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AUTOIMMUNE HEMOLYTIC ANEMIA

(AIHA)

Compiled by:G.A.R. Sampath Kalhari GiharaChanaka LakshanAqeela Manuideen

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ContentIntroductionEpidemiologyClinical Manifestation

Symptoms Diagnosis

Immunological basisTreatments

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Introduction Autoimmune Hemolytic Anemia (AIHA) is characterized by an

abnormal production of antibodies that bind to Antigens on the erythrocyte surface. These antibodies then leads to the destruction of RBC’s thus shortening their life span.

If this destruction is at a high enough rate, & exceeds the bone marrow’s capacity to regenerate RBC’s, the patient develops anemia and the associated signs and symptoms.

AIHA can be primary, where no evidence for a secondary causative disorder exits; or secondary in which hemolytic anemia is directly attributable to another systemic disease.

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Epidemiology

AIHA is a fairly uncommon disorder, with estimates of the incidence at 1-3 cases per 100,000 people per year.

Primarily found in adults (more severe)Also in children with primary immunodeficiency

Major is idiopathicSecondary – malignant lymphoproliferative diseases,

drugs, and viral infections

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Classification of Autoimmune Hemolytic Anemia

1. Warm Autoimmune Hemolytic Anemia

2. Cold Autoimmune Hemolytic Anemia Cold Agglutinin SyndromeParoxysmal Cold Hemoglobinuria

3. Mixed-type Autoimmune Hemolytic Anemia

4. Drug-induced Immune Hemolytic Anemia

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1) WARM AUTOIMMUNE HEMOLYTIC ANEMIA

In the warm antibody type, the autoantibodies attach to and destroy red blood cells at temperatures equal to or in excess of normal body temperature.

It is the most common form of autoimmune hemolytic anemia (AIHA); more common among women.

Primarily due to extravascular hemolysis Usually associated with the development of IgG (also IgA & IgM) Ab’s bind to the surface of the RBC membrane Ab is activated at warm temperature of 37 degrees celcius Maybe either Primary or Secondary in etiology

Primary - Idiopathic in nature Secondary – Due to an underlying disease (eg:

lymphoproliferative disorders, autoimmune disorders etc.)

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2) COLD AUTOIMMUNE HEMOLYTIC ANEMIA

In the cold antibody type, the autoantibodies become mostactive and attack red blood cells only at temperatures well below normal body temperature. Caused by Cold agglutination syndome (CAS) or Paroxysmal

cold hemoglobinuria (PCH) Mainly affects middle-aged or elderly Occurs due to the development of of an IgM antibody Antibody is active at cold temperature (4 degrees celcius) and

not usually physiologically significant

Either primary or secondary in etiology Primary - Idiopathic in nature Secondary – due to an underlying disease

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Mechanism of destruction Intravascular hemolysis

IgM antibodies activate the compliment system resulting in cytolysis

Extravascular hemolysis C3b & iC3b rather than the fc portion of IgM are

recognized Hemolysis occurs in the liver via kuppfer cells

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Cold agglutination syndrome (CAS)

• Cold agglutinin disease (cold antibody disease) is caused by autoantibodies that react at temperatures <37° C.

• Causes includeInfections (especially mycoplasmal pneumonias or infectious mononucleosis)

• Lymphoproliferative disorders (antibodies are usually directed against the I antigen)

• Idiopathic (usually associated with a clonal B-cell population)• Infections tend to cause acute disease, whereas idiopathic disease

(the common form in older adults) tends to be chronic.• The hemolysis occurs largely in the extravascular mononuclear

phagocyte system of the liver and spleen.• The anemia is usually mild (Hb > 7.5 g/dL).• Autoantibodies in cold agglutinin disease are usually IgM. The higher

the temperature (ie, the closer to normal body temperature) at which these antibodies react with the RBC, the greater the hemolysis

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Paroxysmal cold hemoglobinuria (PCH)

• Paroxysmal cold hemoglobinuria is a rare type of cold antibody hemolytic anemia. Destruction of red blood cells results from exposure to cold. (28 – 31 degrees celcius)

• Occurs more in children• Antibody involved is IgG• RBC’s may be destroyed even when cold exposure is limited to a

small area of the body, such as when the person drinks cold water or washes hands in cold water.

• Intravenous hemolysis occurs (• It occurs most often after a bacterial infection (syphilis, mycoplasma

pneumoniae) or a viral illness (measles, mumps, influenza etc.). Can be caused due to vaccines as well.

