more chronic diseases (60.6%). Of these, 99 (22.0%) were given anticoagulant for at least 7 days, 94 of whom were given low molecular weight heparin (LMWH), enoxaparin 40-60 mg/day, and five were given 10,000-15,000 UI/ day of unfractionated heparin (UFH). 9 The study assessed factors predictive of mortality, comparing survivors and non-survivors of COVID-19, with or without treatment with heparin. No significant difference in mortality at 28 days was observed between those given and not given heparin (30.3% vs. 29.7%, p = 0.910). However, anticoagulation with heparin was associated with lower mortality among patients with SIC score ≥ 4 (40.0% vs. 64.2%, p = 0.029), but not among those with SIC score < 4 (29.0% vs. 22 .6%, p = 0.419). In patients with D-dimers elevated to more than six times the upper limit of normality, the use of heparin also reduced mortality by around 20% (32.8% vs. 52.4%, p = 0.017). Hemorrhagic complications were rare and generally mild. 9 This study prompted the creation of a flow diagram to guide anticoagulation decisions in COVID-19 according to disease severity criteria, SIC score, and/or D-dimer levels. The increased risk of thrombi can also be seen in the arteries, not just the veins. Depending on the vessel affected, there may be different clinical manifestations: stroke, mesenteric ischemia, acute myocardial infarction, or lower limb arterial occlusion. 9,51, 52 Oxley et al. reported hospital admission of five patients with SARS-CoV-2 and severe stroke over a period of 2 weeks. According to the publication, this observation constitutes a significant increase in patients under the age of 50 years suffering severe strokes compared to admissions data for the preceding 12 months. Two of these patients had no risk factors or previous history of stroke, one had dyslipidemia and hypertension, one was diagnosed with diabetes at the service, and the last had a history of stroke and diabetes. 54 Compatible with the hypothesis of vascular aggression, some cases with characteristics of shock toxic syndrome or Kawasaki disease were reported by the United Kingdom Paediatric Intensive Care Society, the Spanish Pediatrics Association and the Italian Society of Pediatricians. 55 Kawasaki disease is a vasculitis of the medium vessels and can be triggered by COVID-19. Its etiology is unknown as yet, but epidemiological and clinical presentation suggest that the cause is an abnormal infection or immunoresponse to a pathogen in genetically predisposed children. 55 

In line with the pathophysiology described in the previous sections, and respecting the proposed scope of the article, we will cover the treatments formulated in attempts to improve the resolution of severe forms of the disease. To date, there is no specific treatment with proven efficacy against COVID-19. Therapeutic strategies are based on early recognition of complications and optimized support to relieve symptoms.

A search made on June 25, 2020, on clinicaltrials. gov using the keywords "Covid and treatment" returned 1,563 registered studies, 366 in phases III and IV. Several antiviral and immunomodulatory treatments are being tested in the different stages of COVID-19 and results will be published over the coming months. Until a vaccine is available, we need to increase understanding of what leads some patients to suffer such poor outcomes, to avoid fatal outcomes using the measures and treatments available.

In response to the urgent need to identify effective treatments for COVID-19 in controlled and randomized studies, certain agents are being used in various countries on the basis of evidence obtained in vitro. The results from other viral diseases are being extrapolated and treatments are also being chosen based on observational studies and small clinical trials. Figure 2 illustrates treatment strategies by the disease phase.

The risk factors related to unfavorable disease outcomes can be divided into modifiable and nonmodifiable. Male sex and advanced age are nonmodifiable factors. However, the most elderly people should be isolated as a priority, particularly if they have chronic inflammatory diseases. 25 Active smokers also require greater care, since the lungs are the organ in which the disease's complications set in from phase II onwards and because smoking is an important risk factor for atherosclerosis. 1 Patients with CVD and metabolic syndrome and its principal components (obesity, diabetes, and hypertension) merit great care. 24 Therapeutic management of these factors appears to be a fundamental measure for reducing the reactivity of the endothelium and, as a result, reducing its vulnerability to COVID-19. 40 Optimization of drug treatment with the use of hypoglycemics, antihypertensives, antihyperlipidemics (primarily statins) and platelet antiaggregants such as acetylsalicylic acid (AAS) can help stabilize the endothelium and reduce its reactivity.

Drugs such as ACEi and ARB help to balance the RAAS. As discussed above, this system appears more dysregulated in COVID-19. Additionally, observational studies in patients hospitalized with COVID-19 have suggested that the risk of death is lower among patients on these medications, especially those on ACEi. 18 Once infected with SARS-CoV-2, the first step is the early use of drugs that can prevent replication and facilitate viral clearance. We do not yet have an ideal drug, but studies are ongoing all over the world with antimalarials, antivirals, antibacterials, and antiparasitics. There are unpublished reports of success with a "hit early and hit hard" approach. This hypothesis is being tested in multicenter clinical trials in Brazil and abroad with some of these drug classes. 56, 57 In the midst of the pandemic, conduct is being adjusted as knowledge evolves and much of what is already routine treatment for critical patients is being applied to the treatment of COVID-19. The most important complications of COVID-19 are SARS, SIC, VTE, and DIVC. All of these conditions are well-known in sepsis and in COVID-19 they appear to be the consequence of the dysregulated inflammatory response.

