Immune Immune hemolytic anemiahemolytic anemia
Dr. Yasser AhmedDr. Yasser Ahmed
Immune hemolytic Immune hemolytic anemiasanemias
RBCs hemolysis due to immune RBCs hemolysis due to immune mechanism occurs when antibody and/or mechanism occurs when antibody and/or complement in the circulation binds with complement in the circulation binds with an antigen on the surface of the red an antigen on the surface of the red cells. This causes extravascular or cells. This causes extravascular or intravascular red cell destruction.intravascular red cell destruction.
Immune hemolytic anemias are classified Immune hemolytic anemias are classified into three types: into three types: autoimmuneautoimmune, , iso (or iso (or allo-)allo-) immune, and immune, and drug induceddrug induced..
Classification of immune Classification of immune hemolytic anemiashemolytic anemias
AutoimmuneAutoimmune: Warm reacting : Warm reacting antibody type and cold reacting antibody type and cold reacting antibody type.antibody type.
AlloimmuneAlloimmune: hemolytic disease of : hemolytic disease of the newborn (Rh or ABO) and the newborn (Rh or ABO) and hemolytic transfusion reactions.hemolytic transfusion reactions.
Drug inducedDrug induced..
Evans syndrome Evans syndrome (autoimmune hemolytic (autoimmune hemolytic
anemia & anemia & thrombocytopenia)thrombocytopenia)
Basic mechanisms of Basic mechanisms of immune hemolytic anemia immune hemolytic anemia
In In autoimmune hemolytic anemiaautoimmune hemolytic anemia (AIHA), (AIHA), hemolysis occurs when antibodies and/or hemolysis occurs when antibodies and/or complement in patient’s circulation react complement in patient’s circulation react with and cause destruction of with and cause destruction of patient’s own patient’s own red cellsred cells..
Classification of AIHA is based on Classification of AIHA is based on thermal thermal characteristics of the antibodies. Generally, characteristics of the antibodies. Generally, IgG and IgM antibodies are respectively of IgG and IgM antibodies are respectively of warm and cold typeswarm and cold types; however in ; however in paroxysmal cold hemoglobinuria, IgG paroxysmal cold hemoglobinuria, IgG antibodies are of cold-reactive type.antibodies are of cold-reactive type.
Basic mechanisms of Basic mechanisms of immune hemolytic anemiaimmune hemolytic anemia
In alloimmune hemolytic anemia, In alloimmune hemolytic anemia, hemolysis occurs due to reaction hemolysis occurs due to reaction between red cell antigen from one between red cell antigen from one individual with antibody from individual with antibody from another individual. Alloantibodies another individual. Alloantibodies are usually of IgG class.are usually of IgG class.
AIHA due to warm-reacting AIHA due to warm-reacting autoantibodiesautoantibodies
Warm antibody type (antibody Warm antibody type (antibody maximally active at 37maximally active at 37 ̊C ̊C and mostly and mostly IgG) is classified into:IgG) is classified into:
Primary (Idiopathic).Primary (Idiopathic). Secondary: 1) Autoimmune disorders Secondary: 1) Autoimmune disorders
(e.g. SLE); 2) Neoplastic disorders (e.g. SLE); 2) Neoplastic disorders (lymphoproliferative disorders like (lymphoproliferative disorders like CLL and malignant lymphoma, ovarian CLL and malignant lymphoma, ovarian teratoma); 3) Drugs.teratoma); 3) Drugs.
AIHA due to warm-reacting AIHA due to warm-reacting autoantibodiesautoantibodies
In this type, IgG antibodies or In this type, IgG antibodies or complement (C3b) bind to red cell complement (C3b) bind to red cell membrane and are recognized by membrane and are recognized by specific receptors on macrophages. IgG-specific receptors on macrophages. IgG-coated red cells are trapped in the coated red cells are trapped in the spleen. Macrophages may completely spleen. Macrophages may completely phagocytose the red cell or may remove phagocytose the red cell or may remove a small part of the membrane; in the a small part of the membrane; in the later case, loss of surface area cause later case, loss of surface area cause formation of a micro-spherocyte.formation of a micro-spherocyte.
AIHA due to warm-reacting AIHA due to warm-reacting autoantibodiesautoantibodies
Some such red cells escape into the Some such red cells escape into the circulation and can be recognized on circulation and can be recognized on peripheral blood smear.peripheral blood smear.
Spherocytes are rigid and are Spherocytes are rigid and are sequestered and destroyed during sequestered and destroyed during subsequent passages through subsequent passages through spleen.spleen.
Warm reacting AIHA-Warm reacting AIHA-Clinical featuresClinical features
Mild anemia, jaundice, and Mild anemia, jaundice, and splenomegaly.splenomegaly.
In secondary AIHA, clinical features In secondary AIHA, clinical features of underlying disease predominate.of underlying disease predominate.
