AUTOIMMUNE HEMOLYTIC

ANEMIA

Jennifer Eads

January 23, 2008

Learning Objectives Review epidemiology and pathophysiology

of autoimmune hemolytic anemia

Understand the difference between warm and cold antibody mediated disease

Review treatment optionsWhich treatments are most effective?What work has been done thus far?

Early History of Hemolysis Term “hemolytic” first used in 1888 by

William Hunter in London“excessive blood destruction”

How long does a red cell live?Winifred Ashby (1919) used serologically

distinct red cells—determined RBC to live for approximately 100 days

Radioactive chromium studies—RBC life span of 110 days

Warm AIHA Due to development of an IgG antibody Antibody active at warm temperature of 37°C May be either primary or secondary in

etiologyPrimary-idiopathic in natureSecondary-due to an underlying disease

○ Lymphoproliferative disorders○ Autoimmune diseases○ Infection○ Immunodeficiency disorder○ Tumor

Epidemiology-Warm AIHA Incidence of 1-3 cases per 100,000 per year

Favors females 2:1

Age at time of occurrence dependent on causePrimary more common in women during the 4-

5th decades of lifeSecondary occurs in association with underlying

disease

Mechanism of destruction Primarily due to extravascular hemolysis

Antibodies bind to surface of RBC membrane

Fc portion of antibody binds to macro-phagesInteraction → spherocytes

Spherocytes become trapped in spleen and are destroyed

Extravascular Hemolysis

Cold agglutinin disease Due to development of an IgM antibody Antibody active at cold temperature (4°C)

and not usually physiologically significant Either primary or secondary in etiology

Primary-idiopathic in natureSecondary-due to an underlying disease

○ Lymphoproliferative disorders○ Infection○ Autoimmune diseases○ Immunodeficiency disorder○ Tumor

Epidemiology-Cold agglutinin Disease Accounts for 16-32% of cases of AIHA

Affects older adults approximately 70 years of age

Slight female predilection

Mechanism of destruction Intravascular hemolysis

IgM antibodies activate the compliment system resulting in cytolysis

Extravascular hemolysisC3b and iC3b rather than the Fc portion of

IgM are recognizedHemolysis occurs in the liver via action of

Kupffer cells

Diagnosis Clinical signs and

symptomsFatiguePallorJaundiceShortness of breathHeart failure

Raynaud’s phenomenon, vascular occlusions/necrosis in cold agglutinin disease

Lab dataCBC with peripheral

smearLDHHaptoglobinBilirubin

Diagnosis Disease severity depends on degree of hemolysis

Antibody characteristics○ Quantity○ Specificity○ Thermal amplitude○ Ability to fix compliment○ Ability to bind tissue macrophages

Antigen characteristics○ Density of antigen on cell surface○ Degree of antigen expression○ Patient age

Diagnosis

Serologic evidence of the presence of an antibodyDirect antiglobulin test

○ Patient’s RBC’s mixed with antiglobulinSpecific focus on IgG and C3d

○ Positive in almost all cases○ Non-specific for a RBC autoantibody

Indirect antiglobulin test○ Positive in approximately 80% of cases○ Autoantibodies likely to be panreactive as

compared to alloantibodies

Direct and Indirect Coombs Tests

Treatment-Role of Blood Transfusion Limit to life threatening situations or high

risk patients

Best to use most compatible units

Often difficult to match

Transfusion may stimulate further formation of autoantibody

Treatment-Warm AIHA

Folic acid supplementation Glucocorticoids Splenectomy Cytotoxic drugs Rituximab Plasmapheresis IVIg

Glucocorticoids

Dameshek et al (NEJM, 1951)5 patients given ACTH for acquired AIHAAll showed remission of diseaseWithdrawl of ACTH resulted in recurrence

Subsequent studiesWhat doses are appropriate?Which steroids should be used?How long should treatment continue?

