Prevalence and thrombotic risk of platelet factor 4-dependent platelet-activating antibodies

Platelet-activating anti-platelet factor 4 (PF4) antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis. Vaccine-induced immune thrombocytopenia and thrombosis also occurs independent of vaccination. Prevalence and clinical relevance of heparin-dependent HIT antibodies are well described, but information on heparin-independent anti-PF4 antibodies in larger populations remains limited.

To determine the prevalence of PF4-dependent and heparin-dependent platelet-activating antibodies in patients referred for evaluation of suspected HIT or other anti-PF4 disorders and to assess their association with thrombotic complications and thrombocytopenia.

Over 10 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 immunoglobulin G enzyme immunoassay (EIA) optical density (OD) ≥1.0, by heparin- and PF4-dependent functional assays (heparin-induced platelet activation [HIPA] and PF4-induced platelet activation [PIPA]) and obtained clinical data with focus on thrombosis.

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 of 474 patients (69.4%). In this subgroup, prevalence of thrombosis increased numerically with higher EIA OD values (OD range 1.0 to <1.5, 32.1% [26 of 81]; OD range 1.5 to <2.0, 36.6% [30 of 82]; OD range 2.0 to <2.5, 45.0% [50 of 111]; and OD range 2.5 to <3.5, 50.9% [28 of 55]; P for trend = .10). Thrombosis prevalence increased stepwise from 32.5% in patients with negative results in both functional assays to 40.0% in HIPA+/PIPA- patients and 47.7% in HIPA+/PIPA+ patients (P for trend = .016).

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.