key: cord-0824142-slnncoag authors: Santoliquido, Angelo; Porfidia, Angelo; Nesci, Antonio; De Matteis, Giuseppe; Marrone, Giuseppe; Porceddu, Enrica; Cammà, Giulia; Giarretta, Igor; Fantoni, Massimo; Landi, Francesco; Gasbarrini, Antonio; Pola, Roberto title: Incidence of Deep Vein Thrombosis among non‐ICU Patients Hospitalized for COVID‐19 Despite Pharmacological Thromboprophylaxis date: 2020-07-06 journal: J Thromb Haemost DOI: 10.1111/jth.14992 sha: 19e262fd9d80a34044be38e4e2f8dcdf5e49ba96 doc_id: 824142 cord_uid: slnncoag BACKGROUND: A remarkably high incidence of VTE has been reported among critically ill patients with COVID‐19 assisted in the Intensive Care Unit (ICU). However, VTE burden among non‐ICU patients hospitalized for COVID‐19 that receive guideline‐recommended thromboprophylaxis is unknown. OBJECTIVES: To determine the incidence of VTE among non‐ICU patients hospitalized for COVID‐19 that receive pharmacological thromboprophylaxis. METHODS: We performed a systematic screening for the diagnosis of deep vein thrombosis (DVT) by lower limb vein compression ultrasonography (CUS) in consecutive non‐ICU patients hospitalized for COVID‐19, independently of the presence of signs or symptoms of DVT. All patients were receiving pharmacological thromboprophylaxis with either enoxaparin or fondaparinux. RESULTS: The population that we screened consisted of 84 consecutive patients, with a mean age of 67.6±13.5 years and a mean Padua Prediction Score of 5.1±1.6. Seventy‐two patients (85.7%) had respiratory insufficiency, required oxygen supplementation, and had reduced mobility or were bedridden. In this cohort, we found 10 cases of DVT, with an incidence of 11.9% (95% CI 4.98–18.82). Of these, 2 were proximal DVT (incidence rate 2.4%, 95% CI ‐0.87–5.67) and 8 were distal DVT (incidence rate 9.5%, 95% CI 3.23–5.77). Significant differences between subjects with and without DVT were D‐dimer >3,000 µg/L (P<0.05), current or previous cancer (P<0.05), and need of high flow nasal oxygen therapy and/or non‐invasive ventilation (P<0.01). CONCLUSIONS: DVT may occur among non‐ICU patients hospitalized for COVID‐19, despite guideline‐recommended thromboprophylaxis. Since the beginning of 2020, the infectious disease caused by coronavirus 2 (SARS-CoV-2), named COVID-19, has spread around the world becoming a global emergency [1, 2] . In the last This article is protected by copyright. All rights reserved few months there has been increasing appreciation that venous thromboembolism (VTE) might contribute to acute respiratory failure in COVID-19 patients and affect clinical outcome. Indeed, subjects hospitalized for COVID-19 are the prototypical example of acutely ill medical patients at increased risk of VTE, as they suffer from an acute infection, may have acute respiratory failure, and often are bedridden, or have reduced mobility, since they need oxygen supplementation and/or are isolated in their room due to hospital restrictions. The concomitant presence of these conditions substantially increases the risk of VTE, and this risk may be even higher if other factors, such as cancer, history of previous VTE, and age ≥70 years, exist [3] . In addition, some COVID-19 patients may have significant abnormalities of coagulation parameters, including Ddimer levels above >1,000 μg/L [4] , and this further supports the concept that VTE needs to be properly prevented in these patients. A remarkably high incidence of VTE has been recently reported among COVID-19 patients assisted in the Intensive Care Unit (ICU), although all patients were receiving at least thromboprophylactic doses of anticoagulants [5, 6] . Also, there are autopsy data indicating that deep vein thrombosis (DVT), pulmonary embolism (PE), and various types of microvascular pathology may be found in patients deceased for COVID-19, although such findings have not been confirmed in other autopsy series [7] [8] [9] . Based on this and other anecdotal reports, many physicians are advocating the empiric use of therapeutic anticoagulation even in patients who do not have a documented diagnosis of VTE [10]. On the other hand, the current position of the majority of medical societies still is to use standard prophylactic doses of anticoagulation for hospitalized COVID-19 patients, as it is recommended for other acutely ill medical