1. ADULT HEMATOLOGIST ,ONCOLOGIST IRAN UNIVERSITY OF MEDICAL SCIENCES
September 9, :00 am
HEMOLYTIC ANEMIAS
A.Basi
ADULT HEMATOLOGIST ,ONCOLOGIST
IRAN UNIVERSITY OF MEDICAL SCIENCES

2. Definition
Hemolysis is defined as a reduction in the average life span of the red cell due to destruction of erythrocytes in the peripheral circulation.

4. Definition
 In addition to the death of aging (senescent) RBCs, there is age-independent RBC destruction (random hemolysis) in normal subjects in the range of less than 0.05 to 0.5 percent per day.
This latter process is appreciably increased in hemolytic states.

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Definition
Anemia, however, is not invariably a consequence of hemolysis as the bone marrow can increase erythropoiesis to compensate for the increased destruction.
Under maximal stimulation, the normal marrow is capable of undergoing hyperplasia until its production rate increases about six to eight times.

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Definition
With optimal marrow compensation, the survival of red cells in the circulation can theoretically decrease from the normal 120 days to as few as days without anemia developing.
Such an increase in both destruction and production of RBC can result in a compensated hemolytic state without anemia being present, so-called compensated hemolytic disease.

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Definition
When red cell survival is so short that anemia develops despite a vigorous erythropoietic response,the term hemolytic anemia is appropriate.

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Pathophysiology:
There are two mechanisms of hemolysis: 1.Intravascular hemolysis: is the destruction of red blood cells in the circulation with the release of cell contents into the plasma. 2.Extravascular hemolysis: is the removal and destruction of red blood cells with membrane alterations by the macrophages of the spleen and liver.

9. HEMOLYTIC ANEMIA Anemia of increased destruction:
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HEMOLYTIC ANEMIA
Anemia of increased destruction:
Normochromic,normocytic anemia.
Shortened RBC survival.
Reticulocytosis - Response to increased RBC destruction.
Increased indirect bilirubin.
Increased LDH.

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11. Reticulocytes
Under steady state conditions, the rate of RBC production equals the rate of RBC loss.
In survival of mature RBC of 100 days, 1 percent of RBCs are removed from the circulation each day.
To achieve a constant RBC mass, RBC losses must be replaced with an equal number of reticulocytes during the same time period.

12. Reticulocytes
Reticulocytes normally survive in the circulation for one day; after this time they lose their reticulum (RNA) and become mature red blood cells.
Under steady-state conditions reticulocytes will represent approximately 1 percent of total circulating RBC .
Since the normal RBC count is approximately 5 million/microL, the bone marrow must produce approximately 50,000 reticulocytes/microL of whole blood each day in order to achieve a stable RBC mass.
Lesser rates of RBC production, if persistent, lead to anemia.

13. Reticulocytes
A normal bone marrow replete with iron, folate, and cobalamin can increase erythropoiesis in response to EPO about 5-fold in adults and 7- to 8-fold in children.
Thus, under optimal conditions, steady-state absolute reticulocyte counts as high as 250,000/microL are possible in the adult.

14. Reticulocyte Count Relative reticulocyte count
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Reticulocyte Count
Relative reticulocyte count
% of all RBC (normal %)
Absolute reticulocyte count
Relative reticulocyte count x RBC count
Normal 50,000-75,000/µl
Examples:
1.1% x 4.96 x106 = 55,000/ml
12.2% x 2.05 x106 = 250,000/ml

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17. Corrected reticulocyte count = reticulocyte count (patient hematocrit / 45)
Since the reticulocyte count represents a ratio (number of reticulocytes divided by the total number of erythrocytes), a decrease in the total RBC count may result in an increase in the reticulocyte count even if reticulocyte production by the marrow is not increased.
In order to correct for this, the reticulocyte count is multiplied by the patient’s hematocrit divided by a normal hematocrit (45%):

18. RPI = corrected reticulocyte count / correction factor
Under severe erythropoietin stimulus, reticulocytes may be released from the bone marrow prematurely and must finish their maturation in the peripheral blood (shift reticulocytes).
Since these prematurely released cells exist as reticulocytes for more than 1 day, they are, in effect, “counted” more than once in the reticulocyte count (remember: the normal reticulocyte count presumes that the cells exist as reticulocytes for only 1 day, rather than 2 or more days).
In order to correct for these shift reticulocytes, the corrected reticulocyte count has to be divided by a correction factor, giving the RPI.

