Correction of refractory thrombocytopenia and anemia following withdrawal of extended release niacin
Authors: Casey O'Connell, Kristin Horwood, Mridula Nadamuni
Journal: American Journal of Hematology (2016)

To the Editor: Niacin (Niaspan, Nicotinic acid, Vitamin B3) is an FDA-approved water-soluble vitamin known to reduce serum LDL and triglycerides while boosting HDL. Cutaneous flushing is the most common dose-limiting adverse reaction but other effects, including thrombocytopenia, are documented. FDA prescribing literature states that extended-release (ER) niacin (Niaspan, Abbott Laboratories) is associated with a “statistically significant dose-dependent reduction in platelet counts, with an average drop of −11% on a dose of 2,000 mg/day” 1. In a study reported by Kei and Elisaf, 50 patients with hyperlipidemia undergoing statin therapy experienced a 20% reduction in platelet counts when niacin-ER was added at a starting dose of 1,000 mg/day and titrated to 2,000 mg/day for a period of 3 months 2. Here, we report four patients, evaluated in our clinical practice from 2012 to 2015, in whom long-term treatment with niacin-ER was associated with a progressive and reversible thrombocytopenia. The patients were male, with an average age of 68.8 years (median age 68 years), on niacin-ER for 20 months to 9 years. In general, physical examination was unremarkable with no splenomegaly, and bone marrow biopsies were obtained on all patients. The biopsies revealed normocellularity or hypocellularity with adequate trilineage hematopoiesis. The megakaryocytes were normal in number and morphology. There was no evidence of dysplasia or fibrosis. There was no increase in CD34+ blast cells. Cytogenetics were tested in 3 of 4 patients and found to be normal. In all four of our patients, platelets quickly recovered with improvement noted within a month of cessation. Utilizing the criteria published by Royer et al. to determine the level of evidence for a causal association between niacin-ER and thrombocytopenia 3 (see Supplementary on line material), a “probable” association was found in three patients and a “definite” association was present only in Patient 2 who was re-challenged with niacin-ER. Details of niacin use and blood cell counts are summarized in Table 1 and clinical narratives of Patients 1 and 2 are summarized below. On average, the patients were on niacin-ER daily for 59 months, at a median dose of 2,250 mg. Following cessation of niacin-ER, platelets recovered by an average of 91.5 × 109/L, with mean time to best response of 136 days, based on available laboratory data. Patient 1, a 60-year-old Caucasian male experiencing epistaxis with dialysis-dependent end stage renal disease and coronary artery disease presented for evaluation of severe thrombocytopenia which prohibited clearance for renal transplantation. The patient was taking carvedilol, enalapril, eplerenone, famotidine, sevelamer, and cinacalcet, as well as niacin-ER 750 mg controlled release twice daily, all started 4 years prior to presentation. Two years prior to this presentation, he was noted to have a platelet count of 76 × 109/L and hemoglobin of 10.8 g/dL. A bone marrow biopsy performed 1 year prior to evaluation, when his platelet count had dropped to a nadir of 15 × 109/L showed marked hypocellularity with megakaryocytic hypoplasia and without monoclonal lymphoproliferation or dysplasia. Repeat biopsy 1 month prior demonstrated persistent hypocellularity without other abnormalities and cytogenetics were normal. High-dose prednisone was initiated but failed to improve the platelet count and worsened his epistaxis so he was referred to us. Our evaluation revealed no additional physical examination findings to explain the thrombocytopenia and we recommended cessation of niacin-ER. Within 1 week of discontinuing niacin-ER, platelets increased from 34 × 109/L to 54 × 109/L. In 2 weeks, platelets had rebounded to 94 × 109/L. Five weeks from the date of cessation, platelets had recovered to normal limits at 156 × 109/L, and he was cleared for renal transplant. Patient 2, a 67-year-old Caucasian male with history of hypertriglyceridemia, hyperglycemia, and sleep apnea on 1,000 mg niacin-ER for years presented for evaluation of mild thrombocytopenia with platelet counts of 130–140 × 109/L for at least three years. A bone marrow biopsy performed 2 weeks prior showed no evidence of dysplasia. On presentation, the patient revealed he had voluntarily been off niacin-ER for two months, and his platelets were 154 × 109/L with normal follow-up studies, so we recommended he continue to avoid niacin-ER. Unfortunately, he was intolerant to other lipid-modifying agents and restarted niacin-ER 5 months later. This re-challenge resulted in a drop in platelets to a nadir of 85 × 109/L. Niacin-ER was immediately discontinued. Over two months, platelets rebounded to over 100 × 109/L and remained stable. Niacin-ER may be an overlooked cause of thrombocytopenia, particularly among patients with a slowly progressive effect who have taken the drug for years. Prior published cases reporting an association between niacin and thrombocytopenia did not meet criteria for a probable or definite causality 3, 4.The data presented here adds significantly to the paucity of evidence for the association of nutritional supplements with thrombocytopenia. In addition to this finding, we noted marked improvement in hemoglobin upon discontinuing niacin-ER in two of the four patients who were found to be anemic as well as thrombocytopenic. The average increase in hemoglobin noted was 1.525 g/dL over an average best response time of 108 days. Following cessation of niacin, these patients recovered to baseline. Less is known about niacin-induced anemia, and these findings indicate further study is warranted. In conclusion, Niacin-ER is known to cause reversible thrombocytopenia, but this effect may be insidious and severe and can be accompanied by reversible anemia, both of which may be easily overlooked in patients with multiple medical conditions and concomitant medications. Casey O'Connell,1,2 Kristin Horwood,1 Mridula Nadamuni2* 1Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California 2Keck School of Medicine of the University of Southern California, Los Angeles, California Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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