|HOW I DO IT
|Year : 2022 | Volume
| Issue : 1 | Page : 87-90
How i treat autoimmune hemolytic anemia (Warm Type)
Consultant-Clinical Hematologist, Manipal Hospitals, Bangalore, Karnataka, India
|Date of Submission||13-Apr-2022|
|Date of Decision||18-Apr-2022|
|Date of Acceptance||18-Apr-2022|
|Date of Web Publication||29-Apr-2022|
Dr. Ashish Dixit
Consultant-Clinical Hematologist, Manipal Hospitals, Bangalore, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Dixit A. How i treat autoimmune hemolytic anemia (Warm Type). Glob J Transfus Med 2022;7:87-90
Autoimmune hemolytic anemia (AIHA) is an uncommon entity. Warm-type AIHA (wAIHA) is more common (70%–80%) than cold-type AIHA (10%–20%). The autoantibodies directed against self-erythrocytes causing hemolysis are the basic process. However, pathogenesis is much more complex, with excessive uncompensated erythrocyte destruction being the end result. Autoantibodies are usually IgG and capable of fixing complement. Extravascular hemolysis is predominant in wAIHA-mediated through antibody-induced cell-mediated cytotoxicity. Direct and indirect antiglobulin test (DAT and IAT) have remained the principal diagnostic test. Further advances in diagnostics have reduced the number of Coomb's negative AIHA to <10% now. For this particular article, we will restrict the discussion to wAIHA only.
| How I Evaluate Suspected Autoimmune Hemolytic Anemia|| |
Diagnosis of AIHA starts with confirmation of hemolysis on other markers such as reticulocytosis, low haptoglobin, and high LDH. Merely positive DAT does not confirm hemolysis. False-positive DAT can be seen in some healthy subjects, in paraproteinemia, recently transfused patients or after therapies such as intravenous immunoglobulins (IVIGs) and Rh immunoglobulins. DAT may also remain positive in patients with AIHA who are in remission. In addition, it is important to exclude the presence of alloantibodies, particularly in multiply transfused patients who mimic AIHA; however, unlike true AIHA, the antibodies are not pan-agglutins and offending antigen can be identified on extended screening avoiding falsely diagnosis. In wAIHA, DAT is usually positive with IgG or with IgG along with C3d. If DAT is negative, then other causes of hemolysis, including drugs, should be searched. Advances in testing methods for DAT have evolved, which are much more sensitive and can pick up AIHA. True DAT-negative AIHA is rare (5%–10%) and requires exclusion of all potential causes of hemolysis, including malignancy., Most common reason for DAT-negative AIHA is technical due to the lack of availability of these “enhanced DATs.” Initial evaluation should include the search for underlying cause. AIHA is classified as primary if no underlying cause identified. Causes of secondary AIHA include autoimmune and rheumatologic disorders such as SLE, lymphoproliferative disorders, and drugs. [Figure 1] shows the usual approach to AIHA we follow.**
|Figure 1: Approach to diagnosis of AIHA. AIHA: Autoimmune hemolytic anemia; wAIHA: Warm-type autoimmune hemolytic anemia; IAT: Indirect antiglobulin test; DAT: Direct antiglobulin test; CAD: Cold Agglutinin Disease; LDH: Lactate Dehydrogenase; MCV: Mean Corpuscular Volume; Hb: Hemoglobin; Retic: Reticulocyte count|
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| When Do I Suspect Secondary Autoimmune Hemolytic Anemia|| |
Evaluation for an underlying cause is a continuous process and needs to be done at first diagnosis as well as with each relapse of disease. Lymphoid malignancies are notorious to present with AIHA and can present as steroid-dependent or refractory AIHA in partially treated cases. Computed tomography (CT) scan of the chest, abdomen, and pelvis or positron emission tomography CT is preferable for initial evaluation itself before exposure to steroids. Underlying autoimmune disorder is looked for similarly during the course of follow-up. Choice of therapy is altered with the diagnosis of any other underlying cause and may prompt early initiation of the second-line therapy.
| How We Treat Newly Diagnosed Autoimmune Hemolytic Anemia|| |
Once the diagnosis of primary AIHA is confirmed, first line of therapy is steroids (1–1.5 mg/kg prednisolone) [Figure 2]., High-dose steroids may be considered for early response in case with severe hemolytic crisis with organ dysfunctions. High-dose dexamethasone is an attractive choice in such cases and is being used by us frequently. Response to steroids as first line is seen in up to 80%–90% of patients and brisk recovery can be seen within 2 weeks in majority. Steroid taper is started after 2 weeks and low-dose prolonged taper is preferred to avoid early relapses. However, some patients remain dependent on higher dose of steroids or relapse very early after steroid withdrawal and face toxicity related to continuous steroid use. It is important to recognize the need for early second-line therapy in these cases.
