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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 Hemolysis
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ALLOIMMUNE HEMOLYSISTesting Pre-transfusion
ABO & Rh Type of both donor &recipient
Antibody Screen of Donor & Recipient,including indirect Coombs
Major cross-match by same procedure(recipient serum & donor red cells)
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ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn
Due to incompatibility between mothernegative for an antigen & fetus/fatherpositive for that antigen. Rh incompatibility,
ABO incompatibility most common causes Usually occurs with 2nd or later pregnancies
Requires maternal IgG antibodies vs.RBC
antigens in fetus
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ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn - #2
Can cause severe anemia in fetus, witherythroblastosis and heart failure
Hyperbilirubinemia can lead to severe brain
damage (kernicterus) if not promptly treated
HDN due to Rh incompatibility can be almosttotally prevented by administration of anti-Rh
D to Rh negative mothers after eachpregnancy
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AUTOIMMUNE HEMOLYSIS
Due to formation of autoantibodies thatattack patients own RBCs
Type characterized by ability ofautoantibodies to fix complement & siteof RBC destruction
Often associated with eitherlymphoproliferative disease or collagenvascular disease
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AUTOIMMUNE HEMOLYSISWarm Type
Usually IgG antibodies
Fix complement only to level of C3,if at all
Immunoglobulin binding occurs at all temps
Fc receptors/C3b recognized bymacrophages;
Hemolysis primarily extravascular
70% associated with other illnesses
Responsive to steroids/splenectomy
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AUTOIMMUNE HEMOLYSISCold Type
Most commonly IgM mediated
Antibodies bind best at 30 or lower
Fix entire complement cascade
Leads to formation of membrane attackcomplex, which leads to RBC lysis invasculature
Typically only complement found on cells
90% associated with other illnesses
Poorly responsive to steroids, splenectomy;responsive to plasmapheresis
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HEMOLYTIC ANEMIASummary
Myriad causes of increased RBCdestruction
Marrow function usually normal
Often requires extra folic acid tomaintain hematopoiesis
Anything that turns off the bone
marrow can result in acute, life-threatening anemia
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