key: cord-0972453-xnqz54av authors: Chen, Budong; Jiang, Chunguo; Han, Bing; Guan, Chunshuang; Fang, Gaoli; Yan, Shuo; Wang, Kexin; Liu, Ligai; Conlon, Christopher P.; Xie, Ruming; Song, Rui title: High prevalence of occult thrombosis in mild/moderate COVID-19 date: 2020-12-19 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.12.042 sha: ce0f3652409b6079b43506ffe9b99f865944a7a2 doc_id: 972453 cord_uid: xnqz54av Background and purpose More and more reports had observed the thrombosis in severe COVID-19 cases. The aim of this study was to evaluate the incidence of thromboembolism in mild/ moderate COVID-19. All of the patients had normal coagulation tests and had no overt thrombotic complications. It is important to screen the thrombotic status in mild/moderate COVID-19. Methods From June 11 to July 8, 2020, 23 patients with mild/ moderate COVID-19 pneumonia consented to having a CTPA (CT pulmonary angiography) + CTV (CT venography) scans for the lung and extremity veins. Doppler ultrasound (DUS) was performed in all patients for screening. The incidence, clinical manifestations, laboratory examinations, imaging features and prognosis of patients with venous thromboembolism (VTE) were analyzed and compared with those COVID-19 pneumonia patients without VTE. Results 19 patients (82.6%) had VTE, mainly distal limb thrombosis. Only one of the VTE were screened by DUS, the other VTE were negative by DUS. All of the mild / moderate patients with VTE were screened by CTPA + CTV. The blood tests for inflammatory, coagulation and biochemistry parameters were all in normal scope except for the WBC and LDH. Conclusions With CTV screening for DVT, we found the incidence of thrombosis in mild to moderate COVID-19 patients was soared to 82.6% (19/23). Screening for thrombosis is important in COVID-19. CTV is more sensitive than the DUS in detecting thrombosis. More research is needed to evaluate the significance of thrombosis in COVID-19 pneumonia. With the numbers of confirmed severe cases of COVID-19 increased, more and more reports had suggested that the thrombotic complications in severe to critical COVID-19 cases maybe the important risk [1] . Increasingly researches by autopsy or images had highlighted thrombo-embolism in severe cases of COVID-19 [2] [3] . Few data are available concerning the characteristics of thromboembolic complications in mild to moderate cases. The thrombotic complications include pulmonary thromboembolism (PE) and venous thromboembolism (VTE). Most of the reports have focused on PE but rarely on venous clots, especially sacral thrombosis [4] . Coagulopathy contributes to the severity of COVID-19 infection, with an excess of venous, arterial, or microvascular associated events. The activated coagulation pathway and endothelial dysfunction are the leading factors for thrombosis [5] . The combination of thrombocytopenia, prolonged prothrombin time, and increased D-dimer is suggested to the high incidence markers of thrombosis [6] . Plasma Ddimer measurement is emerging as a direct prognostic marker in COVID-19. However, most of the reports concerned severe patients. In this study, we showed that thrombotic complications occurred in mild to moderately ill patients. Most of them had normal D-dimer and prothrombin time. We collected the mild and moderate patients who were diagnosed with COVID-19 during their hospital stay. 23 patients were enrolled from June 11 to 8 July, 2020. They all consented to have a CTPA (CT pulmonary angiography) + CTV (CT venography) scan for the lung and extremity veins. Doppler ultrasound (DUS) was also used screening for thrombosis in these patients at the same time. Clinical data were retrievable for these patinets, including demographic, comorbidities, symptoms on admission, blood test results, lower limb venous ultrasound doppler, time between admission and CT scan diagnosis, and patients' outcomes. CT scans were performed on a 256-slice spiral CTs (Philips, iCT, Netherlands). CT images were independently reviewed by two experienced thoracic radiologists (CBD and XRM). Discordances in evaluation were solved by consensus. They assessed both lung and lower veins, being blinded to clinical data. All images were examined via dedicated windows. We also evaluated the inflammation of the pneumonia by AI (artificial intelligence, AI) technology. The results were given as the mean ± standard deviation, median (interquartile range), or number (percentage), wherever appropriate. A p-value of < .05 was considered statistically significant. Data were analyzed using SPSS 21.0 for Windows (SPSS Inc.). There were 23 patients (14 males and 9 females) enrolled into this study, and they all had complete clinical information and the laboratory data required for this study. Table 1 lists baseline patient characteristics for the VTE and non-VTE groups. The mean age was 42.7 ± 12.0 years. We performed CTPA + CTV for these patients 10 to 14 days after admission. Their initial symptoms were fever, cough, fatigue along with other non-speicific symptoms. Only 3 patients had a significant past medical history; one had hypertention, one had pulmonay fibrosis (case 10), and the third had breast cancer (case 12). All of these conditions were stable at the time of admission. All patients had pneumonia according to CT scan when they were enrolled. Their CT characterization of pulmonary pathology as AI score were showed (table 1) . Their mean inflammation value of pneumonitis through AI (artificial intelligence AI) were 136.7 ± 166.6. 