INTRODUCTION

Organizations and researchers around the world are concerned about the spread of this new coronavirus called SARS-CoV-2, the v= irus responsible for the outbreak of the new coronavirus 2019 disease (COVID-19), detected on December 31, 2019 in Wuhan, China⁽¹⁾.

Although the clinical manifestations caused by SARS-CoV-2 are similar to those caused by the common flu and a large percen= tage of people manifest mild symptoms, attention should be paid to the elderly a= nd people with comorbidities (such as cardiovascular diseases, diabetes mellit= us, asthma, and chronic obstructive pulmonary disease), pregnant women, and wom= en up to 45 days postpartum, because these conditions increase the chances for= the most serious forms of the disease. The main complications of SARS-CoV-2 infection are pneumonia, severe acute respiratory syndrome (SARS), renal failure, sepsis, cardiomyopathies, and increased clotting activity, which favors the occurrence of thrombotic events⁽²⁾.=

Patients hospitalized in the intensive care unit (= ICU) are particularly in risk to develop pulmonary thromboembolism, so it is essential to take into account the associated fa= ctors, such as prolonged rest, the base illness, age, and comorbidities, in order = to perform anticoagulant prophylaxis⁽³⁾. In addition, in February 2= 020, it was consistently demonstrated that SARS-CoV-2 causes a cytokines storm, which lead to the activation of the coagulation cascade that generate thrombotic complications^(4-5).

Disseminated intravascular coagulation (DIC) is a secondary complication of serious infections, classically related to bacter= ial infections, malaria, hemorrhagic fevers associated with Dengue and Ebola viruses, and is now also related to SARS-CoV-2. One study detected ischemia (acro-ischemia) concomitant with the onset of dyspnea⁽⁶⁾. This observation led researchers to consider the hypothesis of respiratory failu= re, due to the extensive pulmonary capillary obstruction by thrombi, and that t= he DIC may be playing an important role in hypoxemia, as well as in the morbid= ity and mortality results of ICU patients with COVID-19⁽⁶⁾.

Because the disease is currently a pandemic, sever= al research questions are emerging as the disease progresses and manifests its= elf in different parts of the world. Research has been carried out and has alre= ady helped to clarify some themes such as the genome of the virus, the main for= ms of virus transmission and disease prevention, the search for effective and = safe drugs to treat the infection, and the formulation and testing of vaccines. However, much research is still needed to deepen the issues listed above.

In this context, the following questions arose: a) What is the incidence of thrombotic events in patients with SARS-CoV-2 worldwide? b) What are the most common thrombotic events in patients with SARS-CoV-2? c) Is there a difference in the incidence of these thrombotic events with respect to sex, age group and previous presence of comorbiditie= s? d) What are the most common clinical and laboratory manifestations of thrombotic events in patients with SARS-CoV-2? e) Is there a decrease in morbidity and mortality in patients with SARS-CoV-2 treated with anticoagul= ant and/or cardiovascular protector agents?

In view of the aforementioned facts, this study's = main objective is to present the current knowledge about thrombotic events relat= ed with SARS-CoV-2 infection. The relevance of this study lies in the fact that SARS-CoV-2 is a novel virus that can be easily spread and cause a significa= nt number of deaths in the world population, as well as important and serious complications such as thrombotic events. Thus, studies are needed to elucid= ate the issues related to thrombotic events in patients with COVID-19. Its relevance is also given because it presents a synthesis of many works that = have been published on the topic COVID-19, providing relevant information to professional nurses and others that make up the interdisciplinary health te= ams.

METHO= DS

To accomplish this study, the literature review was chosen as the objective was to synthesize research results on a limited top= ic, in a systematic and organized manner, contributing to the deepening of knowledge⁽⁷⁾. The steps of the literature review were: identification of the research questions, literature search, data evaluatio= n, data analysis, and presentation⁽⁸⁾.

