Expert Review of Hematology
ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20
The clinical dilemma and management of red cell autoantibodies Wilma Barcellini To cite this article: Wilma Barcellini (2016): The clinical dilemma and management of red cell autoantibodies, Expert Review of Hematology, DOI: 10.1586/17474086.2016.1152885 To link to this article: http://dx.doi.org/10.1586/17474086.2016.1152885
Accepted author version posted online: 10 Feb 2016.
Submit your article to this journal
Article views: 16
View related articles
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierr20 Download by: [24.235.52.38]
Date: 20 February 2016, At: 08:09
Publisher: Taylor & Francis Journal: Expert Review of Hematology DOI: 10.1586/17474086.2016.1152885 Editorial The clinical dilemma and management of red cell autoantibodies Wilma Barcellini, [email protected] U.O. Oncoematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan
Downloaded by [24.235.52.38] at 08:10 20 February 2016
Keywords: Anti-red cell antibodies, direct antiglobulin test, autoimmune hemolytic anemia
RBC autoantibodies are undoubtedly the causative agents of autoimmune hemolytic anemia (AIHA) by inducing antibody-dependent cell-mediated cytotoxicity and/or sequential activation of the final components of the complement cascade. Their pathogenic role depends on the class (the most frequent are IgG and IgM), thermal amplitude (warm and cold forms), affinity and efficiency in activating complement. These characteristics, together with the activity of the reticuloendothelial system (in spleen, liver and lymphoid organs), and the efficacy of the erythroblast compensatory response, determine the heterogeneous clinical spectrum of AIHA, from asymptomatic/fully compensated to life threatening or even fatal forms [1-3]. RBC autoantibodies are usually detected by the direct antiglobulin test (DAT), which enables the distinction of warm forms (DAT+ for IgG only or IgG plus C3d in the majority of cases, and DAT+ for C3d only in ~10% of cases), cold agglutinin disease (DAT+ for C3d), and mixed forms (DAT+ for IgG and C3d, with coexistent cold agglutinins) [1]. However, the presence of RBC autoantibodies is not always associated with clinically overt AIHA, and, conversely, immune hemolysis cannot always be excluded when the DAT remains negative. In general, results obtained with the DAT are of little value without clinical information on the extent of hemolysis, indicating true RBC destruction: about 1:10,000 healthy individuals and AIHA in complete clinical remission may display a positive DAT without hemolysis; autoimmune diseases and infections may present an unspecific DAT positivity due to 1
the immune activation; a false positive DAT may be found in diseases associated with hypergammaglobulinemia or IvIg treatment. Moreover, DAT positivity may be due to drug-induced autoantibodies: typically, methyldopa causes the production of RBC autoantibodies in about 15% of the patients receiving the drug, but only about 1% develops AIHA [1,4]. The occurrence of “silent” autoantibodies, which result in DAT positivity but do not cause hemolytic anemia, may be observed also during pregnancy, with a frequency of about five times greater than in non-pregnant women. This may generate confusion and concern, resulting in repeated serological, hematological and
Downloaded by [24.235.52.38] at 08:10 20 February 2016
obstetric investigation. The reasons behind the development of these antibodies and their clinical significance are still unknown [5]. The differential diagnosis between true AIHA and harmless DAT positivity is particularly difficult in the hepatopathic patient, due to several possible misleading factors, including hypergammaglobulinemia and HCV, which is a polyclonal immune activator. Lactate dehydrogenase may be increased and haptoglobin decreased for reasons other than hemolysis, and anemia may be due to concomitant bleeding and chronic inflammation. Transfusions may further complicate the picture, resulting in DAT positivity due to the presence of alloantibodies, which may react with donor’s RBC resulting in hemolytic transfusion reactions. These events should be suspected and investigated by extended phenotyping and appropriate serological tests (absorption and elution). Finally, therapy with ribavirin and interferon are known to induce true AIHA, possibly complicated by inadequate reticulocytosis due to bone marrow malfunctioning or folate/vitamin deficiency. The
occurrence
of
puzzling
allo-
and
auto-immunization
is
described
also
in
