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 &
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
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
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
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
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
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
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
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.