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Hematology 425 Increased RBC Destruction, Intracorpuscular Defects

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Title: Hematology 425 Increased RBC Destruction, Intracorpuscular Defects


1
Hematology 425 Increased RBC Destruction,
Intracorpuscular Defects
  • Russ Morrison
  • November 1, 2006

2
Intracorpuscular Defects
  • The RBC membrane consists of 2 interrelated
    parts
  • Outer lipid bilayer with integral embedded
    proteins
  • Underlying protein membrane skeleton
  • The insoluble lipid outer membrane provides a
    barrier to separate the different ion and
    metabolite concentrations of the interior of the
    RBC from the external environment of the blood
    plasma

3
Intracorpuscular Defects
  • The protein skeleton is responsible for shape,
    structure and deformability of the RBC and
    contains the pumps and channels for movement of
    ions and metabolites between the RBCs interior
    and the blood plasma
  • Proteins in the membrane act as receptors, RBC
    antigens and enzymes
  • If a review of RBC membrane structure and
    function is needed, review Chapter 7

4
Intracorpuscular Defects
  • Genetic defects of RBC membranes have been
    classified by morphologic features
  • The two major disorders are
  • Hereditary spherocytosis (HS), characterized by
    microspherocytes
  • Hereditary elliptocytosis (HE), characterized by
    elliptical RBCs

5
Intracorpuscular Defects
  • Other RBC membrane disorders are rare and include
  • Hereditary stomatocytosis (hydrocytosis),
    characterized by waterlogged RBCs
  • Hereditary xerocytosis (desiccocytosis),
    characterized by dehydrated, shrunken RBCs
  • Hereditary pyropoikilocytosis (HPP), a variant of
    HE, characterized by bizarrely shaped, shrunken,
    dehydrated cells that hemolyze when heated to
    temperatures 2-3oC below the temperature
    re1quired to hemolyze normal RBCs (49oC)

6
Hereditary Spherocytosis (HS)
  • HS is a hemolytic anemia characterized by
    numerous microspherocytes on the PB smear
  • Described in the late 1800s, associated with the
    spleen in 1890, and somewhat later with osmotic
    fragility and reticulocytosis
  • Incidence is world-wide, but highest in Northern
    Europeans (1 in 5000 persons)
  • In caucasians it is the most commonly inherited
    anemia having an incidence of 220 per million in
    the US

7
Hereditary Spherocytosis (HS)
  • Most often inherited as an autosomal dominant
    expressed in heterozygotes with one affected
    parent
  • No homozygotes are known, suggesting death of the
    fetus may be the result when two HS genes of this
    type are inherited
  • In approximately 25 of cases, neither parent has
    HS, suggesting a recessive form of the disease
    exists

8
Hereditary Spherocytosis (HS)
9
Hereditary Spherocytosis (HS)
  • The HS RBC is defective upon its exit from the
    bone marrow (BM)
  • Defective RBC's have problems with cellular
    proteins spectrin and actin.
  • 10X more sodium (Na) enters the cell than
    normally (glucose powers the ATP shunt that
    removes Na).
  • As the spleen's environment normally deprives the
    cell of glucose, Na levels increase resulting in
    an accompanying increase of water (to balance the
    osmolarity) into the cell - may result in
    bursting.

10
Hereditary Spherocytosis (HS)
  • Membrane skeletal protein abnormalities cause
    RBCs to progressively lose unsupported membrane
  • The RBCs acquire a decreased surface
    area-to-volume ratio and a spheriodal shape
  • The RBCs are rigid and not as deformable as a
    normal RBC
  • The spleen begins to remove the spherocytes
  • Exact mechanism of HS RBC destruction is unknown

11
Membrane Layer Separation (HS)
12
Hereditary Spherocytosis (HS)
  • Clinical and Laboratory Findings
  • Clinical Presentation
  • Anemia
  • Splenomegaly
  • Intermittent jaundice
  • Aplastic crises
  • Megaloblastic crises
  • Responds well to splenectomy

13
Hereditary Spherocytosis (HS)
  • Clinical and Laboratory Findings
  • Laboratory Findings
  • Reticulocytosis
  • spherocytosis
  • Elevated MCHC
  • Increased osmotic fragility
  • Normal DAT

14
Hereditary Spherocytosis (HS)
  • In the osmotic fragility test RBCs are placed in
    hypotonic solutions of varying concentration. The
    RBC swells forming a near spherical shape. As the
    RBC expands, the membrane is stretched and the
    RBC membrane leaks allowing hemoglobin to exit
    the cell. Equal volumes of blood are placed in a
    series of hypotonic solutions allowed to reach
    equilibrium centrifuged and the optical density
    determined. Most normal RBCs remain intact until
    the saline reaches about 0.50. As the saline
    decreases further the amount of leakage or lysis
    increases. This is easily visualized in the
    osmotic fragility test shown at right. The lower
    the surface area to volume ratio, the more likely
    the cell is to lyse. The SA/V is low in
    hereditary spherocytosis and high in thalassemia.