SARS is the first major complication and specific treatment protocols for it exist. 4, 7 Measures such as supplemental oxygen, support in the ICU, and mechanical ventilation are fundamentally important.

While still in the hyperinflammatory phase, drugs that inhibit or reduce the effects of proinflammatory cytokines appear very relevant. IL-6 inhibitors and also glucocorticoids can avert or minimize the cytokine storm. New medications that modulate inflammatory response are fundamental in this phase to avoid excessive inflammation, which attacks the endothelium and many different organs with great intensity and has the potential to cause multiple organ failure and death. 58 Studies have shown an increased risk of deep venous thrombosis (DVT) and PE in patients hospitalized with COVID-19 49 and it is important to monitor these patients using clinical scores for DVT and PE. 59 In relation to VTE, studies indicate that hospitalized patients should be given pharmacological thromboprophylaxis with LMWH or fondaparinux (preferably with UFH), unless the risk of bleeding outweighs the risk of thrombosis. 31, 47, 51 Adjusting the heparin dose for obesity and for patients with renal failure is recommended (Table 1) . 25 , 51 We do not yet have studies that can support the use of anticoagulants in patients without a clinical need for hospital admissions for COVID-19 or the use of intermediate anticoagulation dosages, without at least a strong suspicion of VTE. Studies are ongoing into the use of anticoagulants in the different phases of COVID-19. There is a tendency to suggest that prophylaxis should be maintained after hospital discharge, because of the hypercoagulable state triggered by the disease. 50, [60] [61] [62] There is a risk of bleeding in anticoagulant patients, particularly so as the disease worsens. The profile of DIVC in COVID-19 is initially thrombotic, but it can progress to hemorrhagic as the disease progresses. It is very important to monitor platelet counts and serum fibrinogen levels and also to calculate the risk of bleeding scores such as IMPROVE (International Medical Prevention Registry on Venous Thromboembolism). Patients with an IMPROVE score < 7 are at a low risk of bleeding and should be kept on pharmacological prophylaxis. Cases with scores > 7 are at high risk of bleeding and mechanical prophylaxis is indicated. 63 With relation to the treatment of COVID-19, the therapeutic strategy is based on early recognition of complications and optimized support for the relief of symptoms. To date, there is no specific treatment with proven efficacy against COVID-19. Figure 2 illustrates the principal therapeutic recommendations by the clinical phase of COVID-19.

COVID-19 immunopathology appears to share the same TLR4 receptor as CVD and metabolic syndrome. It is possible that inappropriate activation of this receptor is the factor responsible for the exaggerated immunoresponse seen in patients with the severe form of SARS-CoV-2.

In summary, while we await a vaccine, the best treatment for COVID-19 is perhaps that which encompasses treatments that improve patients' cardiovascular and metabolic conditions, in addition to medications that reduce viral replication, hyperinflammation, and the risk of thrombosis. Abstract SARS-CoV-2 is responsible for the COVID-19 pandemic. The immune system is a determinant factor in defense against viral infections. Thus, when it acts in a balanced and effective manner the disease is self-limited and benign. Nevertheless, in a significant proportion of the population, the immune response is exaggerated. When infected, patients with diabetes, hypertension, obesity, and cardiovascular disease are more likely to progress to severe forms. These diseases are related to chronic inflammation and endothelial dysfunction. Toll-like receptors are expressed on immune cells and play an important role in the physiopathology of cardiovascular and metabolic diseases. When activated, they can induce release of inflammatory cytokines. Hypercoagulability, hyperinflammation, platelet hyperresponsiveness, and endothelial dysfunction occur in immune system hyperactivity caused by viral activity, thereby increasing the risk of arterial and venous thrombosis. We discuss the interactions between COVID-19, immunity, the endothelium, and coagulation, as well as why cardiometabolic diseases have a negative impact on COVID-19 prognosis.

Keywords: COVID-19; endothelium; immunity; atherosclerosis; thrombosis. O SARS-CoV-2 foi identificado em pacientes com pneumonia atípica, caracterizada por febre, tosse seca e dispneia progressiva 1,4-6 . Os dados iniciais, provenientes da China, mostram que 81% dos casos de COVID-19 apresentam sintomas leves a moderados, incluindo pacientes sem pneumonia ou com pneumonia leve. Entre os pacientes, 14% evoluem para uma doença grave e 5% tornam-se doentes críticos com falência respiratória e de múltiplos órgãos, com altíssimo risco de morte 1,7-9 .

