To the editor
In December 2019 in Wuhan, Hubei province (China), pneumonia of unknown cause with rapid transmission capacity between humans emerged . Posteriorly, the pathogen responsible by this pneumonia was identified such as a new positive-sense single-stranded RNA virus of the genus Betacoronavirus [severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)] and since then the disease has come to be called coronavirus disease 2019 (COVID-19) . COVID-19 quickly spread to several countries, becoming a global public health problem that made WHO decreed a pandemic state in May, 2020 .
Despite respiratory complications being the main factor for referral patients with COVID-19 to intensive care, other clinical manifestations related to hypercoagulability has been associated to an increased risk of mortality and hospitalization in this patients . Herein, around 71.4% of patients infected with SARS-CoV-2 have significant changes in coagulation factors in the laboratory examination and these data are directly related to the greater severity and mortality of the disease . Within the hemostatic parameters evaluated, the elevation of fibrin degradation products (FDP), especially the d-dimer, have been identified as a potential factor associated with the severity of COVID-19 . Thus, since laboratory medicine provides an essential contribution to the clinical decision in infectious diseases , we aimed to investigate here whether serum d-dimer levels are directly related to the evolution and lethality of COVID-19.
We carried out a systematic review second the principle of Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement . To evaluate the role of d-dimer serum levels as a potential biomarker for the early identification of COVID-19 critical cases, was employed the strategy PEOS, as follows: ‘Population’, patients of both sexes and all age ranges; ‘Exposition’, patients with diagnostic of COVID-19; ‘Outcomes’, d-dimer serum levels; ‘Study design’, Prospective/retrospective cohorts. The studies were included only when the diagnostic of COVID-19 was according to WHO interim guidance.
Four databases (PubMed/MEDLINE, Scopus, Cochrane Library, Biblioteca Virtual em Saúde) were searched for articles published until 11 April 2020 using the keywords ‘d-dimer’ AND ‘2019 novel coronavirus’ OR ‘2019-nCoV’ OR ‘SARS-CoV-2’ OR ‘COVID-19’ without date and language restrictions. In addition, the reference list of all included studies and relevant reviews regarding this topic were also screened to identify potential eligible studies. For the study selection, two independent investigators identified and removed all duplicate records. Titles, abstracts and keywords were analyzed to identify relevant studies in accordance with the inclusion criteria. Finally, the articles preselected were subjected to a full text evaluation to assess whether they should be included in the study. Any discrepancy was resolved by discussion with a third investigator to reach a consensus regarding inclusion or exclusion in the study. Finally, the quality of the included studies was independently assessed by two reviewers using the Newcastle-Ottawa Quality Assessment Scale (NOS) .
A meta-analysis was then carried out for calculating the individual and pooled median serum concentrations of d-dimer, with their relative 95% confidence interval (95% CI), measured in patients with COVID-19 who died or were discharged. d-Dimer values were entered as dichotomous variable, that is, below or above the locally defined reference range (typically ≤0.40 μg/ml). Since the heterogeneity (I2 statistics) did have exceeded 50%, a random effects model was used. All the analysis were realized using the Review Manager (RevMan) 5.3. (London, England, UK).
As shown in the flowchart (Fig. 1), we identified 71 articles during the initial search, 68 of which were excluded after title, abstract or full text reading, because they did not report d-dimer values in patients with COVID-19 who survivor or nonsurvivor. The reference lists of the included articles were analyzed and none additional study was identified. Overall, three studies were finally included in our meta-analysis [4,5,9]. The overall quality of the studies is high second NOS, been that two were assigned with eight stars [4,9] and one with seven stars .
A total of 648 patients with COVID-19 (460 recovered and 188 deaths) recruited between 29 December 2019 and 12 February 2020 were analyzed in the selected studies (Table 1). Second the design, all included studies were single centre retrospective cohort and performed in hospitals from China. The age of participants range from 37 to 77 years, with an overall mean of 51.8 and 67 years between the group who survivor and nonsurvivor, respectively. As for sex, the majority of the patients were men (388/648; 59.8%), especially between patients that dead in response to COVID-19 complications (157/188; 83.5%). The pooled median serum concentrations of d-dimer between the patients of these studies is summarized in Fig. 2, which shows the levels d-dimer are positively and significantly correlated to lethality of SARS-CoV-2 infection (inverse variance , −3.37; 95% CI, −5.02; −1.73; P value of overall effect <0.0001). Herein, the mean levels of d-dimer are 11-fold higher between patients that dead by COVID-19 (6.62 ± 0.83 μg/ml) in relation to patients that recovered from the disease (0.6 ± 0.3 μg/ml).
