Severe Thrombocytopenia Complicating Iron Deficiency Anemia: A Diagnostic Challenge?

What mechanisms can explain thrombocytopenia in the setting of severe iron deficiency? Which laboratory parameters help distinguish central from peripheral causes of thrombocytopenia? How can iron deficiency mimic immune-mediated platelet disorders? What is the role of erythropoietin in platelet homeostasis? How should treatment decisions be guided in complex pancytopenia without a clear etiology? A 52-year-old woman was referred to the emergency department after abnormal laboratory results were identified during a routine gynecological follow-up 1 week earlier. She had a long history of chronic abnormal uterine bleeding since adolescence, characterized by menometrorrhagia related to adenomyosis. Her medical history included venous thromboembolic disease related to protein C deficiency, treated with rivaroxaban (20 mg/day), and multiple hospitalizations for acute decompensation of chronic anemia requiring red blood cell transfusions. Oral iron therapy had been repeatedly discontinued because of significant gastrointestinal intolerance. At presentation (Day 7), repeat laboratory testing revealed a marked deterioration compared with results obtained 7 days earlier (Day 0), showing pancytopenia: hemoglobin 37 g/L (3.7 g/dL), platelet count 30 × 109/L, and leukocyte count 2.0 × 109/L, with neutrophils at 1.2 × 109/L (Table 1). Benign ethnic neutropenia was excluded because prior complete blood counts had consistently shown normal neutrophil count. The anemia was microcytic, hypochromic, and associated with a low reticulocyte count. Liver function tests and coagulation parameters were within normal limits. Hematological parameters at day 0 and day 7. Cell counts expressed in 109/L are equivalent to G/L. MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; ANC, absolute neutrophil count. The patient complained of asthenia and exertional dyspnea but was apyretic and hemodynamically stable. There was no hepatosplenomegaly, ascites, or lymphadenopathy. Cardiovascular examination, including electrocardiography, was unremarkable. Despite severe thrombocytopenia, there were no clinical signs of bleeding, such as petechiae, ecchymoses, mucosal bleeding, or hemorrhagic bullae, and she reported no increase in bleeding compared with her usual pattern. Supportive treatment was initiated with transfusion of 5 units of packed red blood cells over 3 days, targeting a hemoglobin level >7 g/dL and clinical tolerance (Fig 1A). A platelet concentrate (8 units) was administered 2 days later. Posttransfusion assessment showed a poor platelet increment, raising concern regarding the underlying mechanism of thrombocytopenia (Fig 1B). Evolution of biological parameters over October 2024 to September 2025. Longitudinal follow-up of hemoglobin (A), platelet count, IPF (B), reticulocyte count (C), ferritin, and transferrin saturation (TSAT) (D). (A) shows hemoglobin levels, with green arrows indicating intravenous iron (Fe IV) administrations and red arrows indicating packed red blood cell (PRBC) transfusions. Given the unusual association of severe chronic anemia, acute thrombocytopenia, leukopenia, and poor response to platelet transfusion, an extensive etiological workup was performed. Concurrently, the etiological assessment of anemia showed normal concentrations of vitamin B12, folate, thyroid-stimulating hormone, creatinine, C-reactive protein, haptoglobin, and bilirubin (assessed on CobasPro, Roche). Serum and urine protein electrophoresis were normal. Iron status revealed a severe iron deficiency, with ferritin at 13.6 µg/L (reference interval 15–252 µg/L) and transferrin saturation at 8% (reference interval 20%–40%) (Fig 1D). Thrombocytopenia was further investigated. Platelet count was evaluated using platelet impedance and fluorescent counting (Sysmex XN-series hematology analyzer). The mean platelet volume remained within the normal range (8–11 fL) throughout the course of the disease. K2EDTA-induced platelet clusters were excluded in sodium citrate-anticoagulated whole blood platelets count. Peripheral blood smear examination showed no platelet aggregates, blasts, or schistocytes. No recent medication changes were identified. Infectious causes were excluded: the patient remained apyretic with no signs of sepsis, serological testing for HIV, hepatitis B and C, Epstein–Barr virus, and parvovirus B19 was negative, and CMV and EBV PCR assays were negative. Disseminated intravascular coagulation and thrombotic microangiopathy were ruled out based on normal coagulation and hemolysis