|Figure 2: Therapy approach for wAIHA. wAIHA: Warm-type autoimmune hemolytic anemia; MMF: Mycophenolate mofetil; IVIG: Intravenous immunoglobulin; LDH: Lactate Dehydrogenase; BM: Bone Marrow study; Hb: Hemoglobin|
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| Rituximab versus Splenectomy as Second Line|| |
Our choice of second-line therapy stays with rituximab. Response to rituximab is 60%–70%. It is slower to work and may take 1–2 months before any obvious response. The response is sustainable for a long time in up to 50%–60% of responders. Another advantage of rituximab has been that the relapses become predictable with slower drop in hemoglobin to suggest loss of response rather than acute drop. It allows planned therapy with rituximab again, and majority of such patients respond on re-exposure.
Dose of rituximab used by us is 375 mg/m2 weekly for four doses. Various low doses and schedules have been reported to be effective as well.
Before administering rituximab, a thorough screening for underlying infections (hepatitis B virus, hepatitis C virus, and HIV) is necessary. Rituximab may activate dormant virus, and fulminant hepatic failures have been reported. Antiviral prophylaxis is suggested for unvaccinated patients positive for anti-HBc and/or anti-HBs antibodies.
| What Do I Do in Patients Refractory to Second Line|| |
The use of splenectomy has declined as the second-line therapy over the years due to risk of complications due to infections even though it is as effective as rituximab. It is still a good option to choose as third-line therapy in patients who are not a responder to rituximab. Long-term responses may be seen in up to 40%–50% of patients. However, there are no reliable predictors of response. Splenectomy is not considered usually if AIHA is secondary to underlying lymphoid malignancy or autoimmune disorders. Splenectomy will also not be considered safe in elderly patients, particularly those with comorbidities.
It is extremely important to vaccinate against encapsulated organisms at least 2 weeks before splenectomy. Risk of infection still remains despite vaccination and antibiotic prophylaxis postsplenectomy; hence, every febrile episode needs to be evaluated for potential bacterial infection.
| What about Refractory Autoimmune Hemolytic Anemia|| |
Patients' refractory or partial responders to the first- and second-line therapies are difficult to manage. Immunosuppressive therapies such as azathioprine, MMF, cyclophosphamide, and cyclosporine are commonly used, with response rates up to 50%. We use danazol, an anabolic steroid in cases refractory to earlier lines of therapy with reported response rates between 20% and 50%. In patients with lymphoproliferative disorder-related secondary AIHA, treatment of underlying cause corrects the AIHA usually.
Some of the newer drugs being evaluated in wAIHA are bortezomib, daratumumab (anti-CD38), complement inhibitors, PI3K inhibitors, tyrosine kinases, and FcRn inhibitors.
| How to Manage Acute Severe Crisis|| |
Patients reporting with acute hemolytic crisis with severe anemia are a medical emergency. Risk of mortality can be very high unless therapy is started early. Multiple drugs are added together since the time to assess is critically short. Initial lines of therapy include IVIG and steroids. Plasmapheresis is useful in some scenarios even though it has temporary response. Rituximab may be used early itself. Furthermore, there is some component of relative erythroid suppression and adding erythropoietin has a value in these scenarios for rapid recovery.
Transfusions are needed in such emergencies or in patients with severe symptomatic anemia. Finding a compatible unit is tough due to the presence of autoantibodies. In addition, there could be the presence of alloantibodies in some cases, which needs to be excluded. In case of emergency, least incompatible unit is used if the blood group of patient was known and documented in the past in the absence of AIHA. Else O-negative units can be used. However, no transfused RBC are lyses fast and transfusion has temporary benefit at best unless other therapies work. In addition, acute hemolytic crisis carries risk of thromboembolism and thromboprophylaxis will be recommended during such situations.,
| Conclusions|| |
wAIHA is a clinically heterogeneous disease which needs careful attention and early therapy intervention. Underlying cause including malignancy needs to be actively search both at diagnosis and during recurrences of AIHA. Proper use of steroids with slow taper and early initiation of rituximab holds the key to avoid potential long-term side effects related to therapy. Treatment of underlying disease leads to long-term remissions in patients with secondary AIHA.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]