15
Osmotic Fragility TestNL on top, HS on bottom
16
Direct Antiglobulin Test (DAT)
  • The direct antiglobulin test looks for antibodies
    attached to your red blood cells (RBCs). RBCs
    normally have structures on their surface called
    antigens. You have your own individual set of
    antigens on your RBCs, determined by inheritance
    from your parents. Your plasma cells may produce
    antibodies to attack these antigens. In addition,
    some people make antibodies to their own RBCs.
    These antibodies are produced in autoimmune
    diseases and are called autoantibodies. In all of
    these situations, antibodies attach to the RBCs
    and can result in their destruction.

17
Differential Diagnosis of HS
  • Family history and evaluation of other family
    members
  • Negative DAT rules out immune disorders with
    spherocytes
  • The classic laboratory features of HS include
    minimal or no anemia, reticulocytosis, an
    increased mean corpuscular hemoglobin
    concentration (MCHC), spherocytes on the
    peripheral blood smear, hyperbilirubinemia, and
    abnormal results on the osmotic fragility test.
  • Disease may be silent to severe (table 21-1)

18
Treatment and Outcome (HS)
  • For practical purposes, the treatment of HS
    involves presplenectomy care, splenectomy, and
    postsplenectomy complications.
  • Neonates with severe hyperbilirubinemia caused by
    HS are at risk for kernicterus, and these infants
    should be treated with phototherapy and/or
    exchange transfusion as clinically indicated.
  • Aplastic crises occasionally can cause the
    hemoglobin level to fall because of ongoing
    destruction of spherocytes that is not balanced
    by new RBC production. Red cell transfusions
    often are necessary.

19
Treatment and Outcome (HS)
  • Folic acid is required to sustain erythropoiesis.
    Patients with HS are instructed to take
    supplementary folic acid (1 mg/d) for life in
    order to prevent a megaloblastic crisis. During
    the first 6 years of life, if patients have
    compensated anemia, are growing well, and can
    keep up with their peers in most activities,
    limiting folic acid supplementation to 1 mg/d is
    prudent.

20
Treatment and Outcome (HS)
  • Subsequently, depending on the severity of the
    disease, splenectomy usually is curative, but not
    always. Some splenectomies fail because of
    accessory spleen, accidental autotransplantation
    of splenic tissue into the peritoneum during
    surgery, another hemolytic disorder, or
    splenosis. Failure to observe Howell-Jolly bodies
    may indicate the presence of functional splenic
    activity

21
Treatment and Outcome (HS)
  • Indications for splenectomy are not always clear.
  • Little doubt exists that patients with more
    severe anemia and symptoms and complications of
    HS should undergo splenectomy. Similarly,
    splenectomy can be deferred safely in patients
    with mild uncomplicated HS (hemoglobin level gt11
    g/dL).
  • No good studies have been performed that provide
    a basis for clinical judgments in patients with
    moderate asymptomatic HS (hemoglobin level 8-11
    g/dL).

22
Treatment and Outcome (HS)
  • Splenectomy usually is curative, except in the
    unusual autosomal recessive variant of HS.
  • Red cell survival is improved significantly but
    is not absolutely normal. The MCV usually falls,
    but the MCHC does not change significantly.
    Postsplenectomy blood changes include an
    increased hemoglobin level, decreased
    reticulocyte count, and the appearance of
    Howell-Jolly inclusion bodies and target cells.
    Leukocytosis and thrombocytosis are expected
    corollaries of splenectomy.

23
Treatment and Outcome (HS)
  • Fatal sepsis caused by capsulated organisms (eg,
    Streptococcus pneumoniae, Haemophilus influenzae)
    is a recognized complication in children who have
    had a splenectomy. The estimated rate of
    mortality from sepsis is approximately 200 times
    greater than that expected in the general
    population. Although most septic episodes have
    been observed in children whose spleens were
    removed in the first years of life, older
    children and adults also are susceptible.
  • A simultaneous cholecystectomy in patients with
    bilirubin stones may eliminate future
    complications and the need for a second operative
    procedure.

24
Treatment and Outcome (HS)
  • Bilirubin gallstones are found in approximately
    50 of patients with HS and frequently are
    present in patients with very mild disease.
    Therefore, periodic ultrasonic evaluation of the
    gallbladder should be performed. If surveillance
    ultrasound examination findings reveal
    gallstones, performing a prophylactic
    laparoscopic cholecystectomy seems reasonable.
    This procedure helps prevent significant biliary
    tract disease and, in some patients with mild HS,
    helps avoid the need for splenectomy.

25
Treatment and Outcome (HS)
  • Children who are candidates for splenectomy
    include those with severe HS requiring red cell
    transfusions and those with moderate HS who
    manifest growth failure or other signs and
    symptoms of anemia. Splenectomy for children with
    HS should be performed when the child is older
    than 6 years.

