Int J Hematol (2014) 100:494–497 DOI 10.1007/s12185-014-1648-1
CASE REPORT
Refractory autoimmune hemolytic anemia in a patient with DiGeorge syndrome treated successfully with plasma exchange: a case report and review of the literature Moussab Damlaj • Chantal Se´guin
Received: 15 April 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published online: 31 July 2014 Ó The Japanese Society of Hematology 2014
Abstract Warm antibody autoimmune hemolytic anemia (AIHA) results from targeted antibodies towards the red blood cells (RBCs) and can be either idiopathic or secondary to certain diseases, such as autoimmune disorders or malignancy, drugs, or infection. Patients with DiGeorge syndrome are particularly vulnerable to autoimmune conditions secondary to thymic hypoplasia and dysfunction of the immune system. First-line therapy for AIHA consists of corticosteroids, with most patients showing signs of response. Relapses are not uncommon and are treated with splenectomy or rituximab. There is a paucity of reports in the literature regarding treatment options beyond this stage. Herein, we describe an unusual case of a 20-year-old female affected by DiGeorge syndrome with a history of immune thrombocytopenia (ITP), who presented with lifethreatening AIHA. Standard first- and second-line therapeutic modalities were ineffective in controlling her disease and she ultimately underwent plasma exchange therapy with successful resolution of hemolysis. At her last follow-up, one year after her initial presentation, she remains clinically well without signs of hemolysis. We conclude that in refractory cases of warm AIHA, plasma exchange therapy can be a valuable tool in the therapeutic armamentarium. Keywords DiGeorge syndrome Autoimmune hemolytic anemia Plasma exchange
M. Damlaj C. Se´guin (&) Division of Hematology, Department of Medicine, McGill University Health Centre (MUHC), Montreal General Hospital, Room A7.117.1, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada e-mail: [email protected]
123
Introduction Warm autoimmune hemolytic anemia (AIHA) results from IgG antibodies targeted towards protein antigens on the red blood cell (RBC) surface. The underlying etiology can be due to many factors such as infections, certain malignancies, autoimmune disease and medications [1]. Furthermore, many cases are idiopathic in nature. Immune deficiency disorders, such as common variable immune deficiency (CVID) are associated with AIHA [2]. DiGeorge syndrome is a condition characterized by an abnormal karyotype with deletion at chromosome 22q11.2 and a highly variable clinical phenotype [3]. Patients with DiGeorge syndrome are particularly vulnerable to autoimmune conditions secondary to thymic hypoplasia and dysfunction of the immune system [4]. The diagnosis of AIHA is suspected on clinical presentation of hemolysis and laboratory workup compatible with anemia. Confirmation is primarily based on the direct antiglobulin test detecting the autoantibody and/or complement on the surface of the RBCs [5]. First-line therapy of warm AIHA consists of corticosteroids with most patients showing signs of significant response [6]. Relapses are not uncommon and are treated with splenectomy or rituximab [7, 8]. There is paucity in the literature regarding treatment options beyond this stage which include cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil and danazol with sparse data on efficacy [9].
Case presentation A 20-year-old female patient presented to the emergency department with warm autoimmune hemolytic anemia. Her past medical history is notable for DiGeorge syndrome.
