Article ID: CJ-20-1302
Background: Suspicion that the coronavirus disease 2019 (COVID-19) caused venous thromboembolism (VTE).
Methods and Results: We conducted a case series study of 5 VTE patients with COVID-19 in Japan. The median body mass index was 27.7 kg/m2, and all patients required mechanical ventilation during hospitalization. Patients were diagnosed as VTE in the intensive care unit (ICU), general ward, and outpatient ward.
Conclusions: The current case series study revealed some clinical features of VTE patients with COVID-19 in Japan, including obese patients and those requiring mechanical ventilation during hospitalization, who should be followed closely for VTE, even after leaving the ICU.
The coronavirus disease 2019 (COVID-19) has become a worldwide pandemic.1,2 The main pathophysiology of COVID-19 is an infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2, which can also cause cardiovascular complications.3,4 Patients with COVID-19 have been reported to develop coagulopathy,5 leading to thromboembolic complications.6 In particular, several studies report a high prevalence of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients hospitalized with COVID-19.7–10 Thus, patients with COVID-19 are recognized as being at high risk for VTE occurrence. However, a recent surveillance questionnaire for COVID-19 and VTE in Japan has reported that the number of patients diagnosed as VTE in COVID-19 in Japan could be quite small compared with reports from other countries.11 It is unknown whether these results suggest under-diagnosis of VTE in COVID-19 or actual lower prevalence of VTE in Japan, and there is still quite limited data on the current status of VTE in patients with COVID-19 in Japan. These issues could be critically important to the establishment of optimal strategies for prevention and treatment of VTE in patients with COVID-19 in Japan. Considering the clinical relevance of the issue, it is important to investigate the clinical features of VTE patients with COVID-19 in Japan. Thus, we conducted a case series study of VTE patients with COVID-19 to clarify the clinical characteristics, management strategies, and outcomes of these patients.
A surveillance questionnaire for COVID-19 and VTE from the Japanese Society of Phlebology and Japanese Society of Pulmonary Embolism Research revealed that 7 patients developed VTE among 1,243 patients hospitalized with COVID-19 at 77 institutions in Japan from March 2020 to June 2020.11 Based on this questionnaire, we requested the detailed patient data from each institution, and we collected 5 patients’ data using an electronic report form. In this retrospective case series, patients were included if they were diagnosed as VTE after they had tested positive for COVID-19. The patients’ characteristics and follow-up information were collected from hospital charts or hospital databases according to the prespecified definitions. The physicians at each institution were responsible for data entry into an electronic case report form. In addition, data were manually checked at the general office for missing or contradictory input and values out of the expected range.
Ethical IssuesAll procedures followed were in accordance with the Declaration of Helsinki. The relevant review board or ethics committee in all participating centers approved the research protocol. In the current retrospective case series study, written informed consent from each patient was waived because we used clinical information obtained in routine clinical practice. This method is concordant with the guidelines for epidemiological studies issued by the Ministry of Health, Labor, and Welfare in Japan.
The 5 patients’ characteristics are described in the Table. The median age was 54 years, and all patients were male. Median body weight was 87.7 kg, and median body mass index (BMI) was 27.7 kg/m2. All patients had comorbidities, such as hypertension, diabetes mellitus, and dyslipidemia.