A grande questão é compreender por que alguns indivíduos progridem para a forma grave da COVID-19. Estudos têm revelado uma relação significativa entre gravidade da doença e marcadores imunes. Foi sugerido que, durante a resposta ao SARS-CoV-2, a desregulação imunológica e o alto nível de citocinas pró-inflamatórias poderiam ser a causa principal de lesão tecidual. Além do mais, indivíduos com doenças cardiovasculares (DCV) e metabólicas apresentam maior risco de morte pela COVID-19 2,10-12 .

Assim, diante desta pandemia, vários desafios foram impostos à medicina, uma vez que a urgência em salvar vidas é uma necessidade. Sabemos que a resposta imune interage intimamente com o endotélio e o sistema de coagulação e que, na fisiopatologia das DCV e metabólicas, processos inflamatórios crônicos estão envolvidos. Nesta revisão, discutiremos sobre a interação entre a COVID-19, a imunidade, o endotélio e a coagulação, como também sobre os possíveis aspectos que levam as doenças cardiometabólicas a impactarem negativamente em casos de COVID-19. O objetivo é provocar uma maior reflexão sobre a influência desses fatores na abordagem terapêutica dessa nova doença.

O sistema imunológico atua na defesa contra agentes infecciosos. Essa função é mediada por reações iniciais da imunidade inata e tardias da imunidade adaptativa, que são determinantes no combate às infecções virais. Na COVID-19, uma resposta inflamatória eficiente e equilibrada permite uma evolução autolimitada e benigna da doença. A forma grave ocorre numa parcela de pacientes que apresenta uma resposta imune exacerbada ao SARS-CoV-2 1, [13] [14] [15] .

O SARS-CoV-2, um membro da família de betacoronavírus, possui RNA de fita simples com proteínas estruturais típicas, envolvendo as proteínas de envelope (proteína E), membrana (proteína M), nucleocapsídeo (proteína N) e espícula (proteína S, do inglês spike), responsáveis pela infectividade viral 16, 17 . As proteínas S na superfície do SARS-CoV-2 se ligam aos receptores humanos ECA2 (enzima conversora de angiotensina 2), uma proteína transmembrana, os quais, por sua vez, transferem seu material genético para dentro da célula e, em seguida, iniciam seu processo de replicação [16] [17] [18] .

As células humanas, quando infectadas por vírus, são reconhecidas pelos sistemas imunes tanto inato como adaptativo, que iniciam a produção de citocinas. Dentre as principais citocinas produzidas, destacam-se o fator de necrose tumoral alfa (TNF-α) e o interferon-gama (IFN-γ). O primeiro é responsável pela ativação neutrofílica, promoção da coagulação e atuação a nível central para produção de febre; o segundo induz atividade macrofágica de destruição do patógeno e amplia a liberação de citocinas (próinflamatórias, pró-fibróticas e regulatórias da resposta imune) 2, 10, 14, [19] [20] [21] .

Adicionalmente, a ECA2 é uma carboxipeptidase capaz de converter a angiotensina 2 em angiotensinas 1-7. Essa enzima é homóloga à ECA1, mas desempenha um papel de contrapeso no sistema renina-angiotensinaaldosterona (SRAA) 16, 18, 22 . Quando o vírus se liga ao receptor ECA2, reduz a produção de angiotensinas 1-7, podendo desencadear uma série de complicações cardiovasculares e pró-inflamatórias (Figura 1) 18 .

As fases da COVID-19 parecem estar relacionadas à intensidade da resposta imune. Quando existe resposta inflamatória adequada, os pacientes não progridem da fase I e ocorre resolução da infecção. À medida que existe uma resposta imune exacerbada, a doença vai evoluindo para as fases II e III.

A forma leve (fase I) geralmente se caracteriza pela presença de febre, tosse seca e fadiga. Outras manifestações são diarreia, mialgia, cefaleia, odinofagia, anosmia, ageusia e coriza. Já a forma grave (fase II) se caracteriza por dispneia, taquipneia, queda na saturação de oxigênio e infiltrado pulmonar ao raio X ou tomografia computadorizada de tórax. Os casos críticos (fase III) apresentam sinais de choque circulatório, falência respiratória e disfunção de múltiplos órgãos 2, 4, 6, 7, [23] [24] [25] .

Uma resposta imune modulada contra o SARS-CoV-2 parece ser fundamental para a resolução da COVID-19. Ela se dá pela coordenada produção de citocinas pró-inflamatórias (IFN-γ e TNF-α) e anti-inflamatórias [interleucina-10 (IL-10)], a qual, junto com a atuação celular e das imunoglobulinas (Ig), age a fim de atingir o máximo potencial de combate ao vírus 14, 19, 20 .

No manejo do paciente, é de grande relevância definir-se a fase da doença através de anamnese adequada 6, 7 . Uma síndrome de inflamação pulmonar e extrapulmonar, chamada de linfohistiocitose hemofagocítica secundária (LHHs), pode estar presente na fase III. A LHHs se caracteriza por hiperativação imunológica devido à eliminação inadequada de macrófagos ativados pelas células natural killer (NK) e pelos linfócitos T citotóxicos, resultando em produção excessiva de citocinas pró-inflamatórias 2 . Em sequência, há uma "tempestade" de citocinas e uma exacerbação dos mecanismos inflamatórios. Esse quadro pode causar o óbito 2, 25 .