patients [11, 12] . In this study, we performed a systematic screening for the diagnosis of DVT in non-ICU consecutive patients hospitalized for COVID-19 that were receiving pharmacological thromboprophylaxis. This article is protected by copyright. All rights reserved Demographic data, clinical characteristics, and laboratory results were collected from the medical charts of our Hospital. Respiratory insufficiency was defined as PaO2 <60 mmHg and/or PaCO2 >50 mmHg in room air, or need for oxygen supplementation. Complete blood tests were available for all patients, including D-dimer levels, which were assessed by using a latex agglutination test. The Padua Prediction Score (PPS) was calculated for all patients. Data are presented as means±standard deviation (SD), or number and percentage when appropriate. T test or Mann-Whitney U test were used to assess differences between groups of patients. P <0.05 was defined as statistically significant. Statistical analysis was conducted using SPSS software version 21.0 (IBM, Armonk, NY, USA). This article is protected by copyright. All rights reserved The study was approved by the Ethics Committee of the 'Fondazione Policlinico Universitario A. Gemelli IRCCS' (Rome, Italy) (ID number 3149). Due to the nature of the study, the Ethics Committee waived the need for informed consent. A total of 84 hospitalized COVID-19 patients were studied. The demographic, clinical, and laboratory data of the studied population are presented in Table 1 performed within the first 48 hours from hospital admission. In none of these cases a diagnosis of DVT was performed. A DVT was found in 10 patients, with an overall incidence of 11.9% (95% CI 4.98-18.82). In 8 cases, they were distal DVT (located in veins below the knee: peroneal, posterior, anterior tibial, and muscular veins), with an incidence rate of 9.5% (95% CI 3.23-15.77). There were 2 proximal DVT, with an incidence rate of 2.4% (95% CI -0.87-5.67). In 4 cases, DVT was bilateral. Signs or symptoms of DVT (such as pain, swelling, warmth, redness, cramps, bluish or whitish skin discoloration at the level of the lower limb) were present only in 2 of the 10 patients with DVT. Subjects with DVT did not differ from those without DVT in terms of age, sex, and frequency of obesity, hypertension, type 2 diabetes mellitus, and CAD/CVD. Also, their PPS was This article is protected by copyright. All rights reserved similar to that displayed by subjects without DVT. Likewise, mean D-dimer levels, PT, and platelet count were similar between the two groups. However, the number of subjects with Ddimer level >3,000 µg/L was significantly higher in the DVT group than in the non-DVT group (P<0.05). In addition, subjects with DVT had higher incidence of cancer (either current or previous) (40.0% vs 13.5%, P<0.05) and more frequently required high flow nasal oxygen therapy and/or NIV, compared with subjects without DVT (60.0% vs 8.1%, P<0.01). These data are summarized in Table 3 . This article is protected by copyright. All rights reserved This study provides information on the incidence of DVT among non-ICU patients hospitalized for COVID-19 that receive guideline-recommended thromboprophylaxis. We found 10 cases of DVT among the 84 patients included in the study, with an overall incidence of 11.9%. Our findings are consistent with those of Demelo-Rodriguez and coll., who recently reported an incidence of DVT of 14.7% among 156 patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia [14] . The incidence of DVT that we found is high, compared with the results of the randomized double-blind MEDENOX trial, which is the landmark study that assessed the incidence of DVT among acutely ill hospitalized medical patients receiving pharmacological thromboprohylaxis. Indeed, in the MEDENOX Study, 16 DVT were found among 291 patients treated with enoxaparin, with an incidence of 5.5% [15] . However, it is important to point out that the increased incidence of DVT that we found in our study was mainly due to a relatively high number of distal DVT, while the incidence of proximal DVT was not substantially different from that observed in the MEDENOX trial. In particular, the incidence of distal DVT in our study and in the MEDENOX trial was 9.5% and 3.8%, respectively, while the incidence of proximal DVT in our study was 