hemoglobinopathies [6-8]. In transfusion-dependent beta-thalassemia, about half of patients showed a positive DAT. However, this positivity does not correlate with decreased response to transfusion, RBC survival, hemolysis, or increased transfusion requirements. Moreover, eluates are found positive for “true” autoantibodies in half cases only. The mechanism leading to development of autoantibodies is not known. DAT positivity is significantly associated with splenectomy, elevated 2
IgG levels, and HCV positivity. The presence of conformational membrane changes of red blood cells, especially in splenectomized patients, and B-lymphocyte activation have been hypothesized to play a role. In sickle cell disease, allo-immunization mostly directed against Rh antigens, is reported in about half of patients, and is frequently associated with laboratory evidence of delayed transfusion reactions. Likewise, in AIHA alloantibodies are described in 15-40% of cases, often masked by the autoantibody. Undetected alloantibodies could be the cause of increased posttransfusion hemolysis, which might falsely be attributed to AIHA worsening. There is no agreement
Downloaded by [24.235.52.38] at 08:10 20 February 2016
on the transfusion policy, whether to ignore or respect the autoantibody specificity. Some authors recommend ignoring the specificity of the autoantibody and this indication has been demonstrated to be safe and effective [9-11]. The clinical dilemma of anti-red cell antibodies is even more challenging in the setting of transplantation, both of hematopoietic stem cell (HSC) and of solid organ. HSC transplantation is performed across the ABO blood group barrier, with the transfer of plasma, red blood cells, and immunocompetent cells from the donor to the recipient. Acute and early hemolysis may occur because of donor’s RBC hemolysis, particularly when bone marrow is the source of transplant. This event may be reduced by removing donor’s RBC from bone marrow sample using treatments such as cell separator (same principle of apheresis), sedimentation or diluition with compatible RBCs. On the other hand, acute hemolysis can be prevented by the reduction of recipient’s isohemagglutinin titers (plasma-exchange or immunoadsorption). In this case, the host anti-donor isohemagglutinins may determine a possible delayed red cell engraftment or even a pure red cell alpasia when recipient’s plasmacells persist for a long time [12]. The “passenger lymphocyte syndrome” is due to the production of antibodies by donor passenger lymphocytes, transplanted with the graft, against the recipient’s red blood cells. It mainly occurs in minor ABO and Rh mismatched transplants and has been reported after kidney, lung, heart-lung, liver, pancreas, pancreas-spleen and HSC transplantation. The onset of hemolysis, usually mild and self-limited, is
3
observed 2-3weeks after the transplant, and the risk increases with a higher mass of lymphocytes of the graft, being more frequent in lung-heart (about 70%), followed by liver (40%), and kidney transplants (17%) [13,14]. It is worth reminding that “true” AIHA occurs in about 5% of HSC transplants, both autologous and allogeneic (even ABO-matched), and is often severe and refractory to treatments. The most important risk factors are unrelated donors, presence of chronic graft versus host disease, therapy with calcineurin inhibitors, and delayed/unbalanced immune reconstitution, with rapid B cell engraftment and postponed recovery of regulatory T cells. Finally, the underlying
Downloaded by [24.235.52.38] at 08:10 20 February 2016
disease, drugs used for conditioning, and concomitant infections may all contribute to the clinical and laboratory picture of post-transplant hemolytic anemia [12,15]. It is known that a small fraction of AIHA (5-10%) is DAT negative, even using non-routinely and more sophisticated techniques [16]. The use of low ionic strength solutions/ cold washings may help in revealing low-affinity antibodies, and monospecific anti-IgA antisera may unravel the diagnosis of the very rare AIHA forms due to isolated IgA antibodies (~ 1-2% of cases); of note, IgA can be identified in ~20% of patients with warm IgG AIHA, although their pathogenic role is uncertain [1]. Particular attention should be given to atypical AIHAs due to “warm” IgM autoantibodies which can be severe and fatal. These forms are also difficult to diagnose, being weakly DAT-positive for anti-C3 or DAT-negative, causing detrimental delay in therapy [1,17]. The dual DAT, performed however in reference laboratories only, may help in the diagnosis [18]. Small amounts of anti RBC antibodies can be detected employing more sensitive techniques, such as microcolumn and solid-phase DAT, or even more sophisticated methods, such as ELISA, flowcytometry, and mitogen-stimulated DAT [19]. Generally, tests that are more sensitive are less specific. Therefore, their positivity should be interpreted with caution, and related to the clinical hemolytic picture. In particular, mitogen stimulation in culture, which probably amplifies the production of autoantibodies, although proven useful in the diagnosis of DAT-negative AIHA, was found positive in a fraction of patients with B-chronic lymphocytic leukemia or myelofibrosis