Desta forma, os pacientes com quadros graves da COVID-19 devem ser rastreados para a hiperinflamação, utilizando marcadores laboratoriais e o HScore 26 . Esse escore foi a primeira pontuação validada para o diagnóstico de síndrome hemofagocítica reativa. A pontuação foi baseada no maior conjunto de dados de pacientes adultos com suspeita de síndrome hemofagocítica reativa e é composta por nove variáveis clínicas, biológicas e citológicas, adequadamente pesadas. As pontuações maiores que 169 do HScore são 93% sensíveis e 86% específicas para LHHs 26 .

A intensidade da resposta imune ao SARS-CoV-2 interfere negativamente com a função endotelial e as doenças preexistentes ligadas ao endotélio são fatores associados à gravidade da COVID-19. Essa rede de comunicação deixa evidente por que, na forma grave, o sistema imune/hiperinflamação, o endotélio e a coagulação estão ciclicamente envolvidos.

O endotélio é um órgão ativo, com funções endócrina, parácrina e autócrina, indispensáveis para a regulação do tônus e a manutenção da homeostase vascular 5, 27 . Na COVID-19, o recrutamento de células imunes, pela agressão direta viral ao endotélio ou imunomediada, pode resultar em disfunção endotelial generalizada associada a apoptose 5, 8, [28] [29] [30] .

Nos casos de maior gravidade, o óbito acontece por falência de múltiplos órgãos. Estudos histológicos post mortem revelaram um quadro de endotelite linfocítica nos pulmões, coração, rins e fígado, bem como necrose celular e presença de microtrombos, que, nos pulmões, piora a insuficiência respiratória 2,10,31-35 .

O endotélio já foi estudado em outras doenças virais, como no vírus da imunodeficiência humana (HIV). Assim como o HIV, o SARS-CoV-2 parece ter um efeito direto de agressão endotelial 36 . Em estudos de autópsias 33, 34 , foram encontradas evidências de infecção direta do SARS-CoV-2 na célula endotelial e inflamação difusa 35 . Adicionalmente ao impacto da imunidade, a disfunção endotelial causada pelo SARS-CoV-2 justificaria por que pacientes com comorbidades relacionadas aos vasos sanguíneos têm maior risco de desenvolver a COVID-19 grave e vice-versa 4,28 .

Pacientes idosos, do sexo masculino ou com DCV e/ou metabólicas têm apresentado maior chance de evolução desfavorável da COVID-19. "Tempestades" de citocinas, proteínas de fase aguda elevadas e biomarcadores de lesão cardíaca são características da forma grave e preditivos de morte 24, 28, 37 .

A ideia de que estados inflamatórios sejam responsáveis pela instalação de doenças ou pelo seu agravamento encontra-se bem estabelecida. A associação de células inflamatórias e seus produtos é bem reconhecida na fisiopatologia da aterosclerose, como também nos componentes da síndrome metabólica (obesidade, diabetes mellitus e hipertensão) 27, 28, 36, 38, 39 .

Richardson et al. 40 avaliaram 5.700 prontuários eletrônicos de pacientes hospitalizados com COVID-19 em seis hospitais de Nova York e observaram que 57% eram hipertensos, 41% eram obesos e 34% eram diabéticos. Os dados mais recentes da literatura mundial relatam a maior mortalidade pela COVID-19 em pacientes com essas comorbidades. Ademais, destaca-se que, nesse estudo novaiorquino, não foram relatadas mortes em menores de 18 anos. Embora as doenças cardiometabólicas possam se iniciar na infância, elas são expressivamente mais prevalentes nas fases adulta e senil.

O desafio é entender por que certas pessoas conseguem restaurar a homeostase imunológica com sucesso após sofrerem um insulto e outras não 2, 10, 12, 14, 19, 20 . Possivelmente, algumas pessoas são geneticamente suscetíveis a uma resposta inflamatória desequilibrada e, nessas pessoas, um único estímulo pode levar a consequências desastrosas, a exemplo da COVID-19 grave 29, 30 .

O SARS-CoV-2 ativa a produção de interleucina 12 (IL-12) e IFN-γ por células dendríticas, macrófagos e NK. Essas citocinas estimulam as células T CD4+ imaturas a diferenciarem em células T H 1. A principal função do fenótipo T H 1 é a produção de IFN-γ e TNF-α. O IFN-γ, além de atuar estimulando a resposta T H 1, possui papel crucial na resposta antiviral como ativador de macrófagos e produtor de IgG pelos linfócitos B 41 .

