Vaccine-induced immune thrombotic thrombocytopenia: current evidence, potential mechanisms, clinical implications, and future directions

Abstract

Vaccine-induced immune thrombotic thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild-to-severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)-polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA; (iv) occurring 5-30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccination. VITT's incidence is 1 per 100 000 vaccinated people irrespective of age and up to 1 in 50 000 for people <50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirus-vectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are thought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia.

Keywords: COVID-19; Cerebral sinus venous thrombosis; PF4; Thrombocytopenia vaccine-induced immune thrombotic thrombocytopenia; Thrombosis; Vaccine; Venous thromboembolism.

Graphical Abstract

Figure 1

Model for VITT. We postulate a simplified model for the pathogenesis of VITT according to current evidence. One, adenovirus-vectored COVID-19 vaccines trigger the production of antiPF4–polyanion antibodies. The precise pathogenesis for the immune response and which components (adenoviral sequence, spike protein, other component) of the Ad26.COV2.S and ChAdOx1 nCoV-19 may be held responsible for the production of anti-PF4 antibodies remain unknown. Two, circulating PF4 antibodies complexes bind platelets and monocytic cells. Three, activation of FcγRIIA receptors causes cell monocytic activation, platelet activation, plasma membrane remodelling, phosphatidylserine exposure, P-selectin’s platelet expression, secretion of alpha granules containing PF4 and release of procoagulant microparticles, leading to further platelet activation that causes thrombosis and thrombocytopenia. Healthcare professionals should be aware of the high frequency of other thrombosis sites most likely to include jugular vein thrombosis, pulmonary embolism, deep vein thrombosis and splanchnic vein thrombosis. Concomitant or secondary bleeding and/or intracerebral haemorrhage is a frequent feature observed in VITT patients. PF4, platelet factor 4; VITT, vaccine-induced immune thrombotic thrombocytopenia; VTE, venous thrombotic events.

Figure 2

Future research in VITT. The molecular basis and multimodality pathways in VITT pathogenesis have not yet been fully elucidated. Future studies should specifically address the following points. (i) Which components (adenoviral sequence, spike protein, other component) of the Ad26.COV2.S and ChAdOx1 nCoV-19 sre responsible for the production of anti-PF4 antibodies. (ii) The role for microparticles in VITT. (iii) The role for a TF-dependent pathway. (iv) The precise mechanisms of a likely pancellular activation including neutrophil activation and NETosis burst, endothelial activation, platelet activation, and monocyte activation. PF4, platelet factor 4; TF, tissue factor); VITT, vaccine-induced immune thrombotic thrombocytopenia.