4
without an overt diagnosis of AIHA [20,21]. AIHA (particularly cold agglutinin disease) is frequently associated with lymphoproliferative diseases, however its prognostic value is still a matter of debate, and even more uncertain is the significance of an isolated positive DAT. Moreover, low amounts of RBC autoantibodies, directed against several cytoskeletal proteins, have been detected by mitogen-stimualted DAT in more than a half of patients with hereditary spherocytosis. Positive cases showed a more evident hemolytic pattern, suggesting that they may be naturally-occurring autoantibodies, involved in the removal of opsonized erythrocytes in the spleen
Downloaded by [24.235.52.38] at 08:10 20 February 2016
[22]. In conclusion, although RBC autoantibodies have a clear pathogenic role in AIHA, there are several conditions in which they seem an innocent bystander, or even may represent a homeostatic mechanism for the clearance of aged, oxidatively damaged and altered self cells. The clinical management of these conditions is clearly different, although poorly evidence-based. For warm AIHA forms corticosteroids +/- IvIg are the first-line, followed by rituximab, which is becoming the preferred second-line treatment, or splenectomy. Further treatments for refractory/relapsed cases are immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil); plasma-exchange, high-dose cyclophosphamide and alemtuzumab are used in severe or ultra-refractory cases as last option treatments. Regarding cold agglutinin disease, rituximab is now recommended as first-line treatment; the drug has better responses in combination with fludarabine, even if with associated toxicities. Promising new drugs include complement blocking agents (eculizumab, compstatin, Cp40, TNT003) and the proteasome inhibitor bortezomib [23]. The management of cases with DAT positivity but doubtful hemolytic disease is uncertain; low doses steroids may be tried, and help clarifying the diagnosis in case of response, but more harmful second- and third-line therapies are difficult to be considered, particularly when the associated conditions (pregnancy, liver disease, hemoglobinopathy) contraindicate their use.
5
Financial and competing interests disclosure This work was supported by research funding from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, grant number RC 2014 and by Ministry of Health, grant number RF 2010 convention N. 141/RF-2010-2303934. The author has no other relevant affiliations or financial
Downloaded by [24.235.52.38] at 08:10 20 February 2016
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
6
References
1. Petz LD and Garratty G. Immune hemolytic anemias. New York: Churchill Livingstone, 2004. 2. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 2014;124:2930-6 3. Fattizzo B, Zaninoni A, Nesa F, et al. Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias. Am J Hematol 2015;90:E149-51
Downloaded by [24.235.52.38] at 08:10 20 February 2016
4. Garratty G: Immune hemolytic anemia caused by drugs. Expert Opin Drug Saf 2012;11:635-42 5. Hoppe B, Stibbe W, Bielefeld A, Pruss A, Salama A. Increased RBC autoantibody production in pregnancy. Transfusion 2001;41:1559-61 6. Arinsburg SA, Skerrett DL, Kleinert D, et al. The significance of a positive DAT in thalassemia patients. Immunohematology 2010;26:87-91 7. Obaid JM, Abo El-Nazar SY, Ghanem AM, et al. Red blood cells alloimmunization and autoimmunization among transfusion-dependent beta-thalassemia patients in Alexandria province, Egypt. Transfus Apher Sci 2015;53:52-7 8. Chou ST, Jackson T, Vege S, et al. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood 2013;122:1062-71 9. Salama A, Berghöfer H, Mueller-Eckhardt C. Red blood cell transfusion in warm-type autoimmune haemolytic anaemia. Lancet 1992;340:1515-7 10. Sümnig A, Mayer B, Kiefel V, Greinacher A, Salama A. 'Chameleonic' Serological Findings Leading to Life-Threatening Hemolytic Transfusion Reactions. Transfus Med Hemother 2015;42:340-3 11. Yürek S, Mayer B, Almahallawi M, Pruss A, Salama A. Precautions surrounding blood transfusion in autoimmune haemolytic anaemias are overestimated. Blood Transfus 2015;13:616-21 12. Holbro A, Passweg JR. Management of hemolytic anemia following allogeneic stem cell transplantation. Hematology Am Soc Hematol Educ Program 2015:378-84 7
