Download Pathology – Lecture 17: Immunohemolytic Anemia 2/25/13

Pathology – Lecture 17: Immunohemolytic Anemia
2/25/13
Immunohemolytic Anemia
 Introduction
o Blood contains…
 ~ 60% plasma (including antibodies)
 ~40% cells (mostly RBCs from bone marrow)
o Immunohemolytic anemias
 Caused by antibodies that bind to red cells  premature destruction
 Classification
 Warm Antibody Type (IgG Abs active @ 37C – body temp)
o Primary (idiopathic)
o Secondary
 Autoimmune disorders (esp. SLE)
 Drugs
 Lymphoid neoplasms
 Cold Agglutinin Type (IgM Abs active below 37C – room temp)
o Acute (mycoplasmal infection, infectious mononucleosis)
o Chronic
 Idiopathic
 Lymphoid neoplasms
 Cold Hemolysin Type (IgG Abs active below 37C – fixes complement)
o Rare; mainly in children following viral infections
o Diagnosis
 Detection of Abs and/or complement on red cells
 How?
 Direct Coombs antiglobulin test
o The pt’s red cells are mixed w/ sera containing antibodies that are
specific for human Ig or complement (anti-human globulin, AHG)
o If agglutination (clumping) occurs = positive test
 Indirect Coombs antiglobulin test
o The pt’s serum is tested for its ability to agglutinate commercially
available red cells bearing particular defined Ags in the presence of
AHG
 Note
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Note for testing that red blood cells have a net negative charge on their surface that
maintains a distance between cells of approximately 25 nanometers. IgG antibodies may coat
cells and not cause visible agglutination but may fix complement, in which case, the direct
Coombs test could demonstrate the presence of IgG and/or complement components. IgG
antibodies react optimally at body temperature and may dissociate into serum at room
temperature, in which case the indirect Coombs test may demonstrate their presence in
serum when the sample is warmed. IgM antibodies react optimally at colder (ex., room)
temperatures and could produce agglutination without AHG.
Warm Antibody Type
o Most common form of immunohemolytic anemia
o Etiology
 ~ 50% are idiopathic (primary)
 Rest due to predisposing condition or drug exposure
o Most causative Abs are of the IgG class; less commonly seen are IgA
o Hemolysis
 Red cell hemolysis is mostly extravascular
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IgG-coated red cells bind Fc receptors on phagocytes in the spleen and
elsewhere, which remove portions of the red cell membrane during
phagocytosis
Loss of membrane converts the cells to spherocytes, which are sequestered
and removed in the spleen
o Moderate splenomegaly may be seen
o Causes
 Primary immunohemolytic anemia – unknown
 Secondary
 SLE
 In many cases, the Abs are directed against the Rh blood group antigens
 Drug-induced – better understood
o Antigenic drugs
 Hemolysis 1-2 wks post therapy
 Includes:
 PCN, cephalosporins, and quinidine
o Bind to red cell membranes and form complexes
that are recognized by anti-drug Abs
 Abs sometimes fix complement and cause
intravascular hemolysis, but usu. act as
opsonins that promote extravascular
hemolysis
o Tolerance-breaking drugs
 The antihypertensive agent -methyldopa is the prototype,
induce production of antibodies against red cell antigens, esp.
