Developing an assay to distinguish between HIT and VITT antibodies

Schönborn, Linda; Wesche, Jan; Fuhrmann, Julia; Esteban, O; Dobosz, P; Broto, M; Serra, J; Llevadot, R; Greinacher, Andreas

doi:10.1055/s-0042-1760584

Cited by 3 publications

(7 citation statements)

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“…We used 2 rapid assays to detect anti-PF4/heparin and anti-PF4 antibodies, respectively, using chemiluminescence technology (described subsequently): the HemosIL AcuStar HIT-IgG (PF4-H) assay, hereafter called rapid anti-PF4/heparin assay (the assay uses PF4/polyvinyl sulfonate complexes [PVS]); and a novel anti-PF4 antibody assay prototype for the ACL AcuStar, hereafter called new rapid anti-PF4 assay. 16 Both assays are 2-step chemiluminescence immunoassays consisting of magnetic particles coated either with PF4 complexed to PVS or with PF4 alone. The new rapid anti-PF4 assay was designed to detect antibodies that only recognize anti-PF4 antibodies (as seen in VITT) with no or minimal cross-reactivity with anti-PF4/heparin antibodies.…”

Section: Methodsmentioning

confidence: 99%

“… 14 Furthermore, antibodies in HIT bind to heparin-dependent antigen sites, whereas VITT antibodies bind at the heparin-binding site on PF4. 15 A problem for clinical laboratories is that VITT antibodies are not recognized by widespread rapid assays for HIT antibodies 16 , 17 ; moreover, VITT antibodies often test negative in the classic functional tests for HIT. These test performances have been overcome by a recently developed rapid chemiluminescence assay, which recognizes VITT antibodies but not most HIT antibodies, 16 and by modifying the functional test by adding PF4 instead of heparin.…”

Section: Introductionmentioning

confidence: 99%

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Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure

Schönborn,

Esteban,

Wesche

et al. 2023

Blood

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Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion EIA and negative/weakly-positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (i.e., VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL® AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained prior to 2020 (n=188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n=3; cerebral venous sinus thrombosis, n=4), thrombocytopenia (median platelet count nadir, 49×109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10min in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure

Schönborn,

Esteban,

Wesche

et al. 2023

Blood

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“…The only obvious common factor in VITT patients after Ad26-CoV2S or ChAdOx1 vaccination and VITT-like syndromes after viral infections is the virus. This hints towards a causative role of the virus in the pathogenesis of VITT [62].…”

Section: Insights Into Vaccine Components and Their Mechanistic Role ...mentioning

confidence: 84%

“…This might explain the lower incidence of VITT after vaccination with Ad26-COV-2S [61]. Recently several patients have been identified who presented with a VITT-like syndrome, including thrombocytopenia, thrombosis at unusual sites, high D-dimer levels and PF4-dependent, platelet-activating antibodies [62]. Several of these patients had a virus infection preceding the VITT-like complications.…”

Section: Insights Into Vaccine Components and Their Mechanistic Role ...mentioning

confidence: 99%

Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT)—Insights from Clinical Cases, In Vitro Studies and Murine Models

Dabbiru,

Müller,

Schönborn

et al. 2023

JCM

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An effective worldwide vaccination campaign started and is still being carried out in the face of the coronavirus disease 2019 (COVID-19) pandemic. While vaccines are great tools to confront the pandemic, predominantly adenoviral vector-based vaccines can cause a rare severe adverse effect, termed vaccine-induced immune thrombocytopenia and thrombosis (VITT), in about 1 in 100,000 vaccinated individuals. VITT is diagnosed 5–30 days post-vaccination and clinically characterized by thrombocytopenia, strongly elevated D-dimer levels, platelet-activating anti-platelet factor 4 (PF4) antibodies and thrombosis, especially at atypical sites such as the cerebral venous sinus and/or splanchnic veins. There are striking similarities between heparin-induced thrombocytopenia (HIT) and VITT. Both are caused by anti-PF4 antibodies, causing platelet and leukocyte activation which results in massive thrombo-inflammation. However, it is still to be determined why PF4 becomes immunogenic in VITT and which constituent of the vaccine triggers the immune response. As VITT-like syndromes are increasingly reported in patients shortly after viral infections, direct virus-PF4 interactions might be most relevant. Here we summarize the current information and hypotheses on the pathogenesis of VITT and address in vivo models, especially murine models for further studies on VITT.

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“…Furthermore, HIT and VITT antibodies bind to different epitopes on PF4 9 10 and recently developed immunoassays are able to differentiate HIT-like and VITT-like antibodies. 11 12 CVST is the most frequent site for the thrombosis in VITT, with a consequently higher rate of ICH. 3 It is not clear why patients with VITT have preponderance of CVST, although this may reflect pathophysiologic consequences of differences in the antigen targeted on PF4.…”

Section: Tablementioning

confidence: 99%

Heparin-induced Thrombocytopenia with Thrombosis in COVID-19 versus Vaccine-induced Immune Thrombocytopenia and Thrombosis in the United Kingdom

Arachchillage,

Rajakaruna,

Makris

et al. 2024

Semin Thromb Hemost

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Developing an assay to distinguish between HIT and VITT antibodies

Cited by 3 publications

References 1 publication

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure

Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT)—Insights from Clinical Cases, In Vitro Studies and Murine Models

Heparin-induced Thrombocytopenia with Thrombosis in COVID-19 versus Vaccine-induced Immune Thrombocytopenia and Thrombosis in the United Kingdom

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