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

Abstract

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 > or =4 (n=44) had significantly higher median levels of F1+2 (2.49 nmol/l), TAT (13.01 microg/l) and D-dimers (3340 microg/l) compared to patients with undetectable antibodies (n=148; F1+2 1.61 nmol/l, TAT 4.95 micro g/l, D-dimers 1911 micro 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 microg/l, p=0.0018; D-dimers 2231 microg/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.

Dosing lepirudin in patients with heparin-induced thrombocytopenia and normal or impaired renal function: a single-center experience with 68 patients

“…3 The rate of thrombotic complications observed during lepirudin treatment in the whole patient population is 5.9% (4 of 68) and compares very well with the values of 11.2% observed in the HAT-3 study 6 and of 13.8% reported by the Groupe d'Etude sur l'Hémostase et la Thrombose (GEHT)-HIT study group. 9 Of note, 3 of the 4 thromboembolic complications occurred among patients who were initially overanticoagulated and required frequent dose reductions (Table 4).…”

“…This might be explained by the development of antibodies decreasing lepirudin clearance 7 or by a reduced lepirudin requirement consecutive to the attenuation of the procoagulant state characteristic of acute HIT. 3 This observation suggests that even lower lepirudin dosages may be required in the course of HIT treatment and that lepirudin dose should be assessed daily by clotting assays and course of platelets and D-dimers.…”

“…Macromolecular ternary complexes (HIT-antibody/PF4/heparin) are able to activate platelets, endothelial cells, and monocytes, leading to excessive in vivo thrombin generation. 3 The treatment of HIT requires not only the immediate discontinuation of all heparin but also the introduction of alternative nonheparin anticoagulation in therapeutic doses, to counterbalance the strong procoagulant state. 1,2 Drugs approved for HIT treatment are the direct thrombin inhibitors lepirudin and argatroban and the heparinoid danaparoid.…”

Anti-Heparin/PF4 Complexes by ELISA in Patients with Disseminated Intravascular Coagulation

“…The titers of IgG-HIT antibodies correlated with those of prothrombin fragments F1 and F2, TAT and D-dimer. Therefore, high levels of IgG-HIT antibodies naturally led to an increase in thrombin generation in HIT [17] . However, we could not clearly distinguish between DIC with a weakly positive result and DIC-HIT based on the 4 coagulation tests.…”

Early heparin-induced thrombocytopaenia (HIT) after cardiac surgery

“…Thrombosis develops in up to 50% of HIT patients managed by heparin cessation alone. Chilver-Stainer and colleagues showed 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 title 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 [13]. Surgical or interventional measures to reopen thrombosed arteries are usually futile because the platelet-rich thrombus (white clot) often extends into the small arterioles.…”