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21. RPI = corrected reticulocyte count / correction factor
RPI > 3: Good marrow response (hyperproliferative)
RPI < 2: Inadequate response (hypoproliferative)
RPI > 2 but < 3 :Appropriate for mild anemia (hemoglobin >10–11 g/dL) but borderline for more severe anemia

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24. HEMOLYTIC ANEMIA INTRACORPUSCULAR (intrinsic) HEMOLYSIS
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HEMOLYTIC ANEMIA
INTRACORPUSCULAR (intrinsic) HEMOLYSIS
Membrane Abnormalities
Metabolic Abnormalities
Hemoglobinopathies
EXTRACORPUSCULAR HEMOLYSIS
Nonimmune
Immune

25. HEMOLYTIC ANEMIA
Mature RBC has lost its nucleus, mitochondria, and RNA and is left with three major components:
Hemoglobin, the major protein of the red cell.
The RBC membrane, the surface area of which must be about 40 percent greater than that of a sphere of identical volume to allow the RBC to undergo elliptical deformation in the microvasculature.Membrane proteins need to allow for such deformation and elastic recoil.
In addition, ion pumps and channels regulate RBC volume via the entry and content of water and the cations sodium, potassium, calcium, and magnesium.

26. HEMOLYTIC ANEMIA
Metabolic machinery to generate ATP needed by the cation pumps, 2,3 DPG that allows hemoglobin to take up and release oxygen, and reducing power (eg, glutathione, NADPH) to protect the oxygen-rich RBC from oxidant injury.

27. HEMOLYTIC ANEMIA
Hemoglobin molecules unstable to oxidant challenge, as in hemoglobin Köln.
Membrane injury due to the production of excess alpha or beta globin chains.
Unstable or missing RBC membrane proteins, as in hereditary (congenital) spherocytosis and paroxysmal nocturnal hemoglobinuria.
Abnormalities of RBC hydration, as in xerocytosis.
Defective glycolysis, as in pyruvate kinase deficiency.
Abnormalities in availability of reducing power (NADPH), rendering the RBC susceptible to oxidant challenge, as in glucose-6-phosphate dehydrogenase (G6PD) deficiency.

28. HEMOLYTIC ANEMIA Membrane Defects
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HEMOLYTIC ANEMIA Membrane Defects
Cytoskeletal defects
Hereditary spherocytosis
Membrane permeability defects
Hereditary stomatocytosis
Increased sensitivity to complement
Paroxysmal nocturnal hemoglobinuria

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30. The red cell membrane consists of three main components:
• A phospholipid bilayer
• Various integral membrane proteins and glycoproteins embedded in the phospholipid bilayer, some of which extend through the membrane into the cytoplasm (transmembrane proteins). Two of the most important of these cell transmembrane proteins are the band 3 protein, an important anion transport protein, and glycophorin, which carries red cell antigens. Both of these proteins also serve as anchoring sites for cytoskeleton proteins.
• A cytoskeleton scaffold, which gives the red cell its characteristic shape.The cytoskeleton is composed predominantly of spectrin. A protein called ankyrin is required to bind spectrin to the band 3 protein.

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32. Pathophysiology
Defective vertical attachment between the phospholipid bilayer and the cytoskeleton scaffold.
Loss of phospholipids from the cell membrane. Consequently, the surface area of the RBC decreases, and the cell gradually assumes the shape of a sphere (the shape with the highest volume to surface area ratio).
Spherocytic RBCs are less flexible than normal (biconcave disk) RBCs, and, consequently, they are selectively trapped and destroyed in the spleen.
The spleen also plays an important role in the loss of cell membranes by the RBCs (a process known as splenic conditioning).

33. Hereditary Spherocytosis
Most cases (approximately three-fourths) are inherited in an autosomal dominant fashion.
The remainder of cases are inherited as autosomal recessive, which are often more severe. A significant number of patients have no family history of the illness and probably represent new mutations.
The prevalence of HS in western countries has been estimated as 1 in approximately 5,000.