13. Yazer MH, Triulzi DJ. Immune hemolysis following ABO-mismatched stem cell or solid organ transplantation. Curr Opin Hematol 2007;14:664-70 14. Romero S, Solves P, Lancharro A, et al. Passenger lymphocyte syndrome in liver transplant recipients: a description of 12 cases. Blood Transfus 2015;13:423-8 15. Wang M, Wang W, Abeywardane A, et al. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital. Biol Blood Marrow Transplant 2015;21:60-6
Downloaded by [24.235.52.38] at 08:10 20 February 2016
16. Barcellini W. Pitfalls in the diagnosis of autoimmune haemolytic anaemia. Blood Transfus 2015;13:3-5. 17. Arndt PA, Leger RM, Garratty G. Serologic findings in autoimmune hemolytic anemia associated with immunoglobulin M warm autoantibodies Transfusion 2009;49:235-42 18. Bartolmas T, Salama A. A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies. Transfusion 2010;50:1131-4 19. Barcellini W, Clerici G, Montesano R, et al. In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia: effect of mitogen and cytokine stimulation. Br J Haematol 2000;111:452-60 20. Barcellini W, Montesano R, Clerici G, et al. In vitro production of anti-RBC antibodies and cytokines in chronic lymphocytic leukemia. Am J Hematol 2002;71:177-83 21. Barcellini W, Iurlo A, Radice T, et al. Increased prevalence of autoimmune phenomena in myelofibrosis:
relationship
with
clinical
and
morphological
characteristics,
and
with
immunoregulatory cytokine patterns. Leuk Res 2013;37:1509-15 22. Zaninoni A, Vercellati C, Imperiali FG, et al. Detection of red blood cell antibodies in mitogenstimulated cultures from patients with hereditary spherocytosis. Transfusion 2015;55:2930-8 23. Barcellini W. Current treatment strategies in autoimmune hemolytic disorders. Expert Rev Hematol 2015;8:681-91
8
9
Downloaded by [24.235.52.38] at 08:10 20 February 2016
ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20
The clinical dilemma and management of red cell autoantibodies Wilma Barcellini To cite this article: Wilma Barcellini (2016): The clinical dilemma and management of red cell autoantibodies, Expert Review of Hematology, DOI: 10.1586/17474086.2016.1152885 To link to this article: http://dx.doi.org/10.1586/17474086.2016.1152885
Accepted author version posted online: 10 Feb 2016.
Submit your article to this journal
Article views: 16
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierr20 Download by: [24.235.52.38]
Date: 20 February 2016, At: 08:09
Publisher: Taylor & Francis Journal: Expert Review of Hematology DOI: 10.1586/17474086.2016.1152885 Editorial The clinical dilemma and management of red cell autoantibodies Wilma Barcellini, [email protected] U.O. Oncoematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan
Downloaded by [24.235.52.38] at 08:10 20 February 2016
Keywords: Anti-red cell antibodies, direct antiglobulin test, autoimmune hemolytic anemia
RBC autoantibodies are undoubtedly the causative agents of autoimmune hemolytic anemia (AIHA) by inducing antibody-dependent cell-mediated cytotoxicity and/or sequential activation of the final components of the complement cascade. Their pathogenic role depends on the class (the most frequent are IgG and IgM), thermal amplitude (warm and cold forms), affinity and efficiency in activating complement. These characteristics, together with the activity of the reticuloendothelial system (in spleen, liver and lymphoid organs), and the efficacy of the erythroblast compensatory response, determine the heterogeneous clinical spectrum of AIHA, from asymptomatic/fully compensated to life threatening or even fatal forms [1-3]. RBC autoantibodies are usually detected by the direct antiglobulin test (DAT), which enables the distinction of warm forms (DAT+ for IgG only or IgG plus C3d in the majority of cases, and DAT+ for C3d only in ~10% of cases), cold agglutinin disease (DAT+ for C3d), and mixed forms (DAT+ for IgG and C3d, with coexistent cold agglutinins) [1]. However, the presence of RBC autoantibodies is not always associated with clinically overt AIHA, and, conversely, immune hemolysis cannot always be excluded when the DAT remains negative. In general, results obtained with the DAT are of little value without clinical information on the extent of hemolysis, indicating true RBC destruction: about 1:10,000 healthy individuals and AIHA in complete clinical remission may display a positive DAT without hemolysis; autoimmune diseases and infections may present an unspecific DAT positivity due to 1