parameters. Autoimmune testing, including antinuclear and antiphospholipid antibodies, was negative. Splenic sequestration was considered unlikely given the absence of splenomegaly and normal liver function tests. Bone marrow aspiration showed a hypercellular marrow with preserved granulocytic and erythroid lineages, no dysplasia, no blast excess, and very rare megakaryocytes. These findings suggested a central mechanism for thrombocytopenia. However, the poor response to platelet transfusion raised the possibility of a peripheral component, complicating the overall interpretation. Based on the clinical and biological findings, 2 main hypotheses were considered: (a) an immune-mediated thrombocytopenia (ITP)-like presentation triggered by severe iron deficiency and (b) a megakaryocytic ITP with central involvement. Given the absence of bleeding symptoms, the atypical bone marrow findings, and the severe iron deficiency, corticosteroid therapy was deliberately withheld. The patient received a single infusion of 1000 mg intravenous ferric carboxymaltose. Two days after iron administration, platelet and leukocyte counts showed a transient further decrease, followed by a rapid and marked recovery. Over the subsequent 10 days, the platelet count increased dramatically from 19 × 109/L to 1317 × 109/L, while the leukocyte count normalized and hemoglobin concentrations augmented (Fig 1A). The immature platelet fraction (IPF) was initially low at 2.5%, followed by a marked transient increase to a peak of 10.6% during the acute phase (+8.1% points), indicating enhanced peripheral platelet turnover and reactive stimulation of thrombopoiesis. IPF levels subsequently normalized over time (N < 7.5%), consistent with resolution of the underlying hematologic stress. Reticulocyte counts progressively declined (Fig 1C). Following red blood cell transfusions and intravenous iron supplementation in early February and in March 2025, a marked reticulocytosis was observed, with subsequent stabilization at moderately elevated levels: consistent with sustained recovery of erythropoietic activity. Thrombopoiesis is primarily regulated by thrombopoietin, produced mainly by the liver, but platelet production results from the integration of multiple signals from cytokines, growth factors, metabolic status, and the bone marrow microenvironment, including iron availability. Iron deficiency classically leads to normal platelet counts or reactive thrombocytosis, both in humans and in animal models. Experimental models, Tmprss6 knockout mice, and low-iron diet mice have shown enhanced megakaryocytic differentiation of megakaryocytic-erythroid progenitors under conditions of low intracellular iron. This process is associated with reduced ERK phosphorylation and slower proliferation and may represent an adaptive mechanism to preserve iron for essential cellular functions while limiting hemorrhagic risk (1). By contrast, severe thrombocytopenia in the setting of iron deficiency is uncommon and has been mainly reported in children with nutritional deficiency or in young women with heavy menstrual bleeding. In these cases, iron repletion typically results in rapid normalization or even increased platelet counts, reinforcing the causal role of iron deficiency (2). The pathophysiology of this paradoxical thrombocytopenia remains incompletely understood. In the case of extreme iron depletion, differentiation of bipotent megakaryocytic-erythroid progenitors may be preferentially directed toward erythropoiesis, leading to reduced availability of progenitors for megakaryopoiesis (3). The involvement of erythropoietin (EPO) is to be questioned. Severe anemia is associated with markedly elevated EPO concentrations, which may directly influence megakaryocyte development (4). Experimental data support a biphasic effect of EPO and iron status on platelet production. Moderate EPO stimulation or moderate iron deficiency tends to promote thrombocytosis, whereas excessive EPO levels or profound iron deficiency may result in thrombocytopenia (5). Animal studies further suggest that the interaction between EPO concentrations and iron stores is critical. Rats with elevated EPO and preserved iron stores develop earlier and more severe thrombocytopenia than iron-supplemented animals with functional iron deficiency. These findings indicate that extreme anemia, high EPO levels, and iron depletion must coexist to induce thrombocytopenia, as observed in this patient (6). At the cellular level, iron is essential for multiple enzymes involved in DNA synthesis, mitochondrial respiration, and epigenetic regulation across all hematopoietic