Autoimmune heparin‐induced thrombocytopenia

Abstract

Summary Autoimmune heparin‐induced thrombocytopenia (aHIT) indicates the presence in patients of anti‐platelet factor 4 (PF4)–polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin‐independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin‐induced thrombocytopenia (HIT), serum‐induced platelet activation is inhibited at high heparin concentrations (10–100 IU mL−1 heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin‐dependent platelet activation. Clinical syndromes associated with aHIT include: delayed‐onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux‐associated HIT, heparin ‘flush’‐induced HIT, and severe HIT (platelet count of < 20 × 109 L−1) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti‐PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non‐heparin platelet‐associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4–aHIT‐IgG complexes recruit additional heparin‐dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D‐dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)‐adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT‐associated DIC, known as ‘APTT confounding’. Thus, non‐APTT‐adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long‐term management of persisting HIT. In addition, emerging data indicate that high‐dose intravenous immunoglobulin can interrupt HIT antibody‐induced platelet activation, leading to rapid platelet count recovery.

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

“…To the best of our knowledge, this is the first reported case of spontaneous HIT treated with IVIG. The lack of proximate heparin exposure, significant thrombocytopenia, extensive thrombosis, and strong HIT serologies (including in the SRA performed without addition of heparin in the assay) support this diagnosis. The absence of a quick response to DTI therapy is consistent with other reports of DTI refractoriness in patients with spontaneous HIT .…”

Laboratory diagnosis of heparin‐induced thrombocytopenia

“…aHIT refers to patients with atypical clinical features explainable by unusual HIT antibodies that can activate platelets strongly even in the absence of heparin (heparin‐ independent platelet activation) . In general, when serum/plasma from such patients is diluted, heparin‐ dependent platelet activation can also be demonstrated.…”

“…Platelet activation assays performed both in the presence and absence of heparin are important in supporting a diagnosis of aHIT: Strong platelet activation at 0 U/mL heparin, which is enhanced in the presence of pharmacological concentrations of heparin (0.1‐0.5 U/mL UFH)—either using neat or diluted serum/plasma—with inhibition at 100 U/mL heparin, is the serological picture . The major U.S. reference laboratories that perform the SRA do not perform the test in the absence of heparin, contributing to aHIT underrecognition.…”

“…Interestingly, there is an inverse relationship between the severity of thrombocytopenia and the degree of heparin‐independent platelet activation induced by patient serum . High‐dose intravenous gamma globulin (IVIG) interrupts HIT antibody‐induced platelet activation, resulting in rapid platelet count recovery …”

Heparininduzierte Thrombozytopenie

“…In seltenen Fällen kann die HIT zur Autoimmunerkrankung werden [29,30]. Hier bilden Patienten Antikörper, die an PF4 auf der Thrombozytenoberfläche binden, ohne dass Heparin gegeben wird.…”