COVID-19 is associated with a high incidence of venous thromboembolism, blood clots in the venous circulation, according to a study conducted by researchers at Brighton and Sussex Medical School (BSMS), UK.
In a series of 274 consecutive cases of COVID-19 admitted to hospital, a significant percentage (7.7%) were diagnosed with venous thromboembolism.
The most common type of venous thromboembolism, seen in 76.2% of these cases, was pulmonary embolism, a blood clot on the lungs.
The research team found that the D-dimer blood test was useful to identify those patients at highest risk of venous thromboembolism when admitted to hospital.
Lead author, Dr. Chi Eziefula, Senior Lecturer in Infection at BSMS, said: “Identifying which patients have a risk of, and clinical evidence of, a venous thromboembolism in COVID-19 is highly important for two reasons.
Firstly, because venous thromboembolism is linked to a risk of death and secondly because it is treatable with anticoagulant medications.”
Dr. Tim Chevassut, Reader in Haematology at BSMS, said: “This study signals the importance of further research to explore the pathological mechanisms specific to COVID-19.
It also highlights the urgent need for clinical trials to evaluate the role of anticoagulation treatment for the prevention of deaths and morbidity from COVID-19 infection.”
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a new type of respiratory transmitted virus. By mid‐March 2020, it had sickened more than 80 000 people and killed more than 3000 in China, triggering a global pandemic.
A number of studies have shown that coagulation dysfunction exists in patients with severe novel coronavirus pneumonia (NCP),1-4 which is clearly correlated with poor prognosis.3 The conventional coagulation parameters of intensive care unit (ICU) patients were significantly higher than those of non‐ICU patients.2
However, the prevalence of venous thromboembolism (VTE) in ICU patients with severe NCP is unknown. Therefore, the purpose of this study was to explore the incidence of VTE in such patients and to investigate the differences between VTE patients and non‐VTE patients.
A total of 81 patients diagnosed with NCP in the ICU of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 30 to March 22, 2020, were included.
All the patients were diagnosed according to the World Health Organization guidelines.5 The severity of NCP was judged according to the Fifth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance.6
The patients were subjected to a series of investigations, including clinical examinations, laboratory tests, chest computed tomography (CT), lower limb venous doppler ultrasound, and real‐time reverse transcriptase polymerase chain reaction (rRT‐PCR) for SARS‐CoV‐2.
All the patients received antiviral and supportive treatment after diagnosis, and no preventive anticoagulant was administered. The study was approved by the Ethics Committee of Union Hospital (Wuhan, China).
Conventional coagulation tests, which included prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), international normalized ratio (INR), fibrinogen (FIB), and D‐dimer were performed using a Succeeder SF8200 automatic coagulation analyzer (China). Clinical and laboratory information was also collected.
Data are presented as means ± standard deviation (SD) or number (percentage) where appropriate. T test or Mann‐Whitney U test were used to analyze the differences between the two groups. P < .05 was defined as statistically significant. Statistical analysis was conducted using SPSS software version 21.0 (IBM).
RESULTS AND DISCUSSION
A total of 81 patients with severe NCP were enrolled in this study, with the mean age of 59.9 years (range, 32‐91 years), including 44 females (54%). Thirty‐three (41%) patients had chronic medical illness, including hypertension, diabetes, and coronary heart disease; 35 (43%) patients had a history of smoking. As of 22 March, 64 (79%) patients had been discharged from hospital, 8 (10%) had died, and the rest (9; 11%) remained hospitalized (Table 1).
Table 1. Baseline characteristics of NCP patients (n = 81)
|Characteristic||Number (%) or mean (SD)|
|Age, years||59.9 (14.1)|
|Chronic medical illness|
|Coronary heart disease||10 (12%)|
|Remained in hospital||9 (11%)|
- Abbreviation: NCP, novel coronavirus pneumonia; SD, standard deviation.
A total of 20 (25%) patients with severe NCP developed lower extremity venous thrombosis, of which 8 patients died. The VTE group had older age (68.4 ± 9.1 versus 57.1 ± 14.3 years, P < .001), lower lymphocyte counts (0.8 ± 0.4 versus 1.3 ± 0.6 × 109/L, P < .001), longer APTT (39.9 ± 6.4 versus 35.6 ± 4.5 seconds, P = .001), and higher D‐dimer (5.2 ± 3.0 versus 0.8 ± 1.2 µg/mL, P < .001). Moreover, the D‐dimer of the two groups was not within the normal range (Table 2).Table 2. Characteristics between the VTE and non‐VTE groups (n = 81)
|Characteristics||Normal range||VTE (n = 20)||Non‐VTE (n = 61)||P‐value|
|Age (years)||‐||68.4 ± 9.1||57.1 ± 14.3||<.001|
|Leucocytes (×109/L)||3.5‐9.5||7.8 ± 3.1||6.6 ± 2.6||.120|
|Lymphocytes (×109/L)||1.1‐3.2||0.8 ± 0.4||1.3 ± 0.6||<.001|
|Platelets (×109/L)||125.0‐350.0||246.6 ± 110.6||248.8 ± 111.7||.938|
|Haemoglobin (g/L)||115.0‐150.0||123.2 ± 16.5||125.3 ± 16.7||.633|
|APTT (s)||27.0‐45.0||39.9 ± 6.4||35.6 ± 4.5||.001|
|Prothrombin time (s)||11.0‐16.0||15.4 ± 1.0||15.6 ± 1.0||.465|
|D‐dimer (µg/mL)||0.0‐0.5||5.2 ± 3.0||0.8 ± 1.2||<.001|
- Abbreviation: APTT, activated partial thromboplastin time; VTE, venous thromboembolism.
Table 3 shows the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of different D‐dimer levels in predicting VTE in patients with severe NCP. If 1.5 µg/mL was used as the cut‐off value for D‐dimer to predict VTE, the sensitivity, specificity, PPV, and NPV were 85.0%, 88.5%, 70.8%, and 94.7%, respectively (Table 3).Table 3. Sensitivity, specificity, PPV, and NPV of different D‐dimer cut‐off levels for predicting VTE in NCP patients
|Cut‐off (µg/mL)||Sensitivity (%)||Specificity (%)||PPV (%)||NPV (%)|
- Abbreviation: NCP, novel coronavirus pneumonia; NPV, negative predictive value; PPV, positive predictive value; VTE, venous thromboembolism.
In this study, the decrease of lymphocytes was common in patients with NCP, especially in patients with VTE. Other studies have also observed that infection with SARS‐CoV‐2 leads to lymphocytopenia.2, 7, 8
In the analysis of lymphocyte subset, T cells were more susceptible to SARS‐CoV‐2, because T cell count was almost half of the lower reference limit, and the severe NCP patients were more likely to be hampered.8
Moreover, abnormal expression of T cell associated mRNA can lead to VTE.9
This meant that older patients with more underlying diseases were more likely to develop immune dysfunction and have a higher risk of VTE because of their poor immunity.
Severe SARS‐CoV‐2 infection in NCP patients can lead to sepsis, which can also lead to the release of inflammatory cytokines such as IL‐6, IL‐8, TNF‐α, etc,8 similar to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).10, 11
Inflammatory cytokines can promote the activation of blood coagulation in many ways, and then promote the occurrence of VTE.12-14 Sepsis is also a common cause of disseminated intravascular coagulation (DIC)15 and the incidence of DIC in dead NCP patients was 71.4%.3
This suggests that abnormal blood coagulation and thrombosis are associated with poor prognosis in patients with NCP.
Elevated D‐dimer level is a sign of excessive coagulation activation and hyperfibrinolysis. Therefore, D‐dimer is often used to detect active thrombus with high sensitivity but low specificity.16 But, if 3.0 µg/mL was used as the cut‐off value, the sensitivity, specificity, and NPV were 76.9%, 94.9%, and 92.5%, respectively.
After receiving anticoagulant therapy, the level of D‐dimer decreased gradually, which means that D‐dimer can not only predict thrombosis but also monitor the effectiveness of anticoagulants.
There are several limitations in our report. First, this is a retrospective, single‐center, small sample study. The results may be biased and need to be confirmed by a large sample study. Second, some patients are still being treated in hospital, and the clinical outcome may change.
Despite that, our study described the incidence of VTE in patients with severe NCP and demonstrated the application of D‐dimer in VTE prediction. We hope that these results will contribute to the prevention, diagnosis, and treatment of VTE.
University of Sussex
- 1Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395: 507‐ 513.Crossref CAS PubMed Web of Science®Google Scholar
- 2Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China. Lancet. 2020; 395: 497‐ 506.Crossref CAS PubMed Web of Science®Google Scholar
- 3Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18: 844– 847.Wiley Online Library CAS PubMed Web of Science®Google Scholar
- 4Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS‐CoV‐2 infection. Clin Chem Lab Med. 2020; Epub ahead of print. https://doi.org/10.1515/cclm‐2020‐0188Crossref Google Scholar
- 5 WHO. Laboratory testing for 2019 novel coronavirus (2019‐nCoV) in suspected human cases. Interim guidance. 2020. https://www.who.int/publications‐detail/laboratory‐testing‐for‐2019‐novel‐coronavirus‐in‐suspectedhuman‐cases‐20200117.Google Scholar
- 6 The fifth revised trial version of the novel coronavirus pneumonia diagnosis and treatment guidance. http://www.nhc.gov.cn/yzygj/s7652m/202002/41c3142b38b84ec4a748e60773cf9d4f.shtmlGoogle Scholar
- 7Wang D, Hu B, Hu C, et al. Novel coronavirus‐infected pneumonia in Wuhan, China. JAMA. 2019; 2020;e201585. https://doi.org/10.1001/jama.2020.1585Google Scholar
- 8Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID‐19 in Wuhan. China. Clin Infect Dis. 2020; ciaa248. https://doi.org/10.1093/cid/ciaa248Crossref PubMed Google Scholar
- 9Duan Q, Gong Z, Song H, et al. Symptomatic venous thromboembolism is a disease related to infection and immune dysfunction. Int J Med Sci. 2012; 9: 453‐ 461.Crossref CAS PubMed Web of Science®Google Scholar
- 10Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136: 95‐ 103.Wiley Online Library CAS PubMed Web of Science®Google Scholar
- 11Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS‐CoV infection in humans is associated with a pro‐inflammatory Th1 and Th17 cytokine profile. Cytokine. 2018; 104: 8‐ 13.Crossref CAS PubMed Web of Science®Google Scholar
- 12Opal SM. Interactions between coagulation and inflammation. Scand J Infect Dis. 2003; 35: 545‐ 554.Crossref CAS PubMed Web of Science®Google Scholar
- 13Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004; 109: 2698‐ 2704.Crossref PubMed Web of Science®Google Scholar
- 14van der Poll T, Levi M. Crosstalk between inflammation and coagulation: the lessons of sepsis. Curr Vasc Pharmacol. 2012; 10: 632‐ 638.Crossref PubMed Web of Science®Google Scholar
- 15Iba T, Thachil J. Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis‐associated disseminated intravascular coagulation: a perspective from Japan. Int J Hematol. 2016; 103: 253‐ 261.Crossref CAS PubMed Web of Science®Google Scholar
- 16Koch V, Biener M, Muller‐Hennessen M, et al. Diagnostic performance of D‐dimer in predicting venous thromboembolism and acute aortic dissection. Eur Heart J Acute Cardiovasc Care. 2020:2048872620907322. https://doi.org/10.1177/2048872620907322Crossref Web of Science®Google Scholar