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Life of a Red Blood Cell
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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
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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
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Initial evaluation: MCV
If MCV >100: megaloblastic or not?
If MCV <80: iron deficient or not?
MCV 80-100: reticulocytosis or not?
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Increased retics: Hemolysis or posthemorrhage
Decreased retics: Renal dz, liver dz,
hypothyroid, anemia of chronic dz,
myelodysplasia, leukemia, myeloma, etc.
Hemolytic Anemia
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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
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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
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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
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Intrinsic RBC causes
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Membranopathies: hereditary spherocytosis
Enzymopathies: G6PD
Hemoglobinopathies: Sickle cell disease
Extrinsic causes
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Immune mediated: Autoimmune (drug, virus, lymphoid
malignance) vs Alloimmune (transfusion reaction)
Microangiopathic (TTP)
Infection (Malaria)
Chemical agents (spider venom)
Diagnosis of Hemolysis
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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
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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
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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
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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
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Bacterial & Viral infections
Drug- induced
Autoimmune
Hemoglobinopathies
Membrane Structural Defects
“Environmental” Disorders- Malignancy
associated DIC, TTP, Eclampsia
Infectious causes of hemolysis
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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
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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
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~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
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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
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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
Autoimmune Hemolytic Anemia
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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
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SLE
Non-Hodgkins lymphomas, CLL
Hodgkins Disease
Myeloma
HIV
Hepatitis C
Chronic Ulcerative Colitis
Management of Hemolysis
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The increase in RBC production requires
adequate iron (intravascular hemolysis) &
folate supplies (all hemolytic states)
Intravascular hemolysis- transfusion reactionstop transfusion, IVFs to induce diuresis and
mannitol (increases renal blood flow &
decreases hemoglobin reabsorption)
Management of Extravascular
Hemolysis
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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
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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
Autoimmune Hemolytic Anemia
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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