Iron Deficiency Anemia, a Rare and Potentially Underestimated Cause of Thrombocytopenia and a Differential Diagnosis of Immune Thrombocytopenia (ITP): Results from a Retrospective Case-Controlled Study

Introduction

Iron deficiency anemia (IDA) is the most common cause of anemia worldwide. It is classically associated with a normal or moderately elevated platelet count, but exceptionally, iron deficiency can lead to thrombocytopenia. Distinguishing IDA-related to mucosal bleeding in the setting of immune thrombocytopenia (ITP) from a true iron deficiency-related thrombocytopenia can be challenging and may lead to misdiagnosis and inappropriate treatment.

The 2 main objectives of this study were: 1) To better describe the clinical and biological baseline characteristics of clearly defined cases of iron deficiency-induced thrombocytopenia (IDIT) and 2) To identify some features that could be helpful for distinguishing IDIT and ITP.

Material and method

We performed a retrospective multicentre case-controlled study throughout the network of the French national referral center for adult' immune cytopenias. Inclusion criteria were the following: thrombocytopenia <100 x 10⁹/L related to an IDA defined by an hemoglobin level <120 g/L and a ferritin level <30 μg/L and platelet recovery without any other treatment than iron ± transfusion of packed RBCs. Patients with pre-existing thrombocytopenia and/or other potential cause of thrombocytopenia or anemia were excluded as well as patients with a possible diagnosis of IDIT who received corticosteroids ± intravenous immunoglobulin for a putative diagnosis of ITP. Clinical and biological characteristics of the patients (i.e, the "cases") were analyzed and each case was compared to 3 newly diagnosed ITP patients (control group) matched on age (+/- 5 years) and gender.

Results

Between February 2000 and May 2018, eight (7 women, 87.5%) patients from 4 participating centers fulfilling the inclusion criteria were included. Median age at IDIT diagnosis was 43.5 years (Range: 16-72) years. Median hemoglobin level at diagnosis was 47 (range: 21 - 71) g/L, with a mean corpuscular volume (MCV) of 64 (54 - 75) fl, and a median platelet count of 30.5 (21 - 80 x 10⁹/L). None of the patients but one had clinical bleeding manifestations such as purpura or mucosal bleeding. The platelet count got back to a normal level within a median of 6 (4 - 39) days after iron supplementation and/or transfusion in all 8 patients. When compared with these 8 cases, ITP controls had a significantly lower platelet count (median platelet count of respectively 7 [range 4 - 59] vs 30.5 [21 - 80] x 10⁹/L , p = 0.002), and more bleeding manifestations (19/24 (79%) versus 1/8 (12.5%) respectively ,p = 0.001). On Day 7 after diagnosis, the median platelet count (after iron deficiency treatment or ITP treatment among the cases was 337 (113-1000 x 10⁹/)L versus only 72 (13-212 x 10⁹/L for the 24 controls (p = 0.001).

Conclusion

In case of profound IDA, and non-severe (platelet count > 20 x 10⁹/L) and generally asymptomatic associated-thrombocytopenia may occur and must not be misdiagnosed and treated as an ITP with secondary IDA. Iron supplementation (either intravenously or orally) allows a quick and complete recovery of the platelet count with sometimes a transient thrombocytosis and may avoid the inappropriate use of steroids. Why profound iron deficiency can seldom lead to thrombocytopenia whereas mild iron deficiency often leads to thrombocytosis needs further investigation.