What are the guideline sources, guidelines and references for Autoimmune hemolytic anemia ?
Guideline sources The following summarized guidelines for the evaluation and management of autoimmune hemolytic anemia (AIHA) are prepared by our editorial team based on guidelines from the First International Consensus Meeting (FICM 2020), the American Society for Apheresis (ASFA 2019), and the British Society for Haematology (BSH 2017). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnosis: obtain direct antiglobulin test (C3d+), a cold agglutinin titer and bone marrow examination (at least by histology and flow cytometry) for the diagnosis of cold agglutinin disease. E Show 2 more 2. Classification and risk stratification https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 1/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway Assessment of thrombotic risk: Take into account the risk of thrombotic events (both venous and arterial), mostly during acute hemolytic flares and in splenectomized patients. E Obtain assessment of general thrombotic risk factors in patients with AIHA: age > 70 years, active cancer, previous VTE, reduced mobility, already known thrombophilic condition, recent trauma and/or surgery, heart and/or respiratory failure, acute infection. E 3. Diagnostic investigations Initial assessment: Assess for signs of acrocyanosis in patients with cold agglutinin disease. E Obtain baseline values of LDH, bilirubin, haptoglobin, reticulocyte count, and review of peripheral smear (looking for spherocytes in warm AIHA, RBC aggregation in cold agglutinin disease, and schiztocytes to exclude thrombotic microangiopethies) in all patients with AIHA. E Direct antiglobulin test: As per FICM 2020 guidelines, obtain direct antiglobulin test with monospecific antisera (anti-IgG, anti-IgA, anti-IgM, anti-C). E Show 2 more As per BSH 2017 guidelines: Include monospecific anti-IgG and anti-C3d in the direct antiglobulin testing. B Retest with a column agglutination direct antiglobulin test method including monospecific anti- IgG, anti-IgA and anti-C3d in patients with unexplained hemolysis and a negative screening direct antiglobulin test. B Consider preparing and investigating a red cell eluate if the latter is also negative. B Direct agglutination test: screen for a cold antibody using a direct agglutination test at room temperature in patients with AIHA and a direct antiglobulin test positive for C3 +/- IgG. B Cold agglutinin test: As per FICM 2020 guidelines, suspect mixed AIHA and obtain cold agglutinin test and titer in patients with direct antiglobulin test positive for IgG and C3 and presence of symptoms of cold agglutinin disease. E As per BSH 2017 guidelines: Obtain further investigation with an antibody titer in a laboratory performing these tests on a regular basis in patients with a positive cold autoantibody screen. B Warm received EDTA- anticoagulated samples to 37 C in a water bath for 1 hour before removing the plasma for testing. B Review all cases of suspected primary cold agglutinin disease by an appropriately constituted hemato-oncology multidisciplinary team. B Donath-Landsteiner test: obtain Donath-Landsteiner biphasic test in an experienced laboratory in case of diagnostic uncertainty after AIHA evaluation in patients with fitting history. E https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 2/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway Evaluation for underlying cause: As per FICM 2020 guidelines: Evaluate all patients with warm AIHA for underlying causes as follows: Situation Guidance ANA Autoimmune diseases RF Antiphospholipid antibody Flow cytometry of peripheral blood Lymphoproliferative disorders Review of peripheral blood smear Possible CT assessing for lymphadenopathy and splenomegaly SPEP with immunofixation. E Immune deficiency Evaluate all patients with suspected cold agglutinin disease for clonal B-cell disorder with SPEP, immunofixation, peripheral blood and bone marrow flow cytometry, bone marrow biopsy, and, if indicated, CT looking for lymphadenopathy and splenomegaly. E As per BSH 2017 guidelines, keep the clotted sample from patients with suspected cold agglutinin disease for protein electrophoresis and immunofixation at 37 C until the serum has been separated. B Assessment of related conditions: Obtain careful evaluation for Evans syndrome, acute renal failure, infections and multi- treatment, as these conditions are associated with increased risk of death (AIHA-related mortality is 3-4%). E Obtain close monitoring in patients with AIHA with severe anemia at onset, and/or presence of Evans syndrome, since these conditions are associated with an increased risk of multiple relapses/refractoriness to several therapy lines. E 4. Medical management Management of primary warm AIHA, indications: As per FICM 2020 guidelines: Initiate treatment in patients with warm AIHA in the setting of symptomatic anemia. E Consider obtaining monitoring (watchful waiting) in rare patients with mild and stable anemia. E As per BSH 2017 guidelines, do not affect the therapeutic approach to warm AIHA by identification of warm IgA antibodies (concurrent with IgM, IgG or as an isolated cause of AIHA). D Management of primary warm AIHA, first-line therapy: https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 3/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway As per FICM 2020 guidelines, initiate oral prednisone/prednisolone starting at 1 mg/kg daily as first-line therapy in patients with warm AIHA. E Show 3 more As per BSH 2017 guidelines, initiate prednisolone 1 mg/kg/day as first-line therapy in patients with warm