Immune hemolytic anemiaDr. Yasser Ahmed
Immune hemolytic anemiasRBCs hemolysis due to immune mechanism occurs when antibody and/or complement in the circulation binds with an antigen on the surface of the red cells. This causes extravascular or intravascular red cell destruction.Immune hemolytic anemias are classified into three types: autoimmune, iso (or allo-) immune, and drug induced.
Classification of immune hemolytic anemiasAutoimmune: Warm reacting antibody type and cold reacting antibody type.Alloimmune: hemolytic disease of the newborn (Rh or ABO) and hemolytic transfusion reactions.Drug induced.
Evans syndrome (autoimmune hemolytic anemia & thrombocytopenia)
Basic mechanisms of immune hemolytic anemia In autoimmune hemolytic anemia (AIHA), hemolysis occurs when antibodies and/or complement in patients circulation react with and cause destruction of patients own red cells.Classification of AIHA is based on thermal characteristics of the antibodies. Generally, IgG and IgM antibodies are respectively of warm and cold types; however in paroxysmal cold hemoglobinuria, IgG antibodies are of cold-reactive type.
Basic mechanisms of immune hemolytic anemiaIn alloimmune hemolytic anemia, hemolysis occurs due to reaction between red cell antigen from one individual with antibody from another individual. Alloantibodies are usually of IgG class.
AIHA due to warm-reacting autoantibodiesWarm antibody type (antibody maximally active at 37C and mostly IgG) is classified into:Primary (Idiopathic).Secondary: 1) Autoimmune disorders (e.g. SLE); 2) Neoplastic disorders (lymphoproliferative disorders like CLL and malignant lymphoma, ovarian teratoma); 3) Drugs.
AIHA due to warm-reacting autoantibodiesIn this type, IgG antibodies or complement (C3b) bind to red cell membrane and are recognized by specific receptors on macrophages. IgG-coated red cells are trapped in the spleen. Macrophages may completely phagocytose the red cell or may remove a small part of the membrane; in the later case, loss of surface area cause formation of a micro-spherocyte.
AIHA due to warm-reacting autoantibodiesSome such red cells escape into the circulation and can be recognized on peripheral blood smear.Spherocytes are rigid and are sequestered and destroyed during subsequent passages through spleen.
Warm reacting AIHA-Clinical featuresMild anemia, jaundice, and splenomegaly.In secondary AIHA, clinical features of underlying disease predominate.
Warm reacting AIHA-Laboratory features1) Peripheral blood examination: This shows variable degree of anemia depending on severity of hemolysis, microspherocytosis of red cells, and reticulocytosis. Fragmented red cells, polychromasia, and nucleated red cells may be present.Mild neutrophilic leucocytosis is usual. Platelet count is normal.
Warm reacting AIHA-Laboratory features2) Antiglobulin (coombs) test: This test determines whether hemolysis has an immunological basis.There are two types of antiglobulin test: direct (DAT) and indirect (IAT). The DAT is used to demonstrate antibodies or the complement attached to red cells in vivo.Diagnosis of warm type AIHA is based on DAT.
Warm reacting AIHA-Differential diagnosis1) Hereditary spherocytosis.2) Drug induced immune hemolytic anemia.3) Microangiopathic hemolytic anemia (schistocytes, thrombocytopenia, and evidence of intravascular coagulation).
Cold reacting AIHAThis is caused by antibodies which react with red cells maximally in cold (0-4 C) and also retain immunological reactivity at higher temperatures (30 C). It is of two types: cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH).
Cold agglutinin diseaseCold-reactive antibodies are usually of IgM class.Either primary CAD (absence of underlying disease), or secondary to EBV and mycoplasma infections, or secondary to large cell lymphoma.
CAD- mechanism of hemolysisIn CAD, cold agglutinins react with red cell antigens in cooler peripheral circulation. This leads to: 1) aggregation of red cells in peripheral circulation with cyanosis; 2) activation of complement via classical pathway and stops at C3b stage.IgM cold agglutinins dissociate from red cells in central warmer circulation, but C3b remains bound to red cells. C3b bound red cells bind to C3b receptors on Kupffer cells in liver which phagocytose the red cells and extravascular hemolysis occurs.
CAD- Clinical featuresAcute or chronic hemolysis during exposure to cold. Raynauds phenomenon and acrocyanosis may result from blockage of cooler peripheral microvasculature by agglutination of red cells.
Gangrene by cold agglutinemia
CAD- Laboratory features1) Anemia and autoagglutination of red cells on peripheral blood smear.2) DAT employing anticomplement reagent is positive.Treatment: treat underlying cause as lymphoma; avoid exposure to cold; corticosteroids and splenectomy; cytotoxic therapy and plasmapheresis.
Paroxysmal cold hemoglobinuria (PCH)Acute intravascular hemolysis with abdominal pain, backache, pallor and hemoglobinuria. IgG antibodies react with red cells and bind complement in colder peripheral circulation (at 4 C). On return of red cells to central warmer (37 C) circulation, IgG antibodies dissociate. Formation of membrane attack complex causes lysis of red cells.
PCHThis is the basis of Donath-Landsteiner diagnostic test (biphasic hemolysin).
Drug induced immune hemolytic anemiaMay result from three mechanisms:1) drug adsorption on red cells with binding of IgG and subsequent destruction by splenic macrophages via Fc receptors. Examples are: penicillin, ampicillin, methicillin.
Drug induced immune hemolytic anemia2) Immune complex mechanism with binding of drug-carrier protein complex to red cells and formation of IgG or IgM antibodies that bind to red cells. This is followed by complement activation and subsequent red cell destruction.Examples are: Quinidine, Quinine, Rifampicin.
Drug induced immune hemolytic anemia3) Production of autoantibodies (IgG) against red cell antigens with subsequent destruction of red cells by splenic macrophages via Fc receptors.Examples are: Methyldopa, mefenamic acid, L-dopa.
Hemolytic disease of the newborn (HDN)HDN is a disease in which destruction of red cells of the foetus or newborn occurs due to the passage of maternal antibodies (only IgG) across the placenta into the foetal circulation.The main red cell antigens responsible for HDN are: RhD; Rhc; Kell; A and B.HDN due to anti-RhD, anti-c and anti-Kell can cause severe foetal hemolytic anemia.
HDN- clinical featuresAnemia, jaundice, hepatosplenomegaly, kernicterus, stillbirth or hydrops foetalis.
HDN- laboratory features Antenatal investigations:A) Maternal investigations: clinical history, blood grouping and antibody detection.B) Blood grouping of the fatherC) Foetal investigations: Amniocentesis or cordocentesis.Investigations of newborn: blood grouping, PBS (erythroblastosis and reticulocytosis), DAT, determination of Hb & bilirubin.
ABO hemolytic disease of newbornIt develops when blood group of the mother is O and that of the foetus is A or B and when maternal high titre IgG anti-A and anti-B antibodies are present. Less commonly it results when blood group of the mother is A or B and that of the foetus is respectively B or A.Blood Hb & bilirubin should be estimated to assess the severity of hemolysis.