Warm reacting AIHA-Warm reacting AIHA-Laboratory featuresLaboratory features
1) 1) Peripheral blood examinationPeripheral blood examination: : This shows variable degree of anemia This shows variable degree of anemia depending on severity of hemolysis, depending on severity of hemolysis, microspherocytosis of red cells, and microspherocytosis of red cells, and reticulocytosis. Fragmented red cells, reticulocytosis. Fragmented red cells, polychromasia, and nucleated red polychromasia, and nucleated red cells may be present.cells may be present.
Mild neutrophilic leucocytosis is Mild neutrophilic leucocytosis is usual. Platelet count is normal.usual. Platelet count is normal.
Warm reacting AIHA-Warm reacting AIHA-Laboratory featuresLaboratory features
2) Antiglobulin (coombs’) test: This 2) Antiglobulin (coombs’) test: This test determines whether hemolysis test determines whether hemolysis has an immunological basis.has an immunological basis.
There are two types of antiglobulin There are two types of antiglobulin test: direct (DAT) and indirect (IAT). test: direct (DAT) and indirect (IAT). The DAT is used to demonstrate The DAT is used to demonstrate antibodies or the complement antibodies or the complement attached to red cells in vivo.attached to red cells in vivo.
Diagnosis of warm type AIHA is based Diagnosis of warm type AIHA is based on DAT.on DAT.
Warm reacting AIHA-Warm reacting AIHA-Differential diagnosisDifferential diagnosis
1) Hereditary spherocytosis.1) Hereditary spherocytosis. 2) Drug induced immune hemolytic 2) Drug induced immune hemolytic
anemia.anemia. 3) Microangiopathic hemolytic 3) Microangiopathic hemolytic
anemia (schistocytes, anemia (schistocytes, thrombocytopenia, and evidence of thrombocytopenia, and evidence of intravascular coagulation).intravascular coagulation).
Cold reacting AIHACold reacting AIHA This is caused by antibodies which This is caused by antibodies which
react with red cells maximally in react with red cells maximally in cold (0-4 cold (0-4 ̊C̊C) and also retain ) and also retain immunological reactivity at higher immunological reactivity at higher temperatures temperatures (30 (30 ̊C̊C). ).
It is of two types: cold agglutinin It is of two types: cold agglutinin disease (CAD) and paroxysmal cold disease (CAD) and paroxysmal cold hemoglobinuria (PCH). hemoglobinuria (PCH).
Cold agglutinin diseaseCold agglutinin disease Cold-reactive antibodies are usually Cold-reactive antibodies are usually
of IgM class.of IgM class. Either primary CAD (absence of Either primary CAD (absence of
underlying disease), or secondary to underlying disease), or secondary to EBV and mycoplasma infections, or EBV and mycoplasma infections, or secondary to large cell lymphoma.secondary to large cell lymphoma.
CAD- mechanism of CAD- mechanism of hemolysishemolysis
In CAD, cold agglutinins react with red In CAD, cold agglutinins react with red cell antigens in cooler peripheral cell antigens in cooler peripheral circulation. This leads to: 1) circulation. This leads to: 1) aggregation of red cells in peripheral aggregation of red cells in peripheral circulation with cyanosis; 2) activation circulation with cyanosis; 2) activation of complement via classical pathway of complement via classical pathway and stops at C3b stage.and stops at C3b stage.
IgM cold agglutinins dissociate from IgM cold agglutinins dissociate from red cells in central warmer circulation, red cells in central warmer circulation, but C3b remains bound to red cells. but C3b remains bound to red cells. C3b bound red cells bind to C3b C3b bound red cells bind to C3b receptors on Kupffer cells in liver receptors on Kupffer cells in liver which phagocytose the red cells and which phagocytose the red cells and extravascular hemolysis occurs.extravascular hemolysis occurs.
CAD- Clinical featuresCAD- Clinical features Acute or chronic hemolysis during Acute or chronic hemolysis during
exposure to cold. Raynaud’s exposure to cold. Raynaud’s phenomenon and acrocyanosis may phenomenon and acrocyanosis may result from blockage of cooler result from blockage of cooler peripheral microvasculature by peripheral microvasculature by agglutination of red cells.agglutination of red cells.
Gangrene by cold Gangrene by cold agglutinemiaagglutinemia
CAD- Laboratory featuresCAD- Laboratory features 1) Anemia and autoagglutination of 1) Anemia and autoagglutination of
red cells on peripheral blood smear.red cells on peripheral blood smear. 2) DAT employing anticomplement 2) DAT employing anticomplement
reagent is positive.reagent is positive. Treatment: treat underlying cause as Treatment: treat underlying cause as
lymphoma; avoid exposure to cold; lymphoma; avoid exposure to cold; corticosteroids and splenectomy; corticosteroids and splenectomy; cytotoxic therapy and plasmapheresis.cytotoxic therapy and plasmapheresis.
