Hemolytic

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    HEMOLYTIC ANEMIAS

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    HEMOLYTIC ANEMIA

    Anemia of increased destruction

    Normochromic, normochromic anemia

    Shortened RBC survival Reticulocytosis - Response to increased

    RBC destruction

    Increased indirect bilirubin

    Increased LDH

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    HEMOLYTIC ANEMIATesting

    Absent haptoglobin Hemoglobinuria

    Hemoglobinemia

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    HEMOLYTIC ANEMIACauses

    INTRACORPUSCULAR HEMOLYSIS

    Membrane Abnormalities

    Metabolic Abnormalities Hemoglobinopathies

    EXTRACORPUSCULAR HEMOLYSIS

    Nonimmune Immune

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    HEMOLYTIC ANEMIAMembrane Defects

    Microskeletal defects

    Hereditary spherocytosis

    Membrane permeability defects Hereditary stomatocytosis

    Increased sensitivity to complement

    Paroxysmal nocturnal hemoglobinuria

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    RED CELL CYTOSKELETON

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    HEREDITARY SPHEROCYTOSIS

    Defective or absent spectrin molecule

    Leads to loss of RBC membrane,

    leading to spherocytosis Decreased deformability of cell

    Increased osmotic fragility

    Extravascular hemolysis in spleen

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    SPLENIC ARCHITECTURE

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    HEREDITARY SPHEROCYTOSISOsmotic Fragility

    0

    20

    40

    60

    80

    100

    0.3 0.4 0.5 0.6

    NaCl (% of normal saline)

    %Hemolysis

    Normal HS

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    Paroxysmal NocturnalHemoglobinuria

    Clonal cell disorder

    Ongoing Intra- & Extravascular hemolysis;classically at night

    TestingAcid hemolysis (Ham test)

    Sucrose hemolysis

    CD-59 negative (Product of PIG-A gene)

    Acquired deficit of GPI-Associated proteins(including Decay Activating Factor)

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    GPI BRIDGE

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    Paroxysmal NocturnalHemoglobinuria

    GPI Proteins

    GPI links a series of proteins to outer leaf ofcell membrane via phosphatidyl inositolbridge, with membrane anchor viadiacylglycerol bridge

    PIG-A gene, on X-chromosome, codes forsynthesis of this bridge; multiple defectsknown to cause lack of this bridge

    Absence of decay accelerating factor leads to

    failure to inactivate complement & thereby toincreased cell lysis

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    HEMOLYTIC ANEMIAMembrane abnormalities - Enzymopathies

    Deficiencies in Hexose MonophosphateShunt

    Glucose 6-Phosphate DehydrogenaseDeficiency

    Deficiencies in the EM Pathway

    Pyruvate Kinase Deficiency

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    G6PD DEFICIENCYFunction of G6PD

    G6PD

    GSSG 2 GSH

    NADPH NADP

    2 H2O H2O2

    6-PG G6P

    Hgb

    Sulf-Hgb

    Heinz bodies

    Hemolysis

    Infections

    Drugs

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    Glucose 6-Phosphate DehydrogenaseFunctions

    Regenerates NADPH, allowing regeneration ofglutathione

    Protects against oxidative stress

    Lack of G6PD leads to hemolysis duringoxidative stress Infection

    Medications

    Fava beans

    Oxidative stress leads to Heinz bodyformation,extravascular hemolysis

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    Glucose 6-Phosphate DehydrogenaseDifferent Isozymes

    0

    0.2

    0.4

    0.6

    0.8

    1

    0 20 40 60 80 100 120

    RBC Age (Days)

    G6PDAc

    tivity(%)

    Normal (GdB) Black Variant (GdA-)

    Mediterranean (Gd Med)

    Level needed for protection vsordinary oxidative stress

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    HEMOLYTIC ANEMIACauses

    INTRACORPUSCULAR HEMOLYSIS

    Membrane Abnormalities

    Metabolic Abnormalities Hemoglobinopathies

    EXTRACORPUSCULAR HEMOLYSIS

    Nonimmune Immune

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    EXTRACORPUSCULAR HEMOLYSISNonimmune

    Mechanical

    Infectious Chemical

    Thermal

    Osmotic

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    Microangiopathic Hemolytic AnemiaCauses

    Vascular abnormalities Thrombotic thrombocytopenic purpura

    Renal lesions

    Malignant hypertension Glomerulonephritis

    Preeclampsia

    Transplant rejection

    Vasculitis

    Polyarteritis nodosa Rocky mountain spotted fever

    Wegeners granulomatosis

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    Microangiopathic Hemolytic AnemiaCauses - #2

    Vascular abnormalities

    AV Fistula Cavernous hemangioma

    Intravascular coagulation predominant

    Abruptio placentae

    Disseminated intravascular coagulation

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    IMMUNE HEMOLYTIC ANEMIAGeneral Principles

    All require antigen-antibody reactions

    Types of reactions dependent on: Class of Antibody

    Number & Spacing of antigenic sites on cellAvailability of complement

    Environmental Temperature

    Functional status of reticuloendothelial system

    Manifestations Intravascular hemolysis

    Extravascular hemolysis

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    IMMUNE HEMOLYTIC ANEMIAGeneral Principles - 2

    Antibodies combine with RBC, & either1. Activate complement cascade, &/or2. Opsonize RBC for immune system

    If 1, if all of complement cascade isfixed to red cell, intravascular cell lysisoccurs

    If 2, &/or if complement is onlypartially fixed, macrophages recognizeFc receptor of Ig &/or C3b ofcomplement & phagocytize RBC,causing extravascular RBC destruction

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    IMMUNE HEMOLYTIC ANEMIACoombs Test - Direct

    Looks for immunoglobulin &/or complementof surface of red blood cell (normally neitherfound on RBC surface)

    Coombs reagent - combination of anti-humanimmunoglobulin & anti-human complement

    Mixed with patients red cells; if

    immunoglobulin or complement are onsurface, Coombs reagent will link cellstogether and cause agglutination of RBCs

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    IMMUNE HEMOLYTIC ANEMIACoombs Test - Indirect

    Looks for anti-red blood cell antibodies in

    the patients serum, using a panel of redcells with known surface antigens

    Combine patients serum with cells from apanel of RBCs with known antigens

    Add Coombs reagent to this mixture

    If anti-RBC antigens are in serum,agglutination occurs

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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

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    IMMUNE HEMOLYSISDrug-Related

    Immune Complex Mechanism

    Quinidine, Quinine, Isoniazid

    Haptenic Immune Mechanism Penicillins, Cephalosporins

    True Autoimmune Mechanism

    Methyldopa, L-DOPA, Procaineamide,Ibuprofen

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    DRUG-INDUCED HEMOLYSISImmune 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 REsystem

    Red cells lysed as innocent bystander ofdestruction of immune complex

    REQUIRES DRUG IN SYSTEM

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    DRUG-INDUCED HEMOLYSISHaptenic Mechanism

    Drug binds to & reacts with red cellsurface proteins

    Antibodies recognize altered protein, drug, as foreign

    Antibodies bind to altered protein &initiate process leading to hemolysis

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    DRUG-INDUCED HEMOLYSISTrue Autoantibody Formation

    Certain drugs appear to causeantibodies that react with antigensnormally found on RBC surface, and doso even in the absence of the drug

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    ALLOIMUNE HEMOLYSIS

    Hemolytic Transfusion Reaction

    Caused by recognition of foreign antigens ontransfused blood cells

    Several types Immediate Intravascular Hemolysis (Minutes) - Due topreformed antibodies; life-threatening

    Slow extravascular hemolysis (Days) - Usually due torepeat exposure to a foreign antigen to which there

    was a previous exposure; usually only mild symptoms Delayed sensitization - (Weeks) - Usually due to 1st

    exposure to foreign antigen; asymptomatic

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    INCOMPATIBLE RBC TRANSFUSIONRate of Hemolysis

    0

    20

    40

    60

    80

    100

    0 1 2 3 4 5 6 7

    Weeks Post-Transfusion

    Surviving

    Cells(%)

    Normal Immediate Intravascular Hemolysis

    Slow Extravascular Hemolysis Delayed Extravascular Hemol

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