Identification of the research questions

The search was carried out on the topic of interes= t: coagulopathies and thrombotic events related to SARS-CoV-2 infection. To ga= ther knowledge about this theme, an integrative literature review was conducted = with the following purpose: To present the current knowledge about thrombotic ev= ents related with SARS-CoV-2 infection.

As already mentioned, the research questions were:= a) What is the incidence of thrombotic events in patients with SARS-CoV-2 worldwide? b) What are the most common thrombotic events in patients with SARS-CoV-2? c) Is there a difference in the incidence of these thrombotic events with respect to sex, age group and previous presence of comorbiditie= s? d) What are the most common clinical and laboratory manifestations of thrombotic events in patients with SARS-CoV-2? e) Is there a decrease in morbidity and mortality in patients with SARS-CoV-2 treated with anticoagul= ant and/or cardiovascular protector agents?

Literature search

The following databases were searched: Virtual Hea= lth Library (which contains the LILACS, BDENF, WHO-IRIS, PAHO-IRIS, and SCIELO = databases), Pubmed (wich contains the Medical Literature An= alysis and Retrieval System Online database), Cochrane and Science Direct (one of = the largest sources of health research databases accessed through the Elsevier portal).

The decision to use these diverse databases, porta= ls, and libraries, was intended to expand the scope of the research and thus minimize possible bias. The search strategy employed a combination of speci= fic descriptors of each database.

The MeSH terms "coronavirus", "SARS", and "thrombus" were used in Pubmed, Science Dir= ect, and Cochrane databases. The DeCS structured and trilingual vocabulary descriptors in the health sciences "SARS Virus" and "Blood Coagulation Disorders" in Portuguese and their respective synonyms in English and Spanish were used in the Virtual Health Library.

We highlight that initially the search was perform= ed using controlled descriptors in each database. However, due to the small nu= mber of studies, the descriptors were used as keywords, expanding the scope of t= he research. The inclusion criteria established for the studies were: a) full-= text articles investigating the theme of coagulopathies and thrombotic events related to SARS-CoV-2 infection; and b) studies that answer at least one of= the research questions.

The literature search was conducted in May 2020 and updated in June 28, 2020. Each database was accessed in a single day, with a recording of the search pages. The selection of studies was carried out in = the following days, through reading of the titles and abstracts. When necessary, the full text was read to check whether it met the inclusion and exclusion criteria.

Figure 1 displays a flowchart describing the selection process of the evaluated stud= ies.

Table 1 shows that most studies included in this review are literature reviews, descriptive studies, and case reports. However, it is opportune to consider that the COVID-19 pandemic is a major health emergency in global public hea= lth, therefore, health information is relevant even from studies with a low leve= l of evidence. The exchange of information between health workers and the consta= nt update of knowledge about the novel coronavirus raise research questions and stimulate the development of case reports, descriptive studies, and literat= ure reviews. Such studies can serve as a basis for the development of research = with more robust methods and can enhance the clinical practice through evidence-based decision making.

The results are presented according to the following thematic categories: relationship betw= een thrombotic events and sociodemographic and clinical factors in patients with SARS-CoV-2; most common thrombotic events in patients with SARS-CoV-2 with = some clinical and laboratory findings; and results of treatments for this clinic= al situation.

Relationship between thrombotic events and sociodemographic and clinical factors in pati= ents with SARS-CoV-2

Evidence of abnormal coagulation parameters associ= ated with COVID-19 appeared at the beginning of reports from China^(=
11). A study developed with the first 99 hospitalized patients in Wuhan(= 12) found that in 36% of the patients had high D-dimer, increased inflammatory biomarkers such as inteleukin-6, high erythrocyte sedimentation volume, and high C-reactive protein. Thrombocytopenia was pre= sent in only 12% of patients and four died of septic shock^(=
12).

A number of authors^(13-17) referenced the study by Tang et al.⁽¹⁸⁾ on coagulopathies and COVID-19. Such research^=
(18) evaluated 183 patients with SARS-CoV-2, among which 21 patients (11.5%) died. From the 21 patients who died 71% met the criteria of the International Society for Thrombosis and Homeostasis for disseminated intravascular coagulation compa= red with 0.6% of the surviving patients.

