Immune Hemolytic Anemia

Red Cell Disorders:
Immune Hemolytic Anemia
Edited by:
Djoko Heri Hermanto
Hematology-Medical Oncology Division, Department of Internal Medicine
Faculty of Medicine, Brawijaya University - Dr. Saiful Anwar General Hospital -
Malang
Faculty of Medicine
University of Brawijaya
Ilustration case
Case:
Mr. P, 35 year-old
History taking: pale 2 week; jaundice; no bleed; history
of fever 2 months ago; acrocyanosis at the tip of the
nose, ears, fingers, and toes.
Physical examination: conjunctiva palpebra anemic;
sclera icteric; spleen enlargement (Schuffner I)
Laboratory results: Hb 6.5 g/dl; WBCs 5640/mm3;
platelet 284,000mm3; MCV, MCH and MCHC normal;
peripheral blood smear: spherocyte (+); DAT positive.
Clinical Competencies
After this session:

 Students can describe:
- the pathogenesis of immune hemolytic anemia
- the classification of immune hemolytic anemia
- the principal management of immune hemolytic
anemia
 Students can diagnose immune hemolytic anemia
based on clinical features and laboratory findings
Definition
• Hemolytic anemia: anemia due to hemolysis, the
abnormal breakdown of RBCs, either in the
blood vessels (intravascular) or elsewhere
(extravascular)
• Immune hemolytic anemia: hemolytic anemia
that induced by abnormal-immune system
Red cell breakdown
Classification
1. Autoimmune hemolytic anemia (AIHA)

a. Warm AIHA
b. Cold AIHA
c. Mixed-type AIHA
2. Alloimmune hemolytic anemia
3. Drug-induced hemolytic anemia
Pathogenesis
Autoimmune Hemolytic Anemia (AIHA)

AIHA are caused by antibody production by the body
against its own red cells: characterized by a positive DAT
or the Coombs’ test : cold, warm and mixed-types.
Cold AIHA
The autoantibody attaches to red cells (IgM) mainly in
the peripheral circulation where the blood temperature is
cooled (00C - 40C):
 are highly efficient at fixing complement
 intravascular & extravascular hemolysis
Figure 1. Direct antiglobulin test (DAT), demonstrating the
presence of autoantibodies (shown here) or complement
on the surface of the red blood cell.
(RBCs = red blood cells)
Pathogenesis.....
Warm AIHA
Warm hemolysis refers to IgG autoantibodies, which
maximally bind RBC at body temperature (37°C).
When warm autoantibodies attach to RBC surface
antigens, these IgG-coated red blood cells are
partially ingested by the macrophages of the spleen,
leaving microspherocytes, the characteristic cells of
AIHA. These spherocytes, which have decreased
deformability compared with normal red blood cells,
are trapped in the splenic sinusoids and removed
from circulation.
Pathogenesis.....
Mixed AIHA
Some patients with warm AIHA also possess a cold
agglutinin. While the majority of these cold agglutinin
are not clinically significant, occasionally they have a
sufficient thermal amplitude (greater than 300C) or
high titer (greater than 1:1,000 at0-400C) to indicate
cold agglutinin syndrome (CAS)
Mixed-type AIHA can be either idiopathic or secondary to
lymphoproliferative disorders or SLE
Pathogenesis.....
Alloimmune Hemolytic Anemia

The most severe alloimmune hemolysis is an acute
transfusion reaction caused by ABO-incompatible
RBCs, e.g. transfusion of A donor into O recipient
(who has circulating anti-A IgM antibodies) leads to
complement fixation and a brisk intravascular
hemolysis: may occur fever, chills, dyspnea,
hypotension, shock.
Delayed hemolytic transfusion reactions (3-10 days
after a transfusion): caused by low titer antibodies to
minor RBC antigens.
Pathogenesis.....
Drug-Induce Hemolytic Anemia

