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Extremely High Incidence of Lower Extremity Deep Venous Thrombosis in 48 Patients With Severe COVID-19 in Wuhan

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.120.047407Circulation. 2020;142:181–183

The coronavirus disease 2019 (COVID-19) pandemic has caused >4 million infections and 280 000 deaths worldwide (as of May 13, 2020). The case fatality ratio in China (as of February 11, 2020) was 2.3%, but that number among hospitalized critical patients was 49.0%.1 The reason for the high case fatality ratio in critical patients with COVID-19 is not completely clear. During the 2002 severe acute respiratory syndrome pandemic, the incidences of deep vein thrombosis (DVT) and pulmonary embolism were 20.5% and 11.4% in autopsy cases.2 Whether thrombosis contributes to the high mortality of COVID-19 remains unclear. As the global fight against COVID-19 continues, our study examined how prevalent thrombosis formation is for patients with COVID-19.

A cross-sectional study was carried out in 2 hospitals in Wuhan, China, from February 29, 2020 to March 2, 2020. Patients were enrolled from the intensive care unit of Zhongnan Hospital of Wuhan University and Leishenshan Hospital, a newly constructed hospital designated for COVID-19 in Wuhan. Patients with confirmed COVID-19 in intensive care unit treatment (excluding patients with prior DVT or recent surgery) received compression ultrasound examinations in the lower extremities. The examinations were performed at least twice by the experienced sonographer team blinded to patient clinical history. Deep veins from the inguinal ligament to the ankle, including the femoral vein, popliteal vein, posterior tibial vein, peroneal vein, and intermuscular vein in the calf, were examined. Laboratory findings were gathered at the first assessment after patients were admitted to the intensive care unit. The study was approved by the Medical Ethical Committee of Zhongnan Hospital of Wuhan University (approval 2020031). Oral consent was obtained from patients or direct relatives.

For the enrolled 48 critically ill patients with COVID-19, the median age was 70 years (interquartile range, 62–80 years; Table). All but 1 patient (with coagulation contradiction) received 30 to 40 mg low-molecular-weight heparin (subcutaneous injection once daily) as anticoagulation. Lower extremity DVTs were detected in 41 patients (85.4%), with 36 (75%) isolated distal DVTs and 5 (10.4%) proximal DVT. The APACHE II (Acute Physiology and Chronic Health Evaluation II) score was 16 (9–24). In terms of comorbidities, the numbers of patients with hypertension, diabetes mellitus, previous cardiovascular disease, and previous cerebrovascular disease were 19 (39.6%), 13 (27.1%), 11 (22.9%), and 7 (14.6%), respectively. All patients exhibited abnormal levels of inflammatory indicators, including an elevation of neutrophil count and a reduction of lymphocyte count. Of the 29 patients who received mechanical ventilation, 18 had endotracheal intubation. The median levels of D-dimer in patients with no DVT, isolated distal DVT, and proximal DVT were 0.90 mg/L (0.51–3.10 mg/L), 5.31 mg/L (1.12–9.78 mg/L), and 3.53 mg/L (1.87–11.64 mg/L), respectively (P=0.09), which were above the superior limit. In terms of patient deaths, as of April 16, 2020, 2 patients (28.6%) in the no DVT group, 10 (27.8%) in the isolated distal DVT group, and 3 (60%) in the proximal DVT group died (P=0.43).