Refractory autoimmune hemolytic anemia
This was suspected as she had neonatal seizures secondary to hypocalcemia shortly after birth. She has dysmorphic facial features including low set ears. Blood work showed lymphopenia with increased B cell and decreased T cell subsets. Chest X-ray showed absence of thymus tissue and an echocardiogram was normal. Fluorescence in situ hybridization studies revealed 22q11.2 micro-deletion. At 13 years of age, she was diagnosed with immune thrombocytopenia (ITP). This was managed with corticosteroids and intermittent doses of intravenous immunoglobulins (IVIG). However, the patient relapsed after corticosteroid tapering and her thrombocytopenia was then treated with rituximab without a significant response. Eventually, she was managed with monthly IVIG infusions (400 mg/kg) and thrombopoietin analogue romiplostim, to maintain her platelet count between 50 and 100 9 109/L. Splenectomy was deferred due to concerns of life threatening infections in the context of preexisting T cell deficiency. During the current presentation she had signs of severe anemia and positive hemolytic markers; hemoglobin (Hb) 55 g/L, platelets (Plt) 146 9 109/L, lactate dehydrogenase (LDH) 541 U/L, total bilirubin 46.6 lmol/L and a positive direct antiglobulin test (4? IgG and negative C3). Her blood group is B? and antibody screen showed pan agglutination and no cross match compatible units of packed red blood cells (PRBC) were available. Previous antibody screen was negative. A diagnosis of AIHA was thus established. Warm autoadsorption was done twice, but results inconclusive due to gross hemolysis. An elution reaction to investigate the presence of an alloantibody done by the provincial reference blood bank only showed a nonspecific autoantibody. As she did not have a history of prior PRBC transfusion, her phenotype was determined to be C? c? E- e? JKa? jKb? K-, and transfusion support was administered with the use of packed red blood cells (PRBC) with phenotype compatible units. Prednisone at 1 mg/kg was initiated along with high dose IVIG (2 consecutive doses at 1 g/kg daily). Due to lack of response requiring transfusions reaching daily frequency, prednisone was increased to 1.5 mg/kg. Rituximab 375 mg/m2 was planned to be administered for 4 doses at weekly intervals and was started but was however interrupted at the second dose due to hemodynamic instability. Hospital course was further complicated by the reoccurrence of thrombocytopenia as romiplostim was held when platelet count [100 9 109/L and thrombosis involving the left brachial and axillary veins at the site of a peripherally inserted central catheter (PICC). Anticoagulation with low molecular weight heparin was instituted. Ineffective erythropoiesis was made evident by inappropriately low reticulocytosis (reticulocyte count 6 9 109/ L, normal range 23–120 9 109/L). In hemolytic states, the
495
reticulocyte count is predicted to be elevated to compensate for the destructive process; however, there are many variables that can blunt or attenuate this response [10]. Transfusions and aplasia state are factors that can lead to paradoxical reticulocytopenia. The expected reticulocytosis was somewhat blunted in this case, perhaps due to transfusions (Fig. 1). Bone marrow aspirate did not show evidence of pure red cell aplasia. In fact, erythroid hyperplasia was seen as expected on the aspirate (M:E ratio of 1:4) with a left shift and normal trilineage hematopoiesis otherwise. There was no evidence of a lymphoproliferative disorder on the trephine biopsy. Post splenectomy, a sharp rise in reticulocyte count was noted and this has been previously described (Fig. 1) [11–13]. Screening for paroxysmal nocturnal hemoglobinuria (PNH), by flow cytometry for CD55, and for glucose-6-phosphate dehydrogenase deficiency (G6PD) was negative. Despite initial concerns, the patient underwent a splenectomy for refractory AIHA causing unstable hemodynamic parameters in the absence of an infectious etiology. Hemolytic markers only transiently improved post splenectomy and were followed by progressive deterioration of her hemolytic picture within a few days post-operatively with resumption of transfusions (Fig. 1). Post-operatively, thrombosis developed within the right portal and splenic vein. Given continuous worsening of her clinical status, a decision was made to proceed with daily plasma exchange for five sessions using fresh frozen plasma fluid replacement. 24 h following her first exchange session, a steady improvement of her hemolytic markers was noted and the patient became persistently transfusion independent for the first time six weeks following her admission to the hospital (Fig. 1). The hemoglobin normalized eight days following the last plasma exchange session. Additionally, platelets normalized following splenectomy and the patient no longer required romiplostim. We conclude that the combination of plasma exchange therapy which followed partial response to splenectomy successfully controlled the severe hemolysis. At the last outpatient follow up, 382 days since her admission and 343 days following her last session of plasma exchange, the hemoglobin and hemolytic markers continue to be within normal range. A total of 42 units of PRBCs were required.
