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
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
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
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