key: cord-0833853-kz3w0nfh
authors: Indes, Jeffrey E.; Koleilat, Issam; Hatch, Ayesha Nzeribe; Choinski, Krystina; Jones, Davis Brent; Aldailami, Hasan; Billett, Henny; Denesopolis, John M.; Lipsitz, Evan
title: Early Experience with Arterial Thromboembolic Complications in Patents with COVID-19
date: 2020-08-28
journal: J Vasc Surg
DOI: 10.1016/j.jvs.2020.07.089
sha: a105ffe0b3b61fb3a87bc85e3acf043af7e0163a
doc_id: 833853
cord_uid: kz3w0nfh

INTRODUCTION: Little is known about the arterial complications and hypercoagulability associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We sought to characterize our experience with arterial thromboembolic complications in patients with hospitalized for coronavirus disease 2019 (COVID-19). METHODS: All patients admitted from March 1 to April 20, 2020 and who underwent carotid, upper, lower and aortoiliac arterial duplex, CT angiogram or MRA for suspected arterial thrombosis were included. A retrospective case-control study design was used to identify, characterize and evaluate potential risk factors for arterial thromboembolic disease in SARS-CoV-2 positive patients. Demographics, characteristics and laboratory values were abstracted and analyzed. RESULTS: During the study period, 424 patients underwent 499 arterial duplex, CT angiogram or MRA imaging studies with overall 9.4% positive for arterial thromboembolism. Of the 40 patients with arterial thromboembolism, 25 (62.5%) were SARS-CoV-2 negative or admitted for unrelated reasons and 15 (37.5%) were SARS-CoV-2 positive. The odds ratio for arterial thrombosis in COVID-19 was 3.37 (95% CI 1.68 – 6.78, p=0.001). Although not statistically significant, in patients with arterial thromboembolism, patients who were SARS-CoV-2 positive compared to those testing negative or not tested tended to be male (66.7 % v. 40.0%, p=0.191), have a less frequent history of former or active smoking (42.9% vs 68.0%, p=0.233) and have a higher white blood cell count (WBC 14.5 vs. 9.9, p=0.208). While the SARS-CoV-2 positive patients trended toward a higher the neutrophil-to-lymphocyte ratio (8.9 vs. 4.1, p=0.134), CPK level (359.0 vs. 144.5, p=0.667), CRP level (24.2 vs. 13.8, p=0.627), LDH level (576.5 vs. 338.0, p=0.313) and ferritin level (974.0 vs. 412.0, p=0.47), these did not reach statistical significance. Patients with arterial thromboembolic complications and SARS-CoV-2 positive when compared to SARS-CoV-2 negative or admitted for unrelated reasons were younger (64 vs. 70 years, p=0.027), had a significantly higher body mass index (BMI) (32.6 vs. 25.5, p=0.012), a higher D-dimer at the time of imaging (17.3 vs. 1.8, p=0.038), a higher average in hospital D-dimer (8.5 vs. 2.0, p=0.038), a greater distribution of patients with clot in the aortoiliac location (5 vs. 1, p=0.040), less prior use of any antiplatelet medication (21.4% vs. 62.5%, p=0.035) and a higher mortality rate (40.0 % vs. 8.0%, p=0.041). Treatment of arterial thromboembolic disease in the COVID-19 positive patients included open thromboembolectomy in 6 patients (40%), anticoagulation alone in 4 (26.7%) and 5 (33.3%) did not require or their overall illness severity precluded additional treatment. CONCLUSIONS: Patients with SAR-CoV-2 are at risk for acute arterial thromboembolic complications despite a lack of conventional risk factors. A hyperinflammatory state may be responsible for this phenomenon with a preponderance for aortoiliac involvement. These findings provide an early characterization of arterial thromboembolic disease in SARS-CoV-2 patients.

