Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study

Abstract

Background: Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers.

Methods: We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis.

Results: All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis.

Conclusion: TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level.

Fig. 1

Process of MR. CCL3, C–C motif chemokine 3; FIII, FVII, FVIII, FX, FXI, coagulation factors; IL-1R1, interleukin-1 receptor type 1 levels; IL-1R2, interleukin-1 receptor type 2 levels; MCFD2, multiple coagulation factor deficiency protein 2 levels; MPV, mean platelet volume; PAI-1, plasminogen activator inhibitor 1; PSGL-1, P-selectin glycoprotein ligand 1 levels; TFPI, tissue factor pathway inhibitor; tPA, plasminogen activator, tissue type; VWF, von Willebrand factor.

Fig. 2

Forest plot for total causal effects of COVID-19 on TFPI. The size of the black dot represents the size of the SE. CI, confidence interval; IVW, inverse-variance weighted; OR, odds ratio.

Fig. 3

Forest plot for total causal effects of COVID-19 on IL-1R1. The size of the black dot represents the size of the SE. CI, confidence interval; IVW, inverse-variance weighted; OR, odds ratio.

Fig. 4

Scatter plots of COVID-19 with IL-1R1. The X -axis displays the SNP effect and SE on each of COVID-19 IVs, while the Y -axis shows the SNP effect and SE on IL-1R1. The regression line for MR-Egger, weighted median, IVW, simple mode, and weighted mode is presented. ( A–D ) Results of COVID-19, severe-a COVID-19, severe-b COVID-19, and hospitalized COVID-19 on IL-1R1.

Fig. 5

Forest plot for total causal effects of COVID-19 on IL-1R2. The size of the black dot represents the size of the SE. CI, confidence interval; IVW, inverse-variance weighted; OR, odds ratio.

Fig. 6

Scatter plots of COVID-19 with IL-1R2. The X -axis shows the SNP effect and SE on each of COVID-19 IVs. The Y -axis shows the SNP effect and SE on IL-1R2. ( A, B ) MR-Egger results of severe-a COVID-19 and severe-b COVID-19 on IL-1R1. The regression line for MR-Egger, weighted median, IVW, simple mode, and weighted mode is shown. SNP, single nucleotide polymorphism.

Fig. 7

Forest plot for total causal effects of COVID-19 on other thrombotic biomarkers. ( A ) MR results of common infection COVID-19 on thrombosis, ( B ) MR results of hospitalized COVID-19 on thrombosis, and ( C ) MR results of severe COVID-19 on thrombosis. The size of the black dot represents the size of the SE. CI, confidence interval; IVW, inverse-variance weighted; MR, Mendelian randomization; OR, odds ratio.