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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Case Report
 :: Discussion
 ::  References
 ::  Article Figures

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  Table of Contents     
CASE REPORT
Year : 2013  |  Volume : 59  |  Issue : 1  |  Page : 51-53

Pure red cell aplasia following autoimmune hemolytic anemia: An enigma


1 Department of Medicine, Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Medicine, Institute of Hematology and Transfusion Medicine, Medical College, Kolkata, West Bengal, India

Date of Submission10-Jul-2012
Date of Decision25-Aug-2012
Date of Acceptance11-Oct-2012
Date of Web Publication22-Mar-2013

Correspondence Address:
S Ray
Department of Medicine, Medical College and Hospital, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.109495

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 :: Abstract 

A 26-year-old previously healthy female presented with a 6-month history of anemia. The laboratory findings revealed hemolytic anemia and direct antiglobulin test was positive. With a diagnosis of autoimmune hemolytic anemia (AIHA), prednisolone was started but was ineffective after 1 month of therapy. A bone marrow trephine biopsy revealed pure red cell aplasia (PRCA) showing severe erythroid hypoplasia. The case was considered PRCA following AIHA. This combination without clear underlying disease is rare. Human parvovirus B19 infection was not detected in the marrow aspirate during reticulocytopenia. The patient received azathioprine, and PRCA improved but significant hemolysis was once again documented with a high reticulocyte count. The short time interval between AIHA and PRCA phase suggested an increased possibility of the evolution of a single disease.


Keywords: Autoimmune hemolytic anemia, azathioprine, direct antiglobulin test, pure red cell aplasia


How to cite this article:
Saha M, Ray S, Kundu S, Chakrabarti P. Pure red cell aplasia following autoimmune hemolytic anemia: An enigma. J Postgrad Med 2013;59:51-3

How to cite this URL:
Saha M, Ray S, Kundu S, Chakrabarti P. Pure red cell aplasia following autoimmune hemolytic anemia: An enigma. J Postgrad Med [serial online] 2013 [cited 2019 Jul 16];59:51-3. Available from: http://www.jpgmonline.com/text.asp?2013/59/1/51/109495



 :: Introduction Top


Pure red cell aplasia (PRCA) is a disease characterized by severe anemia and reticulocytopenia due to reduction in erythroid progenitors in the bone marrow without any abnormalities of the granulopoietic or thrombopoietic system. [1] It is a rare hematological disorder and can develop secondary to infections (especially human parvovirus B19), hematological malignancies, autoimmune diseases, and various drugs and chemicals. [1] The pathogenesis of acquired PRCA is not fully elucidated. Autoimmune mechanism is primarily considered to be responsible. Some are T-lymphocyte mediated, whereas others are due to antibodies to erythroid precursors, erythropoietin (EPO) receptors, or EPO itself, and also viral infection of erythroid precursors. We have encountered a rare instance of PRCA following autoimmune hemolytic anemia (AIHA). The occurrence of PRCA following AIHA is discussed on the basis of our present understanding. To our knowledge, this is the first case report of PRCA secondary to AIHA from India.


 :: Case Report Top


A 26-year-old previously healthy female was admitted to our hospital with fatigue and severe anemia. There was no history of fever, rash, bleeding from any sites in the body, or exposure to related drugs or toxic agents. Past history was unremarkable. Physical examination revealed severe pallor, mild icterus, several soft, non-tender, mobile, peanut-sized cervical and axillary lymph nodes, and mild enlargement of spleen. Laboratory investigations showed marked anemia with reticulocytosis (red cell count: 360 × 10 9 /l, hemoglobin level: 3.4 g/dl, and absolute reticulocyte count: 194 × 10 9 /l). White blood cell count and platelet count were 7.2 × 10 9 /l and 244 × 10 9 /l, respectively. The erythrocyte sedimentation rate was 90 mm in the 1 st h. Peripheral blood picture showed predominantly polychromatic macrocytes, anisocytosis, and nucleated RBCs (4/100 WBC). Direct antiglobulin test (DAT) was positive (anti-human globulin anti-IgG, C3d; polyspecific) with an elevation of lactate dehydrogenase (LDH; 1,301 IU/l). Hemosiderin deposits were detected in the urine. The liver function test revealed mild unconjugated hyperbilirubinemia and slightly elevated globulin levels. The computed tomographic scan of chest showed no evidence of mediastinal lymphadenopathy or thymoma. The ultrasound study of the whole abdomen did not show any intra-abdominal lymph nodes. A lymph node biopsy done from the cervical region showed non-specific reactive hyperplasia. Anti-nuclear antibodies were present in 1:80 titer with a homogenous pattern and anti-ds DNA was negative. On the basis of these hematological and serological findings, she was diagnosed as having AIHA and oral prednisolone, 50 mg/day was started. Serial complete hemogram with reticulocyte count and LDH monitoring was performed. It showed that after initiation of steroid therapy, there was a decrease in the reticulocyte count without improvement in the level of hemoglobin. Serum LDH and bilirubin showed a steady decline. The patient required several units of blood transfusion while on steroid treatment. Since there was inadequate response to 3 weeks of steroid therapy, a bone marrow trephine biopsy was performed and it revealed mildly hypercellular marrow with severely depressed erythropoiesis. There was almost normal representation of myeloid and megakaryocyte precursors. No evidence of granuloma or infiltrative disease was detected. This bone marrow picture was compatible with PRCA rather than AIHA [Figure 1]a and b. Parvovirus B19 infection was not detected in the marrow aspirate by PCR. The patient received azathioprine, 50 mg/day, and 4 weeks later, reticulocytes gradually increased in number and thereafter the anemia improved. The evolution of laboratory data during the clinical course of the patient is summarized in [Figure 2]. At the time of discharge, her hemoglobin level and reticulocyte count were 10.8 g/dl and 3.4%, respectively. The follow-up bone marrow biopsy revealed the appearance of erythroblasts [Figure 3]. Thereafter, no relapse of the PRCA was observed.
Figure 1: (a) Bone marrow aspiration findings (original magnification, ×400). The ratio of red cell precursors was significantly low. No cellular deformation or increase of blast count was found. (b) Bone marrow biopsy of this patient on hospital day 21. There is significant reduction of red cell precursors (H and E, ×200)

