Abstract

The extraordinary prothrombotic manifestations of Coronavirus Disease-2019 (COVID-19), caused by severe acute respiratory syndrome CoV (SARS-CoV-2) virus, presenting as venous and arterial thrombosis have been reported in the literature. The incidence of arterial thrombosis is reported to be 4% in critically ill COVID-19 patients.. Arterial thrombosis in the setting of COVID-19 has been reported to occur in a multitude of organs leading to ischemic strokes, ST-segment elevation myocardial infarction, aortic thrombus and acute limb ischemia. Diffuse endothelial activation, along with aberrant immuno-thrombotic mechanisms have been implicated in the widespread thrombosis occurring in COVID-19 patients. We performed a literature review of 55 reported cases to delineate the clinical characteristics, management patterns and outcomes of patients with COVID-19 who developed complications of acute limb thrombosis and ischemia. Our systematic review revealed that acute limb ischemia had a male predominance, with either hypertension or diabetes mellitus as the most common underlying cardiovascular risk factors. Aortic thrombus was reported in 23.6% of the cases. The majority of the cases involved thrombosis in more than one limb, indicative of a diffuse thrombotic state. The most common artery affected was the left popliteal artery. Upper limb thrombosis occurred in 40% of the cases. Most of the cases (74.5%) were managed with urgent revascularization interventions and anticoagulation. Negative outcomes, including amputations (14.9%) and death (26.5%) occurred at a higher rate in this population, despite the use of standard management.

1. Introduction

Since the spread of severe acute respiratory syndrome CoV (SARS-CoV-2) virus, various manifestations of this novel entity; Coronavirus Disease-2019 (COVID-19) have been reported, including acute respiratory distress syndrome, cytokine storm, multiorgan failure and notably, diffuse venous and arterial thrombosis. The degree of widespread thrombosis reported in COVID-19 has not been previously seen with the SARS-CoV and Middle Eastern respiratory syndrome (MERS) in 2002 and 2012 ¹. Diffuse organ involvement in SARS-CoV2 is likely due the virus’ high affinity to bind to the human angiotensin-converting enzyme 2 receptor (ACE 2) ². ACE-2 is widely expressed throughout the body, including the endothelium ³. Direct viral infection and endothelial inflammation is hypothesized to result in the vascular pathologies seen in COVID-19 ³. We perform a literature review to delineate the clinical characteristics, management patterns and outcomes of patients with COVID-19 who developed complications of acute limb thrombosis and ischemia ^{3, 4, 5, 6, 7}.

2. Methods

A comprehensive computer-based literature search of English language studies was performed, using PubMed, Google Scholar, CINAHL, Cochrane CENTRAL, and Web of Science databases, to identify the relevant literature from December 2019 to November 2020. Our search keywords, “Covid-19”, “Coronavirus” “acute limb ischemia”, and “acute limb thrombosis” were used to determine cases of patients with Covid-19 infection who experienced stent thrombosis. Relevant cases were selected by reviewing the reference list of each article. All non-English and non-human studies were excluded. Furthermore, all meta-analysis, review articles, and abstracts were excluded from this study. The data regarding demographic information, affected vessel and limb, angiogram findings, surgical and medical management methods and patient outcomes were reviewed and analyzed.

3. Results

A total of 35 papers were found which featured 55 cases [4-41] [Table 1]. Patients’ ages range from 29-83 with the mean age being 58.8 years. Patients were predominantly male (73%). The most common presentation of acute limb ischemia was limb pain in 45.5%. Most patients had at least one cardiovascular risk factor; 27.3% of the patients had hypertension and 23.6% had diabetes mellitus. D-Dimer was elevated in 69.09% of the cases. The majority of the cases (67.3%) presented with more than one affected artery while 32.7% of the cases had only one artery affected. Aortic thrombus was reported in 23.6% of the cases. The most commonly affected artery was L Popliteal artery (21.82%), followed by R popliteal artery (18.18%) and left common iliac artery (18.18%). Upper extremity thrombus were reported in 40% of the cases, most commonly involving brachial artery and radial artery.

