Compiled by:

G.A.R. Sampath
Kalhari Gihara
Chanaka Lakshan
Aqeela Manuideen
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 Content
Introduction
Epidemiology
Clinical Manifestation
 Symptoms
 Diagnosis
Immunological basis
Treatments

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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 idiopathic
Secondary – 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 Syndrome
Paroxysmal 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 most

active 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 15
 ANTIBODY
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.
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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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 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 AIHA
Hematocrit level – less than 10%
Platelets are normal

• Cold AIHA
Exhibit mild to moderate anemia
Hematocrit level- low as 15-20%

• Drug induced AIHA

Similar to those warm antibody AIHA

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 Coomb’s Test
Direct 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 plasma

2. Then Coomb’s reagent is added
3. 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.

For Paroxymal Cold Hemoglobinuria

 Treat the infections that lead to paroxysmal cold

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

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Role of Rituximab

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