Life of a Red Blood Cell

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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

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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

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Anemia

• Initial evaluation MCV
• If MCV gt100 megaloblastic or not?
• If MCV lt80 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.

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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)

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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)

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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.

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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)

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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

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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

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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

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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

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Causes of Extravascular Hemolysis

• Bacterial Viral infections
• Drug- induced
• Autoimmune
• Hemoglobinopathies
• Membrane Structural Defects
• Environmental Disorders- Malignancy associated
  DIC, TTP, Eclampsia

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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

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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

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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

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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
  antigensmethyldopa 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

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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

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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

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Causes of Autoimmune Hemolysis

• SLE
• Non-Hodgkins lymphomas, CLL
• Hodgkins Disease
• Myeloma
• HIV
• Hepatitis C
• Chronic Ulcerative Colitis

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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)

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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

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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 patients own blood

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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