key: cord-252013-ehyuflg3
authors: Bozzani, Antonio; Arici, Vittorio; Tavazzi, Guido; Franciscone, Mila Maria; Danesino, Vittorio; Rota, Monica; Rossini, Rosa; Sterpetti, Antonio V.; Ticozzelli, Giulia; Rumi, Elisa; Mojoli, Francesco; Bruno, Raffaele; Ragni, Franco
title: ACUTE ARTERIAL AND DEEP VENOUS THROMBOEMBOLISM IN COVID-19 PATIENTS
date: 2020-09-22
journal: Surgery
DOI: 10.1016/j.surg.2020.09.009
sha: 
doc_id: 252013
cord_uid: ehyuflg3

INTRODUCTION: The Lombardy region (Italy) suffered severe problems during the acute phase of the outbreak of COVID-19 in Italy (March-April 2020) with 16,000 diagnosed COVID-19 related deaths (49% of the total COVID-19 related deaths in Italy). In the area surrounding Pavia during the critical stage of the outbreak (March-April), 1,225 of the documented 4,200 deaths were related to COVID-19 infection, with a mortality rate of 181/100,000 inhabitants and an increase in deaths of 138% compared to the same period in previous years. AIM: Our aim was to report the experience of the Department of Vascular Surgery of Pavia (Lombardy), including the lessons learned and future perspectives regarding the management of COVID-19 patients who developed severe acute ischemia with impending lower limb loss or deep vein thrombosis (DVT). MATERIALS AND METHODS: We carried out a retrospective data collection of COVID-19 patients with severe acute ischemia of the lower limbs or DVT observed in our Department during the period March 1(st) to April 30(th) 2020. Primary outcomes of the analysis were postoperative mortality for all patients and amputation rates only in those COVID-19 patients suffering from acute lower limb ischemia. Secondary outcomes were the prevalence of the disease among admitted COVID-19 patients, and any possible correlation between inflammatory parameters, thrombolytic status, and the presence of acute ischemia or DVT. RESULTS: We observed 38 patients (28 male) with severe COVID-19 infection (6 with lower limb arterial thrombosis and 32 with DVT). The median age was 64 years (range 30-94 years). In the arterial group, 3 had thrombosis on plaque and 3 on healthy arteries ("simple" arterial thrombosis). All underwent operative or hybrid (open/endo) revascularization; 1 patient died from major organ failure (MOF) and one patient underwent major amputation. In the DVT group, 9 (28%) patients died from MOF, despite aggressive medical therapy. In patients with "simple" arterial thrombosis and those with DVT, we observed a decrease in inflammatory parameters (CRP) and in D-dimer and fibrinogen after aggressive therapy (p <0.001). CONCLUSIONS: Our study confirms that critically ill, COVID-19 patients who develop arterial and deep vein thrombosis are at high risk of mortality, but if treated properly, there is an improvement in overall survival rate, especially in patients of 60 years of age or younger.

As of July 9 th , 2020, more than 34,000 deaths from COVID-19 were identified in Italy. The critical phase of the outbreak seemed to be in Italy, as well as in other European countries (e.g. Spain and England). The Lombardy region suffered from severe problems during the acute phase of the outbreak (March-April 2020) with 16,000 diagnosed COVID-19 related deaths (49% of all COVID-19 related deaths in Italy). During the acute phase of the outbreak (March-April), in the area surrounding Pavia, , 1,225 of the documented 4,200 deaths were related to COVID-19 infection with a mortality rate of 181/100,000 inhabitants and an increase in deaths of 138% in comparison to the same period of previous years 1 The mean age of patients dying from the disease was 81 years, and 70% were aged over 75 years . The median age of the patients who died was 20 years older than the median age of infected patients (61 years). Mortality was greater in patients with associated cardiac morbidities (arterial hypertension in 66% of patients who died, coronary artery disease in 28%, atrial fibrillation in 23% congestive heart failure in 16%), renal failure (20% of the patients), and cancer (16%). The mortality rate increased from 14% in patients with only 1 comorbidity to 61% in patients with 3 or more comorbidities 1 . In the elderly population, the simultaneous occurrence of the COVID-19 infection and the presence of diffuse atherosclerotic disease were of course a common clinical scenario, specifically in the Lombardy region, where the outbreak was severe and overwhelming and a high proportion of the population is elderly 2, 3 . Since the end of May, there has been a steady and marked decrease in rates of infection and mortality in Pavia and Italy as a whole.

