2. Introduction
Autoimmune hemolytic anemia (AIHA) is an
immunologic disorder in which antibodies are
produced that target RBCs
shortening of red cell survival due to the
products of an immune response
All require antigen-antibody reactions
4. Characteristics of Erythrocyte Autoantibodies
Warm AIHA caused by IgG autoantibodies that
are optimally reactive at 37 C
CAD is typified by IgM autoantibodies that are
optimally reactive at 4°C
PCH is a form of cold-reacting AIHA caused by
IgG autoantibodies
mixed-type AIHA with both IgG warm and IgM
cold autoantibodies
5. Warm-Reactive Autoantibodies
maximally reactive at 37°C
typically react with a patient’s own RBCs
IgG1 is the most common subclass
IgG1 and IgG3 activate C1 more readily, bind
strongly to FcγRI, FcγRII, and FcγRIII, and
increase RBC destruction in comparison with
IgG2 and IgG4 subtypes
6. Cold-Reactive Autoantibodies
primarily associated with CAD and PCH
PCH is the most common form in children
Both are bind RBCs optimally at temperatures
below 37°C and usually below 31°C
Cold agglutinins are IgM autoantibodies that
primarily cause extravascular hemolysis but can
mediate intravascular hemolysis as well
PCH is IgG mediated and causes intravascular
hemolysis
7. pathogenesis of a cold-reactive autoantibody
bind host RBCs and activate complement
complement fixation by these antibodies occurs
at 20°C to 25°C
Complement fixation cause RBC destruction via
opsonization by macrophages
8. Cold Agglutinin Disease
acute and often a result of Mycoplasma
pneumoniae infection
Other viruses:EBV,varicella and adenovirus
CAD typically occurs in the second or third
week of illness
jaundice and pallor due to rapid onset of
hemolysis
The hemolysis is self-limiting, and the degree of
anemia is typically mild to moderate
9. Cold Agglutinin Disease (cont.)
cold autoantibody is an IgM with anti-I
specificity associated with M. pneumoniae and
anti-i specificity associated with EBV
high (≥256) cold agglutinin titers with
postinfectious CAD
Treatment of postinfectious CAD is supportive
and includes keeping the patient warm and
using a blood warmer if the degree of anemia
warrants RBC transfusion
10. Cold Agglutinin Disease (cont.)
chronic form of CAD is seen in elderly patients
associated with lymphoma, chronic lymphocytic
anemia
hemoglobinuria from intravascular hemolysis and
acrocyanosis of the ears, nose, fingers, and toes
from autoagglutination of RBCs in the skin
capillaries, particularly in cold weathe are seen
Autoagglutination can be enhanced by cooling
the blood to 4°C and is reversed by warming to
37°C
Higher(≥1000) cold agglutinin titers
11. Paroxysmal Cold Hemoglobinuria
PCH occurs primarily in children as an acute
transient condition following an upper
respiratory or viral infection
detected by the Donath-Landsteiner test
PCH is the second most common form of AIHA
in children
12. Clinical manifestation of PCH
In children, PCH classically presents within several
weeks after a viral infection
sudden onset of hemoglobinuria, accompanied by
fever, pallor, and jaundice
headache, abdominal pain, nausea, vomiting, or
diarrhea
Hepatomegaly and splenomegaly were reported in
up to 25% of cases
13. LABORATORY FINDING OF PCH
Reticulocytosis is characteristic, reticulocytopenia
can be observed
PBS demonstrates RBC agglutination,
polychromasia nucleated RBCs, and spherocytes
DAT is negative
Donath-Landsteiner test is positive
↑LDH,↑BUN,Cr,↑ unconjugated bilirubin,
↓haptoglobin
14. PRIMARY AIHA
incidence of about 1 per 75,000 to
median age of diagnosis of 3.8 years
typically after a recent infection
Warm-reactive antibodies are IgG class and
account for the majority of AIHA cases in children
IgM-mediated CAD is uncommon in children and
mostly affects adults and elderly persons
PCH primarily presents in children, with the
median age at diagnosis being 5 years
15. PRIMARY AIHA
Clinical course:
