Thrombosis and Bleeding in Patients with Vaccine-Induced Immune Thrombotic Thrombocytopenia: A Systematic Review of Published Cases

Abstract

Introduction Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic reaction to COVID-19 (coronavirus disease 2019) adenoviral vector vaccines. Its distinct bleeding and thrombotic patterns compared with other platelet consumptive disorders remain unclear.

Methods We performed a systematic review of the literature (PubMed and Embase) up to July 31, 2022, including case reports and case series providing nonaggregate data of VITT patients. Accurate VITT diagnosis required fulfillment of the following criteria: (1) endorsement by the authors, (2) consistent vaccine type and timing, (3) presence of thrombocytopenia and thrombosis, (4) detection of anti-platelet factor 4 antibodies. Data are presented as frequencies with 95% confidence intervals (CIs) calculated with the exact binomial method.

Results We retrieved 143 eligible studies, describing 366 patients. Of 647 thrombotic events, 53% (95% CI: 49–56) were venous thromboses at unusual sites and 30% (95% CI: 27–34) were cerebral venous sinus thromboses (CVSTs). The ratio of venous-to-arterial events was 4.1. Thromboses in most sites were associated with at least another thrombotic event, with the exception of CVST and CNS arterial thrombosis (isolated in 49 and 39% of cases, respectively). Bleeding occurred in 36% (95% CI: 31–41) of patients; 68% (95% CI: 59–75) of bleeding events were intracranial hemorrhages (ICHs). Overall mortality was 24% (95% CI: 19–29), and 77% (95% CI: 58–90) in patients with isolated CVST complicated by ICH.

Conclusion VITT displays a venous-to-arterial thrombosis ratio comparable to heparin-induced thrombocytopenia. However, VITT is characterized by a higher prevalence of CVST and ICH, which contribute to the increased bleeding frequency and mortality.

Keywords

adenovirus - platelet - hemorrhage - thrombocytopenia - thrombosis

• References

• 1 Watson OJ, Barnsley G, Toor J, Hogan AB, Winskill P, Ghani AC. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study. Lancet Infect Dis 2022; 22 (09) 1293-1302
• 2 Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021; 384 (22) 2092-2101
• 3 Huynh A, Kelton JG, Arnold DM, Daka M, Nazy I. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia. Nature 2021; 596 (7873) 565-569
• 4 Warkentin TE. Platelet-activating anti-PF4 disorders: an overview. Semin Hematol 2022; 59 (02) 59-71
• 5 Muir KL, Kallam A, Koepsell SA, Gundabolu K. Thrombotic thrombocytopenia after Ad26.COV2.S vaccination. N Engl J Med 2021; 384 (20) 1964-1965
• 6 COVID-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT). Last updated Feb 07, 2023 . Accessed May 1, 2023 at: https://www.uptodate.com/contents/covid-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt?search=vitt&source=search_result&selectedTitle=1~114&usage_type=default&display_rank=1
• 7 Rydland HT, Friedman J, Stringhini S, Link BJ, Eikemo TA. The radically unequal distribution of Covid-19 vaccinations: a predictable yet avoidable symptom of the fundamental causes of inequality. Humanit Soc Sci Commun 2022; 9: 61
• 8 Holm MR, Poland GA. Critical aspects of packaging, storage, preparation, and administration of mRNA and adenovirus-vectored COVID-19 vaccines for optimal efficacy. Vaccine 2021; 39 (03) 457-459
• 9 WHO. WHO Coronavirus (COVID-19) Dashboard. Accessed August 17, 2023 at: https://covid19.who.int
• 10 American Society of Hematology. Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced thrombotic thrombocytopenia). Version 1.4;. last updated April 29, 2021 . Accessed May 1, 2023 at: https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
• 11 Pavord S, Scully M, Hunt BJ. et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. N Engl J Med 2021; 385 (18) 1680-1689
• 12 van de Munckhof A, Lindgren E, Kleinig TJ. et al; Cerebral Venous Sinus Thrombosis With Thrombocytopenia Syndrome Study Group. Outcomes of cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia after the acute phase. Stroke 2022; 53 (10) 3206-3210
• 13 Schönborn L, Greinacher A. Longitudinal aspects of VITT. Semin Hematol 2022; 59 (02) 108-114
• 14 Kim AY, Woo W, Yon DK. et al. Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: a systematic review and meta-analysis. [published correction appears in Int J Infect Dis. 2022 Oct;123:166] Int J Infect Dis 2022; 119: 130-139
• 15 Hwang J, Park SH, Lee SW. et al. Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score. Eur Heart J 2021; 42 (39) 4053-4063
• 16 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101 (05) 502-507
• 17 Gruel Y, Vayne C, Rollin J. et al. Comparative analysis of a french prospective series of 144 patients with heparin-induced thrombocytopenia (FRIGTIH) and the literature. Thromb Haemost 2020; 120 (07) 1096-1107
• 18 Goel R, Ness PM, Takemoto CM, Krishnamurti L, King KE, Tobian AA. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood 2015; 125 (09) 1470-1476
• 19 John CV, Kumar R, Sivan AK, Jithin S, Abraham R, Philip CC. Vaccine-induced thrombotic thrombocytopenia (VITT): first report from India. Thromb J 2022; 20 (01) 11
• 20 Venier LM, Clerici B, Bissola AL. et al. Unique features of vaccine-induced immune thrombotic thrombocytopenia; a new anti-platelet factor 4 antibody-mediated disorder. Int J Hematol 2023; 117 (03) 341-348
• 21 Huynh A, Arnold DM, Ivetic N. et al. Antibodies against platelet factor 4 and the risk of cerebral venous sinus thrombosis in patients with vaccine-induced immune thrombotic thrombocytopenia. J Thromb Haemost 2023; 21 (10) 2833-2843
• 22 Johansen S, Laegreid IJ, Ernstsen SL. et al. Thrombosis and thrombocytopenia after HPV vaccination. J Thromb Haemost 2022; 20 (03) 700-704