The high mortality rate in patients with severe SARS-CoV2 infection can also be attributed to the non-respiratory complications of COVID-19, although the mechanism by which the virus migrates to these other locations remains poorly understood. Furthermore, COVID-19 predisposes patients to both venous and arterial thromboembolic disease due to high-grade inflammation, hypoxia, J o u r n a l P r e -p r o o f immobilization, and diffuse intravascular coagulation, but direct damage to the endothelium by the virus has not yet been demonstrated 4 .

The aim of our analysis was to report our experience of the Department of Vascular Surgery of Pavia (Lombardy), focusing on the lessons learned and future perspectives regarding the management of COVID-19 patients who developed severe acute ischemia with impending lower limb loss or deep vein thrombosis (DVT).

J o u r n a l P r e -p r o o f

A general lockdown with severe social isolation rules for the general population and health care workers was established in Italy in March, when the high spread/contagiousness and virulence of the virus became apparent. Unfortunately, the dangerous characteristics of the virus were immediately evident due to not only the high number of admissions of infected patients in poor general condition but also to an unexpectedly inadequate health care system overwhelmed with COVID-19 cases; this pandemic exposed comprised poor capacity with respect to hospital and Intensive Care Unit beds and workforce everywhere in the world , not only in Italy . After initial organizational problems, hospitals were divided into sections devoted to COVID-19 patients only.

Admissions to hospitals were decreased, thereby avoiding non-urgent conditions and deferrable elective operations [5] [6] [7] . Our activity as vascular surgeons had been reduced dramatically, and were assigned to perform other duties in the pneumology departments and emergency departments for COVID-19 positive patients, in addition to our consultancy activities. Table 1 

Six patients (4 male, 2 female) with acute ischemia of the lower limbs were admitted to our Department. The median age was 71 years (range 49-83 years). In all 6 patients, the limb was at risk, and the only alternative was a major amputation. Three patients (cases 1, 2, and 5) reported previous symptoms of claudication and CT-angiography posed the diagnosis of acute "super- In the group of 3 patients with occlusion from "superimposed" arterial thrombosis, one patient suffered from early thrombosis postoperatively noted on days 2 and eventually required above-theknee amputation; the mean hospital stay was 9 days, and all patients left the hospital in generally good clinical conditions. In the 3 patients with occlusion from "simple" arterial thrombosis, the superficial femoral artery was involved to the common iliac artery; clinical and diagnostic studies supported the hypothesis of an acute "simple" parietal aortoiliac thrombosis with distal embolization. In this group, proximal and distal embolectomy was performed through the femoral artery with initial success. One patient entered the hospital with critical hemodynamic conditions J o u r n a l P r e -p r o o f and disseminated intravascular coagulation and required immediate mechanical ventilation (pH = 7.437, lactate = 5.5 mmol/L, sO 2 = 76.4%, PO 2 = 44.8 mmHg, pCO 2 = 24.7 mmHg, calculate pO 2 /FiO 2 ratio = 44.8 mmHg) already. A new femoral embolectomy was required from reocclusion one day postoperatively; unfortunately this patient died a month later from multiple organ failure (MOF). The remaining two patients left the hospital in good general conditions. Laboratory parameters varied considerably between patients. Patients with "simple" arterial thrombosis tended to have more increased levels of serum D-Dimer, C-Reactive Protein (CRP), and a decreased platelet count as compared to patients with "superimposed arterial thrombosis". In the two patients with early re-occlusion (one with simple thrombosis and the other with superimposed thrombosis), these parameters were more altered in comparison to the other two patients in each group who had eventual successful arterial revascularization ( Table 2) .

The number of requests for in-hospital consultation for patients with DVT increased by more than 

Discussion COVID-19 can lead to acute respiratory disease syndrome (ARDS), multi-organ involvement, and shock [8] [9] [10] . The review of clinical, laboratory, and imaging findings found an increased risk of thrombotic events in COVID-19 patients 11 . The precise incidence of thrombosis in these patients has not been determined. In a retrospective study of 138 patients, of whom 16.7% of whom were in a critical condition, 17.3% of these patients were diagnosed with DVT at 3 to 18 days after admission despite the use of guideline-recommended thromboprophylaxis 12 . The prevalence of DVT has been shown to vary from 16-49% of patients with COVID-19 admitted to intensive care, and 40% in autopsy studies 10, 13, 14 .

