hemolytic anemia in Children including sickle cell

Hemolytic Anemia in CHildren

1. Life of a Red Blood Cell
Erythroid precursors undergo 4-5 divisions in
marrow, extrude nucleus, become reticulocytes,
enter peripheral blood, and survive ~100-120 days
Must withstand severe mechanical & metabolic
stress, deform to pass thru capillaries half their
size, resist shearing force across heart valves,
survive stasis-induced acidemia & substrate
depletion, avoid removal by macrophages

2. Normal Red Blood Cell
Discoid shape with 7-8 micron diameter
Can squeeze thru 3 micron capillary
As it ages, it loses water & surface area,
impairing deformability
These changes are detected by the RES and
trigger removal of the aged RBCs by
macrophages

3. Anemia
Initial evaluation: MCV
If MCV >100: megaloblastic or not?
If MCV <80: iron deficient or not?
MCV 80-100: reticulocytosis or not?
–Increased retics: Hemolysis or posthemorrhage
–Decreased retics: Renal dz, liver dz,
hypothyroid, anemia of chronic dz,
myelodysplasia, leukemia, myeloma, etc.

4. Hemolytic Anemia
Inadequate number of RBCs caused by
premature destruction of RBCs
Severity depends on rate of destruction and
the marrow capacity to increase erythroid
production (normal marrow can increase
production 5 to 8 fold)

5. Classification of Hemolytic Anemia
Site of RBC destruction-Extravascular or
Intravascular
Cause of destruction-extracorpuscular
(abnormal elements in vascular bed that
“attack” RBCs) or intracorpuscular (erythrocyte
defects-membrane abnormalities, metabolic
disturbances, disorders of hemoglobin)

6. Pathways of RBC Destruction
Extravascular: RBCs phagocytized by RE cells;
RBC membrane broken down; Hemoglobin broken
into CO (lung), bilirubin (conjugation and excretion
by liver), and iron (binds to transferrin, returns to
marrow)
Intravascular: Free hemoglobin binds to
haptoglobin or hemopexin or is converted to
methemalbumin. These proteins are cleared by the
liver where the heme is broken down to recover
iron & produce bilirubin.

7. Hemolytic Anemias
Intrinsic RBC causes
–Membranopathies: hereditary spherocytosis
–Enzymopathies: G6PD
–Hemoglobinopathies: Sickle cell disease
Extrinsic causes
–Immune mediated: Autoimmune (drug, virus, lymphoid
malignance) vs Alloimmune (transfusion reaction)
–Microangiopathic (TTP)
–Infection (Malaria)
–Chemical agents (spider venom)

8. Diagnosis of Hemolysis
Symptoms depend on degree of anemia (ie, rate of
destruction)
Clinical features: anemia, jaundice, reticulocytosis,
high MCV & RDW, elevated indirect bili, elevated
LDH, low haptoglobin, positive DAT (AIHA)
Acute intravascular hemolysis: fever, chills, low
back pain, hemoglobinuria
Smear: polychromatophilia, spherocytosis &
autoagglutination

14. Acute Intravascular Hemolysis
Causes: Blood transfusion, thermal burns, snake
bites, infections (clostridia, malaria, Bartonella,
Mycoplasma), mechanical heart valves, PNH
Hemoglobinemia-pink or red plasma
Hemoglobinuria: brown or red after spinning down
RBCs
Urine hemosiderin: urine hemoglobin reabsorbed
by renal tubular cells; detect by staining sediment
Low haptoglobin: binds free hemoglobin
Methemalbumin: appears after depletion of
haptoglobin

15. Intravascular hemolysis events
Acute intravascular hemolysis
Immediate drop in Haptoglobin; rises at 2 days;
normal at 4 days
Hemoglobinemia detectable 6-12 hrs after
event
Hemoglobinuria detectable 12-24 hrs
Hemosiderinuria detectable 3-12 days
Methemalbumin detectable 1-12 days

16. Acute Extravascular Hemolysis
Sudden fall in hemoglobin level with no
evidence of bleeding or intravascular
hemolysis (no hemoglobinemia or
hemoglobinuria)
Clinical setting usually points to cause

17. Causes of Extravascular Hemolysis
Bacterial & Viral infections
Drug-induced
Autoimmune
Hemoglobinopathies
Membrane Structural Defects
“Environmental” Disorders-Malignancy
associated DIC, TTP, Eclampsia