Discussion Warm AIHA is a rare disease which may occur in the context of infection, malignancy, autoimmune disorders or may be idiopathic in nature. The backbone of treatment in idiopathic warm AIHA is based on corticosteroid therapy, which induces remission from autoantibody production in approximately 80% of the patients [9]. Those who remain
123
496
M. Damlaj, C. Se´guin
Fig. 1 Evolution of patient’s hemolytic parameters during admission. White line graph represents reticulocytes, red shading graph represents the hemoglobin value and blue line graph represents the total bilirubin level. Yellow arrows represent transfusions of pRBCs.
Therapeutic modalities are shown at the top throughout the figure. Note the absence of subsequent transfusion of pRBCs following the first plasma exchange and further normalization of hemoglobin
refractory or who are corticosteroid dependent are offered second-line therapy, namely splenectomy or an anti-CD20 monoclonal antibody therapy like rituximab [14–17]. Therapeutic options beyond second line are extremely limited and based on small case series on the use of immunosuppressive therapy [18]. IVIG can be used as an adjunct treatment but is unlikely to be solely effective [19]. There is lack of randomized data in the literature on the therapeutic options, and the available evidence stems from a handful of prospective phase II data and small case series. Therefore, clinicians faced with refractory cases will find paucity of evidence to help manage their patients. Our patient had a diagnosis of chronic ITP predating the current presentation which was managed with romiplostim and monthly low dose IVIG. One consideration was the possibility of IVIG mediated hemolysis, particularly given her blood group. Hemolytic transfusion reaction has been well recognized, particularly in patients with non-group O blood type and those with autoimmune and inflammatory disorders treated with high-dose gammaglobulins [20]. The reported cases typically showed negative or weak direct antiglobulin test, anti-A or -B on elution studies and mild to moderate hemolysis. Despite the risk factors exhibited by the patient, she had life-threatening hemolysis and strong non-specific auto-antibody reaction; therefore, we diagnosed her with warm AIHA in the context of DiGeorge syndrome. This patient presented a real dilemma given her poor response to standard first- and second-line therapies. The
decision to proceed with splenectomy was initially deferred given concerns of overwhelming post splenectomy infection in a patient with impaired immunity at baseline [21]. Unfortunately, the procedure provided only a transient and modest improvement, lasting a few days, before transfusion requirements ensued (Fig. 1). Oral immunosuppressive agents would have unlikely provided a durable and immediate control of hemolysis in the short term. Faced with a life-threatening hemolysis in a young individual, we opted to proceed with plasma exchange as a last resort, with the goal of acutely decreasing the antibody burden. We witnessed a dramatic improvement of hemolysis markers and the patient promptly became transfusion independent. We conclude that the combination of splenectomy followed shortly by plasma exchange therapy was necessary to control the disease. It is unlikely that each therapeutic approach in isolation would have been successful in achieving remission in this particular patient. Plasma exchange therapy is used in many auto-immune disorders, such as myasthenia gravis or acute demyelinating polyneuropathy to decrease the antibody burden contributing to acute crises [22, 23]. We recognize the limited literature on apheresis in warm AIHA. A small case series involving five patients treated with plasma exchange therapy was not shown to be beneficial in decreasing transfusion requirements when matched to controls [24]. This may be related to the IgG burden predominantly in the extracellular compartment then later accumulating in the intravascular space post exchange. The American Society for
123
Refractory autoimmune hemolytic anemia
Apheresis published guidelines on the use of apheresis in clinical practice rates warm AIHA as category III indication with grade 2C evidence [25]. This report will contribute to the paucity of reported literature on the utility of apheresis in refractory cases.
Conclusion To the author’s knowledge, this is the first described case of DiGeorge syndrome presenting with Evans’ syndrome requiring plasma exchange therapy for the control of the underlying severe autoimmune hemolysis. Additionally, this is the first reported case of splenectomy in a patient with DiGeorge syndrome. The available literature for treatment of AIHA beyond second line is limited to a small case series on the use of immunosuppressive therapy. This case will therefore shed additional insight on plasma exchange as a possible salvage therapy and will certainly aid clinicians caring for patients presenting with severe hemolysis who failed the usual modalities.
Conflict of interest The authors declare that they have no conflicts of interest relevant to the submitted manuscript. No off label use of medication is discussed. This report has been approved by the institutional review board at the McGill University Health Center.
