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Lecture 12

Hemolytic Anemia I: General Principles - Acquired & Hereditary

Definition of hemolysis Premature destruction of red cells
Morpholgic finding of extravascular hemolysis on peripheral blood smear Spherocytes
A process where senescent or abnormal RBCs are ingested by macrophages of the spleen and liver. Extravasulcar hemolysis
What types of RBCs are phaogcytosed by macrophages in extravascular hemolysis? (1) RBCs with surface abnormalities that decreaes its deformability (2) RBCs coated with IgG or C3b
What is the product of oxidative metabolism of heme? Bilirubin is produced in two forms: unconjugated (indirect) and conjugated (direct) forms
Where is bilirubin conjugated? Liver
How is bilirubin excreted from the body? Conjugated bilirubin is excreted into the guy where it is oxidized to urobilinogen and excreted as stercobilinogen in feces. Some urobilinogen is reabsorbed and excreted by the kidney into the urine.
Definition of intravascular hemolysis RBC lysis that occurs in the intravascular space and release their contents into the plasma.
What are the usual causes of increased intravascular hemolysis? (1) Trauma to RBCs (2) Complement fixation of RBC (3) Exogenous toxic factors
What microscopic finding on periperhal blood smear is associated with intravascular hemolysis of RBC due to trauma? Schistocytes
What protein binds free hemoglobin in plasma? Haptoglobin.
How is hemoglobin-haptoglobin complex cleared from the plasma? The complex is cleared by hepatocytes and the reticuloendothelial system
What happens to excess free hemoglobin once the binding capacity of haptoglobin is saturated? Hemoglobin is filtered by the renal glomeruli and reabsorbed by the proximal tubules where it is catabolized and the heme is converted into ferritin and hemosiderin.
What findings in urine would indicate active intravascular hemolysis? Presence of (1) ferritin (2) hemosiderin (3) hemoglobinuria
What percentage of senescent RBCs are recycled by intravascular hemolysis? 10%
What is ferriheme? Ferriheme is the protein plasma transporter of any hemoglobin that is not bound to haptoglobin or excreted by the kidneys.
How is immune mediated hemolytic anemia detected? Coombs Test
What is the Coombs test? Coombs test is used to detect immune mediated hemolytic anemia. It employs anti-human globulin which is specifically directed aganist human IgG, IgM, IgA, and complement (C3d).
An antiglobulin test that detects the presence of antibody or complement on the patient's RBC. Used to detect immune mediated hemolysis. Direct Coombs Test (direct antiglobulin test)
How is the Direct Coombs Test conducted? Patient's RBCs are incubated with anti-human IgG antiserum or anti-human C3 antiserum.If the RBCs are coated with IgG or complement, then the RBCs will agglutinate.
An antiglobulin test that detects the presence of antibody to red cells in the patient's serum. Used to detect autoimmune mediated hemolysis. Indirect Coombs Test (Indirect antiglobulin test)
How is the Indirect Coombs Test conducted? First normal RBCs are incubated with the patient's serum. Then a Direct Coombs Test is conducted with these RBCs. If antibodies aganist RBCs are present in the patient's serum, agglutination of the RBCs occurs.
Pathophysiology of Warm Autoimmune Hemolytic Anemia? Extravascular hemolysis caused by IgG autoantibody capble of reacting with RBC emembrane at an optium temp of 37 deg. Autoantibody coated RBCs bind to macrophages via Fc receptor with subsequent extravascular hemolysis and spherocyte formation.
(T or F) 50% of Warm Autoimmune Hemolytic Anemia indicates the presence of undrelyilng disease or hematologic malignancies. True. Most commonly associated with complications of autoimmune disorders or hematologic malignancies espeically SLE and CLL.
What are the findings of Warm Autoimmune Hemolytic Anemia peripheral blood smear? (1) Sherocytes (2) Evidence of increased red cell production: reticulocytosis, polychromatophilic macrocytes and nucleated RBCs
At what level of serum bilirubin does jaundice? 2.5 mg/dL
Will DAT be positive or negative for Warm Autoimmune Hemolytic Anemia? Positive DAT with IgG only or both IgG and C3b.
First line therapy for Warm Autoimmune Hemolytic Anemia Prednisone
What constitutes failure of prednisone therapy for Warm Autoimmune Hemolytic Anemia? Failure of response after 3 weeks of therapy.
What are additional therapies available for treatment failures with prednisone? (1) Transfusions (sparingly) (2) IV IgG (3) Danazol (4) Splenectomy (5) Immunosuprressive drugs
Etiology of Cold Agglutinin Disease IgM complement-fixing autoantibody binds to RBCs at pathologically high temps (28-31C).
Pathophysiology of Cold Agglutinin Disease IgM autoantibody binds to RBCs in acral parts of body exposed to cold temps. IgM binds complement. As RBC return to core body temp, IgM is released, but complement activation begins. Intravascular hemolysis and extravascular hemolysis may occur.
