Cold autoimmune hemolytic anemia with myelodysplastic syndrome: Not just an “Open and Shut case”

Deepti Mutreja; Gourang Paliwal; Vishal Mangal; Amit K Biswas

doi:10.4103/IJPM.IJPM_981_20

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CASE REPORT

Year : 2022 | Volume : 65 | Issue : 1 | Page : 195-197

Cold autoimmune hemolytic anemia with myelodysplastic syndrome: Not just an “Open and Shut case”

Deepti Mutreja¹, Gourang Paliwal¹, Vishal Mangal², Amit K Biswas³
¹ Department of Pathology, AFMC, Pune, Maharashtra, India
² Department of Internal Medicine, AFMC, Pune, Maharashtra, India
³ Department of Immunohematology and BT, AFMC, Pune, Maharashtra, India

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Date of Submission	14-Aug-2020
Date of Decision	12-Sep-2020
Date of Acceptance	25-Mar-2021
Date of Web Publication	20-Jan-2022

Abstract

Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell neoplasms characterized by bone marrow failure leading to ineffective hematopoiesis, dyspoiesis, and cytopenias with a risk of progression to acute leukemia. Immunological syndromes have been reported to occur along with MDS in literature. However, cold autoimmune hemolytic anemia (AIHA) has rarely been reported in association with MDS. Herein, we report a case of an elderly male who presented with fever and cytopenias. He was being treated as a case of megaloblastic anemia in the past with no response to therapy. At present admission, the peripheral blood smear examination revealed red cell agglutination, thrombocytopenia with 4% blasts. Cold agglutinin disease was confirmed by a thermal agglutination test and bone marrow evaluation showed adequate megakaryocytes with 10% blasts; consistent with the diagnosis of MDS with excess blasts (MDS-EB2). Cytogenetic studies revealed multiple abnormalities. This report is being discussed in view of its rarity of presentation of cold AIHA with MDS.

Keywords: Autoimmune hemolytic anemia, cold agglutinin disease, myelodysplastic syndrome

How to cite this article:
Mutreja D, Paliwal G, Mangal V, Biswas AK. Cold autoimmune hemolytic anemia with myelodysplastic syndrome: Not just an “Open and Shut case”. Indian J Pathol Microbiol 2022;65:195-7

How to cite this URL:
Mutreja D, Paliwal G, Mangal V, Biswas AK. Cold autoimmune hemolytic anemia with myelodysplastic syndrome: Not just an “Open and Shut case”. Indian J Pathol Microbiol [serial online] 2022 [cited 2023 Sep 29];65:195-7. Available from: https://www.ijpmonline.org/text.asp?2022/65/1/195/336096

Introduction

Autoimmune phenomena have been described in approximately 10.–20% patients of myelodysplastic syndrome (MDS).^[1],[2] Of the immune-mediated hematological abnormalities, autoimmune hemolytic anemia (AIHA) in MDS is rare and has been reported to occur with 3% patients only,^[1],[3],[4] although autoantibodies against red cells are found in up to 35% patients.^[5] Cold AIHA has rarely been reported with MDS.^[6] Immune thrombocytopenic purpura (ITP) by itself is commoner with MDS and has been reported in up to 12% cases.^[1],[2] We present a rare case of an elderly male diagnosed as cold AIHA with MDS.

Case History

A 76-year-old male known case of type 2 diabetes mellitus and hypertension was admitted to our center in the month of January with fever and bilateral pedal edema with progressive dyspnea on exertion for last 3 months. He was diagnosed to have megaloblastic anemia a month prior to the present admission and was given a therapeutic trial of Vitamin B12 to which there was no response.

On evaluation, patient was afebrile, pulse was 104/min, bounding in nature, respiratory rate was 22/min, blood pressure was 130/90 mmHg and SpO2 was 91% at room air and 96% on supplemental oxygen. Oral mucosa and tongue showed purpural rash. Jugular venous pressure (JVP) was raised and bilateral periorbital and pedal edema were noted. Respiratory system examination revealed bilateral coarse crackles. Spleen was palpable 3 cm below costal margin. Laboratory evaluation revealed severe anemia (hemoglobin - 4.3 g/dL), total leucocyte count of 12,700/μl, and thrombocytopenia (platelet count - 30 × 10³/μL). Mean corpuscular volume was 109 fL and mean corpuscular hemoglobin was 39.1 pg with total red cell count of 1.1 × 10⁶/μL. Peripheral blood smear showed marked red cell agglutination, giant platelets and 4% blasts. Occasional dyspoietic neutrophils were seen [Figure 1]a. Biochemistry showed markedly deranged sugar levels (fasting and post prandial values of 316 and 464 mg/dL respectively), raised blood urea nitrogen and creatinine of 59 mg/dL and 1.7 mg/dL. Liver function tests and serum electrolytes were normal. Lactate dehydrogenase was raised (312 IU/L). Serum B12 and plasma folate levels were 1525 pg/ml and 24 ng/ml. Imaging revealed mild hepatosplenomegaly, spleen span of 15 cm, and positron emission tomography scan showed diffuse increase in bone marrow and splenic activity.

