Alloimmune Hemolytic Anemia
• Antibody (Ab) appears to an RBC Antigen (Ag) that the individual lacks.
– Individuals are exposed to transfused RBCs from another person.
– The RBC of the recipient lacks Ag on the transfused cells.
– Stimulate the production of Ab (alloAb)
• Ab develops to an RBC Ag that the individual doesn’t have.
– Abs only reacts with cells that have Ag.
▪ Not the individual's own RBC
• Ab develops to an RBC Ag that the individual doesn’t have.
– Detected by Ab screen (indirect AHg test)
– Noticed in transfusion reactions and Hemolytic disease of the fetus or newborn (HDFN)
Hemolytic Transfusion Reactions
• Result of:
– Interaction of foreign Ags with blood transfusion RBC and patient plasma Abs
–Immunologic destruction of donor cells
–Two types of transfusion reactions
▪ Immediate (IgM)
–Occurring within 24 hours, intravascular hemolysis
▪ Delayed (IgG)
–Occurring 2–14 days after transfusion, extravascular hemolysis
Comparison of acute and delayed hemolytic transfusion reactions
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Acute
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Delayed
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Timing
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Immediate (within 24 hours)
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2-14 days
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Underlying cause
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Usually ABO antibodies
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Other antibodies; often Kidd system
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hemolysis
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Intravascular
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Extravascular; rare, slow intravascular if antibody capable of fixing
complement
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Symptoms
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Fever, chills, back pain, hypotension, pain at the site of infusion
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Uncommon (fever, hemoglobinuria)
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Laboratory findings
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May see hemoglobinuria.
Positive DAT (possible)
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Antibody in eluate
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• Therapy
– Acute: Terminate transfusion and supportive care.
– Delayed: No treatment
Hemolytic Disease of the Fetus and Newborn (HDFN)
• Feto-maternal blood group incompatibility
– The mother makes alloantibodies against fetal RBC antigens.
– IgG antibodies cross the placenta and destroy fetal RBCs in utero.
– Three categories:
1. Rh(D) caused by anti-D (more severe disease)
2. ABO due to anti-A and/or anti-B (more common)
3. Other caused by Abs on other blood group system Ags
Comparison of fetal and neonatal hemolytic diseases caused by ABO and Rh(D)
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Rh
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ABO
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Other
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Antibody
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Immune IgG
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No Immune IgG
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Immune IgG
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Blood group
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Mother Rh-negative. Baby Rh positive
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Mother, group O, newborn group A or B
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Mother lacks antigen that is on fetal cells
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Obstetric history
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Only pregnancies after the first are usually affected
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First pregnancy and subsequent pregnancies can be affected
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Pregnancy can be first if the mother previously sensitized by
transfusion. If Pregnancy is a sensitizing event, it usually affects the
second and subsequent pregnancies
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Clinical findings
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Moderate to severe anemia and bilirubinemia
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Mild anemia if present: mild to moderate bilirubinemia with a peak
24-48 hours after birth
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Mild to severe anemia and bilirubinemia
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Laboratory findings
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DAT positive, no spherocytes
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DAT weakly positive or negative, spherocytes present
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DAT positive
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therapy
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Exchange transfusion if severe
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phototherapy
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Phototherapy and /or exchange transfusion if severe
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• Pathophysiology
– Four conditions must be encountered for HDFN to occur:
▪ The mother must be sensitized to RBC Ag that she doesn’t have.
▪ The fetus must have Ag to which the mother has been sensitized.
▪ The mother must generate Abs to foreign Ags.
▪ The mother's Ab must cross the placenta and enter the fetal circulation.
• Laboratory testing
– Mother: ABO and Rh typing, antibody screening (IAT)
– Baby: ABO and Rh typing, DAT (if necessary eluted to identify Ab).
• Laboratory findings
– Baby's peripheral blood:
▪ Macrocytic/normochromic, increase reticulocytes, leukocytosis with left shift, a lot of NRBCs.
▪ Rh HDFN
– Significant polychromasia, mild or lack of poikilocytosis, few (if any) spherocytes, increased bilirubin, positive DAT test.
– Baby's peripheral blood:
▪ ABO HDFN
–NRBCs, schistocytes, spherocytes, polychromasia, ↑ bilirubin, weakly Positive DAT.
• Therapy
– Prevent hyperbilirubinemia and anemia
– Intrauterine transfusion
▪ Viability of fetus affected.
– Phototherapy (after birth) to reduce bilirubin.
– Exchange transfusion if bilirubin is rising.
▪ > 1 mg/dL/hour or significant anemia
• Rh immune globulin (RhIG).
– Passive injection contains anti-D antibodies, which can prevent maternal immunization.
▪ It is given at 28 weeks of gestation and after the birth of Rh+ babies.
▪ The dose depends on the number of fetal cells in the maternal circulation
–Kleihauer-Betke Test
–Rosette Test
–Flow cytometry
Drug-Induced Hemolytic Anemias
• Acquired cause of hemolytic anemia
– Not all people who take the same drugs have HA.
– > 125 drugs identified
–Immune response to drug-induced alteration of RBC
–Must differentiate from:
▪ Drug-induced, nonimmune hemolysis
▪ Spontaneous autoimmune disorders
• Uncommon acquired cause of HA
– Resolution is the withdrawal of the drug.
– Classic mechanisms
▪ Drug absorption, immune complex genesis, autoantibody induction, membrane modification
– New "unifying" hypothesis
– New "unified" hypothesis
▪ The drug binds to the RBC membrane.
– The generated Abs react with drug-specific epitopes
–Combination of drug and RBC proteins
–Epitopes primarily on RBC membrane
▪ Explain how the patient develops more than one drug-inducible antibody
–Two types:
▪ Drug dependent— needs the presence of drug during testing
▪ Drug independent—reacts without the presence of drug
▪ Sensitized RBCs have shortened life span
▪ Positive DAT
Overview of the classic mechanism of drug-induced immune hemolytic anemia
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Drug Type
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Action
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DAT
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Mechanism of cell destruction
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Drug Dependent
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Drug bound to cell ® antibody forms primarily to drug epitopes and binds to the drug.
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Polyspecific AHG positive, anti-IgG positive, anti-C3
can be positive
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Extravascular adhesion to macrophages via FcϓR and phagocytosis
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The drug binds loosely to erythrocyte ® antibody forms to epitopes of drug and cell.
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Polyspecific AHG positive, anti-IgG negative, anti-C3
positive
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Intravascular complement-mediated lysis
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Drug independent
Auto antibody-like
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Drug adheres to the cell membrane ® antibody forms primarily against epitopes on erythrocyte membrane ® antibody reacts with erythrocyte
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Polyspecific AHG positive, anti-IgG positive, anti-C3
positive or negative
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Extravascular adhesion to macrophages via FcϓR and phagocytosis
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Nonimmune protein adsorption
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Modification of cell membrane that results in
nonimmunologically absorbed IgG, IgA, IgM, C3
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Polyspecific AHG positive, monospecific can be positive
or negative
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Hemolysis can result
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