welcome

Presenter

DR.MD.AMINUR RAHMAN

PHASE- B ,RESIDENT

DEPARTMENT OF HAEMATOLOGY

BSMMU

• This Journal feature begins with a case vignette highlighting a common clinical problem.
• Evidence supporting various strategies is then presented, followed by a review of formal guidelines.
• The article ends with the author’s clinical recommendations.

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Case scenario

A 61-year-old woman presented to the emergency department

• fatigue
• increasing dyspnea
• dark urine.

0n examination

• She is pale
• respiratory rate is 30 breaths per minute
• pulse 116 beats per minute
• oxygen saturation 90%
• without splenomegaly or adenopathy

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Investigations

• Hb % :5.4 gm/dl
• HCT :16.1%
• MCV :103 fl
• WBC and platelet counts are normal.
• Reticulocytes :15.7%
• Bilirubin level : 9.7 mg/dl
• PBF: numerous microspherocytes.
• DAT : positive for IgG and weakly positive for C3d.
• Laboratory tests show a panagglutinin.

• She takes no regular medication.
• How would you further evaluate and treat this patient?

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The clinical problem

• Warm autoimmune hemolytic anemia (WAHA) leads to accelerated red-cell destruction due to the presence of warm agglutinins (almost always IgG antibodies) that bind to antigens on erythrocytes at a temperature of 37°C.
• Annual incidence is( 1-3)/1 lac.
• Median age of onset is 52 yr.
• May occur at any age.
• Slight female predominance.
• Up to 30% of patients have a durable remission .
• Rest have a chronic, relapsing course.

Pathogeneis

• Site: spleen,liver.
• Mainly extravascular
• IgG-coated red cells are recognized by splenic macrophages(Fcγ receptors).
• Phagocytosis of RBC.
• Or removal of a portion of the red-cell membrane, resulting in microspherocytes .
• Microspherocytes are less pliable than normal.
• Trapped in the splenic sinusoids during their next passage.
• Extracellular hemolysis in the spleen may also be due to antibody-dependent cell-mediated cytotoxicity from T cells.
• IgG subtypes can also activate complement, leading to deposition of C3 fragments on the red cell that are then removed by liver macrophages .
• In severe cases, complement activation can lead to formation of MAC (C5b-9).

Types of WAHA

• Primary and idiopathic : 50%
• Secondary

SECONDARY WARM AUTOIMMUNE HEMOLYTIC ANEMIA:  ASSOCIATED CONDITIONS

• Autoimmune Diseases 
• Lupus  
• Scleroderma 
• Rheumatoid arthritis 
• Ulcerative colitis 
• Immunodeficiency
• Common variable immunodeficiency 
• Autoimmune lymphoproliferative syndrome (ALPS) 
• Bone marrow transplantation 
• Hypogammaglobulinemia 
• Clonal lymphoproliferative disease 
• Chronic lymphocytic leukemia 
• Hodgkin lymphoma 
• Non‐Hodgkin lymphoma 
• Multiple myeloma 
• Monoclonal gammopathy of indeterminate significance (MGUS) 
• Infections 
• Human immunodeficiency virus 
• Ebstein‐Barr virus 
• Hepatitis C virus 
• Babesia 
• Others 
• Pregnancy 
• Spider bites (brown recluse spider) 
• Medications (eg, penicillins, cephalosporins, methyldopa, fludarabine)

Strategy and evidence�

Sign and symptoms

• common : fatigue, dyspnea, and palpitations.
• Brisk intravascular hemolysis, which can be associated with chest pain, lethargy, and confusion, is a medical emergency
• pallor and jaundice.
• tachycardia, peripheral edema, and elevated jugular venous pressure may occur.
• Splenomegaly may be present, especially in patients with an underlying lymphoproliferative disorder

Common laboratory features �

• Low hemoglobin.
• Reticulocytosis.
• Elevated lactate dehydrogenase .
• Low haptoglobin .
• Elevated indirect bilirubin.
• Positive direct antiglobulin test.

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• 109 consecutive patients with hemolytic anemia included in a retrospective study (approximately 80% had WAHA).
• median hematocrit was 24% .
• median corrected percentage of reticulocytes was 5.0% (range, 0.1 to 45.0).
• In a smaller registry study in France,> than 90% of the patients had a low haptoglobin level and more than 90% had elevated lactate dehydrogenase levels.
• Bilirubin levels were elevated in > 80% of the patients.
• > than 5% presented with chest pain.
• more than 50% required blood transfusion.
• More than 20% of patients with WAHA have a concurrent monoclonal gammopathy(> five times the expected rate).

DIAGNOSIS

• WAHA should be suspected

Anemia and laboratory evidence of hemolysis

Investigations

• complete blood count
• PBF
• Reticulocyte count
• Markers of hemolysis
• Elevated bilirubin
• Elevated LDH
• Reduced haptoglobin
• Direct antiglobulin test

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Other tests

• Peripheral-blood flow cytometry.
• d-dimer
• lower-extremity venous Doppler studies.
• computed tomography (CT) of the chest.
• Autoimmune panels .
• Bone marrow aspiration and biopsy .
• CT of abdomen and pelvis .

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RA Brodsky. N Engl J Med 2019;381:647-654.

Peripheral-Blood Specimens.

RA Brodsky. N Engl J Med 2019;381:647-654.

Direct Antiglobulin Test (Direct Coombs’ Test).

Differences between WAHA and CHAD

Management

• Immediate Management of WAHA with severe anemia
• Hb% <6gm/dl
• hypoxia
• Confusion
• hemodynamic instability
• medical emergency
• urgent blood transfusion is indicated to reduce the likelihood of death from pulmonary edema, myocardial infarction or arrhythmia.

