hemolytic anemia in Children including sickle cell

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

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

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.

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)

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)

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.

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)

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

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

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

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

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

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

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

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

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

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

 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

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

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)

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

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

Management of Cold-Ab
 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

hemolytic anemia in Children including sickle cell

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hemolytic anemia in Children including sickle cell