In the appropriate clinical setting, a negative ELISA test for Hep/PF4 antibodies (Ab) has traditionally been considered sufficient to rule out HIT/HITT. We describe a series of 20 cases of HIT/HITT in which the ELISA at the onset of thrombocytopenia was negative despite high (6/8) “4T’s” scores (Thrombocytopenia, Timing of thrombocytopenia in relation to heparin exposure, Thrombosis, and no oTher explanation of thrombocytopenia) but showed strong seroconversion subsequently. This suggests that the negative predictive value of the ELISA test may be too low to definitively exclude HITT. We retrospectively reviewed 494 consecutive Hep/PF4 ELISA assays (sensitivity >90%) performed on 395 patients (pts). Of the 292 pts who tested negative, 73 pts underwent repeat ELISA testing due to the development of a new thrombotic event or the persistence of strong clinical suspicion of HIT/HITT. Twenty of the 73 pts (27%) were observed to have initial negative Hep/PF4 titers (mean = 0.13) at the time of thrombocytopenia but a positive assay (mean = 1.5) on follow-up testing (figure 1 right panel). All 20 pts presented with high “4T’s” scores (6 of 8) at the time of the negative ELISA and had a history of recent heparin exposure. The M:F ratio was 11:9. Eleven pts had prior cardiopulmonary bypass while six had left ventricular assist devices. Fifteen pts (75%) had >50% drop in platelet count (figure 1 left panel). Mean platelet count at the time of negative ELISA was 71x109/l (vs. baseline mean platelet count of 171x109/l) (figure 2). Fourteen of 15 pts (for which data was available) had thrombotic events (9 arterial, 5 venous). Strong seroconversion was seen in all pts (mean = 8 days after initial test) and surprisingly, it accompanied platelet recovery in 15 of 20 pts (figure 1 left panel), with mean platelet count of 136x109/l at the time of the positive ELISA (figure 2). Argatroban was used as a direct thrombin inhibitor (DTI) in 16/20 pts. The prognosis was poor: 10 pts (50%) succumbed with multi-system organ failure.

Conclusion: We have described 20 cases of HIT/HITT with initial negative Hep/PF4 Ab titers at the time of thrombocytopenia, followed by delayed seroconversion. This observation suggests that in the proper clinical setting one isolated negative ELISA result cannot exclude evolving HIT/HITT. Follow-up testing may be informative even as the platelet count begins to recover. As HIT/HITT may have potentially fatal outcome, clinicians should maintain a high degree of suspicion despite a negative serology by ELISA, especially in pts with “4T’s” scores ≥ six. Empiric treatment with DTI’s may be warranted until two consecutive ELISA tests are negative.

Author notes

Disclosure: No relevant conflicts of interest to declare.