What are the risk factors and effectiveness of prophylaxis for venous thromboembolism in COVID-19 patients?
July 10, 2020
Ashleigh Kernohan¹, Maria Calderon²
On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
¹ Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4AX
² Department of Infection and Tropical Medicine, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, NE1 4LP
Correspondence to firstname.lastname@example.org
This study identified a paucity of evidence for both the risks factors of VTE and the effectiveness of prophylactic strategies to prevent VTE in COVID-19 patients.
Potential risk factors which were identified for thrombolytic events include older age and higher levels of D-dimer, though the actual threshold for a high level D-dimer varied between studies.
Commonly encountered prophylactic strategies which were; low molecular weight heparin (LMWH) or unfractionned heparin, nadroparin and enoxaparin. A number of studies found that despite prophylaxis there was still a high incidence of thrombolytic complications in COVID-19 patients, which led a number of reviews to suggest earlier prophylaxis and in higher doses.
An emerging issue in the management of the novel COVID-19 coronavirus is morbidity and mortality associated with venous thrombolytic events. Apart from respiratory failure, coagulopathy is a common abnormality in patients with COVID‐19, with elevated levels of both fibrinogen and D‐dimer. For example, Oudkerk at al noted a number of case studies describing thrombolytic events in COVID-19 patients in their report, raising concerns about this issue.  When considering management advice for patients with COVID-19 it is important to consider two factors. Firstly, what are the risk factors associated with thrombolytic events in COVID-19 patients? Secondly, what are the optimal strategies for prophylaxis and treatments for thrombolytic events in this patient groups?
Understanding the current evidence for both risk factors and management strategies for venous thrombolytic events (VTE) in the these groups will aid clinical decision making. To contribute to this knowledge base, we conducted a rapid literature review using a systematic search method to identify relevant studies in relation to risk factors or managements of VTEs.
Studies included in this review were primary studies which assess risks and management of thrombolytic events in COVID-19 patients. The following search strategy was applied to Medline and EMBASE on 07/05/2020 with no limits.
(“COVID-19” or COVID19 or COVID-19 or “coronavirus disease 2019” or “coronavirus disease-19” or “2019-nCoV disease” or “severe acute respiratory syndrome coronavirus 2” or “Wuhan coronavirus” or “COVID-19 virus” or “SARS-CoV-2” or “SARS2” or “2019-nCoV” or “2019 novel coronavirus” or “2019 novel coronavirus infection” AND (“D-dimer” or “coagulation parameter” or “venous thromboembolism” or “novel coronavirus pneumonia” or “blood coagulation” or “fibrin fibrinogen degradation products” or “vein thrombosis” or “thrombosis” or “lung embolism” or “PE” or “thromboembolism” or “venous thromboembolism” or “pulmonary embolism “).af.
The search returned 364 studied after duplicates were removed, of which 9 were included. Most of the studies which were included from France (4 studies) the other studies came from Italy (2 studies), China (1 study), the USA (1 study) and the Netherlands (1 study). Most studies were Retrospective case series, this includes Bozzani et al, Cui et al, Griffin et al, Klok et al, Leonard-Lorant et al, Llitjos et al, Poissy et al [2-8]. There was one retrospective cohort study, Lodigiani et al , and one prospective cohort study, Helms et al .
Risk Factors for Thromboembolism in COVID-19 Patients
One study Cui et al  found an incidence of VTE in patients with COVID-19 of 25% (20/81), 8 of which died. It was found that aged differed between the VTE and non VTE group of patients as VTE patients were generally older. VTE patients had an average age of 68.4 (± 9.1) whereas non-VTE patients had an average age of 57.1 (± 14.3 years, P < .001). Klok et al  also found evidence which supported age as a risk of thrombolytic events in their study showing results from 184 COVID-19 patients admitted to the ICU. The participants had an average age of 64 (±12) and the adjusted hazard ratio (aHR) for older age as a predictor of thrombotic complications was 1.05/per year (95%CI 1.004- 1.01).
Cui et al observed higher D-dimer (5.2 ± 3.0 versus 0.8 ± 1.2 µg/mL, P < .001) in the group that had VTE vs the group without VTE. Additionally, using 1.5 µg/mL as a cut off value, the study calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of D-dimer in predicting VTE in patients with severe COVID-19 disease which were 85.0%, 88.5%, 70.8%, and 94.7%, respectively. Leonard-Lorant et al also found an association between D-dimer and embolism in COVID-19 patients. The study included 106 COVID-19 patients who had CT scans, 32 of which were positive for acute pulmonary embolus. They found that patients with pulmonary embolus had higher D-dimer levels than those without pulmonary embolus (median, IQR 6110±4905 versus 1920±3674 µg/L, respectively, p<.001). Leonard-Lorant et al also estimated the sensitivity and specify of D-dimer levels, though the threshold for higher levels was higher than that used in Cui et al at 2660 µg/L. The sensitivity was 32/32 (100%, 95%CI 88-100) and a specificity of 49/74 (67%, 95% CI 52-79) for identification of pulmonary embolism based on CT angiography as a gold standard.