AIHA. B Management of primary warm AIHA, second-line therapy: As per FICM 2020 guidelines, consider initiating second-line therapy in patients not responding to first-line therapy and in patients relapsing as the corticosteroid is weaned. E Show 2 more As per BSH 2017 guidelines: Consider initiating second-line therapy in patients not responding to prednisolone 1 mg/kg/day after 3 weeks and in patients relapsing during or after corticosteroid reduction. C Initiate rituximab as second-line therapy in patients with warm AIHA. B Management of primary warm AIHA, third-line therapy: As per FICM 2020 guidelines, offer azathioprine, cyclosporin, mycophenolate mofetil, and splenectomy as third-line treatment options in patients with warm AIHA, based on the individual assessment of the benefit over risk ratio. E As per BSH 2017 guidelines, offer azathioprine, ciclosporin, danazol, mycophenolate mofetil, and splenectomy as third-line treatment options in patients with warm AIHA. B Management of primary warm AIHA (refractory cases): Refer patients with chronic refractory warm AIHA not responding to at least 3 treatment lines (including splenectomy and or at least one immunosuppressant) to a specialized center and, whenever possible, treat in the setting of a clinical trial. E Consider offering other lines of therapy including cyclophosphamide, continuous low-dose prednisone, danazol, hamatopoietic stem cell transplantation, and bortezomib. E Management of primary warm AIHA, emergency management: As per FICM 2020 guidelines, combine supportive therapies (ESA +/- plasma exchange and/or IVIG), active immunosuppression, and emergency splenectomy/embolization for the management of patients with transfusion-dependent life-threatening warm AIHA. Administer thromboprophylaxis to minimize the risk of venous thrombosis. E As per BSH 2017 guidelines, consider offering IVIG or plasma exchange in patients with severe or life-threatening anemia. C Management of primary cold AIHA (indications): initiate treatment for the indications of symptomatic anemia, severe circulatory symptoms or transfusion dependence. B Management of primary cold AIHA (avoidance of cold): advise patients to avoid cold exposure where possible. B Show 2 more Management of primary cold AIHA, first-line therapy: https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 4/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway As per FICM 2020 guidelines, initiate rituximab, alone or in combination with bendamustine, as first-line therapy in patients with cold AIHA. E As per BSH 2017 guidelines: Initiate rituximab as first-line therapy in patients with cold AIHA. B Consider adding fludarabine if clonality has been demonstrated. B Management of primary cold AIHA (second-line therapy): consider initiating re-treatment with rituximab as monotherapy or in combination with bendamustine or initiating fludarabine as second-line therapy in patients with cold AIHA. E Management of primary cold AIHA (other therapies): Consider offering other potentially useful agents such as tyrosine kinase- or BCL2-inhibitors in patients with cold AIHA. E Recognize that complement inhibition at various levels of the complement cascade is a promising novel approach for later treatment lines or emergencies. E Management of primary cold AIHA, emergency management: As per FICM 2020 guidelines: Manage patients with severe and life-threatening hemolytic anemia requiring repeated transfusions despite high dose of corticosteroids and rituximab in ICU in a tertiary referral center. E Consider offering either intravenous IgAnd/or plasma exchange as a transfusion-sparing strategy. E As per BSH 2017 guidelines, consider offering plasma exchange or corticosteroids in patients with severe or life-threatening anemia. C Management of mixed AIHA: As per FICM 2020 guidelines: Initiate early aggressive therapy with corticosteroids and rituximab and consider offering participation in clinical trials with new drugs, since mixed AIHA generally has a severe onset and exhibits relapse/refractoriness to several therapies. E Do not perform splenectomy in patents with mixed AIHA. D As per BSH 2017 guidelines, initiate prednisolone 1 mg/kg/day as first-line therapy in patients with mixed AIHA. B Show 2 more Management of paroxysmal cold hemoglobinuria: Encourage cold avoidance and avoid active cooling for fever. B Consider initiating corticosteroids only in patients with severe or persistent disease. C Management of drug-induced AIHA: discontinue the suspected drug. A Show 2 more Management of secondary AIHA, lymphoproliferative disorders: https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 5/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway As per FICM 2020 guidelines, take into account the stage and activity of chronic lymphocytic leukemia in the management of chronic lymphocytic leukemia-associated warm AIHA must. E Show 4 more As per BSH 2017 guidelines, take into account the lymphoma type and remission status when deciding whether treatment should be anti-lymphoma or AIHA directed. B Show 3 more Management of secondary AIHA (solid organ neoplasms): perform surgical resection as first- line therapy in patients with ovarian teratoma. Do not perform concomitant splenectomy. B Show 2 more Management of secondary AIHA, immune dysregulations: As per FICM 2020 guidelines, conside initiating rituximab for the management of patients with corticosteroid-refractory or dependent SLE-associated warm AIHA. E Show 4 more As per BSH 2017 guidelines, initiate corticosteroids as first-line therapy and azathioprine, danazol, mycophenolate mofetil, or rituximab as second-line