• In virtually all cases, the cross-match will be incompatible, given that the autoantibodies recognize bloodgroup antigens and will react with virtually all donor red cells.
• ABO- and RhDmatched blood should be administered.

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• The benefits of red-cell transfusion outweigh the risks.
• in previously sensitized patients, blood should be transfused slowly (over 2 to 3 hours) and patients should be monitored for fever, chills, and dyspnea.

Definitive treatment of WAHA

• Lack of RCT.
• Recommendations based upon case series,expert opinion.

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First-Line Treatment

• New diagnosis of symptomatic WAHA

prednisone 1–2 mg/kg/day administered orally

or methylprednisolone administered intravenously

• dose be continued until a hemoglobin level above 10 gm/dl (up to 80% of patients within 2 to 3 weeks)
• A second agent is added if prednisone is not effective within 2 to 3 weeks after initiation.
• If effective, prednisone should be tapered over 4 to 6 months.

• The percentage of patients who remain in remission after discontinuing prednisone is unclear, but retrospective case studies suggest rates of 20 to 30%.
• Most experts aim for a hemoglobin level of 10 mg/dl or higher with a dose of prednisone of less than 10 mg/ day by 3 months after treatment
• Otherwise, a second agent is administered to avoid long-term complications of glucocorticoid use.
• rapid tapers over 3 to 4 weeks are often associated with relapse.

Another option for first-line therapy

use of rituximab with glucocorticoids

• two randomized, controlled trials showed that combined therapy was superior to glucocorticoid monotherapy.
• One open-label, phase 3 trial in which 64 patients were randomly assigned to prednisolone with or without intravenous rituximab (at a dose of 375 mg per square meter of body-surface area weekly for 4 weeks) showed higher rates of relapse-free survival with combined therapy than with monotherapy at 36 months of follow-up (70% vs. 45%).

• another randomized, double-blind trial involving 32 patients with WAHA who had received prednisone for less than 6 weeks, patients assigned to intravenous rituximab (at a dose of 1000 mg, on day 1 and day 15) had higher rates of remission than those assigned to placebo at 1 year (75% vs. 31%) and at 2 years (62% vs. 19%).

Second line treatment

• splenectomy/ Rituximab?
• Rituximab is now preferred
• initially treated with glucocorticoid monotherapy
• do not have a response
• relapses after an initial response.

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• In a meta-analysis of 21 observational studies that included 154 patients with primary or secondary WAHA, the overall response rate among patients with relapsed WAHA or disease that was refractory to rituximab was 79%.
• Response can sometimes take several weeks, and the rate of relapse at 1 to 2 years ranges from 25 to 50%.

Splenectomy

• More than 50% of patients with relapsed or refractory WAHA have a response to splenectomy.
• more than 25% have a relapse within a year.
• many hematologists prefer relatively nontoxic therapies such as mycophenolate mofetil,azathioprine, intravenous immune globulin, or cyclosporine before undergoing splenectomy.

RA Brodsky. N Engl J Med 2019;381:647-654.

r Warm Autoimmune Hemolytic Anemia.

Key Clinical Points�

• Warm autoimmune hemolytic anemia (WAHA) is a chronic, relapsing disease characterized by anemia, reticulocytosis, other laboratory evidence of hemolysis, and, in 95% of cases, a positive direct antiglobulin test (Coombs’ test).

• Autoantibodies in patients with WAHA (panagglutinins) typically lack specificity, in contrast to alloantibodies that are typically specific for red-cell antigens.

• Several retrospective studies have shown that the absolute risk of venous thromboembolic events (pulmonary emboli and deep venous thrombosis) is 15 to 30% among adult patients with WAHA.

• Prompt transfusion of ABO- and RhD-matched blood is warranted for patients with WAHA and severe anemia (hemoglobin level <6 g per deciliter).

• First-line therapy involves glucocorticoids and rituximab. In two randomized, controlled trials, glucocorticoid therapy plus rituximab was superior to glucocorticoid monotherapy as first-line treatment for WAHA.

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Areas of Uncertainty

• Multicenter, randomized, controlled trials with long-term follow-up are needed to compare the benefits, risks, and costs of various treatments.
• A number of targeted therapies are in development but are not approved for WAHA.
• Fostamatinib a spleen tyrosine kinase inhibitor that prevents phagocytosis and immune activation in splenic macrophages, is approved for immune thrombocytopenia and is now being studied in WAHA .
• use of proteasome inhibitors (e.g. ixazomib), B-cell receptor inhibitors (e.g.ibrutinib), and complement inhibitors (NCT03226678), are also being studied.

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Conclusions and Recommendations�

• The woman described in the vignette has severe anemia, reticulocytosis, elevated bilirubin level and a positive direct antiglobulin test, consistent with WAHA.
• Immediate transfusIon of 1 to 2 units of ABO- and RhD-matched blood.
• Monitoring closely for evidence of a transfusion reaction (i.e., fever, chills, and worsening hemoglobinuria).

• prompt initiation of glucocorticoids and rituximab, on the basis of data from randomized trials providing support for the combination over glucocorticoid monotherapy.
• Patient had dyspnea, tachycardia, and hypoxia, and recognizing the increased risk of venous thromboembolism.
• Monitoring her hemoglobin levels every 8 hours until her symptoms improve.
• LDH and reticulocyte count.

• Additional blood transfusions may be necessary, with the goal of maintaining her hemoglobin level above 7 gm/dl.
• Once her condition is stable, a workup for secondary causes of WAHA, including peripheral-blood flow cytometry and other testing as clinically indicated.
• counseling that WAHA is often a chronic, relapsing condition.