Dentre as várias quimiocinas e citocinas existentes, cinco (IL-1, IL-6, TNF-α, IL-8 e CCL2/MCP-1) estão envolvidas em doenças como psoríase, artrite reumatoide e aterosclerose. Alguns papéis já bem estabelecidos por essas citocinas são: aumento da expressão celular de moléculas de adesão, quimiotaxia de células inflamatórias, estímulo à diferenciação celular e à produção de proteínas de fase aguda e proliferação de células musculares lisas. Todos esses processos amplificam a resposta inflamatória local e sistêmica, envolvendo as plaquetas e os sistemas de fibrinólise e de coagulação 2, 14, 22, 38, 42 .

Na aterosclerose, assim como na COVID-19, existe predominância de resposta T H 1, envolvendo IFN-γ, TNF-α e TNF-β, que amplificam a resposta inflamatória. A IFN-γ é considerada uma das principais citocinas pró-aterogênicas que, por ativar macrófagos, favorece a participação dessas células na resposta inflamatória 2,10,14,38,43 .

Adicionalmente, estudos mostram a produção de IL-12 por monócitos em resposta a lipoproteína de baixa densidade oxidada. Esses resultados provam que a IL-12, por sua expressão nas lesões ateroscleróticas, pode levar à amplificação de respostas de linfócitos T CD4+ do tipo T H 1, contribuindo consideravelmente na imunopatologia da aterosclerose. Todavia, esse processo pode apresentar-se altamente regulado pela ação das citocinas anti-inflamatórias, como a IL-10 2,5, 10, 14, 22, 38, 44 . Sendo assim, diante do exposto, torna-se evidente que uma amplificação do processo aterosclerótico ocorre a partir de uma resposta imune específica, que gera citocinas da via T H 1, como a IL-12 e o IFN-γ 27, 38, 39, 43 .

Além das citocinas, as proteínas positivas de fase aguda, principalmente a proteína C reativa, são alvos de vários estudos na patogênese da aterosclerose. Além de exercer o papel clássico de opsonização de antígenos, outros aspectos interessantes são investigados, como o seu aumento nas condições de obesidade, inflamação, síndrome metabólica, diabetes e hipertensão arterial, colocando-a como um marcador de risco preditivo para DCV 10, 22, 44 .

As DCV e a síndrome metabólica são também consequências de desequilíbrio no sistema imunológico. As pessoas com essas doenças, até mesmo as mais jovens com aterosclerose incipiente ou síndrome metabólica, estariam mais suscetíveis à forma grave da COVID-19, uma vez que já possuem um "terreno" imune hiperativo e desregulado.

Considerando que, na aterosclerose e nas doenças cardiometabólicas, os processos inflamatórios crônicos do endotélio, com um componente autoimune secundário e com respostas imunes específicas de antígeno próprio, estão envolvidos na sua fisiopatologia, postulamos que esses indivíduos poderiam expressar mais ativamente células do sistema imune inato prontas para reconhecer o SARS-CoV-2 10, 43 . Após o reconhecimento, essas células estimulariam a produção de IFN-γ pelas células NK que, por sua vez, induziriam a apresentação pelos macrófagos de antígenos virais aos linfócitos T e B, de forma exacerbada e descontrolada, quando comparadas às células de indivíduos saudáveis.

A imunopatologia da COVID-19 se caracteriza por elevação de IL-6 e TNF-α. Essas citocinas são produtos de ativação do receptor do tipo Toll 4 (TLR4), que faz parte da imunidade inata 16, 42, 45 . Em um estudo por simulações computacionais 16 , concluiu-se que a proteína spike do SARS-CoV-2, a mesma proteína que se liga aos receptores ECA2, interage com o TLR4, sugerindo, assim, que esse receptor seria o responsável pelo reconhecimento do sistema imune ao SARS-CoV-2.

O envolvimento do TLR4 na patogênese da aterosclerose é bem conhecido. Diferentes tipos de células presentes na placa aterosclerótica expressam TLR4 e vários ligantes pró-aterogênicos parecem ativar o TLR4. As doenças cardiometabólicas, como obesidade e diabetes, também exprimem na sua fisiopatologia a participação desses receptores, estando os TLR4 envolvidos na lipotoxicidade e disfunção de células beta pancreáticas 16, 42, 45 . A hiperexpressão do TLR4 pode ser inclusive geneticamente codificada 16, 42 .

Outro provável mecanismo responsável pela pior evolução da COVID- 19 18 .

A população idosa apresenta maior risco de morte pela COVID-19. O envelhecimento é uma condição associada à inflamação, enquanto o período neonatal está relacionado a uma resposta imune imatura e anti-inflamatória 25 . Os homens parecem ser mais suscetíveis à forma grave da COVID-19 em relação às mulheres. Diferenças sexuais (genéticas, ambientais e hormonais) refletem em diferenças no sistema imune, levando a respostas variáveis à infecção 9 .

Outra evidência interessante foi demonstrada por uma série de casos com imunodeficiências. A COVID-19 apresentou curso clínico leve em pacientes com agamaglobulinemia sem linfócitos B, enquanto se desenvolveu agressivamente na imunodeficiência comum variável. Esses resultados oferecem mecanismos para possíveis alvos terapêuticos 12, 14, 20 .

