Acute Arterial Lower-Limb Ischemia in COVID-19 Patients: Case Series Report From the Journal of Critical Limb Ischemia

Reprinted with permission from J CRIT LIMB ISCHEM 2021 April 9 (Ahead of Issue). 

Abstract

The COVID-19 pandemic has caused more than 2.8 million deaths worldwide to date. Efforts have been made to clearly understand the pathophysiological mechanisms to achieve comprehensive management and achieve a definitive cure. It is known that at the hematological level, there are certain peculiarities that are notable according to the severity within the general context of a prothrombotic state. We present 5 elderly patients with varying severity of acute respiratory distress syndrome due to SARS-CoV-2. During hospitalization, each patient experienced acute arterial ischemia of the lower extremity despite anticoagulation therapy, requiring surgical intervention.

Key words: acute respiratory distress syndrome, arterial thrombosis, embolism, SARS-CoV-2

Introduction

SARS-CoV-2 virus has been responsible for a significant number of deaths worldwide, and medical researchers are conducting multiple studies to clearly understand the natural history of this infectious-contagious disease, as well as therapeutics to control it. At this point, there is a lack of effective treatments because there are several peculiarities in the pathophysiology of the virus.

An incidence of thromboembolic events between 5%-15% has been reported in patients with severe respiratory syndrome caused by the SARS-CoV-2 virus, in which a combination of pathophysiological mechanisms of disseminated intravascular coagulation (DIC) with thrombotic microangiopathy-localized disease in the lungs and other organs leads to multiorgan dysfunction.¹ These mechanisms are encompassed in 3 main axes: (1) endothelial lesions due to the affinity of the virus for angiotensin-converting enzyme (ACE) II receptors;² (2) blood stasis in immobilized patients, especially those with moderate-to-severe acute respiratory distress syndrome (ARDS); and (3) impact on intensive care and intermediate units.³ Hypercoagulability due to significant systemic inflammation expresses itself through conditions such as myocardial infarction, cerebrovascular accidents, and acute peripheral arterial ischemia and thrombosis.⁴

The relationship between SARS-CoV-2 and ACE II receptors (lung, blood vessels, heart, kidney, liver, and intestine) promotes apoptosis and activation of endothelial cells, as well as high levels of factor Von Willebrand and factor VIII.⁵ This cellular injury activates an enormous amount of proinflammatory cytokines (IL-1, IL-6, TNF), which increase the levels of vascular endothelial growth factor and reduce E-cadherin molecules. In addition, there is an alteration of the binding of tissue factor to factor XI in the extrinsic pathway and expression of several immunoactive molecules, including an increase in the expression of antiphospholipid syndrome antibodies, which leads to a state known as the “cytokine storm” and stimulates the generation of thrombin and deposits of fibrin at the microvascular level, manifesting as microvascular thrombosis in different target organs.⁶

As described, the alteration of hemostasis is widely linked to the pathogenesis of SARS-CoV-2, taking as a starting point the entry of this pathogen into endothelial cells, inducing a significant release of plasminogen activator inhibitor 1 (PAI-1) with the subsequent inhibition of fibrinolysis that is frequently observed in severe stages. A relevant decrease in antithrombin has also been reported due to an increase in vascular permeability within the context of systemic inflammation, which goes hand in hand with the already mentioned expression of tissue factor and with all the pathophysiological circumstances expressed, and places the patient in a significant procoagulant state.⁷ Thromboembolic events, such as acute peripheral arterial thrombosis and embolism, are presented in the following clinical cases of acute arterial ischemia of the limb in 5 COVID-19 patients (Tables 1 and 2). 

Methods and Results

Five clinical cases were collected from the beginning of the contingency due to the current COVID 19 pandemic in March,  2020 through September, 2020 at the IESS Quito Sur Hospital in Ecuador, which is cataloged as a sentinel hospital for the care of infected patients with COVID-19 (Tables 1 and 2). In order to be included, patients had to present a respiratory condition secondary to the SARS-CoV-2 virus confirmed by polymerase chain reaction, associated with acute limb ischemia after having acquired said infection (severity was defined according to the Rutherford classification for acute ischemia), with prior authorization from the institution. A bioethics letter guaranteed the ethical principles of the study, and clinical records were analyzed. All patients were managed by the authors of this article.

