Hematology 425 Increased Destruction of RBCs

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Hematology 425 Increased Destruction of RBCs

• Russ Morrison
• October 30, 2006

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Increased Destruction of RBCs

• Hemolytic anemia (HA) or hemolytic disorder
  describes conditions in which there is increased
  destruction of RBCs
• Increased destruction causes the BM to respond by
  accelerating production
• Provides a picture of vigorous RBC production in
  the midst of accelerated RBC destruction
• HA occurs when RBC survival is so short that
  anemia develops despite the increased RBC
  production

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Increased Destruction of RBCs

• Normal BM can increase RBC production 6 to 8x, so
  significant destruction must be occurring before
  anemia develops
• A compensated hemolytic disorder can be present
  without anemia if the BM can keep up with the
  decreased RBC survival
• Many anemias have a hemolytic component
• Anemia of B12 and Folate deficiency
• Anemia of chronic disorders
• Renal diseease
• IDA
• These conditions demonstrate hemolysis that, in
  itself, is not sufficient to cause anemia

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Increased Destruction of RBCs

• Anemia develops because the BM can not increase
  production of RBCs fast enough to compensate for
  the shortened survival of the RBCs
• These anemias are not classified as hemolytic
  anemias because hemolysis is not the primary
  cause, rather these anemias are known as anemias
  with a hemolytic component

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Increased Destruction of RBCs

• Classification of Hemolytic Anemia
• HA has been classified many ways with one of the
  most useful being division into inherited and
  acquired HA
• HA may also be divided into intrinsic defects in
  the cells themselves, or extrinsic ones caused by
  action of external agents upon normal RBCs
• Most intrinsic defects are inherited and most
  extrinsic ones are acquired
• PNH is an exception being an acquired disorder
  involving an intrinsic defect

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Increased Destruction of RBCs

• With intrinsic defects, if the RBCs of an
  affected patient are transfused into a healthy
  person, they have a shortened life span while if
  normal RBCs are transfused into this person, they
  survive normally
• With extrinsic defects, cross-transfusion studies
  show that the patients RBCs have a normal life
  span in a normal person, but normal cells
  demonstrate a decreased life span when infused
  into the patients circulation

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Increased Destruction of RBCs

• The intrinsic disorders can be divided into
  groups depending on which RBC structure or
  metabolic pathway is impaired and include
• Defects of the RBC membrane
• Defects of RBC enzymes
• Defects of the Hgb molecule

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Increased Destruction of RBCs

• The extrinsic disorders are divided into
• Immunohemolytic
• Traumatic
• Microangiopathic
• As well as anemias caused by
• Invectious agents
• Chemical agents (drugs, venoms)
• Physical agents
• PNH is an acquired, intrinsic disorder
• Box 20-1 shows classification of the HAs

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Erythrocyte Hemolysis - extravascular

• RBCs are produced in the BM and released into the
  PB with a normal life span of 120 days
• During this time in circulation, metabolic and
  chemical changes take place as the RBCs age which
  result in the loss of RBC deformability
• Normally, macrophages recognize these changes and
  phagocytize the aging RBCs
• The organs of this RBC removal system include the
  spleen, BM, liver, lymph nodes and circulating
  monocytes.

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Erythrocyte Hemolysis - extravascular

• Macrophages in the spleen (littoral cells) are
  sensitive to RBC abnormalities and the
  macrophages of the liver (Kupffer cells) target
  severely damaged RBCs
• This normal destruction of aging RBCs is called
  extravascular hemolysis because it takes place
  outside the blood vessels
• 90 of normal RBC destruction occurs
  extravascularly

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Erythrocyte Hemolysis - extravascular

• The phagocytized RBCs are broken down into globin
  and heme, which are, in turn, broken down into
  amino acids and returned to the amino acid pool
• Iron is released from the hem, bound to a protein
  carrier (transferrin), and recycled
• The hem molecule reacts with heme oxygenase
  yielding biliverdin and CO that is excreted by
  the lungs
• The biliverdin is reduced to unconjugated
  bilirubin, released into the blood plasma,
  attached to albumin and carried to the liver

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Erythrocyte Hemolysis - extravascular

• Some of the bilirubin returns to the blood plasma
  resulting in a small amount of unconjugated
  bilirubin in the plasma
• The bilirubin-albumin complex in the liver enters
  parenchymal cells where bilirubin dissociates
  from albumin and is conjugated with glucuronic
  acid via the enzyme glucuronyl transferase
  ultimately forming conjugated or direct bilirubin.