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Figure 2: Clinical course of the patient and response to treatment. Reticulocyte percentage and hemoglobin levels are reported in the graph. The x‑axis showing course in days. PSL – Prednisolone

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Figure 3: Erythroblasts in the follow‑up bone marrow biopsy specimen

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 :: Discussion Top


PRCA is characterized by anemia, reticulocytopenia, and erythroblastopenia in the bone marrow. It may be congenital or acquired. Acquired causes of PRCA include various infections (especially human parvovirus B19), hematological malignancies such as chronic lymphocytic leukemia (CLL), chronic hemolytic anemias, autoimmune diseases, and various drugs and chemicals. [1] The pathogenesis of PRCA is not clearly understood; the mechanism is believed to be mediated by humoral antibody [2] or natural killer (NK) or T cell-mediated damage to precursors. [3] Humoral immunity-mediated damage includes complement-mediated lysis, formation of antibody-EPO complex, EPO receptor blocking antibody, and increased production of autoantibodies due to T-cell dysfunction, [4] or blockade of burst-forming units-erythroid (BFU-E) differentiation. [5],[6] NK/T cell-mediated damage includes cytolysis against bone marrow normoblasts or autoantibody formation against bone marrow normoblasts which is directed toward the Fc receptor. [6] Humoral immunity-mediated damage is seen in systemic lupus erythematosus (SLE), rheumatoid arthritis, lymphoma, and thymoma, [5],[7],[8] whereas NK/T cell-mediated damage occurs in CLL, large granular lymphocytic leukemia, and lymphoma. Formation of anti-EPO antibody and inhibition of EPO-dependent cell line are important mechanisms of PRCA in SLE patients with AIHA. [9] Taniguchi et al. have demonstrated two distinct immunological mechanisms in the pathogenesis of PRCA in their study: One is T-lymphocyte-mediated and the other being complement-dependent IgG-mediated suppression of erythroid progenitors. Both T-lymphocyte and autoantibody-mediated inhibition of erythropoiesis occur at the level of colony-forming units-erythroid (CFU-E) and BFU-E. [10] AIHA is caused by IgG in blood which is directed against mature red blood cells. PRCA associated with AIHA is caused by humoral as well as cytotoxic immunity. An interesting postulation is the coexistence of two different autoantibodies to the erythroid series, and the clinical manifestation may then be determined by a dominant antibody effect. A cytotoxic effect is mediated by both peripheral blood and bone marrow mononuclear cells. [10],[11]

In our case, the patient presented with a 6-month history of symptomatic anemia. The presence of anemia, unconjugated hyperbilirubinemia, striking reticulocytosis, and positive DAT pointed toward the diagnosis of AIHA. While on steroids, reticulocyte count started to decline without any improvement in hemoglobin level. Surprisingly, the bone marrow biopsy revealed severely depressed erythroblastic precursor with normal maturation of other cell lineages. In this case, the short time interval between AIHA and PRCA suggests the same pathogenesis but different manifestation. In an earlier documented case, [11] the interval was of 4 years and they thought the phenomenon to be due to different causal mechanisms. Moreover, the recovery has also been relatively rapid in our case. With respect to AIHA complicated with PRCA, our speculations are: (1) Autoantibodies attacked mature erythroid cells at first and then attack immature erythroid cells in succession; (2) it might be due to some unknown infections which led to both AIHA and PRCA; (3) too much production of erythroid precursor during autoimmune phase might have exhausted erythroid precursors leading to the PRCA phase; and (4) possibility of steroid-induced PRCA. The most plausible explanation appears to be an aplastic crisis in the background of AIHA. However, culture experiments using patient's serum during AIHA, PRCA, and recovery phase and bone marrow cells from the patient and other hematologically normal individuals could have been more helpful for the elucidation of pathomechanism.