Glucocorticoids Initial therapeutic intervention for warm AIHA

Initial prednisone dose of 1-1.5mg/kg/day

Response rates20-30% have a lasting remission50% require low dose maintenance10-20% do not respond

Considered a failure if 15mg or greater of prednisone is required to maintain a Hct of at least 30%

Glucocorticoids

Multiple possible adverse effectsOsteoporosisAvascular necrosisIncreased risk for infectionCataractsGlucose/lipid abnormalitiesBehavioral changesPeptic ulcer diseaseMyopathy

Splenectomy First done in patients with either ITP or

congenital spherocytic anemias

Welch et al (NEJM, 1950)Splenectomy performed in 220 patients with “blood

dyscrasias” at NEMC between July 1939 and June 1949

First evaluation of role for hemolytic anemia○ 34 cases with primary etiology

“Good results” in 50%

○ 18 cases with secondary etiology “Good results” in 33%

Splenectomy Second line treatment

Has multiple benefitsRemoves site of hemolysisDecreases antibody production

Response rate of 60-75%Often will still require steroids

Requires immunization

Cytotoxic Drugs

Moyo et al (Blood, 2002)9 patients with severe refractory AIHA

○ Includes both warm and cold antibodiesTreated with high dose cyclophosphamide

for 4 consecutive days (50mg/kg/day)6 patients achieved a complete response, 3

a partial response

Cytotoxic Drugs

Includes cyclophosphamide, azathioprine and cyclosporine A

Results in a 40-60% response rate

May cause bone marrow suppression

Rituximab

An anti-CD20 monoclonal antibody

Results in B cell destructionComplement mediated cytotoxicityAntibody dependent cytotoxicityInhibition of B cell proliferationInduction of apoptosis

Rituximab Zecca et al (2003)

15 children with AIHA/Evan’s syndrome looked at prospectively

All children had failed two lines to treatmentFound to have an 87% response (13/15)

○ Increase in hemoglobin level by 1.5g/dL○ Decrease in reticulocyte count by 50%○ Fewer patients with positive DAT

All other immunosuppressants stoppedAny patient to relapse (3) had subsequent

remission with further treatments

Plasmapheresis

Current data based on case reports

Has been difficult to assess effectiveness in setting of other treatments

May be useful in fulminant cases until other therapies can take effect

Intravenous immunoglobulin Tried in AIHA after it was found to work

well for patients with ITP

Second line therapy for steroid non-responders

When used, requires higher doses than used for treatment of ITP

Treatment-Cold agglutinin disease Avoidance of cold temperature Folic acid supplementation Cytotoxic drugs α-interferon Plasmapheresis Rituximab

Efforts should be made to limit transfusionDifficult to matchTransfusion worsens hemolysisBlood warmer may reduce the risk of further hemolysis

ReferencesBussel, J.B. et al. Intravenous Treatment of Autoimmune Hemolytic Anemia with Very High

Dose Gammaglobulin, Vox Sang, 1986, 51:264-269

Buetens, O.W., Ness, P.M. Red blood cell transfusion in autoimmune hemolytic anemia, Current Opinion in Hematology, 2003, 10:429-433

Dacie, J.V. The immune hemolytic anemias: a century of exciting progress in understanding, British Journal of Haematology, 2001, 114:770-785

Dameshek, W. et al. The treatment of acquired hemolytic anemia with adrenocorticotrophic hormone (ACTH), The New England Journal of Medicine, Jan 1951, Vol 244, No 4

Gehrs, B.C. and Friedberg, R.C. Autoimmune Hemolytic Anemia, American Journal of Hematology, 2002, 69:258-271

Moyo, V.M. et al. High-dose cyclophosphamide for refractory autoimmune hemolytic anemia, Blood, July 2002, Vol 100, No 2

Perrotta, S. et al. Anti-CD20 monoclonal antibody (Rituximab) for life-threatening autoimmune haemolytic anaemia in a patient with systemic lupus erythematosus, British Journal of Haematology, 2002, 116:465-467

Petz, L. Treatment of autoimmune hemolytic anemias, Current Opinion in Hematology, 2001, 8:411-416

Welch, C.S. et al. Splenectomy in blood dyscrasias, The New England Journal of Medicine, Apr 1950, Vol 242, No 16

Zecca, M. et al. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children, Blood, 2003, Vol 101, No 10