Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

Abstract

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.

Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

“…It seems in agreement with what was said above that females typically produce higher antibody responses and show more adverse effects of vaccination respect to males. In particular it may be due the production of autoantibodies against the Platelet Factor-4 (PF4) in individuals susceptible to autoimmune diseases [199]. We can speculate that the involvement of young women in particular suggests a reaction involving the immune system, which becomes less severe in older women.…”

Untangling the Intricacies of Infection, Thrombosis, Vaccination, and Antiphospholipid Antibodies for COVID-19

“…A role for the complement system and cytokines also merits consideration [ 166 – 168 ]. Theories of pathogenesis abound [ 102 , 169 , 170 ]. These events and many similar published are intriguing but do not guarantee a mechanism understood for post-vaccination thrombosis.…”

Cerebral venous thrombosis after COVID-19 vaccination: is the risk of thrombosis increased by intravascular application of the vaccine?

“…Both above-mentioned vaccines are abbreviated in the following as AdV-S. The above described thrombotic complications after AdV-S have in the meantime be named TTS (thrombosis thrombocytopenia syndrome), VIPIT (vaccine-induced prothrombotic immune thrombocytopenia) or VITT (vaccine-induced thrombocytopenia) [ 3 – 5 ].…”

“…Findings in several of the first patients with unusual thrombosis after AdV-S vaccination showed similarities with heparin-induced thrombocytopenia (HIT) with high levels of antibodies to platelet factor 4 (PF4)–polyanion complexes [ 5 , 24 – 26 ]. PF4 is synonymous with CXCL4, a potent cytokine which is released from activated thrombocytes and associated with vaccine-induced immune thrombotic thrombocytopenia [ 27 , 28 ].…”

“…The antibodies involved in thrombocytopenia after AdV-S vaccination occurred without any prior heparin therapy, and their effect on platelet activation was rather blocked by heparin [ 24 ]. One might speculate that the presumably positively charged structures on the AdV surface which bind negatively charged glycosaminoglycans, might elicit antibodies cross-reacting with PF4, which would explain the finding that both PF4 and the AdV components of the vaccine enhanced platelet activation [ 5 ].…”