82.6% (19/23) of the patients had deep venous thrombosis (DVT) by radiographic scan, but had no related symptoms. All of the patients' Padua prediction scores for embolism were normal. The blood tests for inflammation, coagulation and biochemistry were not statistically significant between the DVT and the non-DVT group, other than plasma LDH and total WBC. The LDH and WBC were higher in VTE group than in the non-VTE group. We also did univariable and multivariable OR for this, only univariable analysis showed these two as risk factors for VTE. In these radiographically-confirmed VTE patients, only in one (patient 8) was VTE observed by ultrasound; her VTE was the most severe of all the patients. This was a 64 year old female who had a pulmonary fibrosis history. Her pulmonary fibrosis was mild and didn't need oxygen support before hospitalisation. After CTPA+CTV, we found there were thrombosis in the anterior tibial, posterior tibial, and fibular veins (figure 1a). She received low molecular weight heparin (LMWH) at therapeutic doses. After two weeks treatment, we repeated the CTV. Her thrombosis had resolved or improved(figure 1b). These 19 VTE were distributed in different veins (table 2). Most of them had distal DVT (18/19), only one patient had thrombosis in the prostatic venous plexus and one had a proximal DVT. (Figure 2 ). Other than patient 8, no other patient received anti-coagulation treatment. All of these patients were discharged according to our guidelines. None of them became severe or critical, and no one had thrombotic related sequelae. Chest CT scan without administration of contrast agent is the most importand and easy way in diagnose of COVID-19 [11] . The incidence of PE in patients with COVID-19 was estimated to be 20.4% to 28% [12, 13] . This data was also had bias because of the number of CTPAs performed in patients were less in patients with COVID-19. In this study, we did a prospective cross-sectional study and we reported 19 mild to moderate COVID-19 patients who had thrombotic events. The percentage of patients with VTE detected by CT was higher to 82.6%. We found that radiographic examination revealed more thromboembolic diagnoses (19/23) than the duplex ultrasound (1/23). None of these VTE patients had any evidence on routine blood counts or by clinic symptoms or signs. Higher WBC and LDH levels might be associated with thrombosis -they were higher in VTE group than in non-VTE group, but only on univariate analysis. Contrary to the severe cases, those who had thrombosis [14] , both VTE and non-VTE groups in mild and moderate disease, had no specific blood test results in infection, immunology, viral load, or in coagulation. Thrombosis in COVID-19 is an important part of the clinical picture that needs to be considered. Ultrasound is one of the most common methods to help clinicians to detect thrombosis. Some reported thrombosis described in COVID-19 was found by CTPA or at autopsy [15] [16] [17] [18] . Almost all the reports have focused on the severe or critically ill patients; little attention has been paid to those with mild to moderate disease [19] . In this study, we observed that thrombosis is common in mild disease (82.6%) compared to the rates described (49%) [20] in severe patients. We used the CTPA+CVT, and increased the sensitivity of clot detection, especially in the distal veins. The patients all had no risk factors for thrombosis on medical history and their Padua scores were all normal. Although we did not treat most of these patients with anticoagulant therapy, this study highlights for us the need to pay more attention to the thromboembolism risk in COVID-19. The mechanism may be a SARS-CoV-2 direct effect or some indirect effects on vascular endothelial cells [21] . We might speculate that some of this occult thrombosis could be associated with some of the post- The limitations of our report are that this is a relatively small, single-center study and we do not have long term follow-up of these cases to determine whether these thromboses have any sequelae. This is a cross sectional study, so we need more serial data to evaluate the value of early surveillance of the thrombosis in vessels among the COVID-19 patients. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. The New England journal of medicine The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications. Circulation research Computed tomography characterization and outcome evaluation of COVID-19 pneumonia complicated by venous thromboembolism Venous thromboembolism in COVID-19: systematic review of reported risks and current guidelines Guidance for anticoagulation management in venous thromboembolism during the coronavirus disease 2019 pandemic in Poland: an expert opinion of the Section on Pulmonary Circulation of the Polish Cardiac Society Prevention, Diagnosis, and Treatment of VTE in Patients With COVID-19: CHEST Guideline and Expert Panel Report Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19 Thromboembolism and anticoagulant therapy during the COVID This study was supported by the Grant DTZLX201709. We thank all the medical staff were involved in treating the patients.