1) Warm Ab:acute illness or intermittent
remissions and relapses
2) Cold Ab:severe but acute self-limited illness
requiring short-term supportive care with
transfusion
improved mortality rate from 18% to 4% result of
improvement in supportive care
16. In a largest cohort study of 265 pediatric
patients with AIHA:
37% were diagnosed with Evans syndrome
4% had died
6% had no response or were in partial remission
90% were in complete remission while either
receiving or not receiving therapy
18. Transfusion Therapy
Mild anemia & no symptom:observation only
Modrate to sever anemia or symptomatic:
transfusion therapy
very severe anemia with hemoglobin levels˂6 :
RBC transfusion should be instituted as soon as
possible
in warm, idiopathic AIHA, antibody is against
blood group antigens that are present on most
RBCs. no truly matched RBC units are possible,
but transfusion can be safely performed
19. Corticosteroid Therapy
Mechanism to improve hemolysis in warm AIHA :
1-decrease in serum antibody concentration
2-decreasing sequestration in the spleen
Dosage:1-2 mg/kg q 6 h for 1-3 day
Then 2 mg/kg/day for children
1 mg/kg/day for adolescent:2-4 week
Then taper slowly in 3-12 mouth
overall clinical response is approximately 80%
20. Intravenous Immunoglobulin
Dose of 0.5-1 mg/kg/day ᵪ 5 day
overall clinical response is approximately 40%
not considered first-line treatment for AIHA in
children
may be considered in a patient who is not
responding to steroids
21. Therapeutic Plasma Exchange
TPE in warm AIHA is considered a category III
intervention
TPE can significantly reduce antibody titers, in
CAD(Ig M)
may be considered as a temporizing measure in a
severely ill child who has a suboptimal response
to RBC transfusion and may not have had time to
respond to corticosteroid therapy
22. Treatment of Chronic or Refractory AIHA
Splenectomy and rituximab are the only second-
line treatments with proven short-term efficacy
1) Rituximab :
monoclonal antibody specific for the CD20 antigen
complement-mediated cytotoxicity
inhibition of B-cell proliferation
induction of apoptosis
375 mg/m2 weekly for 1 to 6 weeks
More than 90% of patients have a complete
response that lasted 7 to 28 months
at least 1.5 gm/dL increase in Hb at a median of
12 days from the time the first dose of rituximab
23. Treatment of Chronic or Refractory AIHA(cont)
2)splenectomy:
complete and partial response in approximately two
thirds of patients
50% of patients will remain in remission for years
mortality and morbidity of laparoscopic splenectomy
for hematologic indications was 0.6% and 18%
prior to surgery immunize with the polyvalent
polysaccharide vaccines against Streptococcus
pneumoniae and Neisseria meningitides H. influenzae
penicillin prophylaxis twice a day for at least several
years after surgery
24. Alternative Immunotherapeutic Agents
indicated in patients who do not respond to
corticosteroids, rituximab, and splenectomy or
who have contraindications to those therapies
Cyclophosphamide, cyclosporine, azathioprine 6-
mercaptopurine and Campath-1H have been used
to treat refractory AIHA
treatment should be continued for up to 6 months
before it is considered to have failed
25. 9 adult patient with severe refractory AIHA treted
with cyclophosphamide 50 mg/kg/day for 4 days :
Six patients achieved complete remission with
normal hemoglobin
three patients had partial remissions,as a
hemoglobin level of at least 10 gm/dL without
transfusion support
Patients became RBC transfusion–independent
after a median of 19 days
High-dose cyclophosphamide was well tolerated
common adverse effects included nausea,
vomiting, and transient myelosuppression
26. T-lymphocyte function inhibitor
Cyclosporine, 6-mercaptopurine, and Cell-Cept
interfere with autoantibody synthesis
cyclosporine has improved the course of
AIHA it is not routinely used because of the
adverse effects