(T or F) Most people have cold IgM antibodies which bind their own RBCs. True. Yet these autoantibodies do not cause Cold Agglutinin Disease.
What is different from the autoantibodies thatcause Cold Agglutinin Disease from normal cold antibodies? (1) Antibody has a much higher thermal amplitude (28-31C) (2) Antibody has a much higher titier than normal cold antibody (3) Antibody is a monoclonal IgM and often the patient has an underlying lymphoreticular disorder.
Clinical manifestations of Cold Agglutinin Disease (1) Episodes of hemoglobinuria and intravascular hemolysis after cold exposure (2) Acrocyanosis and Raynaud's phenomenon upon cold exposure
What are the findings on peripheral blood smear characteristic of Cold Agglutinin Disease? (1) Agglutinated RBCs (2) Spherocytes
Is the Direct Coombs Test negative or positive in Cold Agglutinin Disease? Positive DAT with broad-spectrum Coomb's reagent and complement Coomb's reagent
Laboratory test for diagnosis of Cold Agglutinin Disease (1) Peripheral blood smear demonstrating mild to moderate anemia, spherocytes, agglutination of RBCs (2) Positive DAT (3) Elevated cold agglutinin titer with high thermal amplitude (3) Monoclonal IgM on immunoelectropheresis
Disorder characterized by acute intravascular hemolysis after mycoplasma penumoniae or Epstein Barr Virus infection. Hemolysis is transient with recovery within 2-3 weeks. Acute Postinfectious Cold Agglutinin-Induced Hemolysis
Infections most commonly associated with Acute Postinfectious Cold Agglutinin-Induced Hemolysis (1) Mycoplasma pneumoniae (2) Epstein Barr Virus
(T or F) Cold autoantibodies are monoclonal in Acute Postinfectious Cold Agglutinin-Induced Hemolysis. False. The cold antibodies are heterogeneous unlike cold agglutinin disease.
What are the laboratory findings for the diagnosis of Acute Postinfectious Cold Agglutinin-Induced Hemolysis? (1) Positive DAT (2) Agglutinated RBCs on peripheral blood smear (3) Elevated LDH (4) Low haptoglobin levels (5) Elevated cold agglutinin titer with high thermal amplitude (6) Hemoglobinuria.
Therapy for Acute Postinfectious Cold Agglutinin-Induced Hemolysis Keep patient warm. If transfusion is required, blood must be infused through a blood warmer.
What is the Donath Landsteiner Antibody? IgG antibody that is biphasic hemolysin. The antibody binds to the P antigen on RBC membrane at cold temperature and activates complement at warmer temperature causing intrvascular hemolysis.
The most common causes of Paroxysmal Cold Hemogloinuria (1) Idiopathic, after an acute viral infection (2) Complication of tertiary syphilis
A disorder chracteristized by acute hemoglobinuria after cold exposure caused by Donath Landsteiner antibodies. Paroxysmal Cold Hemogloinuria
How is the Donath-Landsteiner Test conducted? Patient's serum is incubated with RBCs. The mixture is chilled to 4 deg C and then warmed to 37 deg C. Signifianct hemolysis indicates a positive diagnosis for Paroxysmal Cold Hemogloinuria.
What type of hemolysis is associated with hapten mediated drug induced hemolytic anemia? Extravascular hemolysis
Pathophysiology of Hapten mediated drug induced hemolytic anemia Drug binds to RBC. RBC acts as the hapten and the drug as the antigen. IgG antibodies are formed aganist the antigen. The complement pathway is not activated.
Would the Direct Coombs Test be negative or positive for Hapten mediated drug induced hemolytic anemia? DAT would be positive only for IgG.
Pathophysiology of Immune Complex mechanism of drug induced hemolytic anemia There are IgM antibodies against a drug present in the plasma. Drug-antibody interactions create circulating immune complexes that bind to RBC via complement receptor resulting in lysis of the RBC.
What type of hemolysis is associated with Immune Complex Mediated drug induced hemolytic anemia? Intravascular hemolysis
Would the Direct Coombs Test be negative or positive for Immune Complex Mediated drug induced hemolytic anemia? Positive DAT only for complement
Pathophyisology of Membrane Modification Mechanism of drug induced hemolytic anemia The drug damages RBC membrane resulting in nonspecific binding of plasma proteins.
Pathophysiology of Autoimmune Mechanism drug induced hemolytic anemia. The drug induced warm autoimmune directed aganist an RBC antigen resulting in hemolysis.
Will the Direct Coombs Test be negative after discontinuation of the offending drug in autoimmune mediated drug induced hemolytic anemia? No, the DAT will remain positive for several months after the drug is discontinued.
What explains the different clinical syndromes seen with drug-induced antibodies causing hemolytic anemia? Drugs may interact with specific cell membrane components, altering them creating a neoantigen consisting of drug and cell component. The location of the neoantigen explains the different clinical syndromes of drug induced hemolytic anemia.
Created by: UVAPATH4