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Erythrocyte Hemolysis - extravascular

• Direct bilirubin is water soluble
• Unconjugated bilirubin is also referred to as
  indirect bilirubin, it is insoluble in water
• 200 to 300 mg of bilirubin is produced each day
• This conjugated bilirubin is excreted along with
  bile into the intestines where it is convereted
  into urobilinogen by bacteria in the gut.
• Most of the conjugated bilirubin is excreted in
  the stool, but some is reabsorbed by the
  intestines into the blood, reenters the liver and
  is excreted.
• A small amount is filtered by the renal
  glomerulus and excreted into the urine

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Erythrocyte Hemolysis - extravascular

• In hemolytic disorders RBC life span can 15-20
  days without anemia developing if the BM
  compensated the destruction with additional RBC
  production (compensated hemolytic state)
• When destruction exceeds the ability of the BM to
  replace the RBCs, anemia is the result
• Most Has are the result of increased
  extravascular hemolysis

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Erythrocyte Hemolysis - extravascular

• In extravascular Has, there is increased
  unconjugated bilirubin in the serum and increased
  urobilinogen in the urine
• Bilirubin does not appear in the urine because
  unconjugated bilirubin cant pass through the
  renal glomerulus

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Erythrocyte Hemolysis - intravascular

• Intravascular hemolysis, on the other hand, is
  the destruction of severely defective RBCs as
  they circulate and the release of Hgb directly
  into the blood plasma
• 10 of normal RBC destruction takes place in this
  manner
• Typical laboratory findings of excess
  intravascular hemolysis are hemoglobinemia,
  hemoglobinuria and hemosididerinuria
• There will also be methemalbumin ahd
  hemopexin-heme in the plasma

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Erythrocyte Hemolysis - intravascular

• Very high levels of plasma hemoglobin are only
  found in patients whose disorders result in
  predominantly intravascular hemolysis
• Hemoglobinuria will occur when plasma hemoglobin
  exceeds the haptoglobin binding capacity
• Normal plasma hemoglobin is less than 1 mg/dL
• Plasma becomes visibly red at 50 mg/dL
• Patients with sickle cell anemia and thalassemia
  major will have plasma hemoglobin levels of 15-60
  mt/d and values gt100 mg/dL are seen in severe
  acquired immunohemolytic anemia

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Erythrocyte Hemolysis - intravascular

• Plasma hemoglobin is rapidly bound to haptoglobin
  and carried to the liver where it is converted to
  bilirubin
• Low haptoglobin levels are seen in both
  intravascular and extravascular hemolysis
• During excess intravascular hemolysis, after
  plasma haptoglobin is depleted, Hgb passes across
  the glomerular membrane
• Hgb will be reabsorbed by the kidneys to a point
  and after that Hgb spills into the urine
  producing hemoglobinuria

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Erythrocyte Hemolysis - intravascular

• Hgb that is reabsorbed in the kidneys is broken
  down into iron and bilirubin
• Some iron remains in renal tubular cells
  complexed to ferritin or hemosiderin
• These renal sells with the iron are sloughed into
  the urine and may be seen using a Prussian blue
  stain of the urinary sediment
• Prussian blue staining of urinary sediment is an
  easy and inexpensive way to detect intravascular
  hemolysis

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Erythrocyte Hemolysis - intravascular

• Once haptoglobin is depleted hemoglobin is
  converted through multiple pathways to bilirubin
  where plasma bilirubin level, both direct and
  indirect, increase
• Urinary iron can also be measured and in
  increased levels is characteristic of
  intravascular hemolysis

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Clinical Features of HA

• Major clinical features in inherited HA
• Varying degrees of anemia
• Jaundice
• Occurrence of crises
• Splenomegaly
• Development of cholelithiasis (gall stones)
• Less common
• Chronic leg ulcers
• Bony abnormalities
• May manifest in infancy, or if well compensated,
  later in life

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Clinical Features of HA

• Major clinical features in acquired HA
• Anemia insidiously develops over a period of
  weeks or months
• Clinical picture may resemble inherited HA
• This is hemolytic process secondary to another
  disease and signs and symptoms of the primary
  disorder (lymphoma, LE) may overshadow the
  hemolytic process

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Clinical Features of HA

• If the HA develops acutely, such as after
  transfusion of ABO-incompatible blood or the
  ingestion of an oxidant drug by a patient with
  G6PD deficiency, symptoms may suggest an acute
  febrile illness
• Other hemolytic disorders may show
• Back pain
• Vomiting
• Fever
• Profound prostration and shock may develop
• Oliguria or anuria may follow
• Pallor,jaundice,tachycardia and other symptoms of
  severe anemia may be prominent

