Venous thromboembolic events in coronavirus disease 2019 (COVID-19) patients are well recognized, but findings published in the journal Radiology suggest a link between the infection and lower extremity arterial thrombosis, characterized by higher clot burden and a predilection for proximal vessels. The incidence of death and amputation was also significantly more common in COVID-19 patients versus controls, especially if, in addition to leg symptoms, they presented with systemic or respiratory symptoms as well.
During the peak of the pandemic in New York City, the authors led by Inessa A. Goldman, MD, Montefiore Medical Center, Albert Einstein College of Medicine, Department of Radiology, Division of Emergency Radiology, Bronx, NY, noticed an increased number of patients coming in with lower extremity ischemia and extensive arterial thromboses. Patients typically presented with new symptoms of leg pain, coldness, discoloration and ulceration, and underwent lower extremity CT angiogram (CTA). Many tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The study included all emergency department and inpatient cases of CTA of the abdominal aorta with lower extremity runoff performed in March and April of 2020. Thirty-eight patients underwent lower extremity CTA, of whom 16 were positive for SARS-CoV-2 based on RT-PCR testing. These were compared to 32 COVID-19-negative controls selected from a pool of 108 patients who had undergone lower extremity CTAs in previous years — from January to April 2018, January to April 2019, and from January through April of this year as well.
The average age in the COVID-19 cohort was 70±14 years, mean BMI was 28.0 kg/m2±5.6, and 50% (8/16) had a history of peripheral vascular disease (PVD). In the non-COVID-19 group, the average age was 71±15 years, mean BMI was 28.2 kg/m2±5.9, and 59% (19/32) had a history of PVD. Case and control groups were matched for age, sex, BMI, and other factors, and there was no significant difference in prevalence of pre-existing conditions such as PVD, or rate of ICU stay between the two groups.
Blinded to COVID-19 status, images from each case were reviewed by two radiology attendings. The authors also said they knew of no validated scoring system for calculating arterial clot burden in the lower extremities, so in order to test their hypothesis of larger thrombus burden in COVID-19 patients they devised a three-pronged scoring system – proximal weighted, distal weighted, and unweighted proximal only – to approach this task.
They found that all 16 COVID-19 patients (100%, 95%CI: 79-100%) had at least one clot, compared with 22/32 patients (69%, 95%CI: 50-84%) among controls (p= 0.02). When looking only at clots within the popliteal artery and more proximally, the COVID-19 group had clots in 15/16 patients (94%, 95%CI: 70-99.8%), while 15/32 controls (47%, 95%CI: 29-65%) had a clot (p=0.002).
Clot scores were compared, with the mean score for lower extremity vessels in COVID-19 patients being greater than that of matched controls (p<0.001). The authors noted that significance of clot scores in COVID-19 patients persisted even when taking only clot-positive patients into account (p=0.001).
After adjusting for history of PVD, death or limb amputation was more common in patients with COVID-19 infection (odds ratio 25, p<0.001). Specifically, rates of leg amputation and death in COVID-19 patients were 25% and 38%, respectively, versus 3% for both outcomes among controls, regardless of the time elapsed between presentation to the hospital and diagnosis by imaging. Even when patients who died were excluded, limb amputation was significantly more common in the COVID-19 cohort (p=0.02).
Moreover, COVID-19 patients who presented with symptoms of limb ischemia only were significantly more likely to avoid amputation or death than those who came in with limb ischemia plus respiratory or systemic symptoms (p=0.001). Of the five patients who presented only with leg symptoms, none died or had to undergo amputations, whereas among the 11 who had leg and other symptoms, 10 either died or had amputations.
“While the more severe outcomes in COVID-19 patients may reflect greater arterial thrombus burden, which may be a marker of increased mortality by itself, it can also be attributed to the aggressive nature of severe COVID-19 disease, which has been associated with cytokine storm, fulminant myocarditis and atypical hypercoagulability causing development of thromboses despite patients being on therapeutic doses of anticoagulation,” the authors said, although they noted “it is possible that unprecedented stressors on the healthcare system, particularly in the epicenter of the pandemic at its peak, may have indirectly contributed to these outcomes.”
“This study also suggests that pulmonary or systemic symptoms accompanying the lower extremity symptoms portents a worse prognosis regarding death and limb amputation. Conversely, if the presenting symptoms related to the leg only, then amputation or death could be avoided. It is unclear based on our data within what time period from the initial SARS-CoV-2 infection thromboses may set in, but awareness that leg ischemia may be associated with COVID-19 should prompt evaluation and treatment for limb ischemia,” the authors said.
They highlighted the relatively small cohort of COVID-19 patients in their study as a potential limitation, saying the size was dictated by the timing of the peak of disease in their area and the lack of available testing at the time. “Still, we would expect that this cohort would be one of the larger ones available, as our hospital system has seen approximately 6000 COVID-19 patients at the time of this writing,” they added.