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35. Clinical Manifestations
Highly variable, from asymptomatic without anemia to severe chronic hemolysis.
Mild or moderate anemia, and hyperbilirubinemia (which may be intermittent) and mild splenomegaly.
Bilirubin gallstones are common.
Like other patients with chronic hemolytic anemias, patients with HS may have exacerbation of anemia associated with infections, aplastic crises due to parvovirus B19 infection,
Megaloblastic anemia associated with folate deficiency.
Patients with autosomal recessive HS may have severe anemia, with hemoglobin as low as 4 to 6 g/dL.

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37. Diagnosis of Hereditary Spherocytosis
MCV that is normal to slightly low, with an increased MCHC.
The blood smear shows microspherocytes .
The reticulocyte count is increased (~5–20%).
A direct antiglobulin (Coombs’) test should be done to exclude an immune hemolytic anemia.

39. Osmotic fragility test
The classic laboratory test for HS is the osmotic fragility test.
In this test, erythrocytes are incubated in saline solutions with osmolality ranging from normal to pure water.
Percent hemolysis is measured by spectrophotometry.
Erythrocytes from patients with HS hemolyze at higher saline concentrations than normal cells.
The difference is exaggerated by incubating the cells for 24 hours in the absence of glucose.
It is important to remember that increased osmotic fragility is not specific for HS; any cause of spherocytosis results in increased osmotic fragility

40. HEREDITARY SPHEROCYTOSIS Osmotic Fragility
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HEREDITARY SPHEROCYTOSIS Osmotic Fragility

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43. Hereditary Spherocytosis
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Hereditary Spherocytosis
Autosomal dominant disorder
Abnormality in RBC membrane protein
Clinical and laboratory findings
Splenomegaly
Chronic hemolytic anemia
Spherocytes on peripheral smear
Treatment
Splenectomy

44. Hereditary Elliptocytosis
Autosomal dominant
Defective horizontal stability in the cytoskeleton.
Most cases are caused by mutations in alfa spectrin, resulting in impaired assembly of the alfa /beta spectrin tetramers.
The cytoskeleton is less rigid and mor easily deformed.
Neonatal hyperbilirubinemia is common.
Most cases of HE in the United States are asymptomatic, with normal RBC survival and no anemia.
Examination of a peripheral blood smear is the key diagnostic test .
The presence of more than 15% elliptocytes suggests HE.
Splenectomy is not curative but may be beneficial in the rare severe cases that require therapy.

46. HEMOLYTIC ANEMIA Membrane abnormalities - Enzymopathies
September 9, :00 am
HEMOLYTIC ANEMIA Membrane abnormalities - Enzymopathies
Deficiencies in Hexose Monophosphate Shunt
Glucose 6-Phosphate Dehydrogenase Deficiency
Deficiencies in the EM Pathway
Pyruvate Kinase Deficiency

47. Glucose 6-Phosphate Dehydrogenase Functions
Glucose-6-Phosphate Dehydrogenase Deficiency is the first enzyme in the hexose monophosphate shunt, which is required to generate the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH).
NADPH is required for the regeneration of glutathione by the enzyme glutathione reductase.

48. Glucose 6-Phosphate Dehydrogenase deficiency
In the absence of sufficient glutathione, hemoglobin is oxidized and precipitates in the cell.This damages the cell, resulting in hemolysis.
The aggregates of oxidized hemoglobin are plucked out of the cell by the spleen, resulting in characteristic “bite” or “blister” cells.

49. Glucose-6-phosphate dehydrogenase deficiency

50. Glucose 6-Phosphate Dehydrogenase deficiency
The level of G6PD is highest in reticulocytes and declines with increasing age of the red cell.
In normal cells, the half-life of the enzyme is approximately 62 days.
The activity level of the enzyme remains sufficient to protect against oxidative stress even in older cells.
In patients with G6PD deficiency, the enzyme level declines faster, so older cells are not protected against oxidative stress.

