Frequency of Heparin-Induced Thrombocytopenia and Heparin-Dependent IgG Antibodies in Hematopoietic Stem Cell Transplant Recipients.
Authors: Elliott Michelle A. , Schulte Sandra , Plumhoff Elizabeth A. , Pruthi Rajiv K. , Nichols William L. , Litzow Mark R. , Gastineau Dennis A. , Heit John A. 
Published: April 2020

Background

Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction in which heparin-dependant IgG antibodies (HIT-IgG) to heparin-platelet factor 4 complexes form with the potential for platelet activation with resultant thrombocytopenia (HIT) and thrombosis (HITT). The frequency of HIT-IgG formation and clinically apparent HIT or HITT varies considerably, according to the patient population (surgical versus medical) and type of heparin (unfractionated [UFH] vs low molecular weight [LMWH]). One large prospective study showed a frequency of HIT-IgG formation of 7.5% with clinical HITT in 34.5% of these orthopedic patients receiving prophylactic LMWH and corresponding figures in cardiac surgery patients receiving UFH were 50% and 2%, respectively [Warkentin et al. Blood2000;96: 1703]. Due to daily exposure to heparin flushes (UFH) and prophylactic LMWH (to prevent venoocclusive disease) hematopoietic stem cell transplant (HSCT) recipients may be at risk for HIT/HITT. However, due to anticipated post-transplant thrombocytopenia, clinical cases of HIT/HITT may be overlooked. We retrospectively determined the incidence of HIT-IgG formation and its clinical significance in this population.

Methods: HIT-IgG was measured retrospectively using a commercially available ELISA kit in samples collected from patients prior to conditioning therapy and on day 14 post-HSCT. Medical records were reviewed to in order to determine the clinical significance (development of clinical HIT/HITT) in those with detectable HIT-IgG.

Patients

Samples from a total of 103 HSCT recipients with hematologic malignancy (including 25 myeloma, 17 lymphoma, 16 AML, 14 amyloid, 10 MDS, 10 ALL, 8 CML and 3 CLL) were tested, of which 52 and 49 underwent allogeneic and autologous HSCT, respectively. All patients were exposed to UFH flushes during line care. In addition, all allogeneic recipients received prophylactic subcutaneous dalteparin 5000U daily beginning with conditioning until engraftment. Conditioning regimens included high dose melphalan (n=34), cyclophosphamide/TBI (n=30), carmustine, etoposide, cytarabine, melphalan (n=15), busulfan/cyclophosphamide (n=9), fludarabine/melphalan (n=10) and fludarabine/TBI (n=4). The median age was 51.5 years (20–72) and 68 were male.

Results:

The median platelet count prior to initiation of conditioning therapy and at day 14 was 157 × 109/L (range: 10–672) and 40 × 109/L (range: 9–289), respectively. Prior to conditioning, two of 103 (1.9%) patients had a positive HIT-IgG assay, that became negative in one and equivocal in the other by day 14 post-HSCT, and one patient had an equivocal HIT assay that became negative by day 14. All 3 were autologous recipients. None of the previously negative patients had a positive HIT-IgG assay at day 14, although 3 patients (2 autologous and one allogeneic) had an equivocal result of uncertain significance. No patients developed clinical or symptomatic thrombosis (HITT).

Conclusion:

In spite of frequent exposure to heparin, the frequency of seroconversion is low, and in those patients with preexisting HIT-IgG, no patient developed symptomatic thrombosis, including the 2 patients with positive HIT IgG assays prior to conditioning. The low frequency of HIT-IgG formation may reflect the profound immunosuppression of the conditioning regimens employed. Nevertheless, in this population, a high index of clinical suspicion must be maintained.