the Rh group
Cold Agglutinin Type (Cold Hemagglutinin Disease, CHD)
o Less common than warm antibody immunohemolytic anemia
o Caused by IgM antibodies that bind red cells avidly at low tems (0-4C)
 Appear transiently following certain infections:
 Self-limited and rarely cause clinically important hemolysis
o M. pneumoniae
o EBV
o Cytomegalovirus
o Influenza virus
o HIV
 Chronic cold agglutinin immunohemolytic anemia
 Assoc. w/ certain B-cell neoplasms or as an idiopathic condition
o Clinical Symptoms
 Result from binding of IgM to red cells in vascular beds where the temp may fall
below 30C, such as exposed fingers, toes, and ears
 IgM binding agglutinates red cells and fixes complement rapidly
o IgM is released as the blood recirculates and warms, usu. before
complement-mediated hemolysis can occur
 The transient interaction does  sublytic amounts of C3b, an opsonin, to
deposit  removal of affected red cells by phagocytes in the RES
o Hemolysis of variable severity
 Vascular obstruction d/t agglutination  pallor, cyanosis, and Raynaud’s
Cold Hemolysin Type
o Cold hemolysins = autoantibodies that cause paroxysmal cold hemoglobinuria
Rare disorder causing substantial, sometimes fatal, intravascular hemolysis
The autoantibody
 Binds to the P blood group antigen on the red cell surface in cool, peripheral
regions of the body
o Glycophospholipid P antigen = main target
 Is a biphasic, usu. polyclonal, IgG known to bind to various antigens such as I, i-, p-, Pr-, on the RBC surface
o Reaction occurs…
 Upon completion of complement lysis w/in the vascular circulation
 Intravascular hemolysis occurs preferentially @ 37C
 Complement-mediated lysis occurs when the cells recirculate to warm central
regions, since the complement cascade works better at 37C
o Etiology
 Unknown; possibly a form of molecular mimicry
 Close relationship w/ exposure to viral or bacterial agents, w/ development of PCH
w/in 2-3 wks of URI or GI Sxs
 Young children are the most susceptible – most common following viral infections
o May see hemoglobinemia, hemoglobinuria, and sometimes renal failure
o The Ab may persist for 1-8 months to several years
 Treatment for Immunohemolytic Anemia
o Supportive care
o Removal of the underlying initiating factor
o Immunosuppressive drugs and splenectomy are the mainstays
Autoimmune Hemolytic Anemia (AIHA)
 Features autoantibodies against red cells (either warm or cold antibodies)
Hemolytic Anemia Resulting from Trauma to Red Cells
 The most significant hemolysis is seen in pts w/:
o Cardiac valve prostheses
o Microangiopathic d/o (microangiopathic hemolytic anemia, MAHA)
 Most commonly seen in pts w/ DIC
 May be seen in pts w/ TTP, HUS, malignant HTN, SLE, & disseminated cancer
 Common pathogenic feature
 Microvascular lesion  luminal narrowing d/t fibrin and PLT deposits
 Damage  appearance of red cell fragments (schistocytes), “burr cells”,
“helmet cells”, and “triangle cells” in blood smears
Hemolytic Transfusion Reactions
 An immediate rxn occurs when incompatible blood is given to a pt w/ preformed alloantibodies
o ABO antibodies (IgG class) are present
 React w/ blood  massive hemolysis of the transfused blood
 May  hypotension, renal failure, and even death
 Delayed transfusion rxns usu. involve Abs to incompatible, non-ABO red cell antigens
o Ab levels rise and then decline after initial exposure
o Re-exposure elicits an anamnestic antibody response  hemolysis after several days
 Usu. less severe and may be clinically undetectable
 Direct antiglobulin test is positive
Paroxysmal Nocturnal Hemoglobinuria (PNH)
 An acquired clonal stem cell d/o
 Pathology
o Pts develop varyingly severe normocytic or macrocytic anemia
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o Episodic intravascular hemolytic anemia d/t  sensitivity of erythrocytes to complementmediated lysis
o Red urine (d/t hemoglobin) and thrombosis is seen
o PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic
defect in the cell membrane (deficiency of glycophosphatidylinositol, GPI, leading to absence
of protective proteins on the membrane, rendering it more susceptible to hemolysins in an
acid environment (so you see Hgb in the urine following periods of sleep)
Diagnosis
o Sucrose hemolysis test or acidified serum (Ham test)
o Demonstrating loss of GPI-anchored proteins on blood cells by flow cytometry
o Leukopenia dn thrombocytopenia are frequently detected
Clinical Features
o Intermittent intravascular hemolysis
o Venous and arterial thrombosis, notably Budd-Chiari syndrome
o Thrombocytopenia may  bleeding
Tx
o Bone marrow transplant is curative