Titre of anti-heparin/PF4-antibodies and extent of in vivo activation of the coagulation and fibrinolytic systems

Heparin-induced thrombocytopenia (HIT) is mediated by antibodies directed against the heparin/platelet factor 4 (PF4) complex. Our aim was to investigate whether the antibody titre is associated with the degree of in vivo thrombin generation. We measured the anti-heparin/PF4-antibody titre, prothrombin fragments F1+2, thrombin-antithrombin (TAT) complexes and D-dimers in plasma samples from 225 patients with suspected HIT Antibody titres as detected by a particle gel immunoassay strongly correlated with optical density values measured by ELISA (r=0.84, p<0.0001). Patients with titres >= 4 (n=44) had significantly higher median levels of F1+2 (2.49 nmol/l),TAT (13.01 mu g/) and D-dimers (3340 mu g/l) compared to patients with undetectable antibodies (n=148; F1+2 1.61 nmol/l, TAT 4.95 mu g/l, D-dimers 1911 mu g/l; p<0.0001 for all comparisons) or patients with titres of 1-2 (n=33; F1+2 1.44 nmol/l, p=0.0014; TAT 4.37 mug/l, p=0.0018; D-dimers 2231 mug/l, p=0.0016). Multivariate analysis indicated the anti-heparin/PF4-antibody titre as an independent predictor for F1+2 (p=0.0036), TAT (p=0.0176) and D-dimer (p=0.0003) levels. This relationship remained statistically significant after exclusion of patients with concomitant prothrombotic conditions and/or thromboembolic complications during heparin treatment. These data demonstrate that high anti-heparin/PF4-antibody titres are independently associated with an increased in vivo thrombin generation. Rapid determination of the anti-heparin/PF4-antibody titre could help guide clinical management, identifying a subset of HIT-patients who are at high risk of developing thromboembolic complications and possibly require alternative anticoagulation in therapeutic dosage even in the context of isolated HIT.