the immune activation; a false positive DAT may be found in diseases associated with hypergammaglobulinemia or IvIg treatment. Moreover, DAT positivity may be due to drug-induced autoantibodies: typically, methyldopa causes the production of RBC autoantibodies in about 15% of the patients receiving the drug, but only about 1% develops AIHA [1,4]. The occurrence of “silent” autoantibodies, which result in DAT positivity but do not cause hemolytic anemia, may be observed also during pregnancy, with a frequency of about five times greater than in non-pregnant women. This may generate confusion and concern, resulting in repeated serological, hematological and
Downloaded by [24.235.52.38] at 08:10 20 February 2016
obstetric investigation. The reasons behind the development of these antibodies and their clinical significance are still unknown [5]. The differential diagnosis between true AIHA and harmless DAT positivity is particularly difficult in the hepatopathic patient, due to several possible misleading factors, including hypergammaglobulinemia and HCV, which is a polyclonal immune activator. Lactate dehydrogenase may be increased and haptoglobin decreased for reasons other than hemolysis, and anemia may be due to concomitant bleeding and chronic inflammation. Transfusions may further complicate the picture, resulting in DAT positivity due to the presence of alloantibodies, which may react with donor’s RBC resulting in hemolytic transfusion reactions. These events should be suspected and investigated by extended phenotyping and appropriate serological tests (absorption and elution). Finally, therapy with ribavirin and interferon are known to induce true AIHA, possibly complicated by inadequate reticulocytosis due to bone marrow malfunctioning or folate/vitamin deficiency. The
occurrence
of
puzzling
allo-
and
auto-immunization
is
described
also
in
hemoglobinopathies [6-8]. In transfusion-dependent beta-thalassemia, about half of patients showed a positive DAT. However, this positivity does not correlate with decreased response to transfusion, RBC survival, hemolysis, or increased transfusion requirements. Moreover, eluates are found positive for “true” autoantibodies in half cases only. The mechanism leading to development of autoantibodies is not known. DAT positivity is significantly associated with splenectomy, elevated 2
IgG levels, and HCV positivity. The presence of conformational membrane changes of red blood cells, especially in splenectomized patients, and B-lymphocyte activation have been hypothesized to play a role. In sickle cell disease, allo-immunization mostly directed against Rh antigens, is reported in about half of patients, and is frequently associated with laboratory evidence of delayed transfusion reactions. Likewise, in AIHA alloantibodies are described in 15-40% of cases, often masked by the autoantibody. Undetected alloantibodies could be the cause of increased posttransfusion hemolysis, which might falsely be attributed to AIHA worsening. There is no agreement
Downloaded by [24.235.52.38] at 08:10 20 February 2016
on the transfusion policy, whether to ignore or respect the autoantibody specificity. Some authors recommend ignoring the specificity of the autoantibody and this indication has been demonstrated to be safe and effective [9-11]. The clinical dilemma of anti-red cell antibodies is even more challenging in the setting of transplantation, both of hematopoietic stem cell (HSC) and of solid organ. HSC transplantation is performed across the ABO blood group barrier, with the transfer of plasma, red blood cells, and immunocompetent cells from the donor to the recipient. Acute and early hemolysis may occur because of donor’s RBC hemolysis, particularly when bone marrow is the source of transplant. This event may be reduced by removing donor’s RBC from bone marrow sample using treatments such as cell separator (same principle of apheresis), sedimentation or diluition with compatible RBCs. On the other hand, acute hemolysis can be prevented by the reduction of recipient’s isohemagglutinin titers (plasma-exchange or immunoadsorption). In this case, the host anti-donor isohemagglutinins may determine a possible delayed red cell engraftment or even a pure red cell alpasia when recipient’s plasmacells persist for a long time [12]. The “passenger lymphocyte syndrome” is due to the production of antibodies by donor passenger lymphocytes, transplanted with the graft, against the recipient’s red blood cells. It mainly occurs in minor ABO and Rh mismatched transplants and has been reported after kidney, lung, heart-lung, liver, pancreas, pancreas-spleen and HSC transplantation. The onset of hemolysis, usually mild and self-limited, is