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Laboratory Findings in HA

• Patients who have clinical features of HA must
  show both increased erythrocyte destruction and
  compensatory increase in the rate of RBC
  production
• No ideal laboratory test exists for the diagnosis
  of the hemolytic state
• Table 20-1 shows laboratory findings indicating
  accelerated red cell destruction

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Lab Findings, accelerated RBC destruction
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Lab Findings, accelerated RBC destructionHgb
drop of gt 1g/dL/week, with equivalent drops in
RBCs and Hct
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Lab Findings, accelerated RBC destruction
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Laboratory Findings in HA

• Laboratory findings indicating increased
  erythropoiesis are present in chronic hemolytic
  disease and become evident shortly after an acute
  hemolytic episode
• These findings also occur after hemorrhage and
  after specific therapy for anemia caused by iron,
  folate or B12 deficiency
• Table 20-2 shows laboratory findings indicating
  increased RBC production

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Laboratory Findings, Increased RBC Production
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Laboratory Findings, Increased RBC Production
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Reticulocytosis

• The reticulocyte count is the most commonly used
  test to determine accelerated erythropoiesis
• Increased reticulocytes with an increased
  reticulocyte production index supports a
  diagnosis of anemia due to blood loss or
  destruction of RBCs
• When hemolysis is severe enough to produce an
  anemia, the regiculocyte count is usually
  significantly increased

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Reticulocytosis

• Severity of increase in reticulocytes usually
  correlates with severity of hemolysis
• Exceptions to this correlation occur during
  aplastic crisis of HA and in some immunohemolytic
  anemias with hypoplastic marrow this suggests
  that the autoantibodies were directed against BM
  red cell precursors as well as circulating RBCs

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CBC and Morphologic Findings

• PB smear findings of polychromatic RBCs and NRBCs
  represent a response to an increased stimulation
  of the BM due to either hemolysis or blood loss
• Leukocytosis and thrombocytosis may accompany HA,
  most often as a result of acute HA or acute
  hemorrhage
• Platelets are generaly large
• Low platelet counts with other signs of hemolysis
  may indicate DIC

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CBC and Morphologic Findings

• Increased MCV is usually seen with extreme
  reticulocytosis due to premature release of
  shift reticulocytes from the BM
• The degree of reticulocytosis and macrocytosis
  may correspond to the degree of anemia
• Morphologic abnormalities are often associated
  with HA and are shown in table 20-3

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Morphology Associated with HA
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Morphology Associated with HA
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Bone Marrow Examination

• BM of patients with HA will reveal erythroid
  hyperplasis
• ME ratio decreases in HA to less than 1.51 from
  a normal of 21 to 41
• BM is usually not necessary to diagnose HA

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Tests to Determine Specific Hemolytic Processes

• PB Smear findings that reveal the underlying
  cause of the HA
• 1. Spherocytes
• 2. Elliptocytes
• 3. Acanthocytes
• 4. Echinocytes
• 5. Sickle cells
• 6. Target cells

• 7. Schistocytes
• 8. Helmet cells
• 9. Fragmented cells
• 10. Agglutination
• 11. Erythrophagocytosis
• 12. Parasites

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Tests to Determine Specific Hemolytic Processes

• Additional tests that may assist in the diagnosis
  of specific entities involved in HA include
• DAT
• Osmotic fragility
• Autohemolysis
• Heinz body test
• Red cell enzyme studies
• Serologic tests
• Tests for PNH

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Differential Diagnosis of HA

• HAs must be differentiated from anemias seen
  post-hemorrhage or during recovery from
  deficiencies of iron, folate or vitamin B12
• Anemia with jaundice associated with ineffective
  erythropoiesis, loss of blood into a body cavity
  or tissue, or disorders of bilirubin catabolism
  must be excluded to make a diagnosis of HA

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Differential Diagnosis of HA

• The most comon manifestations of chronic HA
  include anemia and reticulocytosis and other
  signs of excessive blood cell destruction
• Acute HA usually presents without the signs of
  acccelerated RBC production, but with
  hemoglobinuria or other signs of intravascular
  hemolysis

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Differential Diagnosis of HA

• A decrease of Hgb of more than 1.0 g/dL/week is
  indicative of hemolysis, hemorrhage, or
  hemodilution
• If hemorrhage and hemodilution can be excluded,
  the presence of HA is established
• We will discuss specific types of HA and the
  causes in the next three chapters