lineages. Hematopoietic stem and progenitor cells tightly regulate their intracellular labile iron pool, and iron deficiency triggers metabolic and epigenetic adaptations that may influence lineage commitment (7). The concept of a dual iron pool, implicating a functional pool required for immediate cellular needs and a regulatory pool involved in signaling pathways governing differentiation, may explain the platelet response. Disruption of this balance could contribute to the biphasic hematological response observed in iron deficiency, including transient cytopenias followed by rebound hyperplasia after iron repletion (1, 8). The bone marrow findings in this patient are atypical compared with previously reported cases, which often describe increased megakaryocytes (9). The observed paucity of megakaryocytes remains unexplained, highlighting the heterogeneity of this condition. The poor platelet increment after transfusion initially raised concern for peripheral destruction, such as immune-mediated thrombocytopenia. However, the absence of bleeding manifestations, lack of autoimmune markers, and subsequent good response to iron therapy alone argue against a primary immune process. This observation highlights a critical diagnostic pitfall: iron deficiency-associated thrombocytopenia may clinically and biologically mimic ITP, leading to unnecessary corticosteroid exposure if iron status is not carefully evaluated. In this regard, IPF is a promising diagnostic tool. IPF reflects the proportion of newly released platelets in circulation and provides an indirect estimate of bone marrow platelet production. IPF is typically elevated in peripheral platelet destruction, such as ITP, where compensatory megakaryopoiesis is preserved, and low in central causes of thrombocytopenia. In iron deficiency-associated thrombocytopenia, IPF is frequently low, consistent with impaired megakaryocyte production. Moreover, IPF increases following iron supplementation, allowing noninvasive monitoring of marrow recovery. The use of IPF could reduce the need for bone marrow examination and facilitate earlier diagnosis (10). In this case, the initial transient worsening of thrombocytopenia after intravenous iron administration may reflect abrupt stimulation of erythropoiesis occurring at the expense of other hematopoietic lineages. The subsequent extreme thrombocytosis likely represents a rebound phenomenon associated with intense marrow regeneration. In conclusion, this case highlights a rare but clinically significant manifestation of severe iron deficiency, characterized by thrombocytopenia and transient pancytopenia with features mimicking immune-mediated disorders. The pathophysiology likely involves a complex interplay between iron availability, erythropoietin signaling, progenitor cell fate decisions, and metabolic regulation of hematopoiesis. Early recognition of this condition is essential to avoid misdiagnosis, unnecessary invasive procedures, and inappropriate immunosuppressive therapy. This case also underscores the need for further research to define better the molecular mechanisms linking iron metabolism to platelet production and to identify biomarkers that may aid in diagnosis and management. Severe iron deficiency can rarely present with thrombocytopenia or pancytopenia. Iron availability influences hematopoietic lineage commitment beyond erythropoiesis. Severe anemia and elevated erythropoietin concentrations may contribute to platelet suppression. IPF is a useful tool for etiological assessment of thrombocytopenia. Correct diagnosis prevents unnecessary immunosuppressive therapy and allows rapid recovery. Nonstandard Abbreviations: ITP, immune-mediated thrombocytopenia; IPF, immature platelet fraction; EPO, erythropoietin. Author Contributions: The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Lina Bahloul (Data curation, Formal analysis, Investigation, Writing—original draft [equal]), Michelle Bedran (Data curation, Formal analysis, Writing—original draft, Writing—review & editing [equal]), Catherine Trichet (Conceptualization, Formal analysis, Writing—original draft, Writing—review & editing [equal]), Katell Peoc'h (Investigation, Supervision, Validation, Writing—original draft, Writing—review & editing [equal]), and Hana Manceau (Conceptualization, Data curation, Investigation, Supervision, Writing—original draft, Writing—review & editing [equal]). Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Research Funding: This work was supported by the France 2030 program through the Idex Université Paris Cité (ANR-18-IDEX-0001). Disclosures: None declared.