2.4% and in the MEDENOX study was 1.7%. Nonetheless, it should be noted that in the MEDENOX study the diagnosis of DVT was done by venography, while we used CUS, which is known to have lower sensitivity for the diagnosis of DVT in asymptomatic patients [16, 17] . Therefore, it is possible to hypothesize that in our study the number of COVID-19 patients with DVT could have been higher if venography had been used. Another important randomized placebo-controlled study that assessed the incidence of DVT among acutely ill hospitalized medical patients receiving pharmacological thromboprohylaxis is the PREVENT trial [18] . In this study, subjects treated with dalteparin displayed a 2.7% incidence of proximal DVT, which is similar to what we found in our study. Of note, in the PREVENT trial, the diagnosis of DVT was done by CUS, as it was done in our study. A difference is that distal DVT were not assessed in the PREVENT trial, based on the concept that their clinical relevance is not well established. We decided instead to search for distal DVT, because we believe that the risk of extension of thrombosis to proximal veins may be high in COVID-19 patients. Whether the incidence of DVT is higher in COVID-19 patients than in subjects affected by other acute viral respiratory infections remains to be determined. Indeed, high rates of thrombotic complications This article is protected by copyright. All rights reserved have been reported also during the H1N1 influenza virus pandemic and the various outbreaks of SARS-CoV infection [19] [20] [21] [22] [23] . Of note, the patients that had DVT in our study did not differ from those without DVT in terms of age, male sex, and comorbidities. Also mean PPS, D-dimer levels, PT, and platelet count were similar between patients with and without DVT. There were though some statistically significant differences. One was that patients with DVT had more often D-dimer levels >3,000 µg/L, compared with subjects without DVT. This is interesting, because a D-dimer cut-off value of 3,000 µg/L has been recently associated with mortality in non-ICU COVID-19 patients treated with heparin [24] . Instead, we did not find a difference between DVT and non-DVT patients when subjects with D-dimer level >1,500 µg/L were considered, although this D-dimer value has been recently proposed as cut-off to predict thrombosis in COVID-19 patients assisted in the ICU [25]. Our study has some limitations. First, the number of patients is relatively small and therefore our findings need to be confirmed in larger samples. Second, CUS was performed relatively early during hospitalization and not at the same time-point for all patients, therefore it is possible that DVT that developed at later stages during hospital stay were not identified. Also, CUS was never performed at the moment of hospitalization. Therefore, we cannot exclude that some patients had developed DVT before hospitalization, when they were not still receiving anticoagulant prophylaxis. Third, we have no data on the clinical outcome of patients with DVT compared to subjects without DVT. Finally, we did not look for PE and this is an important issue that needs to be addressed by additional studies in the future. In conclusion, our study shows that DVT is not uncommon among non-ICU patients hospitalized for COVID-19, despite the use of guideline-recommended thromboprophylaxis. The best thromboprophylactic strategy to use in COVID-19 patients remains to be determined. This article is protected by copyright. All rights reserved The Authors have no conflicts of interest to disclose. 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Subcutaneous low-molecularweight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients Randomized placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients Pandemic H1N1 Influenza Infection and Vascular Thrombosis Thromboembolic Events in Patients With Severe Pandemic Influenza A/H1N1 Chest Radiographic and CT Findings in Novel Swine-Origin Influenza A (H1N1) Virus (S-OIV) Infection Autopsy findings in eight patients with fatal H1N1 influenza Severe acute respiratory syndrome and venous thromboembolism in multiple organs Mean fibrinogen level, mg/dL ± SD 560±151 491±171 n.s. This article is protected by copyright. All rights reservedMean PT, seconds ± SD 11.4±1.0 11.3±0.7 n.s.