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Arterial Thrombosis in Coronavirus Disease 2019 Patients: A Rapid Systematic Review

Background Emerging evidence suggests that severe form of coronavirus disease 2019 (COVID-19) is mediated, in part, by a hypercoagulable state characterized by micro- and macro-vascular thrombotic angiopathy. Although venous thrombotic events in COVID-19 patients have been well described, data on arterial thrombosis (AT) in these patients is still limited. We, therefore, conducted a rapid systematic review of current scientific literature to identify and consolidate evidence of AT in COVID-19 patients. Methods A systematic search of literature was conducted between November 1, 2019, and June 9, 2020, on PubMed and China National Knowledge Infrastructure to identify potentially eligible studies. Results A total of 27 studies (5 cohort, 5 case series, and 17 case reports) describing arterial thrombotic events in 90 COVID-19 patients were included. The pooled incidence of AT in severe/critically ill intensive care unit–admitted COVID-19 patients across the 5 cohort studies was 4.4% (95% confidence interval 2.8–6.4). Most of the patients were male, elderly, and had comorbidities. AT was symptomatic in >95% of these patients and involved multiple arteries in approximately 18% of patients. The anatomical distribution of arterial thrombotic events was wide, occurring in limb arteries (39%), cerebral arteries (24%), great vessels (aorta, common iliac, common carotid, and brachiocephalic trunk; 19%), coronary arteries (9%), and superior mesenteric artery (8%). The mortality rate in these patients is approximately 20%. Conclusions AT occurs in approximately 4% of critically ill COVID-19 patients. It often presents symptomatically and can affect multiple arteries. Further investigation of the underlying mechanism of AT in COVID-19 would be needed to clarify possible therapeutic targets.


INTRODUCTION
Since the initial reports in late December 2019 in Wuhan, China, the coronavirus disease 2019  has rapidly spread to other parts of the world and has been declared a public health emergency of international concern by the World Health Organization. 1 As of June 9, 2020, the disease had spread to more than 203 countries and territories, with >7,039,918 confirmed cases and >404,396 fatalities. 2 The clinical spectrum of COVID-19 spans from an asymptomatic form to severe disease characterized by hypoxemic respiratory failure, septic shock, and multiorgan dysfunction (MOD) that require invasive mechanical ventilation and other forms of organ support in critical care units. 3,4 Emerging evidence suggests that these severe and critical forms of COVID-19 are mediated, in part, by a hypercoagulable state characterized by micro-and macro-vascular thrombotic angiopathy. 5,6 This hypothesis is supported by the laboratory profile seen in patients with severe COVID-19, typified by significant elevation in D-dimer, prothrombin, and fibrinogen levels. 7,8 Furthermore, severe COVID-19 is associated with systemic hyperinflammation with elevated proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-6, and IL-1b), 9,10 which may contribute to the development of intravascular coagulopathies. In their recent report, Klok et al. reported a cumulative incidence of thrombotic complications of 49% in a cohort of critically ill COVID-19 Dutch patients who had received standard doses of thromboprophylaxis, further supporting the occurrence of thrombotic events. 11 Although there is a substantial pool of evidence of venous thrombotic and thromboembolic events in COVID-19 patients, 5e8,11e14 there are a few scattered reports on intra-arterial thrombosis (AT) in these patients. We, therefore, conducted a rapid systematic review of current scientific literature to identify and consolidate data on the incidence of AT in COVID-19 patients, age and sex distribution of these patients, as well as the clinical presentation, anatomical distribution, and outcomes of AT.

METHODS
A rapid systematic review of scientific literature was conducted to consolidate currently available evidence of arterial thrombotic complications in COVID-19 patients. Rapid reviews accelerate the process of evidence synthesis while maintaining a systematic approach.

Literature Search Strategy
A comprehensive and systematic search of literature from November 1, 2019, to June 9, 2020, was conducted on the Medline (PubMed interface) and China National Knowledge Infrastructure to identify studies eligible for inclusion. The electronic search was carried out using the strategy as follows: (1) ((COVID-19) OR (SARS-CoV-2)) OR (2019-nCoV), (2) (((((Arterial Thrombosis) OR (Thrombotic Complication)) OR (Limb Ischemia)) OR (Cerebral Ischemia)) OR (Myocardial Ischemia)) OR (Mesenteric Ischemia), (3) 1 AND 2. No language restriction was applied. When the articles were published by the same study group and there was an overlap of the search period, only the most recent article was included to avoid duplication of data. The PubMed function ''related articles'' was used to extend the search. Also, we searched major infectious disease, hematology, and general medicine journals reporting articles about COVID-19 infection to look for additional studies. We then performed handsearch of the bibliography of included studies to detect other potentially eligible investigations.

Eligibility Criteria
The search results were screened by title and abstract, with those of potential relevance evaluated by full text. Studies were deemed eligible for inclusion if they fulfilled the following criteria: (1) were case reports/case series/cohort studies, (2) included patients with a reverse transcriptase polymerase chain reactioneconfirmed COVID-19 diagnosis, (3) monitored the patients for the development of complications during the course of admission, and (4) reported clear extractable data on arterial thrombotic complications.

Data Extraction
Data extraction was conducted by 3 independent reviewers (I.C., V.K., and B.N.). For each study, the following information was extracted: the surname of the first author and the year of publication, the geographical region where the study was performed, the type of study (case report/case series/ cohort), sample size, demographic characteristics, number of patients with arterial thrombotic complications, anatomical location of the thrombi, imaging modality used in the diagnosis of AT, concurrent venous thrombosis, and comorbidities and mortality in patients with AT. Any variances arising during this were resolved by a consensus.

