Acquired Hemolytic Anemias Flashcards Preview

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Flashcards in Acquired Hemolytic Anemias Deck (18):
1

What is the role of measuring reticulocytes in diagnosis? What do these measurements suggest?

  • Reticulocytes are immature RBCs, that no longer contain a nucleus but retain some RNA
    • Reticulocytes are indicators of increased bone marrow production of RBCs but are not specific for hemolysis
    • They can also be increased in acute blood loss or bone marrow disorders
  • The reticulocyte response is assessed by either the absolute reticulocyte count or the reticulocyte production index (RPI)
    • When the reticulocytes are reported as a percentage, the RPI should be calculated
    • The RPI takes into account the degree of anemia and the reticulocyte maturation time in the circulation (1-2 days)
    • RPI  =  (Reticulocyte percentage/2) x (Patient’s HCT ÷ 45[normal hematocrit])
  • An appropriate bone marrow response to anemia is suggested by a corrected RPI over 2% or an absolute reticulocyte count of over 100,000/μl

2

What are the broad categories of hemolytic anemias? What are the findings in each?

  • Hereditary vs. Acquired or                           
  • Intracorpuscular vs. Extracorpuscular (refers to site of the defect)
  • Extravascular vs. Intravascular 

3

What are some common etiologies of hemolytic anemias? Are these intracorpuscular or extracorpuscular? Hereditary or acquired?

  • Abnormalities of RBC interior
    • Enzyme defects (ex. G-6-PD) - IC, H
    • Hemoglobinopathies (ex. sickle cell) - IC, H
  • RBC membrane abnormalities
    • Hereditary spherocytosis - IC, H
    • Paroxysmal nocturnal hemoglobinuria - IC, A
    • Spur cell anemia - IC, A
  • Extrinsic factors
    • Hypersplenism - EC, A
    • Immunologic hemolysis - EC, A
    • Microangiopathic hemolysis - EC, A
    • Infectious (ex. malaria, babesiosis) - EC, A

4

What distinguishes extravascular from intravascular hemolysis?

  • Extravascular hemolysis: destruction of the red blood cells occurs in the reticuloendothelial system (mononuclear phagocytes), particularly in the spleen and liver
  • Intravascular hemolysis: direct mechanical damage to red blood cells or can be immune-mediated

5

What are hematologic lab findings that suggest hemolytic anemia? What differentiates the intravascular and extravascular forms?

  • Routine blood film
    • extravascular - polychromatophilia
    • intravascular - polychromatophilia
  • Reticulocyte
    • extravascular - increased
    • intravascular - increased
  • Bone marrow exam
    • extravascular - erythroid hyperplasia
    • intravascular - erythroid hyperplasia

6

What are the plasma lab findings that suggest hemolytic anemia? What are the differences between the extravascular and intravascular variants?

  • Bilirubin
    • extravascular - increased unconjugated
    • intravascular - increased unconjugated
  • Haptoglobin
    • extravascular - decreased or absent
    • intravascular - absent
  • Plasma hemoglobin
    • extravascular - normal to slightly increased
    • intravascular - greatly increased
  • Lactate dehydrogenase
    • extravascular - slightly increased (variable)
    • intravascular - greatly increased (variable)

7

What are the urine lab findings that suggest hemolytic anemia? What are the differences between the intravascular and extravascular variants?

  • Bilirubin
    • extravascular - 0
    • intravascular - 0
  • Hemosiderin
    • extravascular - 0
    • intravascular - +
  • Hemoglobin
    • extravascular - 0
    • intravascular - + in severe cases

8

What are the major categories of immune-mediated hemolytic anemia?

  • More common in women
  • Warm antibody or cold antibody type
    • Can be associated with a variety of disorders
    • Warm reactive antibodies are more common than cold
    • About 50-70% are idiopathic, while the rest are secondary to other disorders or medications
    • The antibodies are directed against certain antigens on the RBC
    • Antibodies can be of either IgG, IgM or IgA subtype
    • Can have the ability to fix complement
    • Tissue macrophages, particularly in the spleen, interact with RBCs coated with IgG or complement and result in clearance of the RBC

9

What is the direct Coomb's test?

  • Direct antiglobulin test (DAT): detects immunoglobulins or fragments of complement that have adhered to the patient’s red cells
    • Anti-immunoglobulin or anti-complement antibodies are incubated with patients RBCs
    • If patient RBCs have immunoglobulin or complement bound to them then agglutination of the RBC will occur

10

What is the indirect Coomb's test?

  • Indirect Coomb’s: detects antibodies to red blood cells present in the patient’s plasma
    • The patient’s serum (which includes any circulating antibodies) is incubated with normal RBCs
    • Anti-immunoglobulin antibodies are then added.
    • Agglutination of RBCs will result if the patient’s serum contained any antibodies which recognized antigens on the normal RBCs
    • May be positive in the presence of an alloantibody or autoantibody
  • A positive test does not necessarily mean active hemolysis for either the direct or indirect test

11

What is the pathophysiology, presentation, and management of warm-antibody hemolytic anemia?

  • Pathophysiology
    • Most commonly IgG antibody, can be IgM or IgA
    • Antibodies lead to clearance of RBC by the splenic macrophages
    • Also can have complement mediated lysis of the membrane
    • Microspherocytes are formed when only part of the RBC membrane is removed by the splenic macrophages
  • Clinical
    • Primarily adults – more common in women and older adults
    • 25% have an underlying disease
    • Patients may present with:
      • jaundice
      • pallor
      • splenomegaly
    • Evan’s syndrome is hemolytic anemia with immune thrombocytopenia
  • Laboratory Features
    • Microspherocytes, anemia and elevated reticulocytes
    • Increased bilirubin, primarily indirect
    • Decreased haptoglobin
    • Positive direct Coomb’s test
  • Therapy
    • Cessation of drugs known to cause hemolysis
    • Folate
    • Corticosteroids – first line choice
    • Other immunosuppressive therapy
    • Splenectomy in refractory cases
    • RBC transfusions for significant symptoms only

12

What is the pathophysiology, presentation, and management of cold-antibody hemolytic anemia?