Table 1. Results of DVT Detection, Clinical Characteristics, Comorbidities, Laboratory Findings, and Outcomes in Patients With Severe COVID-19

Total
(n=48)
No DVT
(n=7, 14.6%)
Isolated Distal DVT* (n=36, 75%)Proximal DVT
(n=5, 10.4%)
P Value
Clinical characteristics, median (IQR)
 Age, y70 (62–80)66 (60–75)71 (63–80)66 (63–68)0.59
 Male, sex, n (%)26 (54.2)2 (28.6)21 (58.3)3 (60)0.45
 BMI ≥24 kg/m2, n (%)16 (33.3)2 (28.6)13 (36.1)1 (20)0.88
 APACHE II score16 (9–24)14 (7–16)16 (10–25)15 (9–22)0.34
 Mechanical ventilation, n (%)29 (60.4)4 (57.1)22 (61.1)3 (60)1.00
 Endotracheal intubation, n (%)18 (37.5)3 (42.9)13 (36.1)2 (40)1.00
 Patients with ipsilateral femoral venous catheters, n (%)7 (14.6)1 (14.3)5 (13.9)1 (20)0.82
 Interval between COVID-19 diagnosis and DVT diagnosis, d27 (19–34)27 (21–34)27 (19–29)0.84
 Interval between admission and DVT diagnosis, d23 (15–29)22 (15–30)24 (15–26)0.98
 Interval between ICU admission and DVT diagnosis, d12 (7–14)12 (8–14)7 (6–11)0.39
Comorbidities, n (%)
 Hypertension19 (39.6)3 (42.9)13 (36.1)3 (60)0.70
 Diabetes mellitus13 (27.1)2 (28.6)10 (27.8)1 (20)1.00
 Cardiovascular disease11 (22.9)1 (14.3)8 (22.2)2 (40)0.71
 Cerebrovascular disease7 (14.6)1 (14.3)5 (13.9)1 (20)0.82
Laboratory findings, median (IQR)
 D-dimer (NR: <0.55), mg/L3.48 (0.83–9.23)0.90 (0.51–3.10)5.31 (1.12–9.78)3.53 (1.87–11.64)0.09
 Fibrinogen (NR: 2–4), g/L4.05 (3.50–4.55)4.42 (3.93–4.89)4.05 (3.45–4.55)3.87 (3.50–4.23)0.66
 WBC count (NR: 3.5–9), ×109/L8.55 (5.57–11.16)8.97 (5.94–11.87)7.55 (5.48–11.12)10.40 (10.07–13.92)0.49
 Lymphocyte count (NR: 1.1–3.2), ×109/L0.53 (0.40–0.90)0.70 (0.36–0.90)0.53 (0.40–0.90)0.78 (0.51–0.85)0.91
 Neutrophil count (NR: 1.8–6.3), ×109/L6.91 (4.00–9.78)7.69 (4.96–9.89)6.91 (3.83–9.53)9.77 (8.63–12.36)0.41
 Hypersensitive troponin I (NR: <0.04), ng/mL0.031 (0.012–0.096)0.020 (0.015–0.038)0.040 (0.012–0.097)0.030 (0.012–0.088)0.78
Outcomes,§ n (%)
 Death15 (31.3)2 (28.6)10 (27.8)3 (60)0.43

APACHE II indicates Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; COVID-19, coronavirus disease 2019; DVT, deep venous thrombosis; ICU, intensive care unit; IQR, interquartile range; NR, normal range; and WBC, white blood cell.

*Patients with thrombosis only in the distal lower extremity (including the posterior tibial vein, peroneal vein, and intermuscular vein in the calf) were diagnosed as having isolated distal DVT.

†Patients with thrombosis in the femoral vein or popliteal vein were diagnosed as having proximal DVT.

P values indicated statistical difference between the no DVT, isolated distal DVT, and proximal DVT groups. P values for categorical variables were calculated with the Fisher exact test. P values for continuous variable were calculated with Kruskal-Wallis H test. P<0.05 was considered statistical different.

§Outcomes were observed until April 16, 2020, by which point all the enrolled patients were either discharged or dead.