51. Glucose 6-Phosphate Dehydrogenase Different Isozymes
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Glucose 6-Phosphate Dehydrogenase Different Isozymes
Level needed for protection vs ordinary oxidative stress

52. Glucose 6-Phosphate Dehydrogenase variants
Class I variants: Severe enzyme deficiency (<10% of normal) and
chronic hemolysis
Class II variants: Severe enzyme deficiency, but intermittent instead of chronic hemolysis(G6PD Mediterranean).
Class III variants: Mild to moderate enzyme deficiency (10–60% of
normal), with intermittent hemolysis usually precipitated by infection or oxidative drugs or chemicals(African variant).
Class IV variants: Normal enzyme activity and no anemia or hemolysis
Class V variants: Increased enzyme activity, without anemia or hemolysis

53. Glucose 6-Phosphate Dehydrogenase Functions
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Glucose 6-Phosphate Dehydrogenase Functions
Regenerates NADPH, allowing regeneration of glutathione
Protects against oxidative stress
Lack of G6PD leads to hemolysis during oxidative stress
Infection
Medications
Fava beans
Oxidative stress leads to Heinz body formation, extravascular hemolysis.

54. Glucose-6-Phosphate Dehydrogenase Deficiency
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Glucose-6-Phosphate Dehydrogenase Deficiency
Sex-linked disorder
Effects > 200 million people
Hemolytic anemia occurs in the presence of stress (infection or drugs)
African form - mild hemolysis
Mediterranean form - more severe
Unique sensitivity to fava beans

55. the normal G6PD is designated as type B.
About 20% of individuals of African descent have a G6PD (designated A+) that differs by a single amino acid and is electrophoretically distinguishable but functionally normal.
Among the clinically significant G6PD variants, the most common, the so-called A- type, is due to two base substitutions and is encountered primarily in individuals of central African descent. The A- G6PD has the same electrophoretic mobility as the A+ type, but it is unstable and has abnormal kinetic properties. This variant is found in about 11% of African-American males.
A second relatively common G6PD variant is encountered among groups of Mediterranean origin, particularly Sardinians and Sephardic Jews; this variant is more severe than the A- variant and may result in nonspherocytic hemolytic anemia in the absence of known oxidative stress.

56. Diagnosis of Glucose-6-Phosphate Dehydrogenase Deficiency
There is an easy fluorescent screening test for NADPH production from glucose-6- phosphate and NADP.
If this test is abnormal, a quantitative assay can be performed to confirm the diagnosis and assess the severity of the deficiency.

57. Diagnosis of Glucose-6-Phosphate Dehydrogenase Deficiency
The G6PD level can be normal in a patient with G6PD deficiency shortly after a hemolytic episode, giving a false-negative result.
This occurs if the reticulocyte count is high since reticulocytes have higher G6PD levels than older cells.
If you get a normal G6PD level in a patient who you really think has G6PD deficiency, repeat the laboratory test in a few weeks when cells of all ages are again present.

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59. Treatment of Glucose-6-Phosphate Dehydrogenase Deficiency
The main treatment for G6PD deficiency is to avoid conditions that predispose to hemolysis.
Patients with G6PD deficiency should not be given medications that cause hemolysis; they should be advised to avoid exposure to naphthalene (mothballs), fava beans, and other hemolytic agents.
Infections should be treated promptly.
Infants with marked hyperbilirubinemia may require exchange transfusions.
Women known to be heterozygous for G6PD deficiency should avoid oxidative drugs while pregnant and nursing to prevent inducing hemolytic episodes in a susceptible fetus or infant.

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61. Pyruvate Kinase Deficiency
The most common enzyme deficiency in the Embden-Meyerhof (glycolytic) pathway .
However, it is far less common than G6PD deficiency
Autosomal recessive.
Neonatal hyperbilirubinemia, Older children and adults have chronic hemolysis, Splenomegaly is common.
Infections, surgery, and pregnancy may precipitate acute exacerbations of hemolysis.
Aplastic crises may occur due to infection with parvovirus B19.

62. Pathophysiology
Erythrocytes with PK deficiency generate less adenosine triphosphate (ATP) and NADH from glucose.
There is decreased Na+,K+-ATPase activity, with consequent cellular dehydration.
The exact mechanism of hemolysis is unknown, but it is thought that there are abnormalities in membrane function.
2,3-Diphosphoglycerate (DPG) accumulates in RBCs; since increased 2,3-DPG facilitates O2 unloading, patients tolerate anemia well and are relatively asymptomatic despite decreased blood hemoglobin.

