Review Article

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Ann Phlebology 2022; 20(1): 6-8

Published online June 30, 2022

https://doi.org/10.37923/phle.2022.20.1.6

© Annals of phlebology

Usefulness of D-Dimer for DVT Diagnosis in COVID-19 Patients

Chung Won Lee, M.D., Ph.D.

Department of Thoracic and Cardiovascular Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

Correspondence to : Chung Won Lee, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea, Department of Thoracic and Cardiovascular Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine
Tel: 02-51-240-7295, Fax: 02-51-243-9389
E-mail: vasculardoctorlee@gmail.com

COVID-19, a pandemic currently, is known to cause hypercoagulability, but may cause deep vein thrombosis (DVT). Generally, D-dimer is useful for diagnosing DVT, but in COVID-19 patients, there is a high possibility of false positives due to the accompanying infection. A literature review revealed that D-dimer levels are elevated in patients with COVID-19. Therefore, a new D-dimer cutoff value for DVT in COVID-19 is needed. Higher D-dimer levels in COVID-19 patients are significantly associated with disease progression.

Keywords Deep vein thrombosis, COVID-19, D-dimer, Thrombosis, Coronavirus

COVID-19 has been a pandemic since December 2019. According to a WHO report, in April 2022, more than 500 million people worldwide were confirmed to be COVID-19 positive, and more than 6 million deaths were reported. COVID-19 can cause hypercoagulation due to endothelial damage, which can lead to pulmonary embolism (PE) or deep vein thrombosis (DVT), resulting in a poor prognosis (1,2). Early diagnosis of DVT using ultrasound can help with treatment but using ultrasound for all patients is practically difficult as the number of patients is too high, number of examiners is limited, and disinfection of ultrasound machines is a problem.

As degradation products of fibrin, D-dimers are typically used in the diagnosis of PE and DVT. However, diagnosing DVT with D-dimers is problematic as it shows false positives in cases of infection, pregnancy, malignancy, post surgery, renal disease, heart disease etc. (3). Therefore, it can yield false-positive results for COVID-19 patients as well. In this study, the author has reviewed the literature on the usefulness of D-dimer for DVT diagnosis in COVID-19 and the relevance of D-dimer in COVID-19 patients.

There are many reports of DVT in patients with COVID-19 (4-9). A systematic review of 27 studies with 3342 patients (10) revealed a DVT incidence of 14.8% (95% confidence interval [CI]: 8.5, 24.5; I2=0.94). Studies on patients admitted to the intensive care unit (ICU) or critically ill patients reported a higher incidence of DVT than those on patients not admitted to the ICU or those with various levels of disease severity (21.2% [95% CI: 11.1, 36.8] vs 7.4% [95% CI: 3.2, 16.2]).

Recently, guidelines have recommended standard-dose anticoagulant prophylaxis for critically ill patients with COVID-19 (11). However, despite prophylactic anticoagula-tion, the incidence of DVT remains high in COVID-19 patients. Further research is needed on the anticoagulation strategy for DVT prevention in COVID-19 patients.

Most patients with COVID-19 showed an increase in the D-dimer level regardless of DVT. According to Cho et al. (12), 52 of 158 patients were diagnosed with DVT, all patients had elevated levels of D-dimer using conventional criteria, and 154 of the 158 (97.5%) patients had elevated levels at age-adjusted criteria as well. They reported that an optimal D-dimer cutoff of 6.494 µg/ml was determined to differentiate those with and without DVT. Calculated sensitivity, specificity, and negative predictive value (NPV) for this new cutoff were 80.8%, 68.9%, and 88.0%, respectively (12).

According to Cui et al. (13), when 20 COVID-19 patients with venous thromboembolism (VTE) and 61 COVID-19 patients without VTE were compared, the VTE group had a higher D-dimer (5.2±3.0 versus 0.8±1.2 mg/ml, p<.001) level. Moreover, the D-dimer level of the two groups was not within the reference range. D-dimer levels gradually decreased after anticoagulant therapy. The authors analyzed that sensitivity, specificity, and NPV vary depending on which cutoff value is determined. If 1.0 mg/ml was used as the D-dimer cutoff value to predict VTE, the sensitivity was 85.0%, specificity was 77.0%, and NPV was 94.0%. However, if 3.0 mg/ml was used as the cutoff value, the sensitivity, specificity, and NPV were 76.9%, 94.9%, and 92.5%, respectively (13).

It is less useful in COVID-19 patients to exclude DVT with a conventional cutoff value, warranting a new cutoff value. However, even after analyzing many studies, it is difficult to determine a usable cutoff value because the measurement time points of D-dimer levels are not constant, and the units of measurement are different (D-dimer unit or fibrinogen equivalent unit).

Several studies have reported that an increased D-dimer level is directly related to disease severity and progression and high mortality outcomes in COVID-19 (14-20). According to a systematic review by Rostami et al. (18), the mean D-dimer level was registered to be 0.58 mg/ml in 1551 patients with mild disease and 3.55 mg/ml in 708 patients with severe disease.

In a meta-analysis conducted by Varikasuvu et al. (19), across 68 unadjusted (n=26,960) and 39 adjusted studies (n=15,653) reporting on initial D-dimer levels, a significant association was found in patients with higher D-dimer levels for the risk of overall disease progression (unadjusted odds ratio 3.15; adjusted odds ratio 1.64). The time-to-event outcomes were pooled across 19 unadjusted (n=9,743) and 21 adjusted studies (n=13,287), and a strong association was found in patients with higher D-dimer levels for the risk of overall disease progression (unadjusted hazard ratio 1.41; adjusted hazard ratio 1.10). The prognostic use of higher D-dimer levels was found to be promising for predicting overall progression (studies 68, area under curve 0.75) of COVID-19.

Zhan et al. (20) analyzed 29 studies and reported that the pooled sensitivity of the prognostic performance of D-dimer for the severity, mortality, and VTE in COVID-19 were 77% (95% CI: 73%∼80%), 75% (95% CI: 65%∼82%), and 90% (95% CI: 90%∼90%) respectively, and the specificity was 71% (95% CI: 64%∼77%), 83% (95% CI: 77%∼87%), and 60% (95% CI: 60%∼60%). D-dimer levels can predict severe and fatal progression of COVID-19 with moderate accuracy.

Since D-dimer levels are elevated in patients with COVID-19, it is difficult to screen for DVT by applying a traditional cutoff. Although D-dimer levels are limited in diagnosing DVT in patients with COVID-19, higher D-dimer levels in this patient group are significantly associated with disease progression. Further research is needed on the correlation between DVT and D-dimer levels in COVID-19 patients.

This paper was presented at the 42nd Conference of the Korean Society for Phlebology on April 17, 2022. This work was supported by clinical research grant from Pusan National University Hospital in 2022.

  1. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-7.
  2. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18:1738-42.
  3. Kim H, Yun SS. Clinical Application of D-Dimer in Venous Thromboembolism. Ann Phlebology. 2020;18:4-7.
  4. Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136:489-500.
  5. Artifoni M, Danic G, Gautier G, Gicquel P, Boutoille D, Raffi F, et al. Systematic assessment of venous throm-boembolism in COVID-19 patients receiving thrombopro-phylaxis: incidence and role of D-dimer as predictive factors. J Thromb Thrombolysis. 2020;50:211-6.
  6. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18:1995-2002.
  7. Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID- 19 patients. J Thromb Haemost. 2020;18:1743-6.
  8. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14.
  9. Maatman TK, Jalali F, Feizpour C, Douglas A 2nd, McGuire SP, Kinnaman G, et al. Routine venous throm-boembolism prophylaxis may be inadequate in the hyper-coagulable state of severe coronavirus disease 2019. Crit Care Med. 2020;48:e783-90.
  10. Suh YJ, Hong H, Ohana M, Bompard F, Revel MP, Valle C, et al. Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis. Radiology. 2021;298:E70-80.
  11. Moores LK, Tritschler T, Brosnahan S, Carrier M, Collen JF, Doerschug K, et al. Thromboprophylaxis in Patients With COVID-19 A Brief Update to the CHEST Guideline and Expert Panel Report. Chest. 2022;12:S0012-3692(22)00250-1.
  12. Cho ES, McClelland PH, Cheng O, Kim Y, Hu J, Zenilman ME, et al. Utility of d-dimer for diagnosis of deep vein thrombosis in coronavirus disease-19 infection. J Vasc Surg Venous Lymphat Disord. 2021;9:47-53.
  13. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel corona-virus pneumonia. J Thromb Haemost:1421-4.
  14. Li Y, Zhao K, Wei H, Chen W, Wang W, Jia L, et al. Dynamic relationship between D-dimer and COVID-19 severity. Br J Haematol. 2020;190:e24-7.
  15. Liu J, Zhang S, Wu Z, Shang Y, Dong X, Li G, et al. Clinical outcomes of COVID-19 in Wuhan, China: A large cohort study. Ann Intensive Care. 2020;10:99.
  16. Hanif A, Khan S, Mantri N, Hanif S, Saleh M, Alla Y, et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: A New York City hospital experience. Ann Hematol. 2020;99:2323-8.
  17. Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care. 2020;8:49.
  18. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol. 2020;13:1265-75.
  19. Varikasuvu SR, Varshney S, Dutt N, Munikumar M, Asfahan S, Kulkarni PP, et al. D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies. Sci Rep. 2021;11:21888.
  20. Zhan H, Chen H, Liu C, Cheng L, Yan S, Li H, et al. Diagnostic Value of D-Dimer in COVID-19: A Meta- Analysis and Meta-Regression. Clin Appl Thromb Hemost. 2021;27:10760296211010976.

Review Article

Ann Phlebology 2022; 20(1): 6-8

Published online June 30, 2022 https://doi.org/10.37923/phle.2022.20.1.6

Copyright © Annals of phlebology.

Usefulness of D-Dimer for DVT Diagnosis in COVID-19 Patients

Chung Won Lee, M.D., Ph.D.

Department of Thoracic and Cardiovascular Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

Correspondence to:Chung Won Lee, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea, Department of Thoracic and Cardiovascular Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine
Tel: 02-51-240-7295, Fax: 02-51-243-9389
E-mail: vasculardoctorlee@gmail.com

Abstract

COVID-19, a pandemic currently, is known to cause hypercoagulability, but may cause deep vein thrombosis (DVT). Generally, D-dimer is useful for diagnosing DVT, but in COVID-19 patients, there is a high possibility of false positives due to the accompanying infection. A literature review revealed that D-dimer levels are elevated in patients with COVID-19. Therefore, a new D-dimer cutoff value for DVT in COVID-19 is needed. Higher D-dimer levels in COVID-19 patients are significantly associated with disease progression.

Keywords: Deep vein thrombosis, COVID-19, D-dimer, Thrombosis, Coronavirus

INTRODUCTION

COVID-19 has been a pandemic since December 2019. According to a WHO report, in April 2022, more than 500 million people worldwide were confirmed to be COVID-19 positive, and more than 6 million deaths were reported. COVID-19 can cause hypercoagulation due to endothelial damage, which can lead to pulmonary embolism (PE) or deep vein thrombosis (DVT), resulting in a poor prognosis (1,2). Early diagnosis of DVT using ultrasound can help with treatment but using ultrasound for all patients is practically difficult as the number of patients is too high, number of examiners is limited, and disinfection of ultrasound machines is a problem.

As degradation products of fibrin, D-dimers are typically used in the diagnosis of PE and DVT. However, diagnosing DVT with D-dimers is problematic as it shows false positives in cases of infection, pregnancy, malignancy, post surgery, renal disease, heart disease etc. (3). Therefore, it can yield false-positive results for COVID-19 patients as well. In this study, the author has reviewed the literature on the usefulness of D-dimer for DVT diagnosis in COVID-19 and the relevance of D-dimer in COVID-19 patients.

DVT INCIDENCE IN COVID-19 DISEASE

There are many reports of DVT in patients with COVID-19 (4-9). A systematic review of 27 studies with 3342 patients (10) revealed a DVT incidence of 14.8% (95% confidence interval [CI]: 8.5, 24.5; I2=0.94). Studies on patients admitted to the intensive care unit (ICU) or critically ill patients reported a higher incidence of DVT than those on patients not admitted to the ICU or those with various levels of disease severity (21.2% [95% CI: 11.1, 36.8] vs 7.4% [95% CI: 3.2, 16.2]).

Recently, guidelines have recommended standard-dose anticoagulant prophylaxis for critically ill patients with COVID-19 (11). However, despite prophylactic anticoagula-tion, the incidence of DVT remains high in COVID-19 patients. Further research is needed on the anticoagulation strategy for DVT prevention in COVID-19 patients.

D-DIMER IN DVT PATIENTS WITH COVID-19

Most patients with COVID-19 showed an increase in the D-dimer level regardless of DVT. According to Cho et al. (12), 52 of 158 patients were diagnosed with DVT, all patients had elevated levels of D-dimer using conventional criteria, and 154 of the 158 (97.5%) patients had elevated levels at age-adjusted criteria as well. They reported that an optimal D-dimer cutoff of 6.494 µg/ml was determined to differentiate those with and without DVT. Calculated sensitivity, specificity, and negative predictive value (NPV) for this new cutoff were 80.8%, 68.9%, and 88.0%, respectively (12).

According to Cui et al. (13), when 20 COVID-19 patients with venous thromboembolism (VTE) and 61 COVID-19 patients without VTE were compared, the VTE group had a higher D-dimer (5.2±3.0 versus 0.8±1.2 mg/ml, p<.001) level. Moreover, the D-dimer level of the two groups was not within the reference range. D-dimer levels gradually decreased after anticoagulant therapy. The authors analyzed that sensitivity, specificity, and NPV vary depending on which cutoff value is determined. If 1.0 mg/ml was used as the D-dimer cutoff value to predict VTE, the sensitivity was 85.0%, specificity was 77.0%, and NPV was 94.0%. However, if 3.0 mg/ml was used as the cutoff value, the sensitivity, specificity, and NPV were 76.9%, 94.9%, and 92.5%, respectively (13).

It is less useful in COVID-19 patients to exclude DVT with a conventional cutoff value, warranting a new cutoff value. However, even after analyzing many studies, it is difficult to determine a usable cutoff value because the measurement time points of D-dimer levels are not constant, and the units of measurement are different (D-dimer unit or fibrinogen equivalent unit).

ELEVATED D-DIMER LEVEL AND COVID-19 SEVERITY

Several studies have reported that an increased D-dimer level is directly related to disease severity and progression and high mortality outcomes in COVID-19 (14-20). According to a systematic review by Rostami et al. (18), the mean D-dimer level was registered to be 0.58 mg/ml in 1551 patients with mild disease and 3.55 mg/ml in 708 patients with severe disease.

In a meta-analysis conducted by Varikasuvu et al. (19), across 68 unadjusted (n=26,960) and 39 adjusted studies (n=15,653) reporting on initial D-dimer levels, a significant association was found in patients with higher D-dimer levels for the risk of overall disease progression (unadjusted odds ratio 3.15; adjusted odds ratio 1.64). The time-to-event outcomes were pooled across 19 unadjusted (n=9,743) and 21 adjusted studies (n=13,287), and a strong association was found in patients with higher D-dimer levels for the risk of overall disease progression (unadjusted hazard ratio 1.41; adjusted hazard ratio 1.10). The prognostic use of higher D-dimer levels was found to be promising for predicting overall progression (studies 68, area under curve 0.75) of COVID-19.