therapy in patients with systemic lupus erythematous-associated AIHA. B Show 12 more Management of secondary AIHA (infections): initiate supportive therapy with appropriate antimicrobials, a warm environment and transfusion in symptomatic anemia in patients with cold agglutinin disease secondary to atypical and mycoplasma pneumonia. B Show 5 more Management of Evans syndrome: Initiate corticosteroids or IVIG as first-line therapy in patients with primary Evans syndrome. B Consider initiating azathioprine, ciclosporin, danazol, mycophenolate mofetil, rituximab, vincristine or offering splenectomy as second-line therapy in patients with primary Evans syndrome. C Thromboprophylaxis: As per FICM 2020 guidelines, consider administering VTE prophylaxis in patients with marked hemolysis and associated risk factors. E Show 2 more As per BSH 2017 guidelines, administer thromboprophylaxis with LMWH in inpatients with an acute exacerbation of hemolysis B and consider administering in ambulatory patients during severe exacerbations - Hgb < 85 g/L. B Management of corticosteroid side effects: As per FICM 2020 guidelines, provide dietary and lifestyle advice in all adult patients starting corticosteroids. E Show 3 more As per BSH 2017 guidelines, initiate PPIs in patients receiving corticosteroids at increased risk for peptic ulcer disease (such as concomitant thrombocytopenia, history of history peptic ulcer https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 6/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway disease, concurrent use of NSAIDs, anticoagulant or antiplatelet agents and age 60 years). B Show 2 more 5. Nonpharmacologic interventions Folic acid supplementation: As per FICM 2020 guidelines: Initiate folic acid supplementation in patients with active hemolysis. E Monitor hematinic in case of reticulocytosis, or if anemia worsens. E As per BSH 2017 guidelines, initiate folic acid supplementation in patients with AIHA. B 6. Therapeutic procedures Blood transfusion: Administer transfusion with ABO, Rh and K matched red cells if anemia is life-threatening in the time required for full compatibility testing. B Consider using a blood warmer for transfusion in patients with cold AIHA (cold agglutinin disease, mixed AIHA and paroxysmal cold Hgburia). C 7. Surgical interventions Splenectomy, indications: As per FICM 2020 guidelines, offer splenectomy as a third-line treatment option in patients with primary warm AIHA, based on the individual assessment of the benefit over risk ratio. E Show 3 more As per BSH 2017 guidelines, offer splenectomy as second-line therapy in patients with primary Evans syndrome. B Splenectomy (preoperative evaluation): Do not obtain radioisotope studies to determine the main site of red cell destruction when considering splenectomy. D Counsel patients on infection risk and be vaccinated at least 2 weeks before splenectomy. B Splenectomy (postoperative care): set a low threshold for investigating patients with postoperative fever, abdominal pain or ileus with Doppler ultrasound to exclude portal or splenic vein thrombosis. B Show 3 more 8. Specific circumstances Pediatric patients: https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 7/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway As per BSH 2017 guidelines, include LFTs in the evaluation of pediatric patients with AIHA. B Show 2 more As per BSH 2017 guidelines, suspect giant cell hepatitis and perform liver biopsy in pediatric patients with unexplained elevated hepatic transaminases. B Pregnant patients (evaluation): Elicit a history, obtain examination and laboratory testing promptly to exclude AIHA in pregnant patients with a positive direct antiglobulin test. B Obtain serial ultrasound from 20 weeks to assess fetal growth and Doppler ultrasound of the fetal middle cerebral artery to screen for fetal anemia in pregnant patients with AIHA. B Pregnant patients, antenatal care: As per FICM 2020 guidelines, involve both an obstetrician and a hematologist in the antenatal care of pregnant patients with AIHA. E Show 2 more As per BSH 2017 guidelines, provide antenatal care involving joint hematology and obstetric care with access to a specialist in fetal medicine. B Show 4 more Pregnant patients (postnatal care): obtain direct antiglobulin test in cord blood following delivery. Obtain a full blood count, reticulocyte count, bilirubin, direct antiglobulin test and cross-match (in case exchange transfusion is required) in capillary blood sample from the neonate, if neonatal jaundice is present or direct antiglobulin test is positive. B Show 2 more References 1. Quentin A Hill, Robert Stamps, Edwin Massey et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017 Feb;176 3 395 411. Open 2. Quentin A Hill, Robert Stamps, Edwin Massey et al. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. Br J Haematol. 2017 Apr;177 2 208 220. Open 3. Ulrich J ger, Wilma Barcellini, Catherine M Broome et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020 May;41 100648. Open 4. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui 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 Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 5. David J Kuter, Kerry A Rogers, Michael A Boxer et al. Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open-label study. Am J Hematol. 2022 Jun 1;97 6 691 699. Open 6. Alberto Zanella, Wilma Barcellini. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99 10 1547 54. Open https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 8/9 6/23/23, 3:16 AM Autoimmune hemolytic anemia Pathway https://web.pathway.md/diseases/recPvnwIOFm4Eqibw 9/9