63. Diagnosis of Pyruvate Kinase Deficiency
A variety of enzyme assays are available. It may be difficult to demonstrate decreased enzyme activity if cells with the most severe deficiency are largely destroyed and cells with higher enzyme levels are relatively preserved.
It may be helpful to study relatives, although there is overlap in enzyme levels between heterozygotes and the normal population.

64. Treatment of Pyruvate Kinase Deficiency
Patients with more severe hemolysis may require transfusion support.
Splenectomy can be beneficial in severe cases; it results in striking reticulocytosis (up to 50–60%).

66. HEMOLYTIC ANEMIA Causes
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HEMOLYTIC ANEMIA Causes
INTRACORPUSCULAR HEMOLYSIS
Membrane Abnormalities
Metabolic Abnormalities
Hemoglobinopathies
EXTRACORPUSCULAR HEMOLYSIS
Nonimmune
Immune

67. EXTRACORPUSCULAR HEMOLYSIS Nonimmune
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EXTRACORPUSCULAR HEMOLYSIS Nonimmune
Mechanical: Trauma secondary to high velocity jets (malfunctioning prosthetic aortic valves) or fibrin stands across vessels that shear RBCs in disseminated intravascular coagulation and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
Infectious: malaria and babesiosis.
Thermal burn.
Osmotic: hypotonic solutions(dialysis fluid or infused intravenously, urologic procedures, freshwater near-drowning).
Snake and insect bites.

68. Microangiopathic Hemolytic Anemia Causes
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Microangiopathic Hemolytic Anemia Causes
Vascular abnormalities
Thrombotic thrombocytopenic purpura
Renal lesions
Malignant hypertension
Glomerulonephritis
Preeclampsia
Transplant rejection
Vasculitis
Polyarteritis nodosa
Rocky mountain spotted fever
Wegener’s granulomatosis

69. Microangiopathic Hemolytic Anemia Causes - #2
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Microangiopathic Hemolytic Anemia Causes - #2
Vascular abnormalities
AV Fistula
Cavernous hemangioma
Intravascular coagulation predominant
Disseminated intravascular coagulation

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72. HEMOLYTIC ANEMIA - IMMUNE
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HEMOLYTIC ANEMIA - IMMUNE
Drug-Related Hemolysis
Alloimmune Hemolysis
Hemolytic Transfusion Reaction
Hemolytic Disease of the Newborn
Autoimmune Hemolysis
Warm autoimmune hemolysis
Cold autoimmune hemolysis

73. IMMUNE HEMOLYTIC ANEMIA General Principles
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IMMUNE HEMOLYTIC ANEMIA General Principles
All require antigen-antibody reactions
Types of reactions dependent on:
Class of Antibody
Number & Spacing of antigenic sites on cell
Availability of complement
Environmental Temperature
Functional status of reticuloendothelial system
Manifestations
Intravascular hemolysis
Extravascular hemolysis

74. IMMUNE HEMOLYTIC ANEMIA General Principles - 2
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IMMUNE HEMOLYTIC ANEMIA General Principles - 2
Antibodies combine with RBC, & either
Activate complement cascade, &/or
Opsonize RBC for immune system
If 1, if all of complement cascade is fixed to red cell, intravascular cell lysis occurs.
If 2, &/or if complement is only partially fixed, macrophages recognize Fc receptor of Ig &/or C3b of complement &phagocytize RBC, causing extravascular RBC destruction.

76. IMMUNE HEMOLYTIC ANEMIA Coombs Test - Direct
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IMMUNE HEMOLYTIC ANEMIA Coombs Test - Direct
Looks for immunoglobulin &/or complement of surface of red blood cell (normally neither found on RBC surface)
Coombs reagent ( combination of anti-human immunoglobulin & anti-human complement Mixed with patient’s red cells);
if immunoglobulin or complement are on surface, Coombs reagent will link cells together and cause agglutination of RBCs.