Zhan et al. (20) analyzed 29 studies and reported that the pooled sensitivity of the prognostic performance of D-dimer for the severity, mortality, and VTE in COVID-19 were 77% (95% CI: 73%∼80%), 75% (95% CI: 65%∼82%), and 90% (95% CI: 90%∼90%) respectively, and the specificity was 71% (95% CI: 64%∼77%), 83% (95% CI: 77%∼87%), and 60% (95% CI: 60%∼60%). D-dimer levels can predict severe and fatal progression of COVID-19 with moderate accuracy.

CONCLUSION

Since D-dimer levels are elevated in patients with COVID-19, it is difficult to screen for DVT by applying a traditional cutoff. Although D-dimer levels are limited in diagnosing DVT in patients with COVID-19, higher D-dimer levels in this patient group are significantly associated with disease progression. Further research is needed on the correlation between DVT and D-dimer levels in COVID-19 patients.

ACKNOWLEDGEMENTS

This paper was presented at the 42nd Conference of the Korean Society for Phlebology on April 17, 2022. This work was supported by clinical research grant from Pusan National University Hospital in 2022.

CONFLICTS OF INTEREST

The author declares no potential conflict of interest.

References

  1. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-7.
  2. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18:1738-42.
  3. Kim H, Yun SS. Clinical Application of D-Dimer in Venous Thromboembolism. Ann Phlebology. 2020;18:4-7.
  4. Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136:489-500.
  5. Artifoni M, Danic G, Gautier G, Gicquel P, Boutoille D, Raffi F, et al. Systematic assessment of venous throm-boembolism in COVID-19 patients receiving thrombopro-phylaxis: incidence and role of D-dimer as predictive factors. J Thromb Thrombolysis. 2020;50:211-6.
  6. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Müller MCA, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18:1995-2002.
  7. Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID- 19 patients. J Thromb Haemost. 2020;18:1743-6.
  8. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14.
  9. Maatman TK, Jalali F, Feizpour C, Douglas A 2nd, McGuire SP, Kinnaman G, et al. Routine venous throm-boembolism prophylaxis may be inadequate in the hyper-coagulable state of severe coronavirus disease 2019. Crit Care Med. 2020;48:e783-90.
  10. Suh YJ, Hong H, Ohana M, Bompard F, Revel MP, Valle C, et al. Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis. Radiology. 2021;298:E70-80.
  11. Moores LK, Tritschler T, Brosnahan S, Carrier M, Collen JF, Doerschug K, et al. Thromboprophylaxis in Patients With COVID-19 A Brief Update to the CHEST Guideline and Expert Panel Report. Chest. 2022;12:S0012-3692(22)00250-1.
  12. Cho ES, McClelland PH, Cheng O, Kim Y, Hu J, Zenilman ME, et al. Utility of d-dimer for diagnosis of deep vein thrombosis in coronavirus disease-19 infection. J Vasc Surg Venous Lymphat Disord. 2021;9:47-53.
  13. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel corona-virus pneumonia. J Thromb Haemost:1421-4.
  14. Li Y, Zhao K, Wei H, Chen W, Wang W, Jia L, et al. Dynamic relationship between D-dimer and COVID-19 severity. Br J Haematol. 2020;190:e24-7.
  15. Liu J, Zhang S, Wu Z, Shang Y, Dong X, Li G, et al. Clinical outcomes of COVID-19 in Wuhan, China: A large cohort study. Ann Intensive Care. 2020;10:99.
  16. Hanif A, Khan S, Mantri N, Hanif S, Saleh M, Alla Y, et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: A New York City hospital experience. Ann Hematol. 2020;99:2323-8.
  17. Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care. 2020;8:49.
  18. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol. 2020;13:1265-75.
  19. Varikasuvu SR, Varshney S, Dutt N, Munikumar M, Asfahan S, Kulkarni PP, et al. D-dimer, disease severity, and deaths (3D-study) in patients with COVID-19: a systematic review and meta-analysis of 100 studies. Sci Rep. 2021;11:21888.
  20. Zhan H, Chen H, Liu C, Cheng L, Yan S, Li H, et al. Diagnostic Value of D-Dimer in COVID-19: A Meta- Analysis and Meta-Regression. Clin Appl Thromb Hemost. 2021;27:10760296211010976.
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