Immune hemolysis Flashcards by Emily Barker

Immune hemolysis can be divided into ______ (immune destruction of foreign red cells), ______, and ___-induced immune reactions

isoimmune, autoimmune, drug induced immune

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Antibody or complement on the surface of the erythrocyte can be detected by the _______ test

Direct antiglobulin test

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Describe the DAT

antiglobulin reagent agglutinates red cells by attaching simultaneously to antibody or complement molecules on two or more erythrocytes

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Describe why a false negative DAT test would occur in a patient with antibody-mediated hemolysis

Coombs reagent cannot detect fewer than about 100-500 molecules of antibody or C3 per erythrocyte

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Describe why a false positive DAT test would occur in a patient without immune hemolysis

coexisting autoimmune disease or drug therapy
presence of IgG2 or IgG4 on the erythrocyte may cause a positive test in the absence of overt hemolysis- IgG2 and IgG4 are associated with shortening erythrocyte survival

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Which is more common: extravascular or intravascular immune hemolysis?

Extravascular

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Extravascular immune hemolysis is caused primarily by Ig__ antibodies

IgG

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Extravascular hemolysis is occasionally associated with IgM and _____ complement activation

incomplete

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The _____ is an efficient filter of IgG coated erythrocytes

spleen

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Splenic macrophages have receptors for the Fc fragment of ____

IgG

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Hepatic macrophages have a larger number of receptors for ____

C3b

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Clearance of ____-coated erythrocytes occurs through partial activation of complement , attachment of C3b to the RBC membrane, and removal by a hepatic macrophage

IgM

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The _____ is the predominant site of extravascular hemolysis of IgM coated erythrocytes

liver

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______ hemolysis requires fixation and complete activation of complement

Intravascular

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Although IgM -______ predictably cause intravascular hemolysis, IgM ____ usually do not

isoantibodies (ABO incompatibility) do

autoantibodies do not

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Which is more likely to fully activate complement (through C9): IgG or IgM

IgM
** two molecules of IgG in the form of a doublet are requird to fully activate complement, must be within 400 angstroms on the RBC membrane

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Which IgG subclasses are strong activators of complement?

IgG1 and IgG3 are strong activators
IgG2 is a weak activator
IgG4 does not activate complement

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Why is intravascular hemolysis more likely with ABO mismatch than Rh mismatch?

There are far more A/B antigens on the surface of a cell than Rh antigens

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List three factors of the antibody that determien whether hemolysis will be intravascular or extravascular

ability to activate complement (IgM>IgG)
subclass of IgG
number of antigen binding sites on membrane (AB»Rh)

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List five causes of hemolytic disease of the newborn

hereditary elliptocytosis
hereditary spherocytosis
G6PD deficiency
alpha thalassemia
maternal antibody (ABO or Rh)

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Describe the basic pathogenesis of hemolytic disease of the newborn

Passage of IgG from mother across placenta; IgG attaches to fetal red cell antigens.
Hemolysis is extravascular in the spleen, results in anemia and the production of large amounts of unconjugated bilirubin

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Why is unconjugated bilirubin not dangerous to a fetus in utero?

cleared by the placenta and metabolized in the maternal liver

In ________, severe hemolysis causes red cell precursors to proliferate in the liver and spleen and appear in the blood of the fetus

erythroblastosis fetalis

In _______, the fetal liver becomes obstructed and injured by normoblastic hyperplasia leading to massive hepatosplenomegaly, edema, ascities

hydrops fetalis

____ is damage to the basal ganglia due to very high unconjugated bilirubin in an infant

Kernicterus

List four factors that determine the severity of hemolytic disease of the newborn

1. concentration of IgG that crosses the placenta into fetal circulation 2. capacity of fetal macrophages to destroy antibody coated RBCs 3. ability of fetal bone marrow to increase RBC produciton 4. ability of neonatal liver to synthesize glucuronyl transferase (to conjugate bilirubin)

_______ is the most common cause of hemolytic disease of the newborn

ABO incompatibility

Why does ABO incompatibility cause hemolytic disease of the newborn primarily in type O mothers?