Os estados hiperinflamatórios levam a ativação plaquetária, disfunção endotelial e estase sanguínea, condições diretamente relacionadas a trombose venosa e arterial [46] [47] [48] . A coagulopatia na infecção grave por COVID-19 é semelhante à coagulopatia induzida pela sepse (SIC, de sepsis-induced coagulopathy), caracterizada por coagulação intravascular disseminada (CIVD) e microangiopatia trombótica. Além disso, como os pulmões são prioritariamente afetados na COVID-19, a hipoxemia é um fator de risco para trombose 31 .

A função adequada do pulmão é totalmente dependente de uma membrana alvéolo-capilar íntegra. O vírus SARS-CoV-2 provoca a SARS. Essa síndrome é a resposta do organismo a uma agressão pulmonar grave que dispara uma série de mecanismos fisiológicos de defesa, culminando em uma forma de autoagressão. Assim, amplifica-se a resposta inflamatória que pode evoluir para a síndrome da resposta inflamatória sistêmica e disfunção de múltiplos órgãos 5, 10, 21, 34, 44 .

Autores também observam na SARS um acúmulo de fibrina insolúvel no espaço alveolar devido à fibrinólise incompleta. Uma hipótese é que o fibrinogênio extravasa do plasma pelo dano alveolar difuso e não é eliminado completamente pela hipofibrinólise. Assim, essa fibrina insolúvel vai contribuir para a fibrose pulmonar e seus desdobramentos negativos [49] [50] [51] .

Destaca-se que a microangiopatia trombótica alveolar é uma trombose primária desencadeada na COVID-19 e difere da trombose arterial pulmonar secundária ao tromboembolismo venoso (TEV) clássico. Na embolia pulmonar (EP) clássica, o trombo é na verdade um êmbolo que migra principalmente das veias profundas dos membros inferiores, enquanto na COVID-19, aparentemente, prevalece a trombose primária dos capilares pulmonares 34 . Até o momento, não há estudos conclusivos sobre a incidência de TEV na COVID-19.

As complicações trombóticas parecem emergir como uma questão importante em pacientes infectados pela COVID-19. Um estudo francês retrospectivo sugere a investigação sistemática para TEV e anticoagulação terapêutica precoce em pacientes de unidade de terapia intensiva (UTI) com COVID-19 grave. Do total de 26 pacientes, oito receberam anticoagulação profilática e 18 receberam plena, de acordo com risco de TEV. Desses pacientes, 69% apresentaram TEV, sendo em 100% no grupo da profilaxia e 56% no grupo com anticoagulação plena (p = 0,03). Surpreendentemente, percebemos que a incidência de TEV foi alta, mesmo nos plenamente anticoagulados. Além do mais, nessa casuística, foram relatados seis casos de EP 49 .

De acordo com a experiência acumulada nesses 6 meses da doença, as principais alterações observadas na coagulação foram: aumento na geração de trombina, dímero-D, fibrinogênio (inicialmente) e no tempo de protrombina (TP); e redução na fibrinólise e contagem de plaquetas 3, 8, 31, 48, 49 . Desde os relatórios iniciais da China, esses parâmetros anormais de coagulação foram observados na COVID-19. Entre os primeiros 99 pacientes hospitalizados em Wuhan, foi observado que 6% dos pacientes apresentaram elevação do tempo de tromboplastina parcial ativado (TTPa), 5%, do TP, 36%, do dímero-D, além de aumento em biomarcadores de inflamação, incluindo IL-6, velocidade de hemossedimentação (VHS) e proteína C reativa. Ocorreu trombocitopenia em 12% dos casos, cinco pacientes tiveram outras coinfecções (uma bacteriana e quatro fúngicas) e quatro pacientes tiveram choque séptico 9, 52, 53 .

O dímero-D pode ajudar no reconhecimento precoce de pacientes de maior risco de morte, alertando para mais cuidado. Dados preliminares mostram que, em pacientes com COVID-19 grave, a terapia anticoagulante parece estar associada a menor mortalidade na subpopulação que atende aos critérios de SIC ou com dímero-D acentuadamente elevado 31, 51 .

A trombocitopenia é relativamente comum em pacientes com COVID-19 e está associada a risco aumentado de mortalidade hospitalar. Quanto menor a contagem de plaquetas, maior a mortalidade. Entretanto, muitos pacientes com COVID-19 grave ainda não apresentam esse achado à admissão em UTI 25, 46, 47, 51 .

O alargamento do TP também é importante marcador de gravidade. No cenário de trombocitopenia e TP alargado, pode ser útil dosar o fibrinogênio, conforme recomenda a Sociedade Internacional de Trombose e Hemostasia (SITH) para avaliar a possibilidade de CIVD (DIC em inglês, disseminated vascular coagulopathy) 51 .

A SITH postulou critérios diagnósticos para a CIVD, bem como desenvolveu e validou critérios para SIC. As alterações da coagulação associadas à SIC, em relação às associadas à CIVD, são menos graves e ocorrem de forma mais precoce 51 .

