Mechanisms of COVID-19 vaccine-induced thrombotic thrombocytopenia

Vaccine-induced thrombotic thrombocytopenia (VITT) is caused by anti-PF4 autoantibodies, starting a procoagulatory cascade, eventually leading to a highly prothrombotic state, amplification, and loss of control. This is likely triggered by a response to free proteins and the preservative EDTA in the vaccine.

Since February 2021, several cases of unusual thrombotic events in combination with thrombocytopenia were observed in people who received AstraZeneca’s  nCov-19 vaccine. Prof. Andreas Greinacher (Universitätsmedizin Greifswald, Germany) presented previously published and unpublished data on VITT [1].

The typical VITT pattern is development of thrombocytopenia, cerebral vein, and/or splanchnic vein thrombosis 4–20 days after vaccination with an adenoviral vector-based SARS-CoV-2 vaccine, strongly positive results for platelet factor 4 (PF4)/heparin IgG ELISA, and Fc-gamma receptor-mediated platelet activation in presence of PF4 [2–5].

The current hypothesis of the mechanism of VITT is as follows: early stage (days 1–2) consists of 2 parts, namely antigen formation of PF4/vaccine complexes and danger signalling by vaccine-induced inflammation; in late stage (days 5–14), highly pathogenic anti-PF4 antibodies are produced in high titres, which induce platelet activation and NETosis, leading to prothrombotic state, amplification, and loss of control [1].

The complex formation theory was supported by dynamic light scattering analysis of ChAdOx1 nCOV-19, with the particles being approximately 90 nm long (corresponding to the size of adenovirus). Then, VITT-patient affinity-purified anti-PF4 was added, which significantly increased the size of particles. When DNA was added, complexes increased to approximately 750 nm in size.

The co-inflammatory signal is suggested to come from the HEK cell line in which the vaccine is raised, and which contributes to approximately 50% of protein content (17.5–20 µg) per vaccine dose. Thus, there are many free hexon proteins in the vaccine, which are strong triggers of the innate immune system. Another factor might be EDTA-induced vascular leakage, which allows vaccine components to enter the vasculature at injection site, adding strong pro-inflammatory effects.

Prof. Greinacher also hypothesised that the HEK-cell protein in the vaccine may cause the formation of alloantibodies, which may then induce thrombocytopenia. This is supported by a vaccine-induced foetomaternal incompatibility causing pancytopaenia due to alloantibody formation in cattle and should be investigated further [1,6].

In summary, VITT is caused by anti-PF4 antibodies. Human and free proteins, and EDTA in the vaccine likely trigger the immune response to PF4. Anti-PF4 autoantibodies activate platelets, which recruit granulocytes, which then get into NETosis. This amplifies the reaction and causes a thrombin burst. It remains unclear whether the vaccine induces immune responses against other proteins.

1. 
   
   1. Greinacher A. Vaccine associated thrombotic thrombocytopenia. EHA 2021 Virtual Congress, 9–17 June:p217-3
   2. Greinacher A, et al. N Engl J Med 2021; 384:2092–101.
   3. Schulz NH, et al. N Engl J Med 2021; 384:2124–30.
   4. Scully M, et al. N Engl J Med 2021; 384:2202–11.
   5. Muir KL, et al. N Engl J Med 2021; 384:1964–5.
   6. Bastian M, et al. Vaccine 2011;29(32):5267–75.

 

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Posted on 5 August 20215 August 2021