Type O people (but not A/B/AB) produce IgG anti-A and anti-B which can cross the placenta

Give two reasons why hemolytic disease of the newborn due to ABO incompatibility is usually mild

- most people secrete soluble ABH antigen which binds up much of the antibody and keeps it away from the red blood cell - the ABO blood group antigens are not well developed at birth

In ____ incompatibility, the offending antibodies are naturally occurring and no primary immunization is necessary

ABO

In ___ incompatibility, primary immunization/sensitization is necessary

When pregnancy occurs with an ABO-incompatible, Rh(D) positive fetus, there is less hemolytic disease of the newborn because:

the protective effect of ABO incompatibility, ABO-incompatible fetal erythrocytes enter maternal circulation and are rapidly destroyed by intravascular hemolysis- they never reach the monocyte-macrophage system to allow for primary immunization against Rh

Describe the treatment for severe hemolytic disease of the newborn

Exchange transfusions to help prevent kernicterus by removing unconjugated bilirubin and removing maternal antibody from the newborn's circulation

True or false: Rh sensitization is preventable

True, unsensitized women should be given Rh immunoglobulin at 28 weeks and just after delivery

Warm antibodies are primarily ____

IgG

Cold antibodies are primarily _____

IgM

IgG autoimmune hemolytic anemia is characterized by a ____ DAT and ______ hemolysis

Positive DAT | extravascular hemolysis- primarily spleen

In IgG autoimmune hemolysis, is complement activated?

No or only partially

Describe clinical manifestations of warm autoimmune hemolysis

weakness, malaise, dyspnea, lightheadedness due to anemia congestive heart failure, angina shift cells and spherocytes (injury from contact with macrophages) NO red cell agglutination on blood smear

The clinical manifestations of cold autoimmune hemolysis depend on the amount of antibody, the __________ of the antibody, and the ability of the antibody to ______

thermal amplitude | fix complement

In order to be clinically significant, hemolysis and erythrocyte agglutination in cold autoimmune hemolysis must occur when the thermal limit is above _____ degrees

Hemolysis in cold autoimmune hemolysis is primarily _____

extravascular, primarily in the liver because C3b receptors are expressed primarily by hepatic macrophages

Cold autoantibodies are mostly specific for __, ___

I, i

In cold agglutinin syndrome, the DAT is typically _____ for C3 and ___ for IgG

positive for C3 | negative for IgG

Cold agglutinin syndrome can be associated with _______ infection or in association with malignant ______

Mycoplasma | lymphoma

Drug induced immune hemolysis is associated with a ____ DAT with evidence of increased erythrocyte destruction

DAT

List four classifications of drug induced hemolytic anemia

1. immune adsorption 2. drug adsorption onto erythrocytes 3. membrane modification 4. true autoimmunity

Describe the findings, test, and prototype drug of drug induced hemolytic anemia due to immune adsorption.

Drugs: quinidine Clinical: intravascular hemolysis, hemoglobinuria, hemoglobinemia, thrombocytopenia Mechansim: IgM fixes complement completely Antiglobulin test: drug-antibody complex attaches to erythrocyte. DAT positive for C3

Describe the findings, test, and prototype drug of drug induced hemolytic anemia due to drug adsorption onto erythrocytes

Drugs: penicillins, cephalosporins Clinical: extravascular hemolysis Mechanism: IgG, rarely fixes complement Antiglobulin test: drug coated RBCs and patient serum as a source of antibody

Describe the findings, test, and prototype drug of drug induced hemolytic anemia due to membrane modification

Drugs: cephalosporins Clinical: no hemolysis Mechanism: IgG and other non-specific proteins Antiglobulin test: drug coated RBCs and patient serum as a source of antibody

Describe the findings, test, and prototype drug of drug induced hemolytic anemia due to true autoimmunity

Drugs: a-methyldopa Clinical: extravascular hemolysis Mechanism: IgG, commonly has Rh specificity Antiglobulin test: requires normal erythrocytes and patient serum as a source of antibody

In immune complex adsorption to erythrocytes, drug and anti-drug antibodies combine an are adsorbed onto the RBC membrane causing ____ hemolysis. The DAT will be positive for ____

intravascular (IgM mediated) | C3

Describe how steroids work to treat warm-type IgG mediated immune hemolysis

immediate decrease in macrophage Fc receptors and a slower decrease in the production of the abnormal IgG antibody

Splenectomy is effective in (IgG/IgM) immune hemolysis

IgG: removes both the site of red cell destruction and the site of antibody production not effective in IgM because extravascular hemolysis occurs in the liver