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

 

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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.

Data Availability Statement

The data generated and codes used in the current study are available in this published article and [Supplementary File] associated with it. The data underlying this article are available in IEU OpenGWAS project, at https://gwas.mrcieu.ac.uk/.

Ethical Approval Statement

The data for this study came from a public database, so no such approval was required.

Authors' Contribution

M.Z. collected and organized the data. Z.L. analyzed the data and finished the writing. All authors participated in the writing and review of the article.

^* These authors contributed equally to the research.

Publication History

Received: 19 July 2023

Accepted: 17 November 2023

Accepted Manuscript online:
07 February 2024

Article published online:
05 March 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021; 19 (03) 141-154
  CrossrefPubMedGoogle Scholar
• 2 Suthar AB, Wang J, Seffren V, Wiegand RE, Griffing S, Zell E. Public health impact of covid-19 vaccines in the US: observational study. BMJ 2022; 377: e069317
  CrossrefPubMedGoogle Scholar
• 3 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
  CrossrefPubMedGoogle Scholar
• 4 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395 (10229): 1054-1062
  CrossrefPubMedGoogle Scholar
• 5 Pellicori P, Doolub G, Wong CM. et al. COVID-19 and its cardiovascular effects: a systematic review of prevalence studies. Cochrane Database Syst Rev 2021; 3 (03) CD013879
  PubMedGoogle Scholar
• 6 Kwee RM, Adams HJA, Kwee TC. Pulmonary embolism in patients with COVID-19 and value of D-dimer assessment: a meta-analysis. Eur Radiol 2021; 31 (11) 8168-8186
  CrossrefPubMedGoogle Scholar
• 7 Vincent JL, Levi M, Hunt BJ. Prevention and management of thrombosis in hospitalised patients with COVID-19 pneumonia. Lancet Respir Med 2022; 10 (02) 214-220
  CrossrefPubMedGoogle Scholar
• 8 Antic D, Milic N, Chatzikonstantinou T. et al. Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL. J Hematol Oncol 2022; 15 (01) 116
  CrossrefPubMedGoogle Scholar
• 9 Jiang SQ, Huang QF, Xie WM, Lv C, Quan XQ. The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol 2020; 190 (01) e29-e33
  CrossrefPubMedGoogle Scholar
• 10 Wibowo A, Pranata R, Lim MA, Akbara MR, Martha JW. Endotheliopathy marked by high von Willebrand factor (vWF) antigen in COVID-19 is associated with poor outcome: a systematic review and meta-analysis. Int J Infect Dis 2022; 117: 267-273
  CrossrefPubMedGoogle Scholar
• 11 Gorog DA, Storey RF, Gurbel PA. et al. Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat Rev Cardiol 2022; 19 (07) 475-495
  CrossrefPubMedGoogle Scholar
• 12 Winckers K, ten Cate H, Hackeng TM. The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 2013; 27 (03) 119-132
  CrossrefPubMedGoogle Scholar
• 13 Nayak L, Sweet DR, Thomas A. et al. A targetable pathway in neutrophils mitigates both arterial and venous thrombosis. Sci Transl Med 2022; 14 (660) eabj7465
  CrossrefPubMedGoogle Scholar
• 14 Wang R. Genetic variation of interleukin-1 receptor type 1 is associated with severity of COVID-19 disease. J Infect 2022; 84 (02) e19-e21
  CrossrefPubMedGoogle Scholar
• 15 Mazilu L, Katsiki N, Nikolouzakis TK. et al. Thrombosis and haemostasis challenges in COVID-19 - therapeutic perspectives of heparin and tissue-type plasminogen activator and potential toxicological reactions-a mini review. Food Chem Toxicol 2021; 148: 111974
  CrossrefPubMedGoogle Scholar
• 16 Mir Seyed Nazari P, Marosi C, Moik F. et al. Low systemic levels of chemokine C-C motif ligand 3 (CCL3) are associated with a high risk of venous thromboembolism in patients with glioma. Cancers (Basel) 2019; 11 (12) 14
  CrossrefPubMedGoogle Scholar
• 17 Cheung CL, Ho SC, Krishnamoorthy S, Li GH. COVID-19 and platelet traits: a bidirectional Mendelian randomization study. J Med Virol 2022; 94 (10) 4735-4743
  CrossrefPubMedGoogle Scholar
• 18 Robbins AJ, Che Bakri NA, Toke-Bjolgerud E. et al. The effect of TRV027 on coagulation in COVID-19: a pilot randomized, placebo-controlled trial. Br J Clin Pharmacol 2023; 89 (04) 1495-1501