d-Dimer is a breakdown product of soluble fibrin generated after cleavage of fibrin clot by plasmin . Currently, the detection of d-dimer levels is commonly used to monitor abnormalities coagulation and thrombosis, been it very useful in the evaluation of venous thromboembolism (VTE), disseminated intravascular coagulation (DIC) and monitoring of anticoagulant therapy [11,12]. However, in this meta-analysis, we showed that serum levels of d-dimer can also be useful for early definition of the prognosis of patients with COVID-19 (Fig. 1). In fact, patients infected with the SARS-CoV-2 shown an imbalance of hemostatic function, with emphasis on a marked increase in plasma levels of d-dimer [4,5]. Han et al. demonstrated that in patients with COVID-19, plasma levels of this FDP are significantly higher than in healthy patients (10.36 vs. 0.26 ng; P < 0.001). In addition, an markedly elevated d-dimer as result of abnormal coagulation are common in deaths with novel coronavirus pneumonia (NCP), thus demonstrating a positive correlation between the increase in levels of this biomarker and the lethality of COVID-19 [5,13]. A possible complication arising from the increase in d-dimer is the occurrence of DIC, a thrombotic event that could explain the greater severity for patients infected with SARS-CoV-2 [11,12]. Evidence of DIC was reported at the autopsy of patients killed by COVID-19, where a large number of thrombotic pulmonary veins and hemorrhagic lesions were observed [14,15]. Furthermore, a recent study has showed that the incidence of VTE in patients with severe NCP is considerably high (involving about 31% of patients), which has an obvious negative impact on the prognosis . Thus, monitoring of hemostatic changes becomes a very relevant tool to establish the severity of COVID-19 and the risk of lethality of NCP.
Significantly, the levels of d-dimer are naturally higher between patients of risk group to the complications of COVID-19 such as hypertensive, diabetic, current smoking and seniors . Thus, it is suggested that patients with comorbid are more susceptible to a hypercoagulability which eventually can leading to rapid deterioration of disease. Furthermore, the crosstalk between the inflammation generated by the SARS-CoV-2 infection and the coagulation abnormalities observed mainly among critically ill patients should be taken into account. Recent evidences has shown that an acute elevation of pro-inflammatory cytokines such as interleukin (IL)-2, IL-6, IL-7, tumour necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with COVID-19 (called of ‘cytokines storm’) is associated to progression of NCP and increase in lethality of disease . This exacerbated inflammatory profile can result in sepsis, a condition directly linked to the onset of DIC, which is well known to induce a rapid and marked elevation in serum d-dimer levels [11,12].
Currently, one of the major challenges facing health systems worldwide is the scarcity of hospital beds for all patients with COVID-19. Thus, monitoring of d-dimer levels becomes a key element in the classification of COVID-19 severity, being able to follow the evolution of the disease as well as the effectiveness of the treatment employed. Thus, monitoring of the d-dimer may be a useful laboratory parameter to avoid complications, guide therapeutic procedures and reduce the number of hospitalizations in the ICU because this biomarker is associated to early identification of severe cases.
W.G.L. is grateful to Coordenação de Aperfeiçoamento de Pessoal do Nível Superior (CAPES) for a PhD fellowship.
Sources of support in the form of grants: none.
Conflicts of interest
The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this article.
1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med
2. Park SE. Epidemiology, virology, and clinical features of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2; coronavirus disease-19). Clin Exp Pediatr
3. World Health Organization (WHO). Coronavirus disease 2019. WHO, https://www.who.int/emergencies/diseases/novel-coronavirus-2019
. [Accessed 26 March 2020].
4. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet
5. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost
6. Lippi G, Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chim Acta
7. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ
8. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
2009. [Accessed 2020 February 26].
9. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ
10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. PLoS Med
11. Olson JD. d
-Dimer: an overview of hemostasis and fibrinolysis, assays, and clinical applications. Adv Clin Chem
12. Thachil J, Lippi G, Favaloro EJ. d
-Dimer testing: laboratory aspects and current issues. Methods Mol Biol
13. Han H, Yang L, Liu R, Liu F, Wu K, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med
2020; [Article in press].
14. Liu Q, Wang RS, Qu GQ. Gross examination report of a COVID-19 death autopsy. J Forensic Med
15. Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, Ferraz da Silva LF, Pierre de Oliveira E, Nascimento Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost
2020; [Article in press].
16. 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; [Article in press].
17. Pieper CF, Rao MK, Currie MS, Harris TB, Cohen HJ. Age, functional status, and racial differences in plasma d
-dimer levels in community-dwelling elderly persons. J Gerontol A Biol Sci Med Sci
18. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect