Vaccine‐induced immune thrombocytopenia and thrombosis: The decline in anti‐platelet factor 4 antibodies is assay‐dependent

Platton, Sean; Schönborn, Linda; Charrot, Sarah; Badat, Mohsin; Boot, Jesca; McDonald, Vickie; Sivapalaratnam, Suthesh; Bariana, Tadbir K.; Theodoulou, Angela; Bowles, Louise; MacCallum, Peter

doi:10.1111/bjh.18022

Cited by 6 publications

(2 citation statements)

References 7 publications

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“…In the meantime, more detailed algorithms have been developed in which either a positive anti-PF4 or a positive functional assay is considered sufficient to support a VITT diagnosis [17,38]. Given the discrepancies in our diagnostics test, combining an ELISA with a functional assay-although not widely available-could better distinguish genuine antibody-mediated VITT cases from others testing positive for anti-PF4/polyanion, thus ensuring appropriate treatment [16,[39][40][41]. The large proportion of patients with thrombocytopenia and/or thrombosis in individuals who did not test positive for anti-PF4 may be partially, but not entirely, explained by other underlying conditions such as cancer [17].…”

Section: Platelet Activation In Suspected Vitt Patients Treated With ...mentioning

confidence: 99%

Laboratory approach for vaccine‐induced thrombotic thrombocytopenia diagnosis in the Netherlands

Meier,

Porcelijn,

Hofstede‐van Egmond

et al. 2024

Vox Sanguinis

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Background and ObjectivesVaccine‐induced thrombotic thrombocytopenia (VITT) is a rare adverse effect characterized by thrombocytopenia and thrombosis occurring after COVID‐19 vaccination. VITT pathophysiology is not fully unravelled but shows similarities to heparin‐induced thrombocytopenia (HIT). HIT is characterized by the presence of antibodies against platelet factor 4 (PF4)/heparin complex, which can activate platelets in an FcγRIIa‐dependent manner, whereas IgG‐antibodies directed against PF4 play an important role in VITT.Materials and MethodsWe characterized all clinically suspected VITT cases in the Netherlands from a diagnostic perspective and hypothesized that patients who developed both thrombocytopenia and thrombosis display underlying mechanisms similar to those in HIT. We conducted an anti‐PF4 ELISA and a functional PF4‐induced platelet activation assay (PIPAA) with and without blocking the platelet‐FcγRIIa and found positivity in both tests, suggesting VITT with mechanisms similar to those in VITT.ResultsWe identified 65 patients with both thrombocytopenia and thrombosis among 275 clinically suspected VITT cases. Of these 65 patients, 14 (22%) tested positive for anti‐PF4 and PF4‐dependent platelet activation. The essential role of platelet‐FcγRIIa in VITT with mechanisms similar to those in HIT was evident, as platelet activation was inhibited by an FcγRIIa‐blocking antibody in all 14 patients.ConclusionOur study shows that only a small proportion of clinically suspected VITT patients with thrombocytopenia and thrombosis have anti‐PF4‐inducing, FcɣRIIa‐dependent platelet activation, suggesting an HIT‐like pathophysiology. This leaves the possibility for the presence of another type of pathophysiology (‘non‐HIT like’) leading to VITT. More research on pathophysiology is warranted to improve the diagnostic algorithm and to identify novel therapeutic and preventive strategies.

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Section: Platelet Activation In Suspected Vitt Patients Treated With ...mentioning

confidence: 99%

Laboratory approach for vaccine‐induced thrombotic thrombocytopenia diagnosis in the Netherlands

Meier,

Porcelijn,

Hofstede‐van Egmond

et al. 2024

Vox Sanguinis

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“…96 97 Accordingly, if VITT is strongly suspected on clinical grounds, a sample yielding an unexpected negative EIA should be tested in another EIA (or a functional assay). Interestingly, a VITT study 98 evaluating serial sample EIA reactivity showed that from initial EIA-positive reactivity (at the time of initial diagnosis), different EIAs differed with respect to seroreversion, namely, the IgG-specific Zymutest became negative in all patients prior to another IgG-specific PF4/PVS-EIA becoming negative. This observation suggests there may well be inherent differences in diagnostic sensitivity between these two EIAs.…”

Section: Pf4-dependent Enzyme Immunoassaysmentioning

confidence: 99%

Laboratory Testing for Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia Antibodies: A Narrative Review

Warkentin

Greinacher

2022

Semin Thromb Hemost

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Heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT) are highly prothrombotic (thrombosis frequency ≥50%). Both are caused by platelet-activating anti-platelet factor 4 (PF4) antibodies, forming PF4/IgG-containing immune complexes that engage platelet FcγIIa receptors, producing strong platelet activation. In HIT, heparin crosslinks several PF4 molecules, whereas in VITT, anti-PF4 antibodies alone crosslink PF4. Sufficient levels of circulating anti-PF4 antibodies are needed to create the pathogenic immune complexes on platelet surfaces; this explains why certain serum (plasma)-based assays are highly sensitive for detecting HIT/VITT antibodies. Accordingly, HIT and VITT are “clinical-pathological” disorders, that is, positive testing for such antibodies—together with a compatible clinical picture—is integral for diagnosis. Heparin (low concentrations) enhances HIT antibody-induced platelet activation, but platelet activation by VITT sera is usually inhibited by heparin. For both HIT and VITT, high sensitivity (>99% and >95%, respectively) characterizes PF4-dependent enzyme immunoassays (EIAs) and PF4-enhanced platelet activation assays; in contrast, certain rapid immunoassays have high sensitivity for HIT (>90-97%) but poor sensitivity (<25%) for VITT. HIT and VITT antibodies are directed at distinct sites on PF4: solid-phase EIAs and platelet activation assays are indifferent to these distinct antigen targets, but rapid immunoassays are not. We discuss a conceptual model where PF4 is viewed as a “globe,” with the heparin-binding site the “equator”; in this model, HIT antibodies are primarily directed at antigen site(s) at the north and south “poles” of PF4 (formed when PF4 binds to heparin), whereas VITT antibodies recognize sites on the equator.

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Azd-1222

2022

Reactions Weekly

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Vaccine‐induced immune thrombocytopenia and thrombosis: The decline in anti‐platelet factor 4 antibodies is assay‐dependent

Cited by 6 publications

References 7 publications

Laboratory approach for vaccine‐induced thrombotic thrombocytopenia diagnosis in the Netherlands

Laboratory approach for vaccine‐induced thrombotic thrombocytopenia diagnosis in the Netherlands

Laboratory Testing for Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia Antibodies: A Narrative Review

Azd-1222

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