Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT)

Greinacher, Andreas; Schönborn, Linda; Siegerist, Florian; Steil, Leif; Palankar, Raghavendra; Handtke, Stefan; Reder, Alexander; Thiele, Thomas; Aurich, Konstanze; Methling, Karen; Lalk, Michael; Völker, Uwe; Endlich, Nicole

doi:10.1053/j.seminhematol.2022.02.004

Cited by 37 publications

(40 citation statements)

References 63 publications

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“…The counterargument to this is that adenovirus vector has been utilized in the manufacture of other vaccines such as Ebola and AIDS vaccines, albeit there have been no VITT-like adverse effects reported with either of them [ 8 ]. It may very well be that some other component(s) of the vaccine, such as polysorbate 80 may be the provoking factor in the formation of anti-PF4 antibodies although another source suggests that it is unlikely to play a role in the pathogenesis [ 8 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis

Abbasi¹,

Alsermani²,

Alsegayyir³

et al. 2022

Cureus

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Vaccines have been vital in preventing and curbing the spread of SARS-CoV-2 infection. Adenoviral vector-based vaccines, namely the ChAdOx1-S vaccine (AstraZeneca, Cambridge, UK) and Ad26.COV2.S (Janssen; Johnson & Johnson, New Brunswick, NJ, USA), have been associated with a possibly fatal adverse event known as vaccine-induced thrombotic thrombocytopenia (VITT), wherein thrombi form in unusual sites, mainly the cerebral and splanchnic veins. With the female gender predominantly affected, patients present with headache, abdominal pain, neurological symptoms and fever. It is hypothesized that certain components of the vaccine, including the adenovirus vector, may trigger the formation of antibodies against platelet factor 4 (PF4). The antigen-antibody complexes that form thereafter then activate a cascade of reactions eventually leading to the consumptive coagulopathy. This pathogenesis closely resembles a well-understood complication of heparin, known as heparin-induced thrombocytopenia. The lab results in VITT are reflective of its proposed pathophysiology: low platelets, low fibrinogen and high D-dimer, in addition to elevated anti-PF4 titers are classic findings. Treatment mainly includes non-heparin anticoagulants, intravenous immune globulin (IVIG) and plasma exchange. There is some role for surgical intervention, such as mechanical thrombectomy. Mortality due to VITT is usually caused by cerebral hemorrhage. We describe a case of a 36-year-old female who presented with epigastric pain two weeks after receiving her first dose of the AstraZeneca vaccine, and upon workup, was subsequently found to have thrombosis of her right portal and right common iliac vein.

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Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis

Abbasi¹,

Alsermani²,

Alsegayyir³

et al. 2022

Cureus

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“…In VITT, it has been hypothesized that following microvascular damage during vaccine administration, trace amounts of 50 billion virus particles in each dose come into contact with blood, bringing AdV DNA and polyadenylated hexone proteins the AdV vectors in contact with PF4. Either component of AdV could replace heparin as a scaffold of negative charges leading to the conformational changes of PF4 molecule already described in HIT and to the formation of anti-PF4/polyanion antibodies [39] , [40] , [41] , [42] . These VITT antibodies bind to PF4 epitopes which overlap with the binding site of heparin but differ from those recognized by anti-PF4 antibodies seen in HIT [43] .…”

Section: Potential Mechanisms Of Vaccine-induced Thrombosis and Throm...mentioning

confidence: 99%

“…Indeed, the typical time window of 5–20 days between the vaccine administration and the onset of symptoms in VITT, strongly recall the temporary pattern of a secondary, rather than primary, immune response. The inflammatory response associated to vaccine inoculation could provide an important co-signal that stimulates antibody production by preformed B-cells capable of producing anti-PF4 antibodies, as occurs in the pathogenesis of classic HIT [ 42 , 57 , 58 ].…”

Section: The Core Question: Why Me?mentioning

confidence: 99%

Potential mechanisms of vaccine-induced thrombosis

Coluccio

Luppi

2022

European Journal of Internal Medicine

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“…6 Pathogenic anti-PF4 IgGs subsequently form circulating immune complexes with PF4 tetramers which are thought to drive thrombotic events by Fc gamma receptor IIa (FcγRIIa)dependent platelet activation and to activate granulocytes to release procoagulant neutrophil extracellular traps (NETS). [6][7][8] Serum anti-PF4 antibodies are mostly transient and appear in serum within days of vaccination, suggesting a recall immune response on memory B-cells. 9 Given their causal role in VITT, identification of the molecular composition of the anti-PF4 antibodies and their antigenic target(s) is crucial for developing better diagnostics and treatments and for precise tracking of PF4-specific B-cell clones and secreted clonotypes.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody

Wang

Armour

Chataway

et al. 2022

Preprint

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Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare thromboembolic complication of adenoviral-vectored SARS-CoV2 vaccines, mediated by antibodies directed against platelet factor 4 (PF4). Given their causal role in VITT, identification of the molecular composition of anti-PF4 antibodies is crucial for developing better diagnostics and treatments. Here, we utilised a novel proteomic workflow to analyse the immunoglobulin variable (IgV) region composition of anti-PF4 antibodies at the level of the secreted proteome. Serum anti-PF4 IgG antibodies from five patients with VITT triggered by ChAdOx1 nCoV-19 vaccination were affinity purified by PF4-coupled magnetic beads and sequenced by mass spectrometry. We revealed a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species in all five unrelated patients. Remarkably, all L-chains were encoded by the identical IGLV3-21*02 gene subfamily with identical L-chain third complementarity determining region (LCDR3) lengths. Moreover, striking stereotypic features were also identified in heavy-chains anti-PF4 antibodies characterised by identical HCDR3 length and homologous sequences. In summary, we unravelled the molecular signature of highly stereotyped clonotypic anti-PF4 antibodies, indicating shared pathways of antibody production in VITT patients. These discoveries are critical to understand the molecular basis of this serious condition and develop novel therapies aimed at removing pathogenic clones.KEY POINTSAnti-PF4 antibodies in VITT comprise highly stereotyped clonotypeA single IGLV3-21*02 encoded light chain is found in unrelated patients

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Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT)

Cited by 37 publications

References 63 publications

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis

Potential mechanisms of vaccine-induced thrombosis

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody

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