Synthesis of Findings
The synthesis of results was carried out in 2 steps. First, findings on all eligible studies reporting AT in COVID-19 patients were presented in the form of a summary of findings table (Table I) accompanied by a narrative description. Thereafter, a pooled analysis incorporating only cohort studies with sample 50 patients was conducted to estimate pooled incidence of AT in severe/critically ill intensive care unit (ICU)-admitted COVID-19 patients using the MetaXL (software version 5.3; EpiGear International Pty Ltd., Sunrise Beach, Australia). A random effects model was applied. The magnitude of heterogeneity among the included studies was assessed using the chi-squared test (Chi2) and I-squared statistic (I2). For the Chi2 test, a Cochrane's Q P value of <0.10 was considered significant. An I2 of <40% was considered not significant. In addition, a leave-one-out sensitivity analysis was performed

Annals of Vascular Surgery
to assess the robustness of the results and to further probe the sources of interstudy heterogeneity.

Study Identification
The initial search produced 185 potentially relevant articles. After the removal of duplicates and primary screening, 85 articles were assessed by full text for eligibility in the meta-analysis. Of these, 58 were excluded because the primary and secondary outcomes of the study did not match that of this review. Thus, a total of 27 articles were included in this systematic review and meta-analysis ( Fig. 1 and Table I).

Characteristics of the Included Studies
A total of 27 studies describing arterial thrombotic events in 90 COVID-19 patients were included. 11e 37 The majority of the studies were from Europe (23 studies; France: 8, Italy: 7, Spain: 4, the United Kingdom: 3, and the Netherlands: 1), whereas the rest were from North America (the United States of America: 3 and Canada: 1). Of the included studies, 5 were cohort, 5 were case series, and the rest were case reports. Essential characteristics of the included are outlined in Table I.
Mortality in Patients with AT. Across the 21 case reports and case series that reported outcome data in AT patients, 10 of 52 patients (19.2%) died. Only one cohort study reported mortality specifically in patients with AT, with the mortality rate being 20%. 28

DISCUSSION
The literature reviewed in this article documents AT as a complication of COVID-19. Severe COVID-19 is characterized by among other features hypoxemic respiratory failure, septic shock, and MOD. Of these complications, intra-AT in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is scarcely documented. The present study documents that AT develops in approximately 4.4% of severe/critically ill COVID-19 patients. The mechanisms of AT in these patients is still unclear. Emerging evidence suggests that COVID-19 is associated with endotheliitis, characterized histologically by diffuse endothelial damage and infiltration by inflammatory cells. 38 Damage to the endothelium could be as a result of direct viral infection, 39,40 which is facilitated by the overexpression of angiotensin-converting enzyme receptor 2, the receptor for cell entry of SARS-CoV-2, in endothelial cells. 41,42 COVID-19 is also associated with a hypercoagulable state, characterized by elevation of D-dimers, prothrombin, and fibrinogen, 7,8 with consequently reduced clot formation time and higher maximum clot firmness. 43 The hyperviscosity is thought to be as a result of systemic extrapulmonary hyper inflammation and hypercytokinemia, which activate the coagulation cascade. 9,10 These 2 factors (endotheliitis and hypercoagulability), together with prolonged immobilization of critically ill COVID-19 patients complete the Virchow's triad, providing a plausible explanation for the mechanisms of AT. It is noteworthy that AT developed even in patients without gross evidence of atherosclerosis, 32 which is an established precursor for AT.
The majority of the patients with AT were elderly, which is consistent with the already wellestablished age-associated increase in the plasma concentration of coagulation factors such as fibrinogen, factors V, VII, VIII, and X, as well as the von Willebrand's factor. 44,45 Arterial thromboembolism in the general population commonly affects more males compared with females. 46,47 This observation was similarly reflected in our analysis and has been explained by the differences in hormonal and genetic profiles of the 2 sexes 46,47 with female sex hormones producing a favorable immune modulation. 48 Furthermore, the prevalence and severity of COVID-19 has since been established to be higher in males than in females. 49 Most of the AT patients had pre-existing comorbidities, supporting the current evidence that preexisting chronic illnesses increase both the incidence and severity of COVID-19. 50,51 A similar observation has been reported in pediatric populations where the presence of congenital cardiovascular disease predisposed affected children to severe human coronavirus infections. 52 Viral infections have been known to worsen pre-existing vasculitic conditions besides directly inducing both myocardial and vascular injury. 53e55 Vascular inflammation is an established precursor to the pathogenesis of AT. 56 Pre-existing cardiac diseases have been known to prejudice one to low-grade vascular inflammation, 56,57 which could be exacerbated by the SARS-CoV-2 infection and hence the enhanced prevalence of AT in these particularly predisposed individuals.
The varied presentation of AT in COVID-19 reveals the widespread arterial involvement reflected in our analysis. The nonuniform distribution in the involved arteries reveals that this was an acute thrombotic occlusion since, in acute states, there exist intraindividual regional differences in arterial thrombogenicity. 58 Findings from this study suggest that the mortality rate in COVID-19 patients with AT could be around 20%, and this is mainly driven by the presence of end-organ injury as evidenced by the various acute ischemic events as recorded in our analysis.
Our study was limited by the small number of included studies, which were mainly case reports and case series. Larger well-designed studies are urgently needed to confirm these findings.
In conclusion, AT occurs in approximately 4% of critically ill COVID-19 patients. The majority of the patients are male, elderly, and have comorbid conditions. It often presents symptomatically and can affect multiple arteries. Further investigation of the underlying mechanism of AT in COVID-19 would be needed to clarify possible therapeutic targets.