References 1. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002;69(4):258–71. 2. Seve P, Bourdillon L, Sarrot-Reynauld F, Ruivard M, Jaussaud R, Bouhour D, et al. Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients. Medicine. 2008;87(3):177–84. 3. Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr. 2005;147(1):90–6. 4. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10): 4539–47. 5. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and serologic correlations. Am J Clin Pathol. 2004;122(5):680–5. 6. Zupanska B, Sylwestrowicz T, Pawelski S. The results of prolonged treatment of autoimmune haemolytic anaemia. Haematologia. 1981;14(4):425–33. 7. Penalver FJ, Alvarez-Larran A, Diez-Martin JL, Gallur L, Jarque I, Caballero D, et al. Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia. Ann Hematol. 2010;89(11):1073–80.
497 8. Flowers JL, Lefor AT, Steers J, Heyman M, Graham SM, Imbembo AL. Laparoscopic splenectomy in patients with hematologic diseases. Ann Surg. 1996;224(1):19–28. 9. Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831–8. 10. Crosby WH, Rappaport H. Reticulocytopenia in autoimmune hemolytic anemia. Blood. 1956;11(10):929–36. 11. Lorber M. The effects of splenectomy on the red blood cells of the dog with particular emphasis on the reticulocyte response. Blood. 1958;13(10):972–85. 12. De Haan LD, Werre JM, Ruben AM, Huls AH, de Gier J, Staal GE. Reticulocyte crisis after splenectomy: evidence for delayed red cell maturation? Eur J Haematol. 1988;41(1):74–9. 13. Fiala J, Viktora L. The effect of splenectomy on bone marrow haematopoiesis in mice. Physiologia Bohemoslovaca. 1976;25(5):419–26. 14. Zaja F, Iacona I, Masolini P, Russo D, Sperotto A, Prosdocimo S, et al. B-cell depletion with rituximab as treatment for immune hemolytic anemia and chronic thrombocytopenia. Haematologica. 2002;87(2):189–95. 15. Katkhouda N, Hurwitz MB, Rivera RT, Chandra M, Waldrep DJ, Gugenheim J, et al. Laparoscopic splenectomy: outcome and efficacy in 103 consecutive patients. Ann Surg. 1998;228(4): 568–78. 16. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clinic Proc. 2003;78(11):1340–6. 17. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. Am J Hematol. 2004;77(3):303–10. 18. Pignon JM, Poirson E, Rochant H. Danazol in autoimmune haemolytic anaemia. Br J Haematol. 1993;83(2):343–5. 19. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993;44(4):237–42. 20. Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion. 2008;48(8):1598–601. 21. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med. 1995;122(3):187–8. 22. Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76(23):2017–23. 23. Kaynar L, Altuntas F, Aydogdu I, Turgut B, Kocyigit I, Hacioglu SK, et al. Therapeutic plasma exchange in patients with neurologic diseases: retrospective multicenter study. Transfusion Apheresis Sci. 2008;38(2):109–15. 24. Ruivard M, Tournilhac O, Montel S, Fouilhoux AC, Quainon F, Lenat A, et al. Plasma exchanges do not increase red blood cell transfusion efficiency in severe autoimmune hemolytic anemia: a retrospective case-control study. J Clin Apheresis. 2006; 21(3):202–6. 25. Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apheresis. 2013;28(3):145–284.