Figure 1: (a) Peripheral smear (PBS) showing marked RBC agglutination (red stars), blast (red arrow), dyspoietic neutrophil (blue arrow) and thrombocytopenia, 400x; (b) Bone marrow imprint smears showing increase in erythroid precursors (red arrows), and occasional blast (yellow arrow) in a background of agglutinated RBCs (red star), 400x; (c) BM imprint smear showing dyspoietic multinuclated erythroid precursors (red arrow and inset picture) and blasts (black arrow), 1000x [Leishman Giemsa]

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Patient was managed as a case of congestive cardiac failure, sepsis with acute kidney injury (AKI), uncontrolled hyperglycemia, and bicytopenia under evaluation. He was exhibited diuretics, injectable antibiotics, and blood sugar was optimized. He was also started on oral prednisolone and given transfusion support with blood and platelets. Direct and indirect Coombs test were positive at 37°C, room temperature and 4°C for IgG and anti C3d. Cold agglutinin disease was confirmed by thermal agglutination test [Table 1] IgM and complement mediated with wide thermal amplitude. He responded to therapy with resolution of AKI; however, a complete blood count showed pancytopenia with persistence of red cell agglutination, giant platelets, and few blasts.

Table 1: Thermal agglutination test at 37°C, room temperature and 4°C

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Bone marrow aspirate smears were hemodiluted and imprint smears revealed marked erythroid hyperplasia with reversal of myeloid to erythroid ratio to 1:20 [Figure 1]a, [Figure 1]b. Erythroid series showed megaloblastic maturation with dyspoietic changes in form of binucleation, multinucleation, nuclear budding, and karyorrhectic nuclei. Myeloid precursors were markedly reduced. Myelogram showed erythroid - 82%, myelocytes - 01%, neutrophils and bands - 03%, lymphocytes - 03%, monocytes - 01%, blasts - 10% [Figure 1]c. Blasts were large undifferentiated with scant cytoplasm. Few megakaryocytes with normal morphology were seen. Iron stores were increased; however, no ring sideroblasts were seen.

Bone marrow biopsy was hypercellular (cellularity ~ 90%). Erythroid preponderance was noted [Figure 2]a. Clusters of blasts were seen [Figure 2]b. Megakaryocytes were adequate with normal morphology and distribution [Figure 2]c. Reticulin stain showed grade I marrow fibrosis.

Figure 2: a - Decalcified section of bone marrow biopsy showing hypercellular bone marrow with sheets of erythroid precursors, both mature and immature forms (H and E 100x); b - Clusters of immature cells (black arrow) (H and E, 400X). c - Adequate megakaryocytes (black arrows) showing normal morphology and distribution (H and E, 400X). d - Blasts showing positivity for CD 34 (400x)

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Immunohistochemistry (IHC) highlighted clusters of blasts positive for CD 34 [Figure 2]d and CD117. Fluorescence in situ hybridization (FISH) panel for MDS showed deletion 5q31 in 32% of cells and trisomy 8 in 58% of cells. Marrow morphology, IHC and cytogenetics confirmed MDS with excess blasts (MDS-EB2) in a case of cold AIHA.

Discussion

MDSs are characterized by bone marrow failure leading to ineffective hematopoiesis, dyspoiesis, cytopenias with a risk of progression to acute leukemia. Autoimmune phenomena are known to be associated with MDS, including vasculitides, connective tissue disorders, immune-medicated hematologic abnormalities, and even asymptomatic serological laboratory abnormalities.^[7] Increased apoptosis of cells secondary to immune dysfunction and altered T-cell homeostasis is postulated to be responsible for autoimmunity in MDS.^[1],[2],[7] These manifestations have been reported to be commoner with MDS with single lineage dysplasia (MDS-SLD) and MDS with excess blasts (MDS-EB).^[1] Our patient also had MDS-EB2 as per definition.

In MDS patients, AIHA may precede the diagnosis,^[1],[2],[7] or may present simultaneously like in our case. Our patient presented with an uncommon cold AIHA in association with MDS. There are limited case reports describing cold AIHA with MDS,^[6] we found cold AIHA occurring simultaneously in MDS. AIHA is considered to be commonly associated with lymphoproliferative disorders (LPD). In routine clinical practice its association with MDS is not known to many. Our patient was initially evaluated as a case of lymphoproliferative disorder including PET imaging, which showed diffuse increased activity in the BM and spleen, however there was no evidence of LPD. The diagnosis of AIHA was established by a positive thermal agglutination test, cytopenias, and elevated LDH. Despite western literature being replete with the occurrence of autoimmune disorders with MDS, there are few studies describing the same in Indian population.^[8]

Immunosuppression by either steroids or intravenous immunoglobulin is the first line treatment of AIHA, reducing erythrocyte destruction by macrophages. Transfusing warmed blood cells is done for severe cases.^[5] Not only diagnosis but management of this patient was also challenging as steroid therapy had to be given with uncontrolled diabetes. While it is common knowledge that treatment of autoimmune disorders with immunosuppressive agents like azathioprine and cyclophosphamide can potentially lead to secondary MDS, the complementary effect of managing MDS with a hypomethylating agent is seen as improved outcome of autoimmune disorder.^[1]

Our patient was being managed as a case of megaloblastic anemia prior to the present episode. Macrocytosis may have also been likely because of MDS itself. Thrombocytopenia is seen frequently in patients with MDS. The etiology may range from dysregulated signaling of thrombopoietin or increased platelet destruction by immune or non-immune mechanisms.^[9] ITP is commoner than AIHA in MDS and reported in 12% patients in a large studies.^[10] Anti-platelet antibodies can be positive in 35% of MDS patients even in the absence of thrombocytopenia.^[3] Our patient had thrombocytopenia too, however in the absence of antiplatelet antibodies, we cannot presumptively label this as ITP.

The aim of this presentation was to highlight the rare occurrence of cold AIHA with MDS. An increased awareness of secondary AIHA associated with MDS may help in prompt action that can be taken for earlier recognition of autoimmune phenomena potentially, leading to more positive outcomes for patients. Larger studies investigating occurrence of autoimmune phenomena in MDS need to be undertaken in Indian patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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