Case Presentation: A 74-year-old woman with type II diabetes mellitus, chronic hypertension, and neuropathy, presented to the hospital following a 9-day course of chest and back pain. She was found to have a late-presenting anterolateral myocardial infarction and was transferred to a cardiac ICU after developing cardiogenic shock secondary to a ventricular septal rupture. An intra-aortic balloon pump was placed, and she was initiated on subcutaneous heparin for venous thromboembolism prophylaxis, but 5 days later developed an acute DVT of the right soleus vein. This was in the context of a dropping platelet count, with her platelet nadir reaching 91 x 109/L on hospital day 21. Her 4T score was 7-points, indicating high pre-test probability for heparin induced thrombocytopenia (HIT), and both heparin-PF4 IgG ELISA and serotonin release assays (SRA) were sent while the patient was anticoagulated with bivalirudin. The results of these tests were negative (0.269 optical density) and positive, respectively, and this discordance prompted repeat testing, yielding the same results. Thus, given the strong clinical suspicion of HIT and twice-positive SRA, her case was regarded as confirmed HIT. She required heparin with cardiopulmonary bypass while undergoing open surgical repair of her ventricular septal defect and received IVIG and 3 sessions of peri-operative plasma exchange, which successfully mitigated the recrudescence of HIT. She was discharged on warfarin with plans to follow-up with Vascular Medicine.
Discussion: Heparin induced thrombocytopenia (HIT) is a syndrome characterized by mild to moderate thrombocytopenia and increased propensity for venous and arterial thrombosis. It results from the development of IgG antibodies targeting platelet factor 4 (PF4) in complex with heparin, which are detected with several immune-based assays. These anti-PF4 immunoassays exhibit excellent sensitivity, ranging from 97-100% (1). In many patients, anti-PF4 antibodies can be detected but are not functional; thus, clinically active HIT must be confirmed with functional platelet assays that measure heparin-dependent serotonin release. This is a case of clinically evident and SRA-confirmed HIT, with repeatedly negative ELISA testing, which is an exceedingly rare but increasingly recognized entity (2). This subtype of HIT may be driven by rare PF4-targeting antibodies that are not recognized by any available anti-PF4 immunoassays.
Conclusions: This case demonstrates the presentation, workup, and management for a rare but increasingly recognized subtype of HIT, which is characterized by positive SRA testing and, intriguingly, negative anti-PF4 immunoassays. Given the widespread use of heparin for hospitalized patients, HIT is a relatively prevalent condition in the inpatient setting, and caries a significant mortality rate if left untreated (3). Thus, hospitalists should be aware of this particular HIT entity and consult with subspecialist experts if clinical suspicion for HIT remains high, even after negative anti-PF4 testing.