18. Infectious causes of hemolysis
5-20% of pts with falciparum malaria have
acute intravascular hemolysis (black water
fever); most have mild extravascular hemolysis
Clostridial sepsis may cause severe
intravascular hemolysis
Mild hemolysis occurs with mycoplasma
pneumonia; often associated with high titer
cold agglutinin; self limited

19. Drug-induced Hemolysis
May occur by an immune mechanism or by
challenging the RBC metabolic machinery
Oxidant drugs causing hemolysis in G6PD
deficiency: nitrofurantoin, sulfa drugs, dapsone,
primaquine, pyridium, doxorubicin
Drugs causing immune-mediated hemolysis:
penicillin, quinidine, methyldopa, streptomycin

20. G6PD Deficiency
~10% of African-American males have X-linked
A variant
The older RBCs are lost from circulation
New RBCs have normal or high G6PD levels;
therefore they can usually compensate for the
hemolysis even if the drug is continued

21. Drug Induced Hemolysis
Formation of antibodies specific to the drug: in
high doses PCN binds RBC membrane, if pt forms
Ab against PCN, the RBC are destroyed
Induction of Ab to RBC membrane
antigens:methyldopa induces autoab to Rh ag
Selective binding of streptomycin to RBC
membrane with formation of complement fixing
antibody
All have Coombs (DAT) positive for IgG

22. Autoimmune Hemolytic Anemia
Anticipate this cause of hemolysis in infections,
collagen vascular diseases, lymphoid malignancies
Generally, acute extravascular hemolysis
Spherocytes seen; no fragments; elevated LDH;
suppressed haptoglobin; reticulocytes
Autoantibodies are directed against RBC
components (eg, Kell antigen)
May be warm-reacting (IgG) or cold-reacting (IgM)
antibody

23. Autoimmune Hemolytic Anemia
Warm reacting abs will show IgG +/-C3
Cold reacting abs will have C3 only
RBCs sensitized to IgG only are removed in the
spleen; those with complement are destroyed in
the liver (Kupffer cells have C3b receptors)
Warm reacting abs often respond to steroids
Cold reacting antibodies are more often resistant
to therapy and are associated with lymphoid
malignancy

24. Causes of Autoimmune Hemolysis
SLE
Non-Hodgkins lymphomas, CLL
Hodgkins Disease
Myeloma
HIV
Hepatitis C
Chronic Ulcerative Colitis

25. Management of Hemolysis
The increase in RBC production requires
adequate iron (intravascular hemolysis) &
folate supplies (all hemolytic states)
Intravascular hemolysis-transfusion reaction-
stop transfusion, IVFs to induce diuresis and
mannitol (increases renal blood flow &
decreases hemoglobin reabsorption)

26. Management of Extravascular
Hemolysis
Acute self-limited hemolysis in G6PD pts rarely
needs Rx; pt education important
Severe hemolysis may require transfusion in
addition to therapy aimed at specific trigger
Iron overload becomes a problem in
hemoglobinopathies
Parvovirus infection may cause aplastic episodes
pts with chronic hemolytic states
Pigment gallstones occur in chronic hemolytic
states
Splenectomy reduces RBC destruction in pts with
hereditary spherocytosis

27. Management of Warm-Ab
Autoimmune Hemolysis
Steroids block RE clearance of RBCs with IgG or
C3 on surface and decrease production of IgG
antibody
Prednisone 1 to 1.5 mg/kg/day is usual dose
Most respond within 2 weeks
Very slow taper required
Chemotherapy or splenectomy may help if steroids
fail
Transfusions given if needed, may require “least
incompatible” blood; likely will be destroyed at the
same rate as the patient’s own blood

28. Management of Cold-Ab
Autoimmune Hemolytic Anemia
Usually no treatment required in setting of
mycoplasma or EBV infection.
Occasionally transfusion is needed. Washed RBCs
have less complement and are less likely to trigger
further hemolysis.
Steroids usually do not help
Chemotherapy (eg, cyclophosphamide or
chlorambucil) may help
In severe cases, plasmapheresis can reduce
intravascular antibody titer
May have dramatic cold sensitivity; warm
infusions, avoid cold exposure