The recent study by French authors provides an immunohistological analysis of cerebral thrombi from three fatal cases of cerebral venous thrombosis (CVT) resulting from vaccine-induced immune thrombotic thrombocytopenia (VITT). The findings show that neutrophil extracellular traps, platelets, and complement activation within the thrombi, as well as the antispike immunity triggered by the vaccine, are involved in the pathogenic process.
Thrombocytopenia and major thrombotic events have been described after adenoviral vector–based COVID-19 vaccines (ChAdOX1-nCoV-19, AstraZeneca/Oxford or Ad26.COV2. S. Janssen/Johnson&Johnson). The onset of this disease usually occurs between 5 and 20 days following vaccination, and a disease often has a severe outcome. VITT is characterized by the presence of thrombosis at unusual locations such as the cerebral venous sinuses, thrombocytopenia, and increased titers of antibodies against platelet factor–4.
About the study
In this study, the authors report the immunohistological analysis of clots from three people who died from CVT related to VITT after receiving a single dose of ChAdOX1-nCoV-19 vaccines. Venous thrombi were observed in the brain, liver, and lungs. The anti-PF4 IgG antibodies were detected in premortem blood in all three patients.
An autopsy revealed that all three cases of VITT had extensive thrombosis of cerebral venous sinuses. All three patients had a similar organization of cerebral thrombi despite differences in treatment and time from admission to death, as confirmed by immunohistological analysis. The thrombi from superior sagittal sinus were large (on average 5 cm) and rich in white blood cells.
Also, thrombi from patients who died from VITT showed a remarkable architecture, with a high density of neutrophils in the core and a low density in the tail. The organization of the clot indicated that there was a specific progression of thrombus growth, with platelets and nucleated cells intermingled in the thrombus core. The markers of neutrophil extracellular trap and complement activation were present at the border and within the thrombi. Both processes are highly thrombogenic. The thrombus tail was rich in fibrin and red blood cells.
The SARS-CoV-2 spike protein was found within neutrophils located in the thrombus and in the superior sagittal sinus wall adjacent to the thrombus, particularly in CD45-positive cells. A CVT was also associated with vessel wall injuries. Even at a distance from thrombi, the walls of the superior sagittal sinus were inflamed and hemorrhagic. The CD34 staining revealed that the endothelial cells adjacent to the thrombus were largely destroyed.
Researchers hypothesized that immune complexes activate neutrophils and platelets through FcγRIIa binding. The subsequent release of PF4 further enhances anti-PF4 antibody production, which leads to massive activation of platelets and neutrophil extracellular trap formation. This results in immunothrombosis with local complement activation. It is important to note that immune complexes that contain spike protein and antispike IgG antibodies can induce thrombi formation mediated by platelets.
In conclusion, a remarkable architecture of the thrombi was observed. The results showed mostly neutrophils and platelets in the core, and a low number of leukocytes in the tail, as well as the spike protein within neutrophils located in the thrombus and in the venous sinus walls. The thrombus tail was rich in fibrin and red blood cells. The markers of neutrophil extracellular trap and complement activation were present at the border and within the thrombi. Both processes are highly thrombogenic. These data provide strong evidence for the presence of immunothrombosis during vaccine-induced immune thrombotic thrombocytopenia.
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