Medicine 5th year, 8th lecture/part one (Dr. Sabir)
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Medicine 5th year, 8th lecture/part one (Dr. Sabir)

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The lecture has been given on Apr. 3rd, 2011 by Dr. Sabir.

The lecture has been given on Apr. 3rd, 2011 by Dr. Sabir.

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    Medicine 5th year, 8th lecture/part one (Dr. Sabir) Medicine 5th year, 8th lecture/part one (Dr. Sabir) Presentation Transcript

    • Hemolysis and Hemolytic Anemias Dr. Sabir
    • Hemolytic Anemias-Introduction
      • Definition : a group of disorders characterized by decreased red cell lifespan.
      • Normal red cell lifespan is 120d.
      • The patient may not always be anemic, depending on the degree of marrow compensation.
    • General Clinical Features
      • Splenomegaly is generally present
      • Increased incidence of pigmented gallstones.
      • Dark urine (tea-colored or red)
      • Patients may have chronic ankle ulcers .
      • Aplastic crises associated with Parvovirus B19, may occur
      • Increased requirement for folate
    • Hemolytic Anemias - Classification Schemes
      • Classification by sites of red cell destruction
      • Classification as acquired vs congenital
      • Classification by mechanism of red cell damage
    • Hemolytic Anemias - Sites of Red Cell Destruction
      • Extravascular Hemolysis -
        • Macrophages in spleen, liver, and marrow remove damaged or antibody-coated red cells
      • Intravascular Hemolysis
        • Red cells rupture within the vasculature, releasing free hemoglobin into the circulation
    • Laboratory Evidence for Presence of Hemolysis
      • Evidence for increased red cell production
      • Evidence for increased red cell destruction
    • Evidence for increased red cell production
      • In the blood:
        • Elevated reticulocyte count
        • Circulating NRBCs may be present
      • In the bone marrow:
        • erythroid hyperplasia
        • reduced M/E (myeloid/erythroid) ratio
      • In the bone:
        • Deformities in the skull and long bones (“ frontal bossing ”)
    • Polychromatophilic cell on Wright-Giemsa staining Reticulocytes (supravital staining)
    • Erythroid Hyperplasia
      • Expansion of the erythroid lineage.
      • Arrow is pointing to red cell precursor.
      • Myeloid:erythroid ratio is normally 3:1. The slide above has ratio of 1:10 .
    • Frontal Bossing Results from increased erythropoietic activity and marrow space expansion
    • Evidence for Increased Red Cell Destruction
      • Biochemical consequences of hemolysis in general
      • Morphologic evidence of red cell damage
        • seen on peripheral smear
      • Reduced red cell life-span
        • Measurement of red cell survival no longer routinely done.
    • Biochemical consequences of hemolysis in general
      • Elevated LDH levels
      • Elevated unconjugated bilirubin
        • Only clinically significant if liver function is abnormal
        • Only begins to rise when red cell life span is 50 days or less
    • Biochemical Consequences of Intravascular Hemolysis
      • Reduced serum haptoglobin
      • Hemoglobinemia - red plasma
      • Hemoglobinuria - red urine
      • Hemosiderinuria - stain for iron inside cells in urine
    • Hemolytic Anemias - Classification by Etiology
      • Congenital
        • Defects in membrane skeleton proteins
        • Defects in enzymes involved in energy production
        • Hemoglobin defects
      • Acquired
        • Immune-mediated
        • Non-immune-mediated
    • Congenital Hemolytic Anemias- Membrane Defects
      • Hereditary spherocytosis is the most common defect leading to anemia, affecting 1/5000 Europeans
      • Other
        • Hereditary elliptocytosis
          • Usually no anemia
          • Autosomal dominant, affecting 1/2500 Europeans
        • Hereditary pyropoikilocytosis
    • Hereditary Spherocytosis
      • Defect is in proteins of the membrane skeleton, usually spectrin or ankyrin
      • Lipid microvesicles are pinched off in the spleen and other RE organs, causing decreased MCV and spherocytic change.
    • Hereditary Spherocytosis
      • Autosomal Dominant trait
      • Patients develop hemolysis and abdominal pain with even trivial infectious illnesses
      • Diagnose by  Osmotic Fragility
      • Aplastic crises with Parvovirus B19
      • Treatment:
        • Folate supplementation
        • Splenectomy will stop hemolysis, but spherocytes will persist.
    • HEREDITARY SPHEROCYTOSIS Osmotic Fragility
    • Osmotic Fragility Normal Abnormal- HS cells lyse more readily at low ionic strength
    • Congenital Hemolytic Anemias Enzyme Defects
    • Red Cell Enzyme Defects
      • RBCs require constant energy to maintain biconcave disc shape and hemoglobin in reduced form.
      • Without adequate energy, red cells lyse and/or deform.
      • Energy from glucose is derived from metabolism via anaerobic glycolysis (Embden-Myerhof pathway). There is an alternate aerobic pathway (pentose-phosphate shunt) which starts with G-6-P. Rate-limiting enzyme in this pathway is G6PD
    • RBC Metabolism Simplified Glucose Anaerobic glycolysis Aerobic metabolism Glucose-6-P G6PD
      • Detoxification of metabolites of oxidative stress
      • Elimination of methemoglobin
      F-6-P
    • G6PD Deficiency Pathophysiology
      • Low G6PD activity results in low levels of NADPH and reduced glutathione, which are required to protect hemoglobin from oxidative damage.
      • In the absence of adequate reducing ability (provided by G6PD), oxidizing agents convert hemoglobin to methemoglobin, then denature it, causing it to precipitate as Heinz bodies .
      • The spleen pinches off the Heinz body and the overlying membrane, leaving a “bite cell” or “blister cell”
    • G6PD
      • Two normal forms of enzyme. Most prevalent type is B . 20% of healthy Africans have type A .
      • Deficiency is X-linked .
      • In Africans with G6PD deficiency, mutant protein is A-, which is unstable and loses activity as the red cell ages( 5-15% of normal activity).
      • Mediterranean variant has baseline low activity(1-3%activity).
      • In US, 10-14% of AA men affected
      • In ME, deficiency can be seen in women, since prevalence is high enough.
    • G6PD Deficiency Agents to avoid
      • Primaquine
      • Aspirin
      • Quinolones(cipro)
      • Sulfa drugs
      • Dapsone
      • Vitamin K
      • Fava beans(favism)
      • Naphtha compounds (mothballs)
      Blister cell
    • Favism
      • Hemolysis after hours/days of ingestion of fava beans
      • Beans contain oxidants vicine & convicine>free radicals>oxidise glutathione
      • Shock may develop-may be fatal
    • G6PD Deficiency Clinical Features
      • Typically, hemolysis is triggered by drugs or infections.
      • Anemia is maximal 7-10 d after exposure.
      • Urine becomes dark associated with low back & abd pain
      • Individuals with A- begin to compensate for the anemia by making reticulocytes, despite continuation of drug.
      • Immediately after a hemolytic episode, G6PD levels in pts with A- may be normal , since the mature cells have been lysed, and only younger cells with normal G6PD levels, are present
      • Wait for 6 wk after hemolysis to do enzyme assay
    • Treatment
      • Avoid oxidant drugs
      • Transfuse in severe cases
      • IV fluids to maintain good urine output
      • Splenectomy in severe recurrent hemolysis
      • Folic acid supplements
    • Congenital Hemolytic Anemias Hemoglobinopathies
      • Structural Hemoglobin Defects
        • Hemoglobin S
        • Hemoglobin C
      • Thalassemias
        • Alpha thalassemia
        • Beta thalassemia
    • Acquired Hemolytic Anemias Immune-Mediated Hemolysis
    • Pathophysiology
      • RBCs react with autoAb±complement> premature destruction of RBCs by RE system
      • RBCs opsonized by IgG, recognized by Fc receptors on RES macrophages >phagocytosis
      • If phagocytosis is incomplete > spherocytosis, but usually it is complete if complement is involved
    • Immune hemolytic anemias - Classification
      • Autoimmune
        • Warm antibody-mediated
        • Cold antibody-mediated
        • Paroxysmal Cold Hemoglobinuria
      • Drug-related hemolysis
      • Hemolytic transfusion reactions
      • Hemolytic disease of the newborn
      • Paroxysmal Nocturnal Hemoglobinuria
    • Auto-Immune Hemolytic Anemias
      • Antibodies causing hemolysis can be broken down into 2 general categories: warm and cold.
      • Warm antibodies react with RBCs best at 37° and typically do not agglutinate red cells
      • Cold antibodies typically react best at <32° and do cause RBC agglutination
      • The hallmark of this disease is a positive Coomb’s test
    • Coomb’s Test
      • The Direct Coomb’s = DAT (Direct Antiglobulin Test) - tests for IgG or C3 DIRECTLY ON THE RED CELLS .
      • The Indirect Coomb’s - tests for IgG or C3 in the serum which react with generic normal red cells. This is also known as the antibody screen in blood-banking.
    • Direct Coomb’s Test Patient’s RBCs coated with IgG or C3 Antibodies to human IgG/C3 (Coomb’s reagent) Agglutinationin the test tube
    • Indirect Coomb’s Test Agglutinationin the test tube Patient serum containing anti RBC Abs Normal RBCs and Coomb’s reagent
    • Warm-Antibody Hemolytic Anemias
      • Idiopathic ( most of cases)
      • 2º to lymphoid malignancies (CLL, NHL)
      • 2º to autoimmune dis. Eg: SLE
      • Age: usually pts > 50 yr
      • Clinically: highly variable: from asymptomatic-severely anemic
      • Mild jaundice common
      • Splenomegaly usual
    • Spherocyte Formation Progressive loss of membrane, loss of surface area, more spherocytic shape
    • Warm-Antibody Hemolytic Anemias Diagnosis
      • Spherocytosis
      • Reticulocytosis
      • Coomb’s +ve
      • LDH î
      • Serum haptoglobin low
      • Investigate for underlying cause
    • Warm Autoimmune Hemolytic Anemia - spherocytes
    • Warm-Antibody Hemolytic Anemias Treatment
      • Patients may require red cell transfusions, if they are symptomatic with their anemia
      • However, immunosuppression is the mainstay of therapy .
    • Warm-Antibody Hemolytic Anemias Immunosuppressive Treatment
      • First line is corticosteroids ( prednisone 1mg/kg/d tapering after response)
      • If steroids fail to work, or if patient relapses after steroid taper, splenectomy may be necessary. IVIg can be used as adjunctive therapy.
      • Immunosuppressives such as cyclophosphamide or azathioprine may be required as third-line therapy. Rituximab has been used successfully.
      • Regular folic acid
    • Cold Agglutinin Disease
      • Pathogenic antibodies are usually IgM , which bind to red cells in the cooler extremities, then fix complement. When red cells return to the warmer torso, IgM falls off.
      • Complement-coated red cells can be lysed directly within the vessel (intravascular hemolysis).
      • Alternatively, complement-coated red cells can be engulfed by complement receptors on macrophages within the liver (extravascular hemolysis)
    • Cold Agglutinin Disease
      • In the cold, IgM can lead to red cell agglutination
      • Red cells clumps cannot pass through microvasculature, leading to cyanosis and ischemia in extremities.
      • Smear shows RBC agglutination.
    • Digital ischemia from cold-agglutinin disease
    • Cold Agglutinin Disease Clinical features
      • Can be associated with infection with either Mycoplasma or Mononucleosis ,
      • Can also be idiopathic or associated with a lymphoproliferative disease .
      • Treatment is to keep patient (especially the extremities) warm. Blood and IV fluids should be warmed.
      • Immunosuppression with oral chemotherapy may be required.
      • Steroids and splenectomy are usually ineffective.
    • Paroxysmal Nocturnal Hemoglobinuria
      • An acquired disease in which an abnormal stem cell clone gives rise to abnormal RBCs, WBCs, and platelets all missing proteins which are attached to the cell surface by a GPI (glycero-phosphatidylinositol) anchor .
      • Among these proteins are CD55 and CD59 , which protect red cells from complement-mediated lysis.
      • Diagnose by flow cytometry for CD55 and CD59.
      • Former diagnostic test was Ham’s test - looking for abnormal sensitivity to addition of acidified serum. PNH cells lyse at a higher pH than normal red cells.
    • Paroxysmal Nocturnal Hemoglobinuria - Clinical features
      • Pancytopenia
      • Predisposition to thrombosis.
        • Both arterial and venous
        • Associated with Budd-Chiari syndrome.
      • May develop during the course of aplastic anemia, either preceding or after recovery from aplasia.
      • May develop into acute leukemia
      • Hemolysis is predominantly nocturnal (when pH usually falls), usually mild.
    • Non-Immune Hemolytic Anemia Classification
      • Mechanical trauma to red cells
        • Microangiopathic Hemolytic Anemia
        • Abnormalities in heart and large vessels
        • March Hemoglobinuria
      • Infections
      • Drugs, Chemicals, and Venoms
    • Microangiopathic Hemolytic Anemias
      • Shear damage to red cells as the result of endothelial cell activation/damage.
      • Hallmark is presence of schistocytes on the peripheral smear.
      • Can be caused by the following disorders :
        • TTP/HUS
        • DIC
        • Malignant hypertension
        • Ecclampsia, HELLP syndrome
        • Vasculitis
        • Other, including metastatic cancer, scleroderma renal crisis, solid organ transplant rejection
    • MAHA - Schistocytes
    • Macroangiopathic Hemolytic Anemias
      • Abnormalities within heart and large vessels can cause shear damage to RBCs.
      • Schistocytes
      • Prior to surgery: AS, ruptured sinus of valsalva, ruptured chordae, coarctation, aortic aneurysm and/or dissection.
      • After surgery: complement activation in bypass or dialysis tubing, after “patching” operations, after valve replacement
    • March Hemoglobinuria
      • 1861 - German soldier complained of dark urine after strenuous marches.
      • 1964 - 2 track runners noted dark urine after races. Disappeared after softer shoe insoles used.
      • Mechanical damage to red cells also reported after conga drum playing, head beating, and karate exercises.
    • Hemolysis from Infections
      • Malaria
      • Bartonella bacilliformis
      • Clostridium welchii toxin
        • Hemolysis can be so severe it produces a dissociation b/w hemoglobin and hematocrit
    • Hemolysis Associated with Chemical and Physical Agents
      • Arsenic, especially arsine gas
      • Lead
      • Copper - deliberate ingestion, accumulation from dialysis fluid exposed to copper pipes, and Wilson’s disease.
      • Insect, spider (esp brown recluse), snake venoms
      • Heat/burns