Arterial thrombosis has also been reported, and since the beginning of the pandemic, there have been reports of cases of ischemia (ischemic stroke, myocardial infarction, or systemic arterial embolism). Arterial thrombosis accounts for about 4% of thromboembolic complications during COVID-19 15 .

inflammatory condition associated with hemostatic abnormalities. There is now evidence that some patients respond to COVID-19 with a "cytokine storm" responsible for a hypercoagulability state 8,9 . COVID-19 hospitalized patients displayed hypercoagulability via 3 possible mechanisms: 1) the formation of pro-inflammatory cytokines, which are mediators of atherosclerosis, contributing directly to the rupture of the atherosclerotic plaque by local inflammation, 2) induction of procoagulant factors, and 3) hemodynamic changes that predispose to ischemia and thrombosis 16 ; these thrombotic events contribute to the severity of infections, creating a vicious circle. There is no readily available evidence on any potential therapy or prophylaxis which may provide clinical benefits in patients with severe COVID-19 infections as defined by marked tachypnea with respiratory rate ≥30 breaths per minute, hypoxemia with oxygen saturation ≤93%, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300, and lung infiltrates >50% of the J o u r n a l P r e -p r o o f lung field involved within 24 to 48 hours) 17 . Moreover, clinical trials have not confirmed a clear efficacy of anti-malarial (hydroxychloroquine or chloroquine) with or without azithromycin and anti-retroviral drugs (lopinavir/ritonavir/remdesivir). Currently, several immunomodulating therapies, including glucocorticoids, convalescent plasma, and anti-cytokine therapy, are being investigated 18, 19 . LMWH is recommended for all hospitalized patients, unless there are contraindications [20] [21] [22] [23] .

In our experience with COVID-19 critically ill patients with acute arterial and deep vein thrombosis we found systemic abnormalities in hemostatic and inflammatory parameters. An aggressive medical and surgical therapeutic approach with anticoagulation, anti-inflammatory agents (selective and non-selective), and antibiotic therapy resulted in a survival rate of 74% (28/38) in these very critical conditions 14, 20, 24, 25 . In this specific clinical setting, our analysis of the initial abnormalities in hemostatic and inflammatory parameters, showed that these abnormities appeared to be similar in both patients who survived and those who did not. Even patients with markedly altered parameters recovered after aggressive medical or surgical treatment. Despite the small number of patients in the arterial group of our study, it appears that surgical revascularization in this clinical setting is beneficial for several reasons: 4 of the 6 patients had their legs saved and survived the severe COVID-19 infection. Moreover, in these 4 patients we found a decrease in CRP levels, improved platelet counts, and decreased levels of D-dimers. These data support the possibility that early distal revascularization might reduce the inflammatory storm. The improvement of these parameters was not observed in the 2 patients who suffered from early re-thrombosis postoperatively. We believe that early interventions aimed at decreasing the systemic inflammation may help to prevent thrombosis and its complications. Moreover, while specific or broad-spectrum anti-inflammatory drugs, such as aspirin, decrease the inflammatory condition, their use has been the source of a number of debates. In severe COVID-19 infection a low platelet count is often evident. In the 3 patients with acute "simple" thrombosis, despite the fact that platelet count was normal in 2 J o u r n a l P r e -p r o o f patients, distal embolization suggests an abnormality in platelet function and adhesion.

Conceptually, selective inflammatory inhibitors may prevent the complications related to the simultaneous platelet inhibition; however, in the unregulated and overwhelming inflammatory storm associated with severe COVID-19 infection, alternative activation of other pro-inflammatory cytokines is highly probable 26, 27 . These possibilities support the use of anti-inflammatory inhibitors, either selective or non-selective, according to the specific stage and level of the infection.

We observed the same phenomenon in patients affected by DVT in whom early thromboprophylaxis and anti-inflammatory therapy had been established. In particular, in relation to the known high incidence of DVT (25-31%) despite adequate prophylaxis 28 , we preferred to use an 

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Matthews CA Implementation Guide for Rapid Integration of an Outpatient Telemedicine Program During the COVID-19 Pandemic

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J o u r n a l P r e -p r o o f Our study confirms that critically ill, COVID-19 patients who develop arterial and deep vein thrombosis are at high risk of mortality, but if treated properly, there is an improvement in overall survival rate, especially in patients sixty years of age or younger.