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | |
|---|---|---|---|---|---|
| Baseline characteristics | |||||
| Age (years) | 59 | 51 | 44 | 71 | 54 |
| Sex | Male | Male | Male | Male | Male |
| Body weight (kg) | 70.6 | 98.0 | 136.0 | 60.0 | 87.7 |
| Height (cm) | 171 | 172 | 179 | 162 | 178 |
| Body mass index (kg/m2) |
24.1 | 33.1 | 42.4 | 22.9 | 27.7 |
| Comorbidities | HT, hyperuricemia |
DM | HT, DM, dyslipidemia, AF |
DM, dyslipidemia | HT, DM, IHD |
| On admission | |||||
| Hospitalization on admission |
General ward | General ward | General ward | General ward | ICU |
| D-dimer level on admission (μg/mL) |
3.6 | 1.8 | 1.1 | 0.5 | 0.6 |
| VTE prevention by anticoagulants |
Yes | No | Yes | No | No |
| Details of anticoagulant |
Unfractionated heparin |
– | Unfractionated heparin |
– | – |
| Worst severity of COVID-19 | |||||
| Need oxygen | Yes | Yes | Yes | Yes | Yes |
| Need mechanical ventilation | Yes | Yes | Yes | Yes | Yes |
| Need ECMO | No | No | No | No | No |
| Treatment for COVID-19 |
Ciclesonide | Sivelestat, favipiravir, methylprednisolone |
Favipiravir, nafamostat, immunoglobulins, steroid |
Hydroxychloroquine, azithromycin, tazobactam, piperacillin, budesonide formoterol fumarate, methylprednisolone, prednisolone, tulobuterol |
Favipiravir, steroid |
| Presentation of VTE | |||||
| Days from admission to VTE onset |
10 | 8 | 24 | 8 | 28 |
| VTE diagnosis | Outpatient ward | ICU | General ward | General ward | ICU |
| VTE type | PE with DVT | DVT only | PE without DVT | PE with DVT | DVT only |
| Severity of PE | Non-massive | – | Non-massive | Non-massive | – |
| Location of thrombus in DVT |
Proximal | Distal | – | Distal | Right subclavian vein (central catheter-related) |
| Treatment for VTE | |||||
| Initial anticoagulation therapy |
Rivaroxaban | Unfractionated heparin |
Rivaroxaban | Unfractionated heparin | Unfractionated heparin |
| Anticoagulation therapy at discharge |
Rivaroxaban | None | Rivaroxaban | – | Edoxaban |
| Prognosis at discharge |
Alive | Alive | Alive | Dead | Alive |
Severity of PE classified into 4 groups according to clinical severity: (1) cardiac arrest/collapse PE; (2) massive PE: shock and/or hypotension (systolic blood pressure <90 mmHg or a BP drop ≥40 mmHg for >15 min if not caused by new-onset arrhythmia, hypovolemia or sepsis); (3) submassive PE: hemodynamically stable with right ventricular dysfunction; and (4) non-massive PE: hemodynamically stable without right ventricular dysfunction. Proximal DVT defined as venous thrombosis located in the popliteal, femoral, or iliac vein. AF, atrial fibrillation; DM, diabetes mellitus; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; HT, Hypertension; ICU, intensive care unit; IHD, ischemic heart disease; PE, pulmonary embolism; VTE, venous thromboembolism.
The median D-dimer level on admission was 1.1 μg/mL (range 0.5–3.6 μg/mL). Anticoagulation as primary prevention of VTE with unfractionated heparin was prescribed for 2 of the 5 patients. As for the worst severity of COVID-19 during hospitalization, all patients required mechanical ventilation for respiratory support, but none received extracorporeal membrane oxygenation therapy. Treatment for COVID-19 varied widely for each patient and included use of ciclesonide, favipiravir, immunoglobulins, and steroid.
Presentation and Treatment of VTEThe median number of days from admission to VTE onset was 10 (range 8–28 days) (Table). Patients were diagnosed as VTE in the intensive care unit (ICU), general ward, and outpatient ward. Patients with PE with or without DVT accounted for 3 cases, and patients with only DVT accounted for 2 cases. As for the severity of PE, all were non-massive PEs (hemodynamically stable without right ventricular dysfunction). As for the location of thrombus in DVT, 1, 2, and 1 patient developed proximal DVT, distal DVT, and central catheter-related subclavian DVT, respectively. As initial anticoagulation therapy, 3 patients received unfractionated heparin, and 2 patients received rivaroxaban. Among the 5 patients, 1 patient died of a non-PE-related cause, and 4 patients were discharged alive, among whom 2, 1, and 1 patient received rivaroxaban, edoxaban, and no anticoagulants, respectively, at discharge.
Detailed VTE Presentation in Patients 1 and 3Patient 1 had a fever 9 days before admission and developed worsening dyspnea, and was admitted to the hospital with a diagnosis of pneumonia due to COVID-19. After admission, respiratory function deteriorated, and he received mechanical ventilation with primary prevention of VTE by anticoagulation with unfractionated heparin at 10,000 U/day. He was withdrawn from mechanical ventilation 7 days after admission, and discharged 14 days after admission. During hospitalization he developed swelling of his left lower limb, which did not improve after discharge. On revisiting hospital, and he was diagnosed as PE with proximal DVT by contrast-enhanced computed tomography (Figure 1).