77. IMMUNE HEMOLYTIC ANEMIA Coombs Test - Indirect
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IMMUNE HEMOLYTIC ANEMIA Coombs Test - Indirect
Looks for anti-red blood cell antibodies in the patient’s serum, using a panel of red cells with known surface antigens.
Combine patient’s serum with cells from a panel of RBC’s with known antigens.
Add Coombs’ reagent to this mixture If anti-RBC antigens are in serum, agglutination occurs.

78. Anti-Globulin (Coombs) Testing
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Anti-Globulin (Coombs) Testing
Direct antiglobulin testing +
Anti-C3b
Anti-IgG
Patients RBCs
Indirect antiglobulin testing + +
Patients serum
RBCs
Anti-IgG

80. Autoimmune Hemolytic Anemia
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Autoimmune Hemolytic Anemia
Warm antibodies (IgG-mediated)
Primary %
Secondary 40%
Lymphoproliferative disease
Connective tissue disease
Infectious disease
Drug-induced 15%
Laboratory testing
Normocytic/macrocytic anemia
Peripheral smear: spherocytosis

81. AUTOIMMUNE HEMOLYSIS Warm Type
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AUTOIMMUNE HEMOLYSIS Warm Type
Usually IgG antibodies.
Fix complement only to level of C3,if at all.
Immunoglobulin binding occurs at all temps.
Fc receptors/C3b recognized by macrophages; 
Hemolysis primarily extravascular.
70% associated with other illnesses.
Responsive to steroids/splenectomy.

83. Treatment of Autoimmune Hemolytic Anemia
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Treatment of Autoimmune Hemolytic Anemia
Treat underlying disease if indicated
Prednisone (1 mg/kg/day for 2 weeks, then taper)
Splenectomy
Other
Immunosuppressive agents (Rituximab)
IVIG
Similar approach to ITP

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89. AUTOIMMUNE HEMOLYSIS Cold Type
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AUTOIMMUNE HEMOLYSIS Cold Type
Most commonly IgM mediated.
Antibodies bind best at 30º or lower.
Fix entire complement cascade.
Leads to formation of membrane attack complex, which leads to RBC lysis in vasculature.
Typically only complement found on cells.
90% associated with other illnesses.
Poorly responsive to steroids, splenectomy; but responsive to plasmapheresis&immunosuppressive.

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98. IMMUNE HEMOLYSIS Drug-Related
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IMMUNE HEMOLYSIS Drug-Related
Immune Complex Mechanism
Quinidine, Quinine, Isoniazid,rifampin,phenacetin,tetracyclin, carbamazepine.
“Haptenic” Immune Mechanism
Penicillins, Cephalosporins
True Autoimmune Mechanism
Methyldopa, L-DOPA, Procaineamide, Ibuprofen,interferon-alfa.

99. DRUG-INDUCED HEMOLYSIS Immune Complex Mechanism
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DRUG-INDUCED HEMOLYSIS Immune Complex Mechanism
Drug & antibody bind in the plasma
Immune complexes either
Activate complement in the plasma, or
Sit on red blood cell
Antigen-antibody complex recognized by RE system
Red cells lysed as “innocent bystander” of destruction of immune complex
REQUIRES DRUG IN SYSTEM.
DAT:IgG(-),complement(+).

100. DRUG-INDUCED HEMOLYSIS Haptenic Mechanism
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DRUG-INDUCED HEMOLYSIS Haptenic Mechanism
Drug binds to & reacts with red cell surface proteins.
Antibodies recognize altered protein, ± drug, as foreign.
Antibodies bind to altered protein & initiate process leading to hemolysis: opsonizes the cells for destruction by splenic macrophages.
DAT:IgG(+),complement(-).

101. DRUG-INDUCED HEMOLYSIS True Autoantibody Formation
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DRUG-INDUCED HEMOLYSIS True Autoantibody Formation
Certain drugs appear to cause antibodies that react with antigens normally found on RBC surface, and do so even in the absence of the drug.
DAT:IgG(+),complement(-).

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103. HEMOLYTIC ANEMIA Summary
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HEMOLYTIC ANEMIA Summary
Myriad causes of increased RBC destruction.
Marrow function usually normal.
Often requires extra folic acid to maintain hematopoiesis.
Anything that turns off the bone marrow can result in acute, life-threatening anemia.