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

Vox Sang. 2024 Jul;119(7):728-736. doi: 10.1111/vox.13633. Epub 2024 Apr 10.

Abstract

Background and objectives: Vaccine-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 methods: We 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.

Results: We 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.

Conclusion: Our 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.

Keywords: COVID‐19; platelet factor 4; thrombocytopenia; thrombosis; vaccination.

MeSH terms

  • Adult
  • Aged
  • Blood Platelets / immunology
  • Blood Platelets / metabolism
  • COVID-19
  • COVID-19 Vaccines* / adverse effects
  • COVID-19 Vaccines* / immunology
  • Female
  • Heparin / adverse effects
  • Humans
  • Immunoglobulin G / blood
  • Male
  • Middle Aged
  • Netherlands
  • Platelet Activation* / immunology
  • Platelet Factor 4* / immunology
  • Receptors, IgG*
  • Thrombocytopenia* / blood
  • Thrombocytopenia* / chemically induced
  • Thrombocytopenia* / diagnosis
  • Thrombosis* / blood
  • Thrombosis* / diagnosis
  • Thrombosis* / etiology
  • Thrombosis* / immunology

Substances

  • Platelet Factor 4
  • COVID-19 Vaccines
  • Receptors, IgG
  • PF4 protein, human
  • Fc gamma receptor IIA
  • Heparin
  • Immunoglobulin G