  CrossrefPubMedGoogle Scholar
• 19 Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318 (19) 1925-1926
  CrossrefPubMedGoogle Scholar
• 20 Zhou Y, Qian X, Liu Z. et al. Coagulation factors and the incidence of COVID-19 severity: Mendelian randomization analyses and supporting evidence. Signal Transduct Target Ther 2021; 6 (01) 222
  CrossrefPubMedGoogle Scholar
• 21 COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur J Hum Genet 2020; 28 (06) 715-718
  CrossrefPubMedGoogle Scholar
• 22 Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res 2007; 16 (04) 309-330
  CrossrefPubMedGoogle Scholar
• 23 Palmer TM, Lawlor DA, Harbord RM. et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 2012; 21 (03) 223-242
  CrossrefPubMedGoogle Scholar
• 24 Burgess S, Thompson SG. CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol 2011; 40 (03) 755-764
  CrossrefPubMedGoogle Scholar
• 25 Russell AE, Ford T, Gunnell D. et al. Investigating evidence for a causal association between inflammation and self-harm: a multivariable Mendelian Randomisation study. Brain Behav Immun 2020; 89: 43-50
  CrossrefPubMedGoogle Scholar
• 26 Chumbley JR, Friston KJ. False discovery rate revisited: FDR and topological inference using Gaussian random fields. Neuroimage 2009; 44 (01) 62-70
  CrossrefPubMedGoogle Scholar
• 27 Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50 (05) 693-698
  CrossrefPubMedGoogle Scholar
• 28 Mast AE. Tissue factor pathway inhibitor: multiple anticoagulant activities for a single protein. Arterioscler Thromb Vasc Biol 2016; 36 (01) 9-14
  CrossrefPubMedGoogle Scholar
• 29 Francischetti IMB, Toomer K, Zhang Y. et al. Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection. EClinicalMedicine 2021; 39: 101069
  CrossrefPubMedGoogle Scholar
• 30 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
  CrossrefPubMedGoogle Scholar
• 31 Hackeng TM, Seré KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A 2006; 103 (09) 3106-3111
  CrossrefPubMedGoogle Scholar
• 32 Kyriazopoulou E, Poulakou G, Milionis H. et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med 2021; 27 (10) 1752-1760
  CrossrefPubMedGoogle Scholar
• 33 CORIMUNO-19 Collaborative group. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med 2021; 9 (03) 295-304
  CrossrefPubMedGoogle Scholar
• 34 Caricchio R, Abbate A, Gordeev I. et al; CAN-COVID Investigators. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA 2021; 326 (03) 230-239
  CrossrefPubMedGoogle Scholar
• 35 Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 2010; 6 (04) 232-241
  CrossrefPubMedGoogle Scholar
• 36 Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol 2019; 15 (10) 612-632
  CrossrefPubMedGoogle Scholar
• 37 Colotta F, Re F, Muzio M. et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 1993; 261 (5120) 472-475
  CrossrefPubMedGoogle Scholar
• 38 Garlanda C, Riva F, Bonavita E, Mantovani A. Negative regulatory receptors of the IL-1 family. Semin Immunol 2013; 25 (06) 408-415
  CrossrefPubMedGoogle Scholar
• 39 Myöhänen H, Vaheri A. Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci 2004; 61 (22) 2840-2858
  CrossrefPubMedGoogle Scholar
• 40 Yatsenko T, Skrypnyk M, Troyanovska O. et al. The role of the plasminogen/plasmin system in inflammation of the oral cavity. Cells 2023; 12 (03) 445
  CrossrefPubMedGoogle Scholar
• 41 He S, Waheed AA, Hetrick B. et al. PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity. bioRxiv. Jul 6 2020
  PubMedGoogle Scholar
• 42 Choudhury R, Barrett CD, Moore HB. et al. Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis. World J Emerg Surg 2020; 15 (01) 29
  CrossrefPubMedGoogle Scholar
• 43 Rashidi F, Barco S, Rezaeifar P. et al. Tissue plasminogen activator for the treatment of adults with critical COVID-19: a pilot randomized clinical trial. Thromb Res 2022; 216: 125-128
  CrossrefPubMedGoogle Scholar
• 44 He S, Waheed AA, Hetrick B. et al. PSGL-1 inhibits the incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins into pseudovirions and impairs pseudovirus attachment and infectivity. Viruses 2020; 13 (01) 46
  CrossrefPubMedGoogle Scholar

• Supplementary Material