Worldwide, the= re are no population-based or multicenter studies on the prevalence of thrombo= tic events in people with SARS-CoV-2.

Several studie= s^(13,19-35) point out that most of the thrombotic events related to SARS-CoV-2 occur in elderly people, male, and patients with pre-existing chronic diseases such as cardiovascular, cerebrovascular, lung, cancer, liv= er diseases, nephropathies, obesity, and diabetes mellitus.<= /p>

A st= udy⁽³⁶⁾ about venous thromboembolism in patients with COVID-19 based on autopsy findings found that the presence of neurodegenerative diseases is a risk fa= ctor for thrombotic complications in patients with SARS-CoV-2. An Italian cohort study⁽³⁷⁾ observed that fibrinogen values appeared= to be higher in women affected by COVID-19 compared to the control group. A nonsignificant trend towards increased fibrinogen levels has been demonstrated in male patients. Patients with SARS and COVID-19 tend to have significant levels of fibrinogen compar= ed to those without SARS, and D-dimer levels showed an insignificant upward tr= end.

Guidelines on the prevention and treatment of thromboembolism^{(38) recommend the assessment of the risk for venous thromboembolism based =
on different clinical conditions, such as: age over 40, three days in bed, =
laboratory confirmation of COVID-19 combined with one of following risk fac=
tors: presence of sepsis, presence of severe acute respiratory disease, hea=
rt failure, obesity, history of venous thromboembolism, acute exacerbation =
of obstructive pulmonary disease, acute stroke, acute coronary syndrome, va=
ricose veins in the lower limbs, cancer, inflammatory bowel disease, and ch=
ronic kidney failure.}

Researchers(13,38-39) claim that pregnant women and those in the postpartum period with COVID-19 = are more likely to develop venous thromboembolism. This risk is heightened by a= ge over 35 years, history of venous thromboembolism, preeclampsia, delayed intrauterine growth, genetic thrombophilia, blood transfusion, postpartum infections, systemic lupus, heart disease, obesity, multiple pregnancies, a= nd postpartum hemorrhages^(38-39).

A point of interest in the COVID-19 pandemic has been differences in the pattern of mortality in young people. Some of these patients have a worse prognosis, b= ut without predisposing risk factors. In Italy, high mortality rates have been observed in young patients⁽⁴⁰⁾. One explanation for this finding= may be mutations in the coagulation cascade or complement inhibitory factors, s= uch as complement factor H, which appears to exist in 1% of the Italian populat= ion⁽⁴⁰⁾.

However, a systematic review study⁽⁴¹⁾ with meta-analysis of the impact of cerebrovascular and cardiovascular diseases on the severity and mortality o= f COVID-19 found that such diseases were associated with increased mortality, but gend= er, age, arterial hypertension, diabetes mellitus, and respiratory conditions d= id not influenced this association.

&nbs= p;

Most common thrombotic events in patients with SARS-CoV-2 with some clinical and laboratory findings

Thromboembolism related to the SARS-CoV-2 virus can be seen in the pulmonary vessels in addition to cases of acute fibrinous and organizing pneumonia. Pulmonary le= sion of small blood vessels is a common manifestation in patients dying from COV= ID 19, with microvascular thrombosis in the lungs and thromboembolism with hemorrhagic infarction in larger vessels. In COVID-19, microvascular thromb= osis is largely observed^{(21,24,25,28,30-34,36,42-46)}.

Several researchers^{(11,12,17,25-28,33,34,37,45,47-53)} described the occurrence of manifestations of thrombotic events in patients with SARS-CoV -2 in addition to pulmonary thromboembolism, stroke, venous thromboembolism, acute myocardial infarctio= n, cerebral venous sinus thrombosis, disseminated intravascular coagulation, a= nd sepsis-induced coagulopathies.

Other studies^(19,28,54)reported that small vessel thrombosis led to intestinal ischemia, cholestasis and distention of the gallbladder and acute infarction of organs such as spleen, liver and kidneys in people with COVID-19. A research⁽³⁶⁾ also described, based on autopsy results, that pulmonary emboli are due to deep venous thrombosis of the lower limbs and t= hat complications such as thrombosis in the prostate venous plexus are also pre= sent in people with SARS-CoV-2 infection.

Rega= rding cardiovascular complications related to COVID-19, these involve heart failu= re, myocarditis, pericarditis, vasculitis, and cardiac arrhythmias. The presence of microangiop= athy and microthrombi can also predispose the patient to microinfarctions in multiple organs, such as liver, heart or kidney, further exacerbating the s= tate of injury and multiple organ failure^{(29,50-51,55)<=
/span>}.

Two s= tudies described thrombotic events in the skin capillaries, which generate the necrotizing capillary lesion, manifesting through slightly purplish reticul= ated eruptions on the chest, legs and arms, consistent with livedo reticularis(56-57). The explanation for this manifestation is that as endothelial cells also express the ACE2 gene, SARS-CoV-2 may cause direct endothelial dysfunction after binding to ACE2, leading to subsequent thrombosis⁽¹⁵⁾.

Other research⁽⁴⁰⁾ developed on the anal= ysis of the deposition of the SARS-CoV-2 virus in five placentas reported that t= here was thrombosis in larger vessels of the fetal circulation, frank thrombosis= in three cases, while in the other two cases, vascular thrombosis confined to = the villi of the trunk was confirmed, generating poor fetal perfusion due to thrombosis in placental vessels.

The clinical and laboratory manifestations of thrombotic events in people with SARS-CoV-2 are correlated with the specific signs and symptoms of central venous thrombosis^(26,48), stroke^{(41,47,49,53)}, acute myocardial infarction^{(13,21,29,41)}, pulmonary thrombosis^{(28=
,31,33,45,58)}, deep peripheral venous thrombosis⁽²⁰⁾, disseminated intravascular coagulation^(14,45,58), and acute renal failure^(53,59-60).

Rese= arch on intestinal abnormalities⁽¹⁹⁾ found abnormalities in the intestinal wall of ICU patien= ts affected by SARS-CoV-2 = using CT scans. The researche= rs found gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdomin= al pain, and thickening of the intestinal wall, associated with pneumatosis and portal venous gas due to mesenteric ischemia.

Regar= ding laboratory tests, several studies^{(11,16,17,24,30,46,49,61)} cited high D-dimer values as a predisposing factor for the occurren= ce of thrombotic events in patients with COVID-19.

Results of treatments for this clinical situation

Current reports demonst= rate benefits of heparins in the prophylaxis of thrombotic events in patients wi= th COVID-19. Treatments with low molecular weight heparin (enoxaparin) or unfractionated heparin have been adopted and the success of the treatment depends on age and D-dimer values. When the value of this marker exceeds six times the normal upper limit, mortality becomes lower with the treatment^(22,55).

ICU patients with COVID= -19 should use higher doses of low molecular weight heparin, as it has been sho= wn that they develop pulmonary thromboembolism even with prophylactic treatmen= t. Thus, both ICU and regular ward patients, even receiving low molecular weig= ht heparin, are developing deep venous thrombosis or pulmonary embolism, which reinforces that heparin doses must be doubled in this clinical context^{(11,16,18,20,22-23,25,27,30,33,38,43,45,62-63)}.

Another study on pulmon= ary embolism in patients with COVID-19 added that there was an improvement in t= he antithrombotic effect when there was a change from enoxaparin to rivaroxaba= n⁽²⁴⁾. Researchers⁽²⁵⁾ add that for patients = with stroke and COVID-19 it seems reasonable to treat with = tPA. In addition, AT1 receptor blockers, such as losartan, may have a protective effect in stroke patients.

Researchers^{=
(16,18,34,64)} report the results on the use of intravenous immunoglobulin (IVIG) and anticoagulant therapy with low molecular weight heparin as early as possibl= e, especially when the number of circulating T and B lymphocytes decreases and inflammatory cytokines and D-Dimer increases drastically. Although intraven= ous immunoglobulin has been shown to be effective in treating patients with influenza and SARS, more clinical data is needed to determine immunoglobulin efficacy in patients with COVID-19.

It should be noted that preclinical studies^(6=
6-67) document the anti-thrombotic effects of vitamin D supplementation. Research= ers also point out that most intervention studies do not clearly show the protective effects of vitamin D supplementation in preventing cardiovascular events. However, most studies have not evaluated people with severe vitamin= D deficiency^(67-68). Vitamin D deficiency is a prevalent problem worldwide – 7% of the world population has severe deficiency and about 40% = have borderline levels of vitamin D in the body⁽⁶⁶⁾.

Regar= ding cardiovascular protection, two studies^(29,51) describe that pati= ents with COVID-19 and cardiac injury must be closely monitored for the increase= in cardiac enzymes – the markers of cardiac stress, and that the administratio= n of cardioprotective agents is necessary.

DISCU= SSION

Among the explanations about the formation of micr= othrombi with lesions in several target organs, we find that the SARS-CoV-2 virus ha= s an extensive tissue distribution causing the release of a high number of pro-inflammatory cytokines (cytokine storm), promoting a systemic inflammat= ory response syndrome with an important impact on the hematopoietic system and hemostasis, leading to infarction of organs such as lungs, heart, liver, and kidneys^(14,50,68).

It is= worth mentioning that specific changes in hemostasis are already present in the initial stage of the SARS-CoV-2 infection^(11,18,37). COVID-19-associated coagulopathy due to acute systemic inflammatory respons= e is characterized by an elevation of several coagulation markers, such as D-dim= er (a fibrin or fibrinogen degradation product), concomitant increase in inflammatory markers (including C-reactive protein), and mild thrombocytope= nia^(49,61).

Some hypotheses that justify the increased incidence of thrombotic events in older people a= nd with pre-existing chronic diseases are: a) the tendency of these people to have a higher D-dimer value^{(16,18,34);
b) the use of antihypertensive drugs, such as ACE inhibitors and angiotensi=
n II
receptor blockers, which increase the expression of the ECA2 gene, and favor
the replication of the SARS-CoV-2 virus⁽³⁰⁾; and c) alteration of
the renin-angiotensin-aldosterone system that is intrinsically linked to the
coagulation cascade and can aggravate the immunothromb=
osis
process, further stimulating the formation of microthrombi in COVID-19^=
(69).}

There is strong evidence that occlusion and format= ion of microthrombi in small pulmonary vessels exists in critically ill patients with COVID-19 and that, therefore, the early application of anticoagulant therapy in these patients is important to improve the prognosis^{(18).
Every patient at risk of deep venous thrombosis admitted to the ICU should
receive some preventive treatment (pharmacological, mechanical, or both), as
prevention is essential, as long as it is safe and effective. The nursing t=
eam
is essential in this process, from the administration of prescribed drugs to
the performance of non-pharmacological measures that contribute as part of =
this
preventive treatment described.}

Nurses and other professionals should also be awar= e of the signs and symptoms of thrombotic events manifested by patients with COVID-19, because it is proven to be a disease that can generate such complications, which require timely effective clinical decision-making. Such complications affect the morbidity and mortality profile, as described. This responsibility applies even more to the nursing team, as they are the professionals who most provide direct care to clients.

The recommendation for nurses and other health professionals who provide nursing care to critical or semi-critical patients in referral hospitals for COVID-= 19 is to closely monitor sick patients. It is noteworthy to pay attention to t= he signs and symptoms of thrombotic events, the inflammatory markers and the hypercoagulable state they present. In addition, they can early recognize t= he high risk of thrombosis in these patients, especially in the elderly with comorbidities, especially cardiovascular, pulmonary, endocrine - diabetes mellitus - and metabolic - obesity, for the early and effective implementat= ion of anticoagulant therapy.

