key: cord-0810891-t8ynd1ew
authors: Mietto, Cristina; Salice, Valentina; Ferraris, Matteo; Zuccon, Gianmarco; Valdambrini, Federico; Piazzalunga, Giorgio; Socrate, Anna Maria; Radrizzani, Danilo
title: Acute lower limb ischemia as clinical presentation of COVID-19 infection
date: 2020-08-11
journal: Ann Vasc Surg
DOI: 10.1016/j.avsg.2020.08.004
sha: 31363d1532d71f1edc262bcdcb29213a1a416e21
doc_id: 810891
cord_uid: t8ynd1ew

Novel 2019 coronavirus (COVID-19) infection usually causes a respiratory disease, that may vary in severity from mild symptoms to severe pneumonia with multiple organ failure. Coagulation abnormalities are frequent, and reports suggest that COVID-19 may predispose to venous and arterial thrombotic complications. We report a case of acute lower limb ischemia and resistance to heparin as the onset of COVID-19 disease, preceding the development of respiratory failure. This case highlights that the shift of coagulation profile towards hypercoagulability was associated with the acute ischemic event and influenced the therapy.

Novel 2019 coronavirus infection usually causes a respiratory disease, that may 20 vary in severity from mild symptoms to severe pneumonia with multiple organ failure. 21

Coagulation abnormalities are frequent, and reports suggest that COVID-19 may predispose 22

to venous and arterial thrombotic complications. We report a case of acute lower limb 23 ischemia and resistance to heparin as the onset of COVID-19 disease, preceding the 24 development of respiratory failure. This case highlights that the shift of coagulation profile 25 towards hypercoagulability was associated with the acute ischemic event and influenced the 26 therapy. coagulopathy has been associated with poor prognosis [1, 2] . Venous thrombosis and 36 pulmonary embolism are the most represented complications, while thrombotic arterial 37 events are relatively uncommon and reported in severe cases [1, 3, 4] . 38

We report the case of a patient with acute left lower limb ischemia (ALI) and resistance to 39 unfractionated heparin (UFH) as clinical onset of COVID-19 disease, preceding the 40 development of respiratory failure. 41

A 53 years-old man was admitted to our ED for acute left lower limb ischemia, leg pain 44 started the previous day associated with walking difficulties. Absence of blood flow in the 45 entire left femoral-popliteal axis was detected at duplex scan ultrasonography. A 46 subsequent thoraco-abdominal Computed Tomography Angiography (CTA) scan confirmed 47 thrombotic occlusion at the iliac level extended to femoro-popliteal arteries and distal 48 circulation, collaterally a focal thrombotic defect within the right tibio-peroneal trunk was 49 evident too, with reperfusion of distal posterior tibial artery ( Figure 1 ). Clinical and imaging 50 findings were consistent with the diagnosis of left ALI (Rutherford Category IIb). Lung 51 imaging showed diffuse bilateral interstitial infiltrating shadows, mainly at subpleural level. 52

Patient complained no recent respiratory symptoms or fever; oxygenation and vital signs 53 were normal. Medical history showed hypertension on medical treatment and mild obesity 54 (BMI 33 kg/m 2 ). The nucleic acid detection of COVID-19 was negative at ED. An emergent 55 surgical thromboembolectomy of the left lower limb was performed (standard observed from the superficial femoral artery. Diagnostic angiography revealed a patent 59 femoro-popliteal axis with occlusion of the anterior, posterior and peroneal artery at the 60 mid-calf level. Posterior tibial artery was perfused by collaterals at the ankle level, while a 61 typical aspect of "desert foot" with absence of forefoot microcirculation was discovered, 62

probably due to acute microvascular virus-related thrombosis. Then, selective regional intra- was below the therapeutic range (0.08 U/ml). Therefore, UFH infusion was increased up to 89 79.200 U/day to obtain aPTT ratio> 2.5. ROTEM intem profile showed increased CT (300 s), 90 while both MCF pathways (intem and extem) did not changed. Afterwards AFXa resulted in 91 the therapeutic range (0.43 U/ml). Platelets count and fibrinogen level were normal at ED 92 admission, but the latter steadily increased after two days of hospital stay. 93