Contrast-enhanced computed tomography of Patient 1 shows a thrombus (red arrows) in the left pulmonary artery (A), left superficial femoral vein (B), and in the left popliteal vein (C).
Patient 3 was admitted to hospital with a diagnosis of pneumonia due to COVID-19. He received mechanical ventilation with primary prevention of VTE by anticoagulation with unfractionated heparin at 10,000 U/day. During hospitalization, D-dimer levels increased gradually (10.6 μg/mL), and he underwent contrast-enhanced computed tomography for the purpose of evaluating the pneumonia as well as thrombosis, which revealed thrombus in both pulmonary arteries (Figure 2).
(A,B) Contrast-enhanced computed tomography of Patient 3 shows thrombus (red arrows) in both pulmonary arteries.
The main findings of the current case series study were: (1) VTE patients with COVID-19 seemed to have a relatively high BMI; (2) all patients required mechanical ventilation during hospitalization, and some of them developed VTE despite prevention with anticoagulants; and (3) some patients developed and were diagnosed with VTE in places other than the ICU.
Although all hospitalized patients are at risk of developing VTE, the risk differs according to each patient. A previous study reported that VTE patients with COVID-19 are mostly male (77%), with a high median BMI (30.2 kg/m2).8 Another study also reported a high prevalence of males (76%) and a high mean body weight (87 kg).9 Consistent with those previous reports, the current case series study in Japan also found that VTE patients with COVID-19 had a relatively high BMI. Obesity is a well-known risk factor for the development of VTE,12 and might be considered as an especially important risk factor for developing VTE in COVID-19 patients.
Previous studies report a high prevalence of VTE among patients hospitalized in the ICU.7–10 Furthermore, most of those patients received anticoagulants as VTE prevention. Thus, patients with severe conditions are thought to be at especially high risk of VTE despite administration of anticoagulants. In line with previous studies, the current case series study in Japan also showed that all patients required mechanical ventilation for respiratory support, as they were thought to be in a severe condition due to COVID-19. Now, based on the concept of a high risk of VTE in patients with COVID-19, primary prevention of VTE in COVID-19 by anticoagulants has been drawing attention. In fact, some studies report that use of anticoagulants was associated with reduced mortality in patients hospitalized with COVID-19,13,14 which was remarkable in patients with severe conditions. These results suggest the potential benefit of anticoagulants for the prevention of VTE in COVID-19, especially in patients with severe conditions such as those in ICU. Although several consensus statements recommend thromboprophylactic anticoagulants in all patients hospitalized due to COVID-19,15,16 the optimal strategies for the prevention of VTE in COVID-19, including appropriate candidates, intensity (prophylactic dose or treatment dose), and duration of anticoagulation therapy, still remain unknown, but should be revealed through further studies.
The risk of developing VTE in COVID-19 patients seems especially high in patients in the ICU.17 However, interestingly, in the current case series study some patients were diagnosed as VTE outside of the ICU, including general and outpatient wards. Patient 1 was diagnosed as PE with proximal DVT after discharge, although he had suspected DVT symptoms during hospitalization. Due to the risk of infection to healthcare providers, it might be more difficult to conduct imaging examinations, which could lead to under-diagnosis of VTE in COVID-19 patients. However, clinicians need to know that patients with COVID-19 can develop VTE even after leaving the ICU.
As a future perspective, further studies in Japan, including cohort/registry-based studies, are warranted to confirm these results. Currently, a registry-based study focusing on patients with COVID-19 assessed by imaging examinations in Japan is ongoing (UMIN000042235: Venous Thromboembolism in Patients with COVID-19 in Japan Study).
The current case series study revealed some clinical features of VTE patients with COVID-19 in Japan, including those who are obese and those requiring mechanical ventilation during hospitalization, who need careful monitoring for VTE even after leaving the ICU.
We appreciate the support and collaboration of the Japanese Society of Phlebology (JSP) and the Japanese Society of Pulmonary Embolism Research (JaSPER) during the current study.
T.K. has received honorariums for lectures from Nippon Covidien Ltd. All other authors report no relationships relevant to the contents of this paper.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
T.K. has received honorariums for lectures from Nippon Covidien Ltd. All other authors report no relationships relevant to the contents of this paper. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
The relevant review boards or ethics committees in all participating centers approved the research protocol. The ethics committee of the primary institution was the Ethics Committee of Kuwana City Medical Center (approval no. 2020-168).