  • Pathophysiology
    • These RBC autoantibodies bind at lower temperatures, ex. 4º C
    • Also called cold agglutinins
    • Usually are IgM antibodies
    • Hemolysis occurs through complement fixation
    • Many patients without active hemolysis can have cold-reacting antibodies
    • May arise due to neoplasm (monoclonal antibody) or infection (polyclonal antibody)
    • Neoplasms – often in the elderly.  Can be a monoclonal gammopathy, lymphoma, and rarely solid tumors.
    • Infections associated with cold agglutinins include mycoplasma and infectious mononucleosis
  • Clinical
    • Acrocyanosis – purple extremities, due to lack of oxygenation
      • Occurs when the blood gets cold enough to cause RBC agglutination and improves on warming
    • Hemolysis – the degree depends on several factors
      • Antibody titer – more agglutination with higher titer
      • Thermal amplitude – higher amplitude react more in vivo
      • Environmental temperature – cold outside = more agglutination
  • Laboratory
    • RBC agglutination on peripheral smear
    • Hemoglobinemia, hemoglobinuria, hemosiderinuria
    • DAT is positive with complement
    • Antibody testing is done with fetal (i) and with adult (I) RBCs
      • anti-I – react more strongly against the adult cells; seen in monoclonal gammopathy and mycoplasma
      • anti-i – react more strongly against the fetal cells, seen in lymphomas and mononucleosis
  • Therapy
    • Keep the patient warm
    • Transfusion can make the hemolysis worse
    • Treat the underlying disorder
    • Corticosteroids are ineffective, Rituximab can be effective

13

What are the major types of drug-induced immune hemolytic anemia?

  • Hapten/drug adsorption, ex. Penicillin
    • Drug binds to red cell membrane, antibody attaches to drug without interacting with the red cell
    • Occurs in a minority of patients exposed; usually with high-dose of drug
    • Red cells are removed by splenic macrophages; anemia develops gradually
    • Direct Coomb’s is positive, indirect antiglobulin test would be positive only with drug-coated red cells
    • Hemolysis stops when medication is discontinued
  • Neoantigen (Immune-complex), ex. Quinidine
    • Antibody develops to a combined antigen, neoantigen, formed by the drug and the red cell membrane.
    • Only small dose of drug is required
    • Complement-mediated lysis
  • Autoimmune mechanism, ex. a-methyldopa, levodopa, procainamide
    • Causes production of an antibody which is directed against a red cell antigen
      • only a minority of patients develop hemolysis
    • Features very similar to autoimmune hemolytic anemia

14

What is paroxysmal cold hemoglobinuria?

  • Formation of Donath-Landsteiner antibodies
    • IgG directed against the P antigen which can cause hemolysis
    • Associated with syphilis
  • Transient attacks after exposure to cold with:
    • fever
    • chills
    • back, leg, abdominal pain
    • headache
    • malaise
  • Coombs may be negative
  • Test for the specific antibody

15

What are some causes of traumatic RBC lysis?

  • Microangiopathic hemolytic anemia
    • Thrombotic thrombocytopenic purpura (TTP)
    • Hemolytic-uremic syndrome (HUS)
    • Disseminated intravascular coagulation (DIC)
    • Malignant hypertension
    • Preeclampsia, eclampsia, HELLP syndrome
    • Cavernous hemangioma (Kasabach-Merritt syndrome)
  • March hemoglobinuria – traumatic red cell destruction after long marches
  • Cardiac valvular disease

16

What are the major acquired RBC membrane disorders?

  • Spur cell anemia
  • Paroxysmal nocturnal hemoglobinuria (PNH)

17

What is spur cell anemia. How is it managed?

  • Hemolysis, peripheral smear notable for acanthocytes
  • Occurs in liver disease – 5% of severe cirrhosis
  • Severe anemia and splenomegaly
  • Due to excess cholesterol but normal phospholipids
    • This is different from target cells that have both an increased cholesterol and phospholipid
  • Transfused cells acquire the same problem
  • Splenectomy may help, but >90% die of the liver disease within a year

18

What is the pathophysiology, presentation, and management of paroxysmal nocturnal hemoglobinuria (PNH)?

  • Pathophysiology
    • Acquired disorder of the stem cells
    • Mutations in phosphatidyl-inositol-glycan A (PIGA)
      • Glycosylphosphatidylinositol (GPI) anchors proteins to lipid bilayer of cells
      • Mutations in PIGA are responsible for GPI-anchored protein deficiencies
      • Leads to complement-mediated lysis of cells
  • Clinical features
    • Venous thrombosis is a major complication, particularly in unusual sites: ex. Budd-Chiari syndrome (hepatic vein thrombosis)
    • Can also be associated with aplastic anemia
  • Laboratory features
    • Chronic hemolytic anemia
      • Can occur at night, therefore hemoglobinuria is visible in the morning
    • Granulocytopenia or thrombocytopenia may also be present
    • Gross hemoglobinuria occurs intermittently but there is hemosiderinuria
  • Diagnosis
    • Acid hemolysis test (Ham test) or sucrose hemolysis test
    • More accurately, flow cytometry for CD 55 and 59
      • ​Lack of these antigens on surface of cells is suggestive of PNH
  • Treatment - Mainly supportive
    • Immunosuppresants may be effective – corticosteroids
    • Eculizumab
    • Allogeneic stem cell transplant