Tang et al. identificaram que 71% dos pacientes que morreram de COVID-19 preenchiam os critérios da SITH para CIVD, enquanto, nos sobreviventes, apenas 0,6% tinham CIVD. Esses pesquisadores também observaram um aumento estatisticamente significante nos níveis de dímero-D e TP e uma diminuição nos níveis de fibrinogênio em não sobreviventes entre os dias 10 e 14 da doença 52 .

Um estudo retrospectivo chinês sugere que a disfunção endotelial induzida pela COVID-19 seja responsável pela geração de excesso de trombina e deficiência da fibrinólise, que indica um estado hipercoagulável 9 Diante da necessidade urgente de se encontrar tratamentos eficazes para a COVID-19 por meio de estudos controlados e randomizados, certos agentes estão sendo usados em diferentes países com base em evidências in vitro. Também estão sendo realizadas extrapolações de resultados em outras doenças virais ou ainda sendo feitos tratamentos baseados em estudos observacionais e pequenos ensaios clínicos. Na Figura 2, organizamos as estratégias de tratamento de acordo com a fase da doença. Entre os fatores de risco relacionados à evolução desfavorável da doença, podemos dividi-los em não modificáveis e modificáveis. Sexo masculino e idade avançada são fatores não modificáveis. Entretanto, as pessoas mais idosas devem ser prioritariamente isoladas, principalmente se apresentam doenças inflamatórias crônicas 25 . Os tabagistas ativos também inspiram mais cuidado, visto que o pulmão é o órgão onde se iniciam as complicações da doença a partir da fase II, além de ser um importante fator de risco para aterosclerose 1 .

Os pacientes com DCV, síndrome metabólica e seus principais componentes (obesidade, diabetes e hipertensão) merecem muita atenção 24 . O controle terapêutico desses fatores parece uma medida fundamental como forma de deixar o endotélio menos reativo e, assim, menos vulnerável à COVID-19 40 . A otimização do tratamento medicamentoso com o uso de hipoglicemiantes, anti-hipertensivos, hipolipemiantes (principalmente as estatinas) e antiagregantes plaquetários [como o ácido acetil salicílico (AAS)] poderia ajudar a estabilizar o endotélio na tentativa de deixá-lo menos reativo.

As drogas como IECA e BRA ajudam a equilibrar o SRAA. Como discutido anteriormente, esse sistema parece estar mais desregulado na COVID-19. Além do mais, estudos observacionais em pacientes hospitalizados com COVID-19 têm sugerido menor risco de morte nos pacientes em uso dessas medicações, especialmente IECA 18 .

Uma vez infectado com o SARS-CoV-2, o primeiro passo seria o uso precoce de drogas que possam impedir a replicação e favorecer o clareamento viral. Ainda não temos a droga ideal, mas estão em andamento no mundo inteiro estudos com antimaláricos, antivirais, antibacterianos e antiparasitários. Há relatos não publicados de sucesso com a abordagem de hit early and hit hard (ataque precocemente e ataque intensamente). Essa hipótese está sendo testada em ensaios clínicos multicêntricos em âmbito nacional e em outros países com algumas dessas classes de drogas 56, 57 .

Diante de uma pandemia, as condutas vão sendo readequadas de acordo com a evolução do conhecimento e muito do que já é rotina no tratamento de pacientes graves está sendo aplicado no tratamento da COVID-19. As principais complicações da COVID-19 são SARS, SIC, TEV e CIVD. Todas elas são bem conhecidas na sepse e na COVID-19 parecem ser consequência da resposta inflamatória desregulada.

A SARS seria a primeira grande complicação e existem protocolos específicos de tratamento 4, 7 . Medidas como suplementação de oxigênio, suporte em UTI e ventilação mecânica são fundamentais.

Ainda na fase hiperinflamatória, as drogas que inibam ou reduzam os efeitos das citocinas próinflamatórias parecem muito pertinentes. Os inibidores de IL-6, assim como glicocorticoides, poderiam evitar ou amenizar a tempestade de citocinas. Novas medicações moduladoras da resposta inflamatória são fundamentais nessa fase para evitar a inflamação excessiva, que agride intensamente o endotélio e diversos órgãos, podendo culminar com falência de múltiplos órgãos até a morte 58 .

Estudos mostram maior risco de trombose venosa profunda (TVP) e EP em pacientes em pacientes hospitalizados com COVID-19 49 , sendo importante acompanhar esses pacientes com escore clínico para TVP e EP 59 . Em relação ao TEV, os estudos indicam que pacientes hospitalizados devem receber tromboprofilaxia farmacológica com HBPM ou fondaparinux (preferencialmente com HNF), a menos que o risco de sangramento exceda o risco de trombose 31, 47, 51 .

