Heparin Re-Exposure in Patients with Heparin-Induced Thrombocytopenia (HIT)

Introduction

Patients with a history of HIT, who require cardiopulmonary bypass (CPB), have limited anticoagulation options. Unfractionated heparin (UFH) is preferred by surgeons during CPB because of their extensive experience, short half-life of the drug, and the availability of protamine sulfate to reverse its effect. However, heparin re-challenge may be associated with a risk of recurrence of HIT. A number of instances of successful heparin re-exposure during CPB have been reported in HIT patients. However, small sample size of these reports and a lack of systemic review have prevented better understanding of the potential complications. The objective of this study was to determine the safety of heparin re-exposure in HIT patients and various strategies utilized to reduce the recurrence of HIT.

Methods

Using several search terms, all cases of heparin re-exposure in HIT patients published and indexed in English language in Pubmed by June 2014 were reviewed. The bibliography of each relevant article was searched for additional related reports. The diagnosis of HIT was based on the clinical probability or 4T scoring system and laboratory tests. The exposure to either UFH or low molecular weight heparin (LMWH) in patients with a history of HIT was considered a re-exposure. In two cases, heparin was used multiple times for repeated cardiovascular surgeries after an initial diagnosis of HIT. Each re-exposure was determined as a different instance of re-exposure during analysis.

Results

A total of 136 patients with a history of HIT had 141 instances of heparin re-exposure. Median age was 56 years (6 weeks -87 yrs) and 67% were males. Regarding the original HIT diagnosis, UFH (98%) and nadroparin (2%) were the causative agents. Thrombotic complications occurred in 23%. The pretest probability score was high in 79% and moderate in 21%. Platelet aggregation studies (66%), enzyme linked immunosorbent assay (ELISA)/enzyme immunoassay (EIA) (20%), serotonin release assay (SRA) (2%), and both SRA and EIA (12%) were performed for diagnosis.

Cardiac (76%) and vascular surgeries (11%) were the most common indications for heparin re-exposure. Although 67% were re-exposed to heparin after 3 months of HIT diagnosis, 11%, 8% and 15% were re-exposed within 1 week, between 1 week to 1 month, and 1 month to 3 months of HIT diagnosis respectively. Anti-platelet factor 4/heparin antibodies were positive in 63% before re-exposure. UFH (93%) or LMWH (7%) were the utilized agents during re-exposure.

Sixteen patients (11%) underwent plasmapheresis to lower the level of anti-platelet factor 4/heparin antibodies before the re-exposure. Non-heparin anticoagulants such as bivalirudin, fondaparinux, danaparoid, r-hirudin, argatroban, lepirudin, and warfarin were used singly or in combination after the exposure in 63% of patients.

With heparin re-exposure, 4.2% had complications, which included recurrence of HIT (2.1%), and bleeding (2.1%). Among the patients with HIT recurrence (n=3), one patient was re-exposed to UFH within a week of HIT diagnosis and shortly after platelet recovery with LMWH (Intensive Care Med. 1991;17(3):185-6.). The other two patients were initially diagnosed with HIT more than 5 years back and tested negative for anti-platelet factor 4/heparin antibody prior to heparin re-exposure.

Conclusion

A review of the published reports indicates that intra-operative heparin re-exposure in patients with HIT has a small risk of developing thrombocytopenia or recurrence of HIT. The use of pre-exposure plasmapheresis in patients with positive anti-platelet factor 4/heparin antibody and post-exposure non-heparin anticoagulants may have reduced the risk of recurrence of HIT. Given several limitations of such retrospective review, prospective studies are needed to validate these results.