Discussion

The SARS-CoV-2 virus has particular pathophysiological mechanisms that are importantly related to coagulation system alteration, which causes both arterial and venous thromboembolic events that are more noticeable in a seriously ill patient. A study by Klok et al reports an incidence of thrombotic conditions of 31% in the intensive care unit, with 3.7% due to arterial conditions.¹ We report 5 cases in our hospital of acute arterial ischemia of lower limbs due to thrombosis.

All of our patients were older adults, and included 4 men and 1 woman. A similar reality is expressed in an article by Bellosta et al for the European Society for Vascular Surgery that reported a series of 20 patients, in which 90% were male, with an age range between 62 and 95 years.⁹ The predominance of hypercoagulability in Virchow’s triad is generally exhibited by patients with hemostasis alterations, such as young women; however, our cases correspond to older male patients, thus contributing to the prothrombotic state generated by infection with SARS-CoV-2 virus as the etiology of acute arterial ischemia, despite anticoagulation with low-molecular-weight heparin. Bellosta et al observed that 75% of their patients had acute arterial limb ischemia in stage IIB according to Rutherford classification.⁹ Similarly, the 5 patients in the current case series include 1 patient (20%) in Rutherford class I, 3 patients (60%) in Rutherford class IIb, and 1 patient (20%) in Rutherford class III.

Kashi et al reported 7 cases in intensive care patients, of which 5 were classified with irreversible ischemia despite the anticoagulant treatment they received, and emphasize the concern about rapid progression as well as unusual disease sites, such as at the aortic level.¹⁰ This is largely explained by the exaggerated activation of coagulation in the context of systemic inflammation with widely elevated levels of interleukin, such as IL-6, manifesting itself with fibrinogen levels, D-dimer, and sedimentation rate globular cells increased in correlation with the severity of the disease.⁶

The severity of the clinical picture expressed by significant respiratory distress that required management with non-invasive mechanical ventilation at high flows or with invasive mechanical ventilation in our patients highlights the vulnerability to developing thrombosis. As previously mentioned, the activation of the cascade of coagulation, together with the cytokine storm,² increases the probability of pulmonary microthrombosis or macrothrombosis with the worsening of patients, and of course the development of peripheral vascular thrombosis.¹¹

Diffuse thrombotic microangiopathy as a consequence of aggressive complement activation and its possible relationship with endothelial damage by this virus¹² explain the findings in autopsies where diffuse alveolar damage and inflammation of the airways have been evidenced.¹³ Given the intimate association between the severity of the respiratory condition and the increased probability of presenting with thromboembolic events, it was therefore determined that 4 of our 5 reported patients presented with severe respiratory insufficiency (PO₂/FiO₂ ratio <200), and 2 of the patients died due to multiple organ failure. Furthermore, there is a lack of evidence to determine whether or not the endothelial damage produced by COVID-19 would result in successful revascularization, as 2 of the patients required major amputation due to an unfavorable outcome after thrombembolectomy.

It is important, therefore, to highlight the high probability of developing thromboembolic events in positive COVID-19 patients despite anticoagulation and become familiar with their clinical manifestations, which can identify patients who are candidates for revascularization, such as palpation of distal pulses in patients with severe acute respiratory syndrome, and maintaining the recommendations on therapeutic anticoagulation, with an emphasis on the control of risk factors clearly related to a worse prognosis of the disease, such as arterial hypertension, diabetes, cardiovascular disease, and obesity.¹⁴

Conclusion

We present a series of 5 positive COVID-19 patients who developed acute arterial lower-limb ischemia that required surgical management. All of the patients were older adults, and most had severe acute respiratory syndrome. These cases emphasize the importance of vascular semiology in COVID-19 patients due to the likelihood of thromboembolic events despite anticoagulation.

Disclosures

From the Department of Vascular Surgery, IESS Quito Sur Hospital, Quito, Ecuador.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript accepted February 23, 2021. 

The authors report that patient and/or family consent was provided for publication of the images used herein.

Address for correspondence: Juan Tacuri, MD, Department of Vascular Surgery, IESS Quito Sur Hospital, Instituto Ecuatoriano de Seguridad Social (IESS), Moraspungo, Quito 170111, Ecuador. Email: hvjx4@hotmail.com

Reprinted with permission from J CRIT LIMB ISCHEM 2021 April 9 (Ahead of Issue).