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

Linda Schönborn, Olga Esteban, Jan Wesche, Paulina Dobosz, Marta Broto, Sara Rovira Puig, Jessica Fuhrmann, Raquel Torres, Josep Serra , Roser Llevadot, Marta Palicio, Jing Jing Wang, Tom Paul Gordon, Edelgard Lindhoff-Last, Till Hoffmann, Lorenzo Alberio, Florian Langer, Christian Boehme, Eugenia Biguzzi, Leonie GrosseMatthias Endres, Thomas G. Liman, Thomas Thiele, Theodore E. Warkentin, Andreas Greinacher

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
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Abstract

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 enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, 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 before 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 <10 minutes 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.

Original languageEnglish
Pages (from-to)2305-2314
Number of pages10
JournalBlood
Volume142
Issue number26
Early online date26 Oct 2023
DOIs
Publication statusPublished - 28 Dec 2023

Keywords

  • VITT
  • HIT
  • TTS
  • platelet factor 4
  • vaccination
  • thrombosis

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