In our investigation, the overall rate of developing DVT in patients receiving intensive care unit treatment for COVID-19 was much higher than what was shown previously. The Prophylaxis for Thromboembolism in Critical Care randomized trial showed that the rates of lower extremity VTE for patients receiving dalteparin and heparin as anticoagulation were 5.1% (96 of 1873) and 5.8% (109 of 1873). Even in critically ill patients with H1N1 infection, the incidence of lower extremity DVT was 12.7% (9 of 71).3

Severe infection and inflammation might be important contributors to the development of DVT in patients with severe COVID-19. The high level of neutrophilia counts may be related to the cytokine storm induced by virus infection. Coagulation activation could also have been associated with a sustained inflammatory response.4 Besides the infection itself, complete bed rest, mechanical ventilation, and venous catheterization are possible factors that contribute to the high risk of thrombosis observed in the critically ill patients with COVID-19.

We found in our study that the majority of the thrombi were detected in the distal part of the lower extremity, whereas only 10.4% were in the proximal lower limb deep veins. The low incidence of proximal DVT may be attributed to low-molecular-weight heparin as prophylactic anticoagulation during hospitalization. Although the risk of pulmonary embolism caused by distal DVT is lower than that of proximal DVT, the literature also indicates that most of the thrombi originating in the calf tend to spread upward.5 Therefore, the clinical relevance of distal DVT should not be ignored.

Our study is limited by several factors. We have a small sample size of critically ill patients with COVID-19. Furthermore, the cross-sectional study design limits the interpretation of a causal relation between COVID-19 and DVT.

In conclusion, we found an extremely high incidence of lower extremity DVT in critically ill patients with COVID-19. More attention should be paid to the prevention and clinical management of pulmonary embolism and DVT. Timely evaluation of DVT and preventive measures against pulmonary embolism are necessary to treat patients with severe COVID-19.

Acknowledgments

Drs Ren and Cai had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: F. Yan, B. Ren, M. Wu, L. Cai. Data acquisition and analysis: S. Zhang, Z. Deng, L. Xiao. Interpretation of results: Z. Deng, S. Zhang. Statistical analysis: S. Zhang, L. Xiao. Drafting of the manuscript: B. Ren, F. Yan, Z. Deng, S. Zhang. Critical revision of the manuscript and approval of the final version: B. Ren, F. Yan, Z. Deng, S. Zhang, M. Wu, L. Cai.

Footnotes

*Drs Ren, Yan, Deng, and Zhang contributed equally.

†Drs Wu and Cai contributed equally.

https://www.ahajournals.org/journal/circ

The data that support the findings of this study are available from the corresponding author on reasonable request.

Meng Wu, MD, Department of Ultrasound, Zhongnan Hospital of Wuhan University, No. 169, Donghu Rd, Wuhan, Hubei Province, China. Email
Lin Cai, MD, Department of Orthopedics, Zhongnan Hospital of Wuhan University, No. 169, Donghu Rd, Wuhan, Hubei Province, China. Email

References

  • 1. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention [published online February 24, 2020].JAMA. 2020. doi: 10.1001/jama.2020.2648CrossrefGoogle Scholar
  • 2. Chong PY, Chui P, Ling AE, Franks TJ, Tai DY, Leo YS, Kaw GJ, Wansaicheong G, Chan KP, Ean Oon LL, et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis.Arch Pathol Lab Med. 2004; 128:195–204. doi: 10.1043/1543-2165(2004)128<195:AODDTS>2.0.CO;2CrossrefMedlineGoogle Scholar
  • 3. Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, Henke PK, Napolitano LM. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients.J Vasc Surg Venous Lymphat Disord. 2019; 7:317–324. doi: 10.1016/j.jvsv.2018.08.010CrossrefMedlineGoogle Scholar
  • 4. Beristain-Covarrubias N, Perez-Toledo M, Thomas MR, Henderson IR, Watson SP, Cunningham AF. Understanding infection-induced thrombosis: lessons learned from animal models.Front Immunol. 2019; 10:2569. doi: 10.3389/fimmu.2019.02569CrossrefMedlineGoogle Scholar
  • 5. Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis: implications for simplifying the diagnostic process with compression ultrasound.Arch Intern Med. 1993; 153:2777–2780.CrossrefMedlineGoogle Scholar

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