O ajuste de dose da heparina para obesidade e para pacientes com insuficiência renal é recomendado (Tabela 1) 25, 51 . Não temos ainda estudos que possam embasar o uso de anticoagulantes em pacientes sem necessidade clínica de hospitalização pela COVID-19, bem como o uso de doses intermediárias de anticoagulação, sem que ao menos exista uma forte suspeição de TEV. Pesquisas estão em andamento para o uso de anticoagulantes nas diferentes fases da COVID-19. A sugestão da manutenção da profilaxia após a alta hospitalar é uma tendência devido ao estado de hipercoagulação desencadeado pela doença 50,60-62 .

O risco de sangramento em pacientes anticoagulados existe, sobretudo à medida que a doença agrava. O padrão de CIVD na COVID-19 é inicialmente trombótico, mas pode evoluir para hemorrágico com a progressão da doença. É muito importante o acompanhamento da contagem de plaquetas e do nível sérico de fibrinogênio, como também a aplicação dos escores de risco de sangramento tipo IMPROVE (International Medical Prevention Registry on Venous Thromboembolism). Pacientes com escore IMPROVE < 7 apresentam baixo risco de sangramento e devem seguir com a profilaxia farmacológica. Nos casos de escore > 7, existe alto risco de sangramento, sendo indicada a profilaxia mecânica 63 .

Em relação ao tratamento da COVID-19, a estratégia terapêutica tem se baseado no reconhecimento precoce das complicações e no suporte otimizado para aliviar os sintomas. Até o momento, não existe tratamento específico que seja comprovadamente eficaz para a COVID-19. Na Figura 2, seguem as principais recomendações terapêuticas de acordo com as fases clínicas da COVID-19.

A imunopatologia da COVID-19 parece compartilhar o mesmo receptor TLR4 das DCV e síndrome metabólica. Talvez a ativação inapropriada desse receptor seja o fator responsável pela resposta imune exacerbada ao SARS-CoV-2 evidenciada em pacientes com a forma grave da doença.

Em resumo, enquanto aguardamos a vacina, talvez o melhor tratamento para a COVID-19 seja aquele que englobe terapias que melhoram as condições cardiovasculares e metabólicas dos pacientes, além de medicações que reduzam a replicação viral, a hiperinflamação e o risco de trombose. Tabela 1. Sumário adaptado do consenso de recomendações de terapia antitrombótica durante a pandemia da COVID-19.

Terapia antitrombótica AMBULATORIAIS · Estimular deambulação; FASE I · Avaliar risco de TEV versus risco hemorrágico; · Considerar profilaxia farmacológica se alto risco trombótico SEM alto risco hemorrágico; · Pacientes em uso de terapia antitrombótica: manter tratamento; · Pacientes usuários de antivitamina K sem controle adequado: sugerir transição para anticoagulante oral direto ou enoxaparina. HOSPITALIZADOS · Avaliar risco de TEV versus risco hemorrágico; FASE II e III SEM CIVD · Iniciar HBPM dose profilática -Enoxaparina 40 mg via subcutânea 1 vez ao dia* (se contraindicada, usar profilaxia mecânica).

HOSPITALIZADOS · Profilaxia farmacológica se risco de sangramento ausente; FASE III · Sem recomendação de doses intermediárias ou plenas de HBPM ou de HNF de rotina; COM CIVD · Usuários de anticoagulação plena: manter tratamento. Considerar redução de dose de acordo com risco de sangramento; · Usuários de dupla antiagregação plaquetária: avaliar risco/benefício individualizado de suspensão ou manutenção. Se plaquetas > 50.000, manter a terapia dupla; plaquetas entre 25.000 e 50.000, deixar um único antiplaquetário; plaquetas < 25.000, suspender antiagregação; · Pós-hospitalização: avaliar risco de TEV e considerar profilaxia farmacológica por até 45 dias. Estimular atividade física e deambulação.

*Evitar enoxaparina se clearance de creatinina < 30 mL/min; optar por HNF 5.000 UI 2 ou 3 vezes/dia. CIVD = coagulação intravascular disseminada; HBPM = heparina de baixo peso molecular; HNF = heparina não fracionada; TEV = tromboembolismo venoso.

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E-mail: godoiemmanuelle@hotmail.com Informações sobre os autores SCSB -Professora, Departamento de Medicina Clínica, Pósgraduação em Cirurgia

Especialista em Cardiologia

Especialista em Patologias Cardiovasculares, Université Toulouse III Paul Sabatier; Doutora em Cardiologia

Membro titular

Comissão de Métodos Diagnósticos Não-invasivos e da Pós-graduação em Cirurgia, UFPE; Especialista em Angiologia e Ecografia Vascular, SBACV, Colégio Brasileiro de Radiologia e Diagnóstico por Imagem (CBR) e Université Toulouse III Paul Sabatier; Pós-doutorado

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular

Supervisor da Residência Médica em Alergia e Imunologia Clínica, Hospital das Clínicas

Contribuições dos autores Concepção e desenho

*Todos os autores leram e aprovaram a versão final submetida ao J Vasc Bras