Research
Heparin-Induced Thrombocytopenia (HIT)
My research is aimed at understanding why people treated with the drug heparin get a severe, immune reaction called heparin-induced thrombocytopenia (HIT). HIT is an immune-mediated adverse drug reaction where a subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). HIT develops in up to 2.4% of patients receiving heparin, and the mortality rate of HIT patients can reach as high as 30%. The inability to predict HIT before the manifestation of symptoms poses a serious risk in heparin therapy. Heparin treatment is further complicated by the complex pathogenesis of the antibody response.
The focus of my Ph.D. was to interrogate the genetic, demographic and laboratory factors that predispose people to this reaction. Given the small proportion of heparin-treated patients who progress to HIT, genetic predispositions were hypothesized to be a factor in disease progression. However, limited work has been conducted on the genetic influence in HIT. Additionally, little is known of the potential influences of demographic and clinical factors that play a role in a person’s progression from heparin-treated to antibody positive to full-blown HIT. Some demographic factors such as age, body mass index and gender, and clinical factors such as surgery, diabetes status and dosing have been associated with HIT status, but replication and validation of many associations are lacking. Furthermore, speculation of other factors such as chronically altered metal cation milieu, prior bacterial infections, and immune cell tolerance breakdown, among others, have been speculated to influence HIT risk but findings remain sparse. Specifically, as antibodies are necessary but not sufficient for HIT to occur, the focus of my work was the identification of risk factors related to the antibody response seen in HIT.
This work was accomplished by leveraging a number of methodologies underutilized in HIT research. In Aim 1 of my doctorate, we implemented the use of genomic studies with the largest genome-wide association study (GWAS), to date, to identify genomic variation responsible for the disparate antibody response seen in heparin-treated patients. The second aim integrated three large cohort of suspected HIT patients to interrogate the influence of laboratory and demographic variables on anti-PF4/heparin antibody positivity and HIT risk (functional assay positivity). The study design allowed us to interrogate factors that influence the antibody response or HIT itself due to patients having both antibody levels, as determined via ELISA, and platelet reactivity results (HIT positivity) using functional assays. Aim 3 encompassed an independent clinical study performed at University of Arizona – Banner Hospital, where we collected a cohort of patients and analyzed physiologically relevant metal cations in patients’ plasma to determine potential correlation of cation concentrations and anti-PF4/heparin optical density levels.