76.4% of the cases presented with unilateral limb involvement. 43.6% of the cases also had complications of respiratory failure. 85.5% received anticoagulation, while 12.7% of the cases also received antiplatelet therapy and 10.9% received thrombolytics (tpa, alteplase). 41 patients (74.5%) underwent emergent revascularization including surgical/catheter based thrombectomy/embolectomy (50.9%), catheter directed thrombolysis (10.9%), angioplasty (7.3%), stent placement (3.6%) and bypass surgery (1.8%). 49 cases reported outcomes. Clinical recovery occurred in 73.4% of the cases and limb amputation resulted in 14.9% of the patients. Death occurred in 26.5% of the reported cases.

4. Discussion

There have been many serious and fatal complications of Coronavirus disease 2019 (COVID-19) affecting various organ systems. In addition to admission to intensive care units and multi-organ failure, laboratory parameters such as elevation of acute phase reactants such as C-reactive protein and ferritin, aberrancy in hematologic parameters such as elevation of D-dimer and thrombocytopenia has also been associated with severity of infection ⁴². Additionally, the occurrence of thrombosis appears to correlate with severity of illness and elevation of D-Dimer ³⁶.

The incidence of arterial thrombosis is reported to be 4% in critically ill COVID-19 patients, based on a systematic review of literature ^{43, 44}. Arterial thrombosis in COVID-19 patients have been less commonly described. Nevertheless, there are still reports of arterial thrombosis manifesting as ischemic strokes, coronary artery disease, aortic thrombus, acute limb ischemia as well as arterial thrombi in unusual sites resulting in acute mesenteric ischemia and splenic infarct ^{45, 46}. Many pathophysiologic mechanisms have been implicated in the hypercoagulable state which leads to diffuse thrombosis including direct viral-related endothelial injury, leukocyte- and cytokine-mediated platelet activation, unchecked complement activation and more recently, elevated Von Willebrand factor antigen to ADAMTS13 (a disintegrin and metallo-proteinase with a thrombospondin type 1 motif, member 13) activity ratio ^{47, 48}.

In COVID-19 infection, it is unclear which patients will develop arterial thromboembolism, as opposed to the more common presentation of venous thromboembolism. Some risk factors which have been implicated include advanced age and cardiovascular risk factors, however in the setting of severe COVID-19, there are also reports of younger patients without risk factors developing arterial thrombotic manifestations ²⁴.

We attempt to describe the patient and clinical characteristics associated with patients with COVID-19 who present with acute limb ischemia. Consistent with prior reports, there was a male preponderance. Most of the patients had at least one cardiovascular risk factor, with the most predominant being hypertension and diabetes. Only three patients had a prior diagnosis of peripheral vascular disease. This further highlights that the hyper-coagulable state in COVID-19 infection operates via mechanisms independent of atherosclerosis and plaque rupture. In one large prospective study involving 18000 patients, hypertension was identified as an independent risk factor for deep vein thrombosis ⁴⁹.

Although autopsy reports in COVID-19 patients revealed extensive microvascular thrombosis ⁵⁰, our review found that aortic thrombus, whether isolated or when present concomitantly with other large vessels, occurred in 13 of the cases.

Laboratory parameters such as D-Dimer, prolongation of PT/PTT and the presence of antiphospholipid antibodies have been implicated as predictive markers of venous and arterial thrombosis ¹.

Emergent revascularization along with antiplatelet and anticoagulation are part of the standard management for acute limb ischemia. Lower success rates with revascularization have been reported with COVID-19 associated acute limb ischemia ⁵¹. This is likely due to a widespread, ongoing hypercoagulable state. In the patients with acute limb ischemia, post-intervention heparin appeared to provide better outcomes ⁵¹.

Additionally, several of the thrombotic events occurred despite the administration of prophylactic anticoagulation. This may be suggestive that prophylactic doses of anticoagulation may not be sufficient to counteract the prothrombotic state. However, there is still a lack of evidence as to how to determine which patients may benefit from therapeutic anticoagulation. Additionally, while most patients are managed on intravenous heparin or subcutaneous LMWH during admission, many patients are discharged on novel anticoagulants. The long-term outcomes of these patients are yet to be determined.

5. Conclusion

COVID-19 confers a hyper-coagulable state which leads to acute limb ischemia. Physicians should maintain a high index of suspicion for the diagnosis of acute limb ischemia, in both upper and lower limbs in patients developing acute limb pain, despite the absence of prior cardiovascular risk factors. Undesirable outcomes, including amputations and death occurred at a higher rate in this population.

Acknowledgements

This work is supported in part by Dr. Moro O. Salifu's efforts through NIH Grant # S21MD012474.

References