The exact relationship between the occurrence of arterial thrombotic events and SARS-CoV-2, 13 remains unclear. We therefore set out to identify and characterize patients in the early stage of 14 the epidemic with arterial thromboembolic disease and its relationship to SARS-CoV-2 infection 15 at our institution. 7 imaging studies performed during the study period were reviewed. These studies included 1 computed tomography angiography (CTA), magnetic resonance angiography (MRA), and/or 2 arterial duplex. The choice of imaging modality (CTA, MRA or arterial duplex) was obtained at 3 the provider's discretion and was based on the presenting clinical complaints. For patients 4 requiring duplex testing, the majority of these studies were conducted as portable bedside tests.

Patients presenting with neurologic events underwent MRA in addition to carotid duplex 6 evaluation as part of the stroke protocol. SARS-CoV-2 status was obtained from the medical record. Patients were tested for SARS-CoV-9 2 based on clinical suspicion and in those requiring surgical treatment as part of their pre-10 procedural evaluation. Nasopharyngeal swab specimens were tested for SARS-CoV-2 by in-11 house polymerase chain reaction (PCR) testing. Confirmatory repeat testing was obtained in 12 patients with high clinical suspicion for COVID-19 and negative initial testing. Patients were 13 excluded if SARS-CoV-2 test results were pending at the time of data abstraction. Patients were 14 divided into one of three groups: SARS-CoV-2 positive, SARS-CoV-2 negative, and patients not 15 tested. The SARS-CoV-2 positive group included patients with a range of COVID-19 16 symptomatology (mild to severe) as well as those tested as part of routine preoperative 17 preparation. The SARS-CoV-2 negative group included patients who presented with respiratory 18 symptoms or other influenza-like illness symptoms and who were found to have a negative PCR 19 result. Patients admitted for other reasons and without suspicion for COVID-19 were not tested 20 and categorized as such. Of the 25 patients who are SARS-CoV-2 negative or not tested 5 were 21 negative, 19 were not tested (admitted for unrelated reasons) and 1 patient was under Patients with imaging that confirmed acute thrombosis were further evaluated. SARS-CoV-2 2 positive patients were compared to the combined SARS-CoV-2 negative and not tested groups.

Retrospective chart review abstracted demographic variables including age, race, body mass 4 index (BMI), gender, ethnicity, medical comorbidities and treatment for further evaluation. The 5 presence of metabolic syndrome was defined as patients with three or more of the following: 6 BMI greater than 30, serum triglyceride level 150 mg/dL or greater within the last 6 months, 7 serum high-density lipoprotein (HDL) level less than 40 mg/dL in men or 50 mg/dL in women 8 within the last 6 months, systolic blood pressure greater than 130 mmHg or diastolic blood 9 pressure greater than 85 mmHg, and fasting serum glucose greater than 100 mg/dL. Additional Missing data was assumed to be missing at random and excluded from the analysis for that 2 variable. The odds ratio for acute arterial thrombosis in COVID-19 was evaluated with a two-3 tailed Fisher's exact test. This study was approved by the Institutional Review Board of 4 MMC/AECOM with a waiver of informed consent for this observational review (#2020-11452). (Table I) .

Patients positive for SARS-CoV-2 had significantly higher D-dimer levels at the time of imaging 4 (217.3 vs.1.8, p=0.038) and average in-hospital D-dimer levels (8.5 vs. 2.0, p=0.043) than 5 SARS-CoV-2 negative or not tested patients (Table II) . SARS-CoV-2 positive patients exhibited 6 a higher white blood cell count (WBC) despite lack of statistical significance (14.5 vs. 9.9, 7 p=0.208). There were no significant differences in prothrombin time (PT), aPTT, platelet count, (Table III) . The SARS-CoV-2 positive patients were treated with a left ventricular assist device. Amputation was required in 3 of the patients in the SARS-CoV-2 1 negative or untested group.

There were significantly more SARS-CoV-2 positive patients with aortoiliac involvement 4 compared to the SARS-CoV-2 negative or not tested patients (33.3% vs. 4.0%, p=0.040). There 5 was a trend towards less tibial/pedal (13.3% vs. 40.0%, p=0.154) and more upper 6 extremity(20.0% vs. 8.0%, p=0.537) involvement in the SARS-CoV-2 positive patients when 7 compared to SARS-CoV-2 negative or not tested patients . Carotid and femoropopliteal 8 involvement was relatively equal between the two groups (Table III) .