Three mechanisms of action:
1. drug-absorption (hapten-induced)
2. immune complex
3. autoantibody
These IgG- and IgM-mediated disorders produce a
positive DAT and are clinically and serologically
indistinct from AIHA.
Cold AIHA
Etiologic classification:
1. Idiopathic
2. Secondary:
- Infections: M. pneumonia, infectious mononucleosis
- Lymphoma
- Paroxysmal cold hemoglobinuria (rare, sometimes
associated with infections, e.g. syphilis)
Clinical features
– Mild jaundice & splenomegaly may be present
– May develop acrocyanosis (purplish skin discoloration)
at the tip of the nose, ears, fingers, and toes caused
by the agglutination of red cells in small vessles
Cold AIHA…..
Laboratory findings
Similar to those of warm AIHA, except that spherocytosis
is less marked, red cells agglutinate in the cold and
the DAT reveals complement (C3d) only on the RBC
surface
Management
 Treating the underlying cause
 Splenectomy does not usually help unless massive
splenomegaly is present, and steroids are not helpful
Warm AIHA
Etiologic classification
1. Idiopathic
2. Secondary:
- SLE, other autoimmune disease
- CLL, lymphomas
- Drugs, e.g. methyldopa, fludarabine
Clinical features
– Occur at any age in either sex and varying severity
– The spleen in often enlarged
– Tend to remit and relapse
– May occur alone or in association with other diseases
e.g. ITP, SLE or arise as a result of methyldopa therapy
Warm AIHA…..
Laboratory findings
– Peripheral blood: typical of an extravascular hemolytic
anemia with spherocytosis prominent
– The DAT (+): antibodies are best detected at 370C
Figure 2. Blood film in warm autoimmune hemolytic anemia.
The hematological and biochemical findings are typical of an extravascular
hemolytic anemia with spherocytosis prominent in the peripheral blood
Figure 3. Blood film in cold autoimmune hemolytic anemia.
Laboratory findings are similar to those of warm AIHA, except that spherocytosis is
less marked, red cells agglutinate in the cold temperature (4oC) and the DAT reveals
complement (C3d) only on the red cell surface.
Treatment
TREATMENT OF WARM AIHA
• Remove the underlying cause (e.g. methyldopa, fludarabine)
• Corticosteroids. Prednisone is the usual first-line treatment;
60 mg daily is a typical starting dose in adults and should
then be tapered down
• Splenectomy
• Immunosupression : azathioprine, cyclophosphamide,
chlorambucil, cyclosporine, and mycophenolate mofetil
• Folic acid
• Blood transfusion
• High-dose immunoglobulin
Treatment
TREATMENT OF COLD AIHA
• Treating the underlying cause
• Steroids are not helpful
• Splenectomy does not usually help unless
massive splenomegaly is present,
Treatment of Refractory AIHA
1. Intravenous immune globulin (IVIG)

2. Danazol
3. immunosuppressive agents: Azathioprin,
mycophenolate mofetil
4. Monoclonal antibodies : Rituximab (Rituxan®), and
Alemtuzumab (Campath-1H®)
Complications
Thromboembolism
– The most common cause of death was pulmonary
embolism and 27% patients suffered from an
episode of venous thromboembolism
– AIHA in patients with SLE: the risk of thrombosis to
be increased more than 4-fold
Lymphoproliferative disorders
Associated immune disorder (e.g., rheumatoid arthritis,
temporal arteritis, Crohn’s disease, lupus, thyroiditis,
Sjögren’s syndrome) and chronic lymphocytic leukemia
Ilustration case
Case:
Mr. P, 35 year-old
History taking: pale 2 week; jaundice; no bleed; history
of fever 2 months ago; acrocyanosis at the tip of the
nose, ears, fingers, and toes.
Physical examination: conjunctiva palpebra anemic;
sclera icteric; spleen enlargement (Schuffner I)
Laboratory results: Hb 6.5 g/dl; WBCs 5640/mm3;
platelet 284,000mm3; MCV, MCH and MCHC normal;
peripheral blood smear: spherocyte (+); DAT positive.
Questions:
1.What is THE MOST PROBABLE DIAGNOSIS of this
patient?
2.Describe in brief CLASSIFICATION & PATHOGENESIS of
this disease!
3.How TO DIAGNOSE each type (warm and cold type) of
this disease based on the clinical features and laboratory
findings?
4.How TO TREAT each type (warm and cold type) of this
disease?
5.What are COMPLICATIONS of this disease?
Please…….discuss this case in your group!!

Immune Hemolytic Anemia

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Red Cell Disorders:

Immune Hemolytic Anemia

After this session:

1. Autoimmune hemolytic anemia (AIHA)

Autoimmune Hemolytic Anemia (AIHA)

Alloimmune Hemolytic Anemia

Drug-Induce Hemolytic Anemia

1. Intravenous immune globulin (IVIG)

Please…….discuss this case in your group!!

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