Left lower limb perfusion slowly improved during the following days, with restoration of 94 direct blood flow within the posterior and anterior tibial artery in the proximal foot (CW 95 doppler). Foot sensitivity and motility improved, however a permanent superficial peroneal 96 nerve impairment persisted. Skin cyanosis was limited at the forefoot and dry necrosis 97 developed at the distal phalanx. On 18 th PO day the patient was transferred to infectious 98 disease unit. Upon ICU discharge no respiratory or renal support was required: cytolysis 99 enzymes decreased during the days and renal function recovered (creatine phosphokinase 100 826 U/l, myoglobin 266 µg/l, creatinine 1.06 mg/dl). Continuous infusion of UFH was 101 stopped and low-molecular weight heparin (LMWH) was introduced (100 U/kg/die b.i.d.). 102

No bleeding complication was observed. On 40 th PO day the patient has been discharged to persistent feature during the disease and associated to increased mortality [1, 2] . While this 119 patient had low risk of arterial thrombotic event (hypertension and mild obesity), he showed 120 coagulation abnormalities described in COVID-19 infection as high fibrinogen level and 121 hypercoagulability state at ROTEM analysis (increased MCF). Maximal clot amplitude at 122 thromboelastography analysis above normal value was reported in more than 80% of COVID 123 patients [9] . Even in absence of preexisting atherosclerotic arterial disease, the procoagulant 124 and inflammatory state induced by COVID-19 probably acts like a trigger in arterial 125 thrombosis, especially of microcirculation vessels. A recent paper reported higher failure 126 rate of revascularization surgery in patients with ALI and COVID-19 pneumonia [4] . Frequent 127 early recurrent thrombosis and absence of forefoot microcirculation are also described. coagulation target was difficult to achieve despite the increase of UFH doses. Heparin 131 resistance has been associated to high fibrinogen, Factor VIII and von Willebrand factor in 132 COVID-19 patients [10] . Surgical thromboembolectomy, intra-operative fibrinolysis, 133 vasodilation therapy (prostacyclin), optimization of anti-coagulation with antithrombin 134 monitoring and supplementation and AFXa determination to confirm suboptimal heparin 135 level were successful in restoring perfusion and avoided major amputation in the case 136

Lastly, at admission in absence of respiratory symptoms, CT scan showed multifocal bilateral 138 peripheral ground glass areas consistent with characteristic COVID-19 pulmonary findings. 139

First nasopharyngeal swab was negative, however RT-PCR screening has a limit in sensitivity 140 at initial presentation (60%-79%) [11, 12] . Typical CT scan with bilateral peripheral ground 141 glass opacifications led the physicians to repeat RT-PCR test that confirmed COVID-19 142 diagnosis. Pathological CT scan findings may be present before respiratory symptoms onset, 143 as it occurred in the reported case [13] . Respiratory impairment and moderate acute 144 respiratory distress syndrome (ARDS) could be treated successfully with non-invasive 145 ventilation, while the major disease features were associated to hypercoagulability and 146 arterial thrombotic occlusion event, which was the first reason for ED admission. 147

Thrombotic events associated with COVID-19 infection warrant advance coagulation 148 monitoring in order to resolve acute problems and improve our understanding of patients' 149 coagulation state. Arterial thrombotic events causing ALI associated with COVID-19 infection 150 are mainly located within microcirculation vessels, with associated high rate of recurrent 151 thrombosis. Therefore, we decided to shift our policy towards a more aggressive regimen of 152 hypercoagulable state during COVID-19 pandemic are needed to fully understand the 155 pathogenesis of thrombotic effects. 156

Incidence of thrombotic complications 159 in critically ill ICU patients with COVID-19

With Poor Prognosis in Patients With Novel Coronavirus Pneumonia

Coagulopathy and Antiphospholipid Antibodies in 165

Patients With Covid-19

Acute limb ischemia in patients with COVID-19 168 pneumonia

Humanitas COVID-19 Task Force. Venous 181 and Arterial Thromboembolic Complications in COVID-19 Patients Admitted to an 182

Hypercoagulability of COVID-19 Patients in 185

COVID-19 and Its Implications for Thrombosis and 188

Sensitivity of Chest CT for COVID-19: Comparison to RT-190

Diagnostic Performance Between CT and Initial Real-Time 192

Figure 1. A, anterior CTA reconstruction showing occlusion of the left iliac axis (white dotted 202 arrows), reperfusion of the common and deep femoral arteries and sequent occlusion at the 203 origin of the superficial femoral artery

CTA reconstruction 204 showing left popliteal-tibial vessel occlusion (grey arrow) and right tibioperoneal trunk 205 occlusion with reperfusion of distal posterior tibial artery

Figure 2. Final digital subtraction angiography (DSA) showing incomplete tibial vessel 208 recanalization and absence of forefoot vessels (i.e., "desert foot"). PA popliteal artery, ATA 209 anterior tibial artery, PLA peroneal artery