The COVID-19 specific severity of disease on presentation was documented (Table IV) . Most of 11 the patients with arterial thrombosis had critically severe disease (60.0 %). Three patients (20.0% 12 ) were asymptomatic, and one each had mild, moderate and severe COVID-19 presentation 13 (6.7% each). There was no observed correlation between the severity of COVID-19 disease and 14 the degree of arterial thrombosis. None of the patients in the study had bleeding complications. 15 30 day outcomes resulted in 6 deaths due to COVID 19 complications, 4 major amputations, 3 16 patients were discharged to skilled nursing facilities (SNF) and one to home. ranged from mild to severe in intensity. Patients with arterial thrombosis who were SARS-CoV-10 2 positive had significantly higher D-dimer levels, BMI, were younger, and less often on 11 antiplatelet medications as compared to patients who were SARS-CoV-2 negative or not tested.

In addition, we noticed that SARS-CoV-2 positive patients with arterial thromboembolic 13 complications exhibited a trend towards higher WBC count and neutrophil to lymphocyte ratio 14 which may indicate an increased inflammatory response. Other markers of increased 15 inflammation such as CRP and CPK were also greater in the SARS-CoV-2 positive group when 16 compared to their negative counterparts, but these did not reach statistical significance. All 17 patients with acute arterial ischemia are placed on a heparin drip upon diagnosis.

We did not observe a typical cardioembolic pattern in the SARS-CoV-2 positive group but rather 20 a picture that was more consistent with in situ thrombosis. The arterial thrombotic events Figure 1C ).

The majority of arterial emboli originate in the heart and travel to the extremities, with the lower 13 extremities being affected more frequently than the upper extremities and carotid arteries. There remains much to learn about the SARS CoV-2 and the disease it causes. In addition to an 2 early lack of comprehensive testing for both active disease as well as prior infection, the 3 reliability of many of these tests have been called into question. False negative rates ranging 4 from 20% to as high as 50% for diagnostic tests have been quoted and more recently it has been 5 suggested that antibody tests may not be as indicative of prior infection as first believed. 11,12 6 Whether these are issues with the tests themselves or a peculiarity of the virus is unclear. We do 7 not know whether the virus can remain dormant and "reactivate" in an individual nor whether 8 individuals develop immunity and if so to what degree and for how long. We also do not know 9 whether the impact of inflammatory changes and possible endothelial damage will resolve with 10 convalescence or whether the changes may persist and lead to symptomatic vascular disease in 11 the future at an undetermined time point. If the latter is the case, we will need to anticipate this 12 eventuality and investigate therapies to help delay or prevent these occurrences. 

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Table 1: Demographic factors and clinical characteristics for patients with COVID-19. IQR, interquartile range. DVT, deep venous thrombosis. PE, pulmonary embolism. BMI, body mass index

HTN, hypertension. DM, diabetes mellitus. HLD, hyperlipidemia. CAD, coronary artery disease

PVV, peripheral vascular disease. COPD, chronic obstructive pulmonary disease. CHF, congestive heart failure. CKD, chronic kidney disease. COVID-19, coronavirus disease 2019. ALI, acute limb ischemia

Table 2: Laboratory values and treatment characteristics for patients with COVID-19. IQR, interquartile range. WBC, white blood cell. aPTT, activated partial thromboplastin time. SCr, serum creatinine. CPK, creatine phosphokinase. CRP, c-reactive protein. LDH, lactate dehydrogenase

Anatomic distribution, treatment details and outcomes for patients with acute arterial thrombosis. AC, anticoagulation. COVID-19, coronavirus disease. LOS, length of stay

COVID-19, coronavirus disease. ARDS, acute respiratory distress syndrome, CIA, common iliac artery, EIA, external iliac artery, SFA, superficial femoral artery, CCA, common carotid artery, SCA, subclavian artery, ICA, internal carotid artery, HCQ, hydrochloroquine, RLE right lower extremity