Discussion
The incidence of AITP is unknown due to the rarity of this complication and paucity of documented cases. DITP has been associated with increased risk of in-hospital mortality1. A distinctive feature of one of the well-known examples of DITP such as quinine induced DITP involves a platelet reactive antibody that bind tightly to platelets only in the presence of quinidine leading to immune destruction of platelets after 5-7 days of continuous drug administration. In addition to the above, Aster and Bougie have summarized various mechanisms for DITP, some of which include hapten-dependent antibody (e.g. penicillin), autoantibodies which elicit immune response in the absence of drug (gold salt, procainamide) and immune complex formation (heparin)2. Weinberger et al was the first to postulate delayed hypersensitivity as a mechanism for AITP by performing a lymphocyte stimulation test6. Monitoring drop in platelet counts two weeks after starting amiodarone was recommended. Amiodarone-dependent antibodies causing platelet destruction cannot be identified using traditional serological methods owing to water insolubility of the drug. This issue was elucidated by Sahud et al who described a case series of three patients with AITP and employed elaborate laboratory techniques to demonstrate amiodarone-dependent antibodies specific for platelet glycoproteins GPIa/IIa and/or GPIIb/IIIa to explain thrombocytopenia in these patients5.
Thrombocytopenia is one of the commonest reasons for inpatient hematology consultation. The differential diagnosis is long and sometimes multifactorial. Thrombocytopenia workup guidelines described by Arnold and Lim were useful to approach our case. They have described a handy 6 step approach to evaluate thrombocytopenia: exclude thrombocytopenic emergencies, peripheral blood smear examination, consider clinical context, degree timing and lastly assess for bleeding/thrombosis12. In the case discussed here, firstly a citrated platelet level ensured that severely low platelet count was not a lab error. Fatal etiologies of severe (sometimes referred as significant ) thrombocytopenia like disseminated intravascular coagulation (no overt bleeding, normal hemolysis markers, normal fibrinogen), and thrombotic thrombocytopenic purpura (no schistocytes, no hemolysis), heparin-induced thrombocytopenia (negative HIT ELISA screen, typical platelet nadir is 60 K/mm3in HIT) were ruled out. DITP as a possible cause of severe thrombocytopenia was suspected given worsening thrombocytopenia to less than 20 K/mm3 despite prompt resolution of sepsis with appropriate antibiotic, timing of onset at day 5 after starting amiodarone, and, presence of giant platelets on the blood smear, high immature platelet fraction (20.1%) both indicating an immune mediated phenomenon. Severe sepsis can sometimes cause severe thrombocytopenia but that is usually associated with severe leukopenia as a marker of severe bone marrow suppression. Amiodarone was listed as a possible cause of DITP in a commonly referred expanded online list of drugs and their level of association with thrombocytopenia athttps://www.ouhsc.edu/platelets/ditp.html13. Later during the clinical course, recurrence of thrombocytopenia with amiodarone introduction and improvement after drug discontinuation lent more support to the diagnosis. It must be pointed that drug rechallenge is not required to diagnose any DITP. Platelet reactive antibodies were not tested since amiodarone-dependent platelet-responsive antibodies are not detectable by conventional methods5. It was not feasible to apply criteria laid out by George et al to establish causal relation of amiodarone to immune thrombocytopenia since the patient died prematurely before platelet count could return to normal14. Regardless, the clinical picture pointed to AITP and there was no alternate explanation. Although platelet recovery may be relatively prompt after drug discontinuation, complete recovery may take a few weeks owing to the long half-life of amiodarone from its large volume of distribution3,7. Antibodies can persist for years and hence re-exposure of the drug even months to years later can elicit a similar immune destruction of platelets15. Offending medication must be added to the allergy list in order to maximize safety.