Meta-Analysis and Systematic Review of Coagulation Disbalances in COVID-19: 41 Studies and 17,601 Patients

Abstract

Introduction: Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the association between early hemostatic parameters and infection severity.

Methods: Electronic search was made for papers that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference (SMD) with 95% confidence interval (CI) for D-dimers, fibrinogen, prothrombin time, platelet count (PLT), activated partial thromboplastin time. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger's test by linear regression. Coagulation parameters data from retrospective cohort study of 451 patients with COVID-19 at National Research Center for Cardiac Surgery were included in meta-analysis of published studies.

Results: Overall, 41 original studies (17,601 patients) on SARS-CoV-2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group [SMD 0.6985 with 95%CI (0.5155; 0.8815); SMD 0.661 with 95%CI (0.3387; 0.9833); SMD 0.2683 with 95%CI (0.1357; 0.4009); SMD 0.284 with 95%CI (0.1472; 0.4208)]. In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 [SMD -0.1684 with 95%CI (-0.2826; -0.0542)]. Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger's test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias.

Conclusions: The hemostatic laboratory parameters, with exception of platelets, are significantly elevated in patients with severe COVID-19. The two variables with strongest association to disease severity were D-dimers and fibrinogen levels. Future research should aim outside conventional coagulation tests and include analysis of clotting formation and platelet/platelet progenitors characteristics.

Keywords: COVID-19; D-dimers; coagulopathy; fibrinogen; megakaryocyte; platelets; prothrombin time; thrombosis.

Figure 1

Flow diagram illustrating the process of data collection.

Figure 2

Diagram depicting characteristics of selected studies: (A) number of publications per country, (B) number of patients per country, and (C) number of publications per severity assessment criterion. The latter (C) indicates the total number of research articles to be 42 instead of 41 because one study reported two populations of patients admitted to the hospital at different periods.

Figure 3

Forest plot of association between COVID-19 severity and PLT (A), DD (B).

Figure 4

Forest plots of the association between COVID-19 severity and (A) FIB, (B) APTT, (C) PT.

Figure 5

GOSH diagnostic for influential cases in meta-analysis models (A) PLT, (B) DD.

Figure 6

GOSH plots fixed for influential studies in meta-analysis models. (A,B) FIB, (C–E) APTT, and (F-I) PT.

Figure 7

Contour-enhanced funnel plots evaluating the presence of publication bias in the pool of articles that report association between COVID-19 severity and (A) PLT; (B) DD; (C) FIB; (D) APTT; (E) PT.