Other risk factors were identified in the individual studies. Cui et al noted that VTE patients also had lower lymphocyte counts (0.8 ± 0.4 versus 1.3 ± 0.6 × 109/L, P < .001) and longer APTT (39.9 ± 6.4 versus 35.6 ± 4.5 seconds, P = .001). Leonard-Lorant et al found that patients positive for embolisms on CT scans were more likely be attended in the intensive care unit (24/32 (75%) versus those not in the intensive care unit 24/74 (32%), p<.001). Klok et al found that coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 seconds or activated partial thromboplastin time > 5 seconds had an aHR of 4.1 (95%CI 1.9-9.1).
Benefits of prophylaxis strategies for VTE in COVID-19 Patients
A number of studies investigated the effects of different prophylactic strategies for embolisms in COVID-19 patients. Moreover, some of these found that despite of VTE prophylactic treatment in COVID-19 patients there was still a high incidence of thrombolytic events. For example Klok et al  analysed 184 ICU patients in three different hospitals. Patients were treated with three different thromboprophylaxis medications (which were given depending on which hospital they attended). This included; nadroparin 2850 IU sc per day, nadroparin 5700 IU per day if body weight > 100 kg or nadroparin 5700 IU per day. Despite these prophylaxis regimens, there was a 31% incidence of thrombotic complications in ICU patients with COVID-19. The authors recommend prophylaxis towards high-prophylactic doses to address this.
Helms et al found similar results in their prospective study of 150 consecutive COVID-19 patients and 233 non COVID-19 patients admitted to ICU with severe disease. Of the 150 COVID-19 patients 70 were given prophylactic treatments 4000 UI/day for low molecular weight heparin or if contra-indicated, unfractioned heparin at 5–8 U/kg/h. Study showed that 27(18%) patients experienced thromboembolic complications, namely pulmonary embolisms (N=25, 16.7%) and deep vein thrombosis (N=3, 2%). However, the non-COVID-19 group showed 14 thromboembolic complications (6%). The authors conclude that despite prophylactic anticoagulation, a high number of patients with severe COVID-19 develop life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.
Lodigiani et al  carried out a retrospective analysis of 388 patients COVID-19 at university hospital in Milan, Italy. Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward. In 362 cases (general ward=314, ICU=48 on the ICU), there was 28 (general ward=20, ICU=8) cases of thromboembolic events (a rate of 7.7%). Of the 28 thromboembolic patients 7 died. The authors conclude that thromboembolic events (particularly venous thrombolytic events) are high in COVID-19 patients and there is an urgent need to improve specific VTE diagnostic strategies as well as investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.
Griffin et al  did find that anticoagulation is associated with a decrease in mortality rates for COVID-19 patients, specifically using enoxaparin (40 mg/d subcutaneously). In contrast, Llitjos et al  retrospectively analysed the case records of 26 patients admitted to ICU with COVID-19, of which 8 had been treated with prophylactic anti-coagulation and 18 had been treated with therapeutic anti-coagulation treatments. In the study 18/26 had VTEs (69%). The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with the other group (100% vs 56%, respectively, P = .03). As such the authors suggest the importance of systematic screening of VTE and early therapeutic anticoagulation in severe COVID-19 patients. It should be noted that this is another study with a smaller sample than other studies described, only giving detail information of three patients..
The relatively low number of papers in this area suggests a paucity of evidence for risk factors and prophylaxis of thrombolytic events in COVID 19 patients. Of the available evidence on risk factors, the two factors which have the most evidence for being predictive of VTEs are older age and higher D-dimer levels. Other factors which have been associated with VTEs are lower lymphocyte counts, being admitted to ICU and prothrombin time > 3 seconds or activated partial thromboplastin time > 5 seconds.
The most commonly given prophylactic strategies which were; low molecular weight heparin (LMWH) or unfractionned heparin, nadroparin and enoxaparin. When considering the benefits of prophylaxis a number of studies found a high incidence of thrombolytic complications in COVID-19 patients even when prophylactic treatment had been given. Some studies recommended extra vigilance for VTE and earlier anticoagulation therapy. Further research is needed to quantify the risk factors of VTEs and the effectiveness of prophylactic treatments in COVID-19 patients.
Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.
- Oudkerk, M., et al., Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology, 2020: p. 201629.
- Bozzani, A., et al., SARSCoV-2 infection and the upper limbs deep vein thrombosis risk. Annals of vascular surgery, 2020.
- Cui, S., et al., Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis, 2020.
- Griffin, D.O., et al., Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease. Emerging infectious diseases, 2020. 26(8).
- Klok, F.A., et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research, 2020.
- Leonard-Lorant, I., et al., Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-Dimer Levels. Radiology, 2020: p. 201561.
- Llitjos, J.F., et al., High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. Journal of thrombosis and haemostasis : JTH, 2020.
- Poissy, J., et al., Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation, 2020.
- Lodigiani, C., et al., Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thrombosis Research, 2020. 191: p. 9-14.
- Helms, J., et al., High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive care medicine, 2020.