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3) MIXED-TYPE AUTOIMMUNE HEMOLYTIC ANEMIA

• Features similar to both WAIHA & CAS• Both IgG & C3d are detected• IgG – warm antibody• C3d – activated by IgM cold autoantibody• Idiopathic• Secondary (lymphoproliferative disorders, autoimmune disorders)

4)DRUG INDUCED IMMUNE HEMOLYTIC ANEMIA

• Antibodies directed against or one of its metabolites• All may involve IgG & C3• Mechanisms:• Autoimmune type• Drug adsorption type• Neo antigen type

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Immunological View

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Warm Autoimmune Hemolytic Anemia

• IgG binds to RBC surface antigens• This drives monocytes & macrophages to grab &

pick off portions of RBC membrane• RBCs become spherocytes• Destructed in spleen

EXTRAVASCULAR HEMOLYSIS

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Cold Agglutination Disease

• In cold temperature, IgM binds to polysaccharide region of glycoproteins on RBC surface

• This triggers complement system to lyse RBC

INRAVASCULAR HEMOLYSIS

• If complement system fails to form membrane attack complex (when trigger is insufficient), complement proteins deposit on RBC surface

• This opsonisation enhances RBC phagocytosis in liver, spleen & lungs

EXTRAVASCULAR HEMOLYSIS

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Paroxysmal Cold Hemoglobinuria

• During certain infections, microbes trigger formation of Abs that react with the P antigen of RBC surface

• After the infection, these polyclonal anti-P autoantibody binds to P-Ag of RBC in cold temperature

• When temperature increased, complement system lyses these RBCs

INTRAVASCULAR HEMOLYSIS

• This leads to hemoglobinuria & anemia whereas the anemia would either be mild or severe

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AIHA cannot be attributed to any single autoantibody. To determine autoantibody/ies in a patient, direct Antiglobulin test (DAT) is performed. Classification of the Abs is based on their activity at different temperatures and their etiology;

1) Warm Autoantibodies. - High activity at physiological temperature (approximately 37 °C)

2) Cold Autoantibodies - Act best at temperatures of 0–4 °C

Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state.

Antibody becomes active when it reaches the limbs & opsonizes RBCs. When these RBCs return to central regions, they are damaged by complement. Patients may present with one or both types of Autoantibodies; if both are present, it is called "mixed-type" AIHA.

ANTIBODY

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Clinical Manifestation

The common symptoms are; •Paleness of the skin •Fatigue•Fever•Confusion•Lightheadedness•Dizziness•Weakness or inability to do physical activity

Less common;•Dark urine•Yellowing of the skin and the whites of the eyes (jaundice)•Heart murmur•Increased Heart rate•Enlarged spleen•Enlarged liver

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Diagnosis

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Tests• FBC (hemoglobin, hematocrit)• Absolute reticulocyte count• Coomb’s Test ( direct, Indirect)• Hemosiderin in the urine• Protein electrophoresis

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Full Blood count

• Warm Antibody AIHAHematocrit level – less than 10%Platelets are normal

• Cold AIHAExhibit mild to moderate anemiaHematocrit level- low as 15-20%

• Drug induced AIHASimilar to those warm antibody AIHA

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Coomb’s TestDirect Coomb’s Test ( Direct Antiglobulin Test)• This test is used to determine whether the RBC-binding

autoantibody (IgG) or compliment (C3) is bound to Ag on RBC membranes.

• Coomb’s reagent is added to washed RBC’s from the patient.• If IgG or C3 is bound to RBC membranes, agglutination occurs it is

a positive result.

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Indirect Coombs Test (Indirect Antiglobulin Test)

• The indirect antiglobulin (indirect Coomb’s) test is a complementary test that consists of mixing the patient’s plasma with normal RBCs to determine whether autoantibodies are free in the plasma.

1. Normal RBCs are added to patient’s plasma2. Then Coomb’s reagent is added3. Agglutination occurs if autoantibodies are present in patient’s plasma

– positive test

• INDIRECT TEST is used to determine if there’s a potential bad reaction to a blood transfusion

• DIRECT TEST is used to check for AUTOIMMUNE HEMOLYTIC ANEMIA

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TREATMENTS

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Treatments

For Warm autoimmune hemolytic anemia

• Corticosteroids & immunoglobulins are 2 common treatments.

• Initial medical treatment consists of prednisone• Other options include rituximab, donazol,

cyclosphosphamide, azathioprine & ciclosporine.• High dose immunoglobulin IV is possible; it controls

hemolysis, but the benefit is short lasting (1-4 weeks); also expensive.

• If ineffective, splenectomy is considered.

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For cold agglutination disease

Removal of underlying cause is important. [i.e. if caused by a pathology, treat it].

Rituximab treatment [medication for autoimmune diseases & types of cancer].

Avoiding cold weather & cold drinks is important.

Treat the infections that lead to paroxysmal cold hemoglobinuria.

i.e. if caused by syphilis, treat with narrow spectrum penicillin.

For Paroxymal Cold Hemoglobinuria

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Role of Rituximab

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SUMMARY

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