Corticosteroids (CS) were the first immunosuppressive drugs used in the treatment of PRCA and so far have been considered the treatment of first choice, especially in young adults. To date, the efficacy of CS for patients with PRCA has been reported to be between 30% and 62%. [12]

Our patient was refractory to prednisolone but was responsive to azathioprine. With the assumption that acquired red cell aplasia is an autoimmune disorder, therapy with azathioprine was tried. There are reports where azathioprine was used to obtain remission in steroid-refractory PRCA. [11],[13] Cyclosporine A (CsA) has also become established as one of the leading drugs for treatment of PRCA. However, an individualized approach to management should be followed for those patients who have failed CS therapy. [14]

The present case is still remaining an enigma to us and no previous documentation of such association has been found in the literature. We would like to stress on further investigation of the control of erythropoiesis and the pathogenesis of PRCA in the context of immunological disorders. Clinicians may keep this phenomenon in mind when they counter steroid-refractory AIHA.

 
 :: References Top

1.Ammus SS, Yunis AA. Acquired pure red cell aplasia. Am J Hematol 1987;24:311-26.  Back to cited text no. 1
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2.Krantz SB, Moore WH, Zaentz SD. Studies on red cell aplasia. V. Presence of erythroblast cytotoxicity in G-globulin fraction of plasma. J Clin Invest 1973;52:324-36.  Back to cited text no. 2
    
3.Kay NE, Oken MM, Ascensao J, Kaplan ME. Lymphocytotoxic T lymphocytes in a patient with B-chronic lymphocytic leukemia and pure red cell aplasia. Leuk Res 1985;9:1189-94.  Back to cited text no. 3
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4.Fujisao S, Tsuda H. Th1/Th2 balance alteration in the clinical course of a patient with pure red cell aplasia and thymoma. Br J Haematol 1998;103:308-10.  Back to cited text no. 4
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5.Kiely PD, McGuckin CP, Collins DA, Bevan DH, Marsh JC. Erythrocyte aplasia and systemic lupus erythematosus. Lupus 1995;4:407-11.  Back to cited text no. 5
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6.Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol 2000;111:1010-22.  Back to cited text no. 6
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7.Wong KF, Chau KF, Chan JK, Chu YC, Li CS. Pure red cell aplasia associated with thymic lymphoid hyperplasia and secondary erythropoietin resistance. Am J Clin Pathol 1995;103:346-7.  Back to cited text no. 7
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8.Dainiak N, Hardin J, Floyd V, Callahan M, Hoffman R. Humoral suppression of erythropoiesis in systemic lupus erythematosus (SLE) and rheumatoid arthritis. Am J Med 1980;69:537-44.  Back to cited text no. 8
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9.Hara A, Wada T, Kitajima S, Toyama T, Okumura T, Kitagawa K, et al. Combined pure red cell aplasia and autoimmune hemolytic anemia in systemic lupus erythematosus with anti-erythropoietin autoantibodies. Am J Hematol 2008;83:750-2.  Back to cited text no. 9
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10.Taniguchi S, Shibuya T, Morioka E, Okamura T, Okamura S, Inaba S, et al. Demonstration of three distinct immunological disorders on erythropoiesis in a patient with pure red cell aplasia and autoimmune haemolytic anaemia associated with thymoma. Br J Haematol 1988;68:473-7.  Back to cited text no. 10
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11.Tohda S, Nara N, Tanikawa S, Imai Y, Murakami N, Aoki N. Pure red cell aplasia following autoimmune haemolytic anaemia. Cell-mediated suppression of erythropoiesis as a possible pathogenesis of pure red cell aplasia. Acta Haematol 1992;87:98-102.  Back to cited text no. 11
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12.Clark DA, Dessypris EN, Krantz SB. Studies on pure red cell aplasia. XI. Results of immunosuppressive treatment of 37 patients. Blood 1984;63:277-86.  Back to cited text no. 12
    
13.Zuber J, Beldjord K, Casadevall N, Thervet E, Legendre C, Varet B. Immune-mediated pure red cell aplasia in renal transplant recipients. Haematologica 2008;93:1750-2.  Back to cited text no. 13
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14.Sawada K, Fujishima N, Hirokawa M. Acquired pure red cell aplasia: Updated review of treatment. Br J Haematol 2008;142:505-14.  Back to cited text no. 14
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    Figures

  [Figure 1], [Figure 2], [Figure 3]

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