26
Treatment and Outcome (HS)
  • Another interesting approach has been the use of
    partial splenectomy to retain splenic immunologic
    function while at the same time reducing the rate
    of hemolysis.

27
Prognosis (HS)
  • After splenectomy, RBC survival improves
    dramatically, enabling most patients with HS to
    maintain a normal hemoglobin level.

28
Hereditary Elliptocytosis (HE)
  • HE is characterized by the presence of elliptical
    or oval RBCs on the PB smear
  • HE was first reported in 1904
  • A very heterogeneous disorder clinically,
    genetically and biochemically
  • Exists in all forms in 1 in 2000 to 4000 of
    people in the US in all racial and ethnic groups
  • Inherited in an autosomal dominant fashion and my
    be linked to blood group antigens

29
Hereditary Elliptocytosis (HE)
30
Hereditary Elliptocytosis (HE)
  • HE and its related disorders are caused by
    mutations that disrupt the red blood cell
    cytoskeleton, a multiprotein complex responsible
    for the elasticity and durability of the
    circulating erythrocytes. Spectrin tetramers form
    a large part of the skeletal framework and are
    composed of heterodimers of alpha and beta
    subunits. These are tethered to the plasma
    membrane proteins AE1 (band 3) and glycophorin C
    through the ankyrin/protein 4.2 complex and
    through protein 4.1R and its associated actin
    filaments.

31
Hereditary Elliptocytosis (HE)
  • Mutations that disrupt the formation of spectrin
    tetramers result in HE. These qualitative defects
    create a red blood cell membrane that is less
    tolerant of shear stress and more susceptible to
    permanent deformation. A few mutations of the
    alpha-spectrin subunit are responsible for most
    cases of HE. HE also occurs with deficiencies in
    protein 4.1 or glycophorin C or when defects of
    band 3 protein or beta-spectrin impair ankyrin
    binding.

32
Hereditary Elliptocytosis (HE)
  • The principal functional consequence of the
    spectrin mutations is a weakening or disruption
    of the 2-dimensional integrity of the membrane
    skeleton. These horizontal membrane defects lead
    to mechanical instability, which can be
    sufficient to cause hemolytic anemia with red
    blood cell fragmentation. How elliptocytes are
    formed is unclear.

33
Hereditary Elliptocytosis (HE)
  • Table 21-3 shows the morphologic classification
    of HE
  • No treatment is usually required for HE unless
    hemolytic crises occur
  • Surgical removal of the spleen may decrease RBC
    lysis
  • The majority of individuals with HE have no
    problems and are unaware of their condition

34
Hereditary Elliptocytosis (HE)
  • Clinical Presentation
  • Symptoms  
  • A family history of hereditary elliptocytosis
  • Prolonged jaundice in the newborn
  • Jaundice (not in the newborn)
  • Fatigue
  • Shortness of breath

35
Hereditary Elliptocytosis (HE)
  • A CBC (complete blood count) may show anemia
    and/or cell destruction.
  • A smear of the blood may show elliptical red
    blood cells.
  • Bilirubin may be elevated.
  • LDH may be elevated.
  • Cholecystogram (X-ray of gallbladder) may show
    gallstones.

36
Hereditary Elliptocytosis (HE)
  • Most cases of HE are caused by membrane
    instability due to skeletal protein defects
  • The most common form of HE is common HE
  • Common HE demonstrates several sub-groups
    including mild common HE, comon HE with chronic
    hemolysis and common HE with infantile
    poikilocytosis

37
Hereditary Elliptocytosis (HE)
  • The second type of HE is a hybrid disorder that
    combines features of mild HE and mild HS seen in
    people of northern European origin, called
    Spherocytic Hereditary Elliptocytosis
  • The third type of HE is Stomatocytic HE common
    only in Melanesian and Malaysian populations

38
HE - Stomatocytic
39
Hereditary Pyropoikilocytosis
  • HPP is a rare disorder that presents in infancy
    or early childhood as a severe hemolytic anemia
    with extreme poikilocytosis
  • Resembles the blood picture of severe burns
  • May be a subtype of HE
  • Most victims of the disease are black

40
Hereditary Pyropoikilocytosis
  • is characterized by an abnormal sensitivity of
    RBCs to heat
  • erythrocyte morphology similar to that seen in
    thermal burns
  • Patients with HPP tend to experience severe
    hemolysis and anemia in infancy that gradually
    improves, evolving toward typical ellyptocytosis
    later in life.
  • HPP has been associated with a defect of the
    erythrocyte membrane protein spectrin and with
    spectrin deficiency

41
Hereditary Pyropoikilocytosis
42
Additional Intracorpuscular Defects
  • Still to discuss next time
  • Inherited disorders of RBC cation permeability
    and volume
  • RBC enzymopathies (selected)
  • PNH
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