3
observed 2-3weeks after the transplant, and the risk increases with a higher mass of lymphocytes of the graft, being more frequent in lung-heart (about 70%), followed by liver (40%), and kidney transplants (17%) [13,14]. It is worth reminding that “true” AIHA occurs in about 5% of HSC transplants, both autologous and allogeneic (even ABO-matched), and is often severe and refractory to treatments. The most important risk factors are unrelated donors, presence of chronic graft versus host disease, therapy with calcineurin inhibitors, and delayed/unbalanced immune reconstitution, with rapid B cell engraftment and postponed recovery of regulatory T cells. Finally, the underlying
Downloaded by [24.235.52.38] at 08:10 20 February 2016
disease, drugs used for conditioning, and concomitant infections may all contribute to the clinical and laboratory picture of post-transplant hemolytic anemia [12,15]. It is known that a small fraction of AIHA (5-10%) is DAT negative, even using non-routinely and more sophisticated techniques [16]. The use of low ionic strength solutions/ cold washings may help in revealing low-affinity antibodies, and monospecific anti-IgA antisera may unravel the diagnosis of the very rare AIHA forms due to isolated IgA antibodies (~ 1-2% of cases); of note, IgA can be identified in ~20% of patients with warm IgG AIHA, although their pathogenic role is uncertain [1]. Particular attention should be given to atypical AIHAs due to “warm” IgM autoantibodies which can be severe and fatal. These forms are also difficult to diagnose, being weakly DAT-positive for anti-C3 or DAT-negative, causing detrimental delay in therapy [1,17]. The dual DAT, performed however in reference laboratories only, may help in the diagnosis [18]. Small amounts of anti RBC antibodies can be detected employing more sensitive techniques, such as microcolumn and solid-phase DAT, or even more sophisticated methods, such as ELISA, flowcytometry, and mitogen-stimulated DAT [19]. Generally, tests that are more sensitive are less specific. Therefore, their positivity should be interpreted with caution, and related to the clinical hemolytic picture. In particular, mitogen stimulation in culture, which probably amplifies the production of autoantibodies, although proven useful in the diagnosis of DAT-negative AIHA, was found positive in a fraction of patients with B-chronic lymphocytic leukemia or myelofibrosis
4
without an overt diagnosis of AIHA [20,21]. AIHA (particularly cold agglutinin disease) is frequently associated with lymphoproliferative diseases, however its prognostic value is still a matter of debate, and even more uncertain is the significance of an isolated positive DAT. Moreover, low amounts of RBC autoantibodies, directed against several cytoskeletal proteins, have been detected by mitogen-stimualted DAT in more than a half of patients with hereditary spherocytosis. Positive cases showed a more evident hemolytic pattern, suggesting that they may be naturally-occurring autoantibodies, involved in the removal of opsonized erythrocytes in the spleen
Downloaded by [24.235.52.38] at 08:10 20 February 2016
[22]. In conclusion, although RBC autoantibodies have a clear pathogenic role in AIHA, there are several conditions in which they seem an innocent bystander, or even may represent a homeostatic mechanism for the clearance of aged, oxidatively damaged and altered self cells. The clinical management of these conditions is clearly different, although poorly evidence-based. For warm AIHA forms corticosteroids +/- IvIg are the first-line, followed by rituximab, which is becoming the preferred second-line treatment, or splenectomy. Further treatments for refractory/relapsed cases are immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil); plasma-exchange, high-dose cyclophosphamide and alemtuzumab are used in severe or ultra-refractory cases as last option treatments. Regarding cold agglutinin disease, rituximab is now recommended as first-line treatment; the drug has better responses in combination with fludarabine, even if with associated toxicities. Promising new drugs include complement blocking agents (eculizumab, compstatin, Cp40, TNT003) and the proteasome inhibitor bortezomib [23]. The management of cases with DAT positivity but doubtful hemolytic disease is uncertain; low doses steroids may be tried, and help clarifying the diagnosis in case of response, but more harmful second- and third-line therapies are difficult to be considered, particularly when the associated conditions (pregnancy, liver disease, hemoglobinopathy) contraindicate their use.