6-MP in 7 pediatric patients with AIHA was
reported (five cases of primary AIHA and two
cases of secondary AIHA) all responded
Cell-cept use in 3 adult all responded (Hb˃10)
Campath-1H monoclonal antibodies improve
refractory disease but do not induce a
prolonged remission
27. Hematopoietic Stem Cell Transplantation
36 patients with severe refractory autoimmune
cytopenia, two underwent allogeneic HSCT and five
patients autologous HSCT:
– two allogeneic HSCT achieved continuous remission
– five autologous HSCT, one died of treatment-related
causes, one died of progressive disease, two had no
response, and one had a transient response
– this treatment option should be reserved for patients
with severe life-threatening disease for whom all other
therapies have failed
28. Treatment Cold-Reactive AIHA
In children, CAD typically occurs after an infection
In mild, compensated anemia not require
treatment or transfusions
If transfusion is indicated, a blood warmer need
In severe cases of cold, IgM-mediated AIHA,
plasmapheresis can remove autoantibodies
treatment of PCH is also supportive with
transfusion
30. SECONDARY AUTOIMMUNE HEMOLYTIC ANEMIA
24% to 63% of all pediatric AIHA case
1) Evans Syndrome:
– combination of ITP, AIHA, and/or autoimmune
neutropenia, or immune pancytopenia
– Autoantibodies are directed at specific antigens on
RBCs, plt, or neutrophils but are not cross-reactive
– 13% to 73% of published pediatric AIHA cases
– Evans is a chronic disorder, by frequent exacerbations
and remissions
– Neutropenia occurs in up to 55% of patients at
presentation
31. management of Evans syndrome :
treat symptomatic cytopenias including moderate to
severe anemia, thrombocytopenia with bleeding, or
prolonged and/or severe neutropenia (ANC˂ 500/μL)
first-line therapy is corticosteroids with or without IVIG
steroids are useful in the acute setting, most patients
will require adjuvant or alternative therapy to sustain a
remission
IVIG as a single agent has not been reported for
treatment
Rituximab,an anti-CD20 monoclonal antibody, is an
effective second-line
32. management of Evans syndrome(cont.)
Splenectomy can achieve improvement of cytopenias,
but the response is often transient and relapse occurs in
most cases 1 to 2 months later
splenectomy should be reserved for patients who do not
respond to other second-line therapies
Cyclophosphamide has induced remission
Alemtuzumab (Campath-1H) is an IgG monoclonal AB
directed the CD52 antigen on T and B lymphocyte
in the European Group study, of 22 patients who
underwent HSCT for refractory autoimmune cytopenias,
11 had Evans syndrome two autologous 9 allogeneic
- in autologous: one no response ,one relaps
- in allogeneic HSCT five continuous remission, one
relapse, and three died of treatment-related causes
33. Acute Lymphoproliferative Syndrome
ALPS, an inherited disorder of abnormal
lymphocyte survival caused by dysregulation of
the Fas apoptotic pathway
excess of T-cell receptor αβ+CD3+CD4−CD8− T
(double-negative T [DNT]) lymphocytes that
accumulate in the lymph nodes, spleen, and
peripheral blood
results in chronic lymphoproliferation,
autoimmune disease, increased risk of
malignancy
34. Acute Lymphoproliferative Syndrome (cont.)
clinical presentation : chronic lymphadenopathy,
splenomegaly, multilineage cytopenias resulting
from sequestration and autoimmune destruction,
and an increased risk of B-cell lymphoma
60% to 70% have heterozygous germline
mutations in FAS, autosomal-dominant fashion
10% of FAS mutations are acquired and no
genetic defect in 30%
35. Treatment of ALPS
High-dose pulse therapy with intravenous
methylprednisolone (5 to 10 mg/kg)
IVIG in combination with corticosteroids
low-dose GCSF (1 to 2 μg/kg) 2-3 times weekly for
patients with isolated chronic neutropenia and
associated infections
CellCept and sirolimus : ˃ 80% responses for their
cytopenias