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CASE REPORT
Refractory autoimmune hemolytic anemia in a patient with DiGeorge syndrome treated successfully with plasma exchange: a case report and review of the literature Moussab Damlaj • Chantal Se´guin
Received: 15 April 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published online: 31 July 2014 Ó The Japanese Society of Hematology 2014
Abstract Warm antibody autoimmune hemolytic anemia (AIHA) results from targeted antibodies towards the red blood cells (RBCs) and can be either idiopathic or secondary to certain diseases, such as autoimmune disorders or malignancy, drugs, or infection. Patients with DiGeorge syndrome are particularly vulnerable to autoimmune conditions secondary to thymic hypoplasia and dysfunction of the immune system. First-line therapy for AIHA consists of corticosteroids, with most patients showing signs of response. Relapses are not uncommon and are treated with splenectomy or rituximab. There is a paucity of reports in the literature regarding treatment options beyond this stage. Herein, we describe an unusual case of a 20-year-old female affected by DiGeorge syndrome with a history of immune thrombocytopenia (ITP), who presented with lifethreatening AIHA. Standard first- and second-line therapeutic modalities were ineffective in controlling her disease and she ultimately underwent plasma exchange therapy with successful resolution of hemolysis. At her last follow-up, one year after her initial presentation, she remains clinically well without signs of hemolysis. We conclude that in refractory cases of warm AIHA, plasma exchange therapy can be a valuable tool in the therapeutic armamentarium. Keywords DiGeorge syndrome Autoimmune hemolytic anemia Plasma exchange
M. Damlaj C. Se´guin (&) Division of Hematology, Department of Medicine, McGill University Health Centre (MUHC), Montreal General Hospital, Room A7.117.1, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada e-mail: [email protected]
123
Introduction Warm autoimmune hemolytic anemia (AIHA) results from IgG antibodies targeted towards protein antigens on the red blood cell (RBC) surface. The underlying etiology can be due to many factors such as infections, certain malignancies, autoimmune disease and medications [1]. Furthermore, many cases are idiopathic in nature. Immune deficiency disorders, such as common variable immune deficiency (CVID) are associated with AIHA [2]. DiGeorge syndrome is a condition characterized by an abnormal karyotype with deletion at chromosome 22q11.2 and a highly variable clinical phenotype [3]. Patients with DiGeorge syndrome are particularly vulnerable to autoimmune conditions secondary to thymic hypoplasia and dysfunction of the immune system [4]. The diagnosis of AIHA is suspected on clinical presentation of hemolysis and laboratory workup compatible with anemia. Confirmation is primarily based on the direct antiglobulin test detecting the autoantibody and/or complement on the surface of the RBCs [5]. First-line therapy of warm AIHA consists of corticosteroids with most patients showing signs of significant response [6]. Relapses are not uncommon and are treated with splenectomy or rituximab [7, 8]. There is paucity in the literature regarding treatment options beyond this stage which include cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil and danazol with sparse data on efficacy [9].
Case presentation A 20-year-old female patient presented to the emergency department with warm autoimmune hemolytic anemia. Her past medical history is notable for DiGeorge syndrome.
Refractory autoimmune hemolytic anemia
This was suspected as she had neonatal seizures secondary to hypocalcemia shortly after birth. She has dysmorphic facial features including low set ears. Blood work showed lymphopenia with increased B cell and decreased T cell subsets. Chest X-ray showed absence of thymus tissue and an echocardiogram was normal. Fluorescence in situ hybridization studies revealed 22q11.2 micro-deletion. At 13 years of age, she was diagnosed with immune thrombocytopenia (ITP). This was managed with corticosteroids and intermittent doses of intravenous immunoglobulins (IVIG). However, the patient relapsed after corticosteroid tapering and her thrombocytopenia was then treated with rituximab without a significant response. Eventually, she was managed with monthly IVIG infusions (400 mg/kg) and thrombopoietin analogue romiplostim, to maintain her platelet count between 50 and 100 9 109/L. Splenectomy was deferred due to concerns of life threatening infections in the context of preexisting T cell deficiency. During the current presentation she had signs of severe anemia and positive hemolytic markers; hemoglobin (Hb) 55 g/L, platelets (Plt) 146 9 109/L, lactate dehydrogenase (LDH) 541 U/L, total bilirubin 46.6 lmol/L and a positive direct antiglobulin test (4? IgG and negative C3). Her blood group is B? and antibody screen showed pan agglutination and no cross match compatible units of packed red blood cells (PRBC) were available. Previous antibody screen was negative. A diagnosis of AIHA was thus established. Warm autoadsorption was done twice, but results inconclusive due to gross hemolysis. An elution reaction to investigate the presence of an alloantibody done by the provincial reference blood bank only showed a nonspecific autoantibody. As she did not have a history of prior PRBC transfusion, her phenotype was determined to be C? c? E- e? JKa? jKb? K-, and transfusion support was administered with the use of packed red blood cells (PRBC) with phenotype compatible units. Prednisone at 1 mg/kg was initiated along with high dose IVIG (2 consecutive doses at 1 g/kg daily). Due to lack of response requiring transfusions reaching daily frequency, prednisone was increased to 1.5 mg/kg. Rituximab 375 mg/m2 was planned to be administered for 4 doses at weekly intervals and was started but was however interrupted at the second dose due to hemodynamic instability. Hospital course was further complicated by the reoccurrence of thrombocytopenia as romiplostim was held when platelet count [100 9 109/L and thrombosis involving the left brachial and axillary veins at the site of a peripherally inserted central catheter (PICC). Anticoagulation with low molecular weight heparin was instituted. Ineffective erythropoiesis was made evident by inappropriately low reticulocytosis (reticulocyte count 6 9 109/ L, normal range 23–120 9 109/L). In hemolytic states, the
495
reticulocyte count is predicted to be elevated to compensate for the destructive process; however, there are many variables that can blunt or attenuate this response [10]. Transfusions and aplasia state are factors that can lead to paradoxical reticulocytopenia. The expected reticulocytosis was somewhat blunted in this case, perhaps due to transfusions (Fig. 1). Bone marrow aspirate did not show evidence of pure red cell aplasia. In fact, erythroid hyperplasia was seen as expected on the aspirate (M:E ratio of 1:4) with a left shift and normal trilineage hematopoiesis otherwise. There was no evidence of a lymphoproliferative disorder on the trephine biopsy. Post splenectomy, a sharp rise in reticulocyte count was noted and this has been previously described (Fig. 1) [11–13]. Screening for paroxysmal nocturnal hemoglobinuria (PNH), by flow cytometry for CD55, and for glucose-6-phosphate dehydrogenase deficiency (G6PD) was negative. Despite initial concerns, the patient underwent a splenectomy for refractory AIHA causing unstable hemodynamic parameters in the absence of an infectious etiology. Hemolytic markers only transiently improved post splenectomy and were followed by progressive deterioration of her hemolytic picture within a few days post-operatively with resumption of transfusions (Fig. 1). Post-operatively, thrombosis developed within the right portal and splenic vein. Given continuous worsening of her clinical status, a decision was made to proceed with daily plasma exchange for five sessions using fresh frozen plasma fluid replacement. 24 h following her first exchange session, a steady improvement of her hemolytic markers was noted and the patient became persistently transfusion independent for the first time six weeks following her admission to the hospital (Fig. 1). The hemoglobin normalized eight days following the last plasma exchange session. Additionally, platelets normalized following splenectomy and the patient no longer required romiplostim. We conclude that the combination of plasma exchange therapy which followed partial response to splenectomy successfully controlled the severe hemolysis. At the last outpatient follow up, 382 days since her admission and 343 days following her last session of plasma exchange, the hemoglobin and hemolytic markers continue to be within normal range. A total of 42 units of PRBCs were required.
Discussion Warm AIHA is a rare disease which may occur in the context of infection, malignancy, autoimmune disorders or may be idiopathic in nature. The backbone of treatment in idiopathic warm AIHA is based on corticosteroid therapy, which induces remission from autoantibody production in approximately 80% of the patients [9]. Those who remain
123
496
M. Damlaj, C. Se´guin
Fig. 1 Evolution of patient’s hemolytic parameters during admission. White line graph represents reticulocytes, red shading graph represents the hemoglobin value and blue line graph represents the total bilirubin level. Yellow arrows represent transfusions of pRBCs.