5
Financial and competing interests disclosure This work was supported by research funding from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, grant number RC 2014 and by Ministry of Health, grant number RF 2010 convention N. 141/RF-2010-2303934. The author has no other relevant affiliations or financial
Downloaded by [24.235.52.38] at 08:10 20 February 2016
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
6
References
1. Petz LD and Garratty G. Immune hemolytic anemias. New York: Churchill Livingstone, 2004. 2. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 2014;124:2930-6 3. Fattizzo B, Zaninoni A, Nesa F, et al. Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias. Am J Hematol 2015;90:E149-51
Downloaded by [24.235.52.38] at 08:10 20 February 2016
4. Garratty G: Immune hemolytic anemia caused by drugs. Expert Opin Drug Saf 2012;11:635-42 5. Hoppe B, Stibbe W, Bielefeld A, Pruss A, Salama A. Increased RBC autoantibody production in pregnancy. Transfusion 2001;41:1559-61 6. Arinsburg SA, Skerrett DL, Kleinert D, et al. The significance of a positive DAT in thalassemia patients. Immunohematology 2010;26:87-91 7. Obaid JM, Abo El-Nazar SY, Ghanem AM, et al. Red blood cells alloimmunization and autoimmunization among transfusion-dependent beta-thalassemia patients in Alexandria province, Egypt. Transfus Apher Sci 2015;53:52-7 8. Chou ST, Jackson T, Vege S, et al. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood 2013;122:1062-71 9. Salama A, Berghöfer H, Mueller-Eckhardt C. Red blood cell transfusion in warm-type autoimmune haemolytic anaemia. Lancet 1992;340:1515-7 10. Sümnig A, Mayer B, Kiefel V, Greinacher A, Salama A. 'Chameleonic' Serological Findings Leading to Life-Threatening Hemolytic Transfusion Reactions. Transfus Med Hemother 2015;42:340-3 11. Yürek S, Mayer B, Almahallawi M, Pruss A, Salama A. Precautions surrounding blood transfusion in autoimmune haemolytic anaemias are overestimated. Blood Transfus 2015;13:616-21 12. Holbro A, Passweg JR. Management of hemolytic anemia following allogeneic stem cell transplantation. Hematology Am Soc Hematol Educ Program 2015:378-84 7
13. Yazer MH, Triulzi DJ. Immune hemolysis following ABO-mismatched stem cell or solid organ transplantation. Curr Opin Hematol 2007;14:664-70 14. Romero S, Solves P, Lancharro A, et al. Passenger lymphocyte syndrome in liver transplant recipients: a description of 12 cases. Blood Transfus 2015;13:423-8 15. Wang M, Wang W, Abeywardane A, et al. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital. Biol Blood Marrow Transplant 2015;21:60-6
Downloaded by [24.235.52.38] at 08:10 20 February 2016
16. Barcellini W. Pitfalls in the diagnosis of autoimmune haemolytic anaemia. Blood Transfus 2015;13:3-5. 17. Arndt PA, Leger RM, Garratty G. Serologic findings in autoimmune hemolytic anemia associated with immunoglobulin M warm autoantibodies Transfusion 2009;49:235-42 18. Bartolmas T, Salama A. A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies. Transfusion 2010;50:1131-4 19. Barcellini W, Clerici G, Montesano R, et al. In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia: effect of mitogen and cytokine stimulation. Br J Haematol 2000;111:452-60 20. Barcellini W, Montesano R, Clerici G, et al. In vitro production of anti-RBC antibodies and cytokines in chronic lymphocytic leukemia. Am J Hematol 2002;71:177-83 21. Barcellini W, Iurlo A, Radice T, et al. Increased prevalence of autoimmune phenomena in myelofibrosis:
relationship
with
clinical
and
morphological
characteristics,
and
with
immunoregulatory cytokine patterns. Leuk Res 2013;37:1509-15 22. Zaninoni A, Vercellati C, Imperiali FG, et al. Detection of red blood cell antibodies in mitogenstimulated cultures from patients with hereditary spherocytosis. Transfusion 2015;55:2930-8 23. Barcellini W. Current treatment strategies in autoimmune hemolytic disorders. Expert Rev Hematol 2015;8:681-91
8
9
Downloaded by [24.235.52.38] at 08:10 20 February 2016