Some = research questions were not answered, such as the incidence of thrombotic events in people with SARS-CoV-2 worldwide and the effects of cardiovascular protecti= ve drugs on the reduction of morbidity and mortality. It is important that researchers from the most diverse areas of health can seek to answer them o= ver time so that their findings are promptly published.

This literature review has the following implications: a) it brings an in-depth = and updated synthesis of the knowledge produced by researchers from different countries about serious complications arising from the SARS-CoV-2 virus, su= ch as thrombotic events; b) it can assist decision-making by doctors and nurse= s to monitor and treat COVID-19 patients; c) it describes knowledge gaps and research questions that need to be investigated further to contribute to the advancement of knowledge in the field; and d) in the context of this pandem= ic, studies involving the topic of infection by SARS-CoV-2 and COVID 19 are very important, regardless of the approaches, as this is a new disease and the knowledge that has been produced and disseminated has contributed to reduci= ng the severe impacts caused by the SARS-CoV-2 virus.

Many = issues highlighted in this integrative review need to be further investigated for further clarification, such as problems of thrombotic events related to SARS-CoV-2 virus infection in different continents; and whether there are proven effective protective factors (clinical, laboratory, pharmacological) that would decrease the chances of developing thrombotic events in people infected with SARS-CoV-2; and what are the effective tools used by the nurs= ing team to reduce the incidence of this problem in this population.

Other issues also raised, which also need to be investigated, were whether vitami= n D supplementation is effective in preventing thrombotic events in people with COVID-19; the comparison between non-pharmacological and pharmacological methods of preventing venous thrombosis in people with COVID 19; and follow= -up studies of people who have had COVID-19 to determine the incidence of thrombotic events at a later stage or to investigate the recurrence of new events among those who manifested some thrombotic disease at an early stage= of SARS infection. CoV-2.

FINAL CONSIDERATIONS

The s= tudies included in this review indicate that there is a relationship between the pathophysiology of SARS-CoV-2 infection and thrombotic events, through cyto= kine storm and disseminated intravascular coagulation. The literature also showed that the chances of occurrence of thrombotic events in COVID-19 increase in= the elderly and associated comorbidities. It also suggested that the most appropriate thrombotic events in this clinical setting were microvascular pulmonary thrombosis, lower limb venous thromboembolism, acute coronary syndrome, and stroke.

The assessment and follow-up of patients, especially those admitted to the ICU, regarding their inflammatory status and their hypercoagulability markers, s= uch as D-dimer, were considered important for early detection and decision-maki= ng regarding the administration of anticoagulants. Nursing is essential for the follow-up and monitoring of these patients, as well as for quick and effect= ive decision-making for the stability of the clinical picture of patients in cr= itical care until the arrival of other professionals who make up the intensive care team.

Discr= imination of thrombotic events in people with COVID-19 worldwide is already available= in the literature, but further clinical and epidemiological studies are still = needed to better explain this relationship. It is also important to determine whet= her this disease can really be classified as belonging to the group of vascular diseases. The results of this study can support research in this thematic l= ine.

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Autor correspondente

José Erivelton de S= ouza Maciel Ferreira. Rua Antônia Vicente, Baturité-CE 62.760-000, +558599811657= 8, eriveltonsmf@gmail.com.

=

Submission= : 2021-05-14

Approval= : 2021-06-12

Levels of Evidence	Absolute frequency of studies	Relative frequency of= studies
1	1⁽⁴¹⁾<= /p>	2.0%
2	0	0.0%
3	0	0,0%
4	6^{(19,28,32,36,37,62)}<= /p>	11.1%
5	20^{(11,13,22,23,25,27,29,30,33-35,43-46,49,52,55,= 68,70)}	37.0%
6	17^{(15,20,21,24,26,40,42,47,48,53,54,56-58,61,63)=}	31.4%
7	10^{(14,16,17,31,38,51,60,64,65,69)}	18.5%