Therapeutic modalities are shown at the top throughout the figure. Note the absence of subsequent transfusion of pRBCs following the first plasma exchange and further normalization of hemoglobin
refractory or who are corticosteroid dependent are offered second-line therapy, namely splenectomy or an anti-CD20 monoclonal antibody therapy like rituximab [14–17]. Therapeutic options beyond second line are extremely limited and based on small case series on the use of immunosuppressive therapy [18]. IVIG can be used as an adjunct treatment but is unlikely to be solely effective [19]. There is lack of randomized data in the literature on the therapeutic options, and the available evidence stems from a handful of prospective phase II data and small case series. Therefore, clinicians faced with refractory cases will find paucity of evidence to help manage their patients. Our patient had a diagnosis of chronic ITP predating the current presentation which was managed with romiplostim and monthly low dose IVIG. One consideration was the possibility of IVIG mediated hemolysis, particularly given her blood group. Hemolytic transfusion reaction has been well recognized, particularly in patients with non-group O blood type and those with autoimmune and inflammatory disorders treated with high-dose gammaglobulins [20]. The reported cases typically showed negative or weak direct antiglobulin test, anti-A or -B on elution studies and mild to moderate hemolysis. Despite the risk factors exhibited by the patient, she had life-threatening hemolysis and strong non-specific auto-antibody reaction; therefore, we diagnosed her with warm AIHA in the context of DiGeorge syndrome. This patient presented a real dilemma given her poor response to standard first- and second-line therapies. The
decision to proceed with splenectomy was initially deferred given concerns of overwhelming post splenectomy infection in a patient with impaired immunity at baseline [21]. Unfortunately, the procedure provided only a transient and modest improvement, lasting a few days, before transfusion requirements ensued (Fig. 1). Oral immunosuppressive agents would have unlikely provided a durable and immediate control of hemolysis in the short term. Faced with a life-threatening hemolysis in a young individual, we opted to proceed with plasma exchange as a last resort, with the goal of acutely decreasing the antibody burden. We witnessed a dramatic improvement of hemolysis markers and the patient promptly became transfusion independent. We conclude that the combination of splenectomy followed shortly by plasma exchange therapy was necessary to control the disease. It is unlikely that each therapeutic approach in isolation would have been successful in achieving remission in this particular patient. Plasma exchange therapy is used in many auto-immune disorders, such as myasthenia gravis or acute demyelinating polyneuropathy to decrease the antibody burden contributing to acute crises [22, 23]. We recognize the limited literature on apheresis in warm AIHA. A small case series involving five patients treated with plasma exchange therapy was not shown to be beneficial in decreasing transfusion requirements when matched to controls [24]. This may be related to the IgG burden predominantly in the extracellular compartment then later accumulating in the intravascular space post exchange. The American Society for
123
Refractory autoimmune hemolytic anemia
Apheresis published guidelines on the use of apheresis in clinical practice rates warm AIHA as category III indication with grade 2C evidence [25]. This report will contribute to the paucity of reported literature on the utility of apheresis in refractory cases.
Conclusion To the author’s knowledge, this is the first described case of DiGeorge syndrome presenting with Evans’ syndrome requiring plasma exchange therapy for the control of the underlying severe autoimmune hemolysis. Additionally, this is the first reported case of splenectomy in a patient with DiGeorge syndrome. The available literature for treatment of AIHA beyond second line is limited to a small case series on the use of immunosuppressive therapy. This case will therefore shed additional insight on plasma exchange as a possible salvage therapy and will certainly aid clinicians caring for patients presenting with severe hemolysis who failed the usual modalities.
Conflict of interest The authors declare that they have no conflicts of interest relevant to the submitted manuscript. No off label use of medication is discussed. This report has been approved by the institutional review board at the McGill University Health Center.
References 1. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002;69(4):258–71. 2. Seve P, Bourdillon L, Sarrot-Reynauld F, Ruivard M, Jaussaud R, Bouhour D, et al. Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients. Medicine. 2008;87(3):177–84. 3. Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr. 2005;147(1):90–6. 4. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10): 4539–47. 5. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and serologic correlations. Am J Clin Pathol. 2004;122(5):680–5. 6. Zupanska B, Sylwestrowicz T, Pawelski S. The results of prolonged treatment of autoimmune haemolytic anaemia. Haematologia. 1981;14(4):425–33. 7. Penalver FJ, Alvarez-Larran A, Diez-Martin JL, Gallur L, Jarque I, Caballero D, et al. Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia. Ann Hematol. 2010;89(11):1073–80.
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