Hemolytic

7/27/2019 Hemolytic Anemia.ppt
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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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