Paroxysmal cold Paroxysmal cold hemoglobinuria (PCH)hemoglobinuria (PCH)
Acute intravascular hemolysis with Acute intravascular hemolysis with abdominal pain, backache, pallor and abdominal pain, backache, pallor and hemoglobinuria. hemoglobinuria.
IgG antibodies react with red cells and IgG antibodies react with red cells and bind complement in colder peripheral bind complement in colder peripheral circulation (at 4 circulation (at 4 ̊C̊C)). On return of red cells . On return of red cells to central warmer (37 to central warmer (37 ̊C̊C) ) circulation, IgG circulation, IgG antibodies dissociate. Formation of antibodies dissociate. Formation of membrane attack complex causes lysis of membrane attack complex causes lysis of red cells.red cells.
PCHPCH This is the basis of Donath-This is the basis of Donath-
Landsteiner diagnostic test (biphasic Landsteiner diagnostic test (biphasic hemolysin).hemolysin).
Drug induced immune Drug induced immune hemolytic anemiahemolytic anemia
May result from three mechanisms:May result from three mechanisms: 1) drug adsorption on red cells with 1) drug adsorption on red cells with
binding of IgG and subsequent binding of IgG and subsequent destruction by splenic macrophages destruction by splenic macrophages via Fc receptors. via Fc receptors.
Examples are: penicillin, ampicillin, Examples are: penicillin, ampicillin, methicillin.methicillin.
Drug induced immune Drug induced immune hemolytic anemiahemolytic anemia
2) Immune complex mechanism with 2) Immune complex mechanism with binding of drug-carrier protein binding of drug-carrier protein complex to red cells and formation of complex to red cells and formation of IgG or IgM antibodies that bind to IgG or IgM antibodies that bind to red cells. This is followed by red cells. This is followed by complement activation and complement activation and subsequent red cell destruction.subsequent red cell destruction.
Examples are: Quinidine, Quinine, Examples are: Quinidine, Quinine, Rifampicin.Rifampicin.
Drug induced immune Drug induced immune hemolytic anemiahemolytic anemia
3) Production of autoantibodies 3) Production of autoantibodies (IgG) against red cell antigens with (IgG) against red cell antigens with subsequent destruction of red cells subsequent destruction of red cells by splenic macrophages via Fc by splenic macrophages via Fc receptors.receptors.
Examples are: Methyldopa, Examples are: Methyldopa, mefenamic acid, L-dopa.mefenamic acid, L-dopa.
Hemolytic disease of the Hemolytic disease of the newborn (HDN)newborn (HDN)
HDN is a disease in which destruction of HDN is a disease in which destruction of red cells of the foetus or newborn occurs red cells of the foetus or newborn occurs due to the passage of maternal antibodies due to the passage of maternal antibodies (only IgG) across the placenta into the (only IgG) across the placenta into the foetal circulation.foetal circulation.
The main red cell antigens responsible for The main red cell antigens responsible for HDN are: RhD; Rhc; Kell; A and B.HDN are: RhD; Rhc; Kell; A and B.
HDN due to anti-RhD, anti-c and anti-Kell HDN due to anti-RhD, anti-c and anti-Kell can cause severe foetal hemolytic anemia. can cause severe foetal hemolytic anemia.
HDN- clinical featuresHDN- clinical features Anemia, jaundice, Anemia, jaundice,
hepatosplenomegaly, kernicterus, hepatosplenomegaly, kernicterus, stillbirth or hydrops foetalis.stillbirth or hydrops foetalis.
HDN- laboratory features HDN- laboratory features Antenatal investigations:Antenatal investigations: A) Maternal investigations: clinical history, A) Maternal investigations: clinical history,
blood grouping and antibody detection.blood grouping and antibody detection. B) Blood grouping of the fatherB) Blood grouping of the father C) Foetal investigations: Amniocentesis or C) Foetal investigations: Amniocentesis or
cordocentesis.cordocentesis. Investigations of newborn: blood grouping, Investigations of newborn: blood grouping,
PBS (erythroblastosis and reticulocytosis), PBS (erythroblastosis and reticulocytosis), DAT, determination of Hb & bilirubin. DAT, determination of Hb & bilirubin.
ABO hemolytic disease of ABO hemolytic disease of newbornnewborn
It develops when blood group of the It develops when blood group of the mother is O and that of the foetus is A mother is O and that of the foetus is A or B and when maternal high titre IgG or B and when maternal high titre IgG anti-A and anti-B antibodies are present. anti-A and anti-B antibodies are present.
Less commonly it results when blood Less commonly it results when blood group of the mother is A or B and that group of the mother is A or B and that of the foetus is respectively B or A.of the foetus is respectively B or A.
Blood Hb & bilirubin should be Blood Hb & bilirubin should be estimated to assess the severity of estimated to assess the severity of hemolysis.hemolysis.
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