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Postmortem immunohistologic analysis of cerebral venous thrombi related to vaccine-induced immune thrombotic thrombocytopenia

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by thrombosis at unusual locations such as the cerebral venous sinuses, thrombocytopenia, and increased titers of antibodies against platelet factor–4 (PF-4). Thrombocytopenia and major thrombotic events have been described after the administration of adenoviral vector-based COVID-19 vaccines (ChAdOX1-nCoV-19, AstraZeneca/Oxford or Ad26.COV2. S. Janssen/Johnson&Johnson). These diseases usually occur between 5 and 20 days after the vaccination and often have a severe outcome. In this study, French authors performed an immunohistological analysis of cerebral thrombi obtained from three fatal cases of cerebral venous thrombosis (CVT) related to vaccine-induced immune thrombotic thrombocytopenia (VITT). 

About the study

The authors performed the immunohistological analysis of clots from three people who died from CVT related to VITT after receiving a single dose of ChAdOX1-nCoV-19, AstraZeneca/Oxford vaccines. In all three patients, the premortem blood analysis revealed the presence of anti-PF4 IgG antibodies.

In all three cases of VITT, the autopsy demonstrated extensive thrombosis of cerebral venous sinuses. Importantly, a similar organization of cerebral thrombi has been found in all cases despite differences in treatment and time from admission to death. Thrombi from patients who died of VITT showed a remarkable architecture and specific progression of thrombus growth. The clot organization exhibited a high density of neutrophils and intermingled platelets and nucleated cells in the thrombus core. The SARS-CoV-2 S protein was found within neutrophils in the thrombus. The thrombus tail was rich in fibrin and red blood cells, with a low density of neutrophils. 

The processes, such as neutrophil extracellular trap and complement activation, which are both highly thrombogenic, were present at the border and within the thrombi. 

The CVT was also associated with injuries to vessel walls. Even at a distance from the thrombi, the walls of the superior sagittal sinus were inflamed and hemorrhagic. The CD34 staining showed that the endothelial cells adjacent to the thrombus were largely destroyed. The SARS-CoV-2 S protein was also found in the wall of the superior sagittal sinus adjacent to the thrombus, particularly in CD45-positive cells.

The authors stated that immune complexes activate neutrophils and platelets through FcγRIIa binding. The subsequent release of PF4 further enhances the production of anti-PF4 antibodies. This leads to the massive activation of platelets and the formation of neutrophil extracellular traps. Importantly, immune complexes that contain SARS-CoV-2 S protein and anti-S protein IgG antibodies can induce thrombi formation mediated by platelets.

Conclusion

This postmortem analysis demonstrated extensive thrombosis of cerebral venous sinuses and similar organization of cerebral thrombi in all three cases of VITT. These findings provided strong evidence of immunothrombosis related to vaccine-induced immune thrombotic thrombocytopenia.

This article was published in Neurology, Neuroimmunology & Neuroinflammation.

Journal Reference

 

Geeraerts T et al. Immunohistologic Features of Cerebral Venous Thrombosis Due to Vaccine-Induced Immune Thrombotic Thrombocytopenia. Neurol Neuroimmunol Neuroinflamm 2023; 10: e200127. (Open Access).  https://nn.neurology.org/content/10/4/e200127

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