key: cord-0067025-0nkenrvs
authors: Marchandot, Benjamin; Curtiaud, Anais; Trimaille, Antonin; Sattler, Laurent; Grunebaum, Lelia; Morel, Olivier
title: Vaccine-induced Immune Thrombotic Thrombocytopenia: Current Evidence, Potential Mechanisms, Clinical Implications, and Future Directions
date: 2021-08-02
journal: nan
DOI: 10.1093/ehjopen/oeab014
sha: 4c2d9c03197dc7c4f2cd2305fa845c36be982648
doc_id: 67025
cord_uid: 0nkenrvs

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 assay (iv) occurring 5 to 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 sought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia.

Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia 3 syndrome by the CDC and FDA or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune 4 thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild to severe thrombocytopenia ; (iii) 5 positive antiplatelet factor 4 (PF4)-polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT 6 (heparin-induced thrombocytopenia) ELISA assay (iv) occurring 5 to 30 days after ChAdOx1 nCoV-19 7 (AstraZeneca) or Ad26.COV2.S (Johnson&Johnson/Janssen) vaccination (5). This definition stands for the 8 classical and typical VITT syndrome described in initial reports (6-13) (Table1). Apart from the "typical VITT 9 syndrome" that associates cerebral sinus venous thrombosis (CSVT) and low platelet count, healthcare 10 professionals should be aware of the high frequency of other thrombosis sites such as jugular vein thrombosis and 11 splanchnic vein thrombosis (Table1). Concomitant or secondary bleeding and intracerebral hemorrhage in 12 particular, is a frequent feature observed in VITT patients.

The whole spectrum of the VITT syndrome is not yet fully elucidated as this may include hemorragic events only 15 (8) , thrombotic microangiopathy (12), thrombocytopenic purpura (14) 

(iv) The role for a TF-dependant pathway. Indeed, tissue factor (TF) exhibits a nonuniform tissue distribution and 1 is highly expressed in the brain (43). Cerebral microvascular thrombogenesis was further evidenced as an 2 endothelial cell-associated TF response in venules, but not arterioles (44) and platelet-neutrophil interaction 3 triggered by HIT antibodies is known to activate vascular endothelium (45). Tissue factor activates factor VII and 4 therefore the extrinsic pathway of the coagulation cascade, resulting in generation of thrombin that cleaves soluble 5 fibrinogen to insoluble fibrin and activates platelets via protease-associated receptors 1 and 4 (46) . Altogether, 6 these data support a close interplay between a TF-dependant pathway and VITT induced CSVT. . .

. .

. Figure 1 . Model for Vaccine-Induced Immune Thrombocytopenia (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 remodeling, 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 hemorrhage is a frequent feature observed in VITT patients. 

Morphological analysis 3 of microparticle generation in heparin-induced thrombocytopenia

Platelet-Derived and Leukocyte-Derived Circulating Microparticles and the Risk of Thrombosis in Heparin-7

Induced Thrombocytopenia: A Role for PF4-Bearing Microparticles?

Sources of tissue factor

Role of coagulation factors in 12 cerebral venous sinus and cerebral microvascular thrombosis

Newer insights on the mechanism of heparin-induced 15 thrombocytopenia

Platelets and the Endothelium: Active Participants in Severe

Studies of the immune response in heparin-19 induced thrombocytopenia

An observational study to identify the prevalence of 22 thrombocytopenia and anti-PF4/polyanion antibodies in Norwegian health care workers after COVID-19 23 vaccination

Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca

Vaccination: Guidance Statement from the GTH. Hamostaseologie

Frequency of positive anti-PF4/polyanion antibody tests after COVID-29 19 vaccination with ChAdOx1 nCoV-19 and BNT162b2

Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)

Vaccine-induced prothrombotic immune 4 thrombocytopenia (VIPIT): Consider IVIG batch in the treatment

SARS-CoV-2 vaccine and thrombosis: Expert opinions

High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced 10 thrombocytopenia: a review

Haemostasis and Thrombosis Task Force of the British Committee for 12

Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: 13 second edition

Management of Cerebral Venous Sinus Thrombosis with Vaccine-Induced Thrombotic Thrombocytopenia

Vaccine-induced immune thrombotic thrombocytopenia 19 (VITT): targeting pathomechanisms with Bruton tyrosine kinase inhibitors

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 is responsible for the production of anti-PF4 antibodies (ii) The role for microparticles in VITT (iii) The role for a Tissue factor (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; Tissue factor (TF); VITT = Vaccine-induced Immune Thrombotic Thrombocytopenia