Prevalence and thrombotic risk of PF4-dependent platelet-activating antibodies.

BACKGROUND: Platelet-activating anti-platelet factor 4 (PF4) antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT). VITT also occurs independent of vaccination. Prevalence and clinical relevance for heparin-dependent HIT antibodies are well described, but information on heparin-independent anti-PF4 antibodies in larger populations remains limited. METHODS: Over ten months, we conducted a cohort study assessing consecutive patient sera referred to the Greifswald laboratory for anti-PF4 antibody testing, with an in-house anti-PF4/heparin IgG enzyme immunoassay (EIA) optical density (OD) ≥1.0, by heparin- and PF4-dependent functional assays (HIPA and PIPA) and obtained clinical data with focus on thrombosis. RESULTS: In 474 study subjects (EIA OD≥1.0) platelet-activating PF4-dependent antibodies were detected in 227 patients (47.9%) by functional assays including 22 patients (6.7%) with isolated PF4-dependent platelet activation (PIPA+/HIPA-). Clinical data on thrombosis were available for 329/474 patients (69.4%). In this subgroup, prevalence of thrombosis increased numerically with higher EIA OD values (OD range 1.0-<1.5, 32.1% [26/81]; 1.5-<2.0, 36.6% [30/82]; 2.0-<2.5, 45.0% [50/111]; and 2.5-<3.5, 50.9% [28/55]; p for trend = 0.10). Thrombosis prevalence increased stepwise from 32.5% in patients negative in both functional assays to 40.0% in HIPA+/PIPA- patients and 47.7% in HIPA+/PIPA+ patients (p for trend=0.016). CONCLUSIONS: PF4-dependent platelet-activating antibodies are more frequent than previously anticipated. Combined HIPA and PIPA testing may help identify functional antibody phenotypes associated with increasing thrombotic risk. Testing for PF4-dependent antibodies should be particularly considered in patients in whom thrombosis and thrombocytopenia precede heparin exposure, as these may be missed by standard HIT assays.