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Autoimmune Haemolytic Anemias

Mechanisms of immune hemolysis

INTRAVASCULAR – direct complement mediated

  • Caused by IgM or IgG Abs that fix complement
  • Complement cascade proceeds to the terminal MAC (C5b-9)
    • This requires sufficient activation of the system to overwhelm the complement inhibitors
    • (C1 inhibitor + C4b binding protein) and the RBC’s own defence mechanisms against comp-mediated hemolysis (CD59 + CD55)

EXTRAVASCULAR – phagocytosis by macrophages of RES

  • M of the RES have receptors for the Fc part of IgG and for complement components
  • Presence of IgG and complement on RBCs results in phagocytosis of the er
  • Occurs mainly in spleen or in liver (Kupffer cells)

Cold-Reactive Immune Hemolytic Anemia (IHA) – IgM

  • Mediated by IgM Abs – which react optimally at 4-18oC
  • They bind to cells at the cooler temp of the extremities, fix complement and then dissociate from cell surface after the RBC returns to the warmer temp of central circulation
    • The complement components remain on cell surface after Ab dissociates
  • IgM Abs can cause intra or extravascular hemolysis depending on titre of Ab (↑titre = intravascular hemolysis)
    • Extravascular hemolysis (in the liver) is MC
  • IgM Abs are large enough to bridge between RBCs so are able to cause RBC agglutination by themselves (unlike the smaller IgG Abs)

Cold Agglutinin Disease (CAD)

  • Primary (idiopathic) CAD
    • No obvious precipitating cause.
    • MC in older patients – chronic course
    • Agglutination of erythrocytes on exposure to cold – MC on fingers, toes, nose, ears
    • Associated with CLL/NHL
  • Secondary CAD
    • Assoc with M.pneumoniae/EBV infections
    • Pts are young and otherwise healthy
  • Diagnosis
    • ↓RCC, ↑MCV, ↑MCHC
    • Smear – large round clusters of RBCs (graininess)
      • Re-warming smear to 37oC reverses it
    • DAT/Coombs’ test  – to detect presence of Ab or complement
      • Patient’s cells and Coomb’s reagent (Abs against human IgG/complement) are combined
      • If IgG/comp is present on RBC surface, then the cells will combine (+DAT)
      • In CAD there is complement on the pt’s RBCs but not immunoglobulin
    • IAT/indirect Coombs’ – tests for unexpected anti-RBC Abs in patient’s serum
  • Treatment of CAD
    • Primary CAD – avoid cold temps. Cyclophosphamide. Plasmapheresis
    • Secondary CAD – supportive

Paroxysmal Cold Hemoglobinuria (PCH)

  • Characterised by intravascular hemolysis and consequent hemoglobinuria following exposure to cold
  • Caused by a biphasic IgG Ab (Donath-Landsteiner)
    • Which reacts and fixes comp at cold temps
    • Then after re-warming the comp cascade goes to completion with formation of MAC, which causes intravascular hemolysis
    • Usually directed against the P blood group Ag
  • 3 clinical forms
    • Acute form following infection
    • Chronic form assoc with tertiary/congenital syphilis
    • Chronic idiopathic form
  • Clinical features
    • Back/leg/abd pain; fever, N, V, headache.
    • Dark urine. Severe anemia
  • Diagnosis – DAT is positive for complement but not for IgG
    • Diagnosis confirmed by the Donath-Landsteiner test
      • Pt serum incubated in ice water with group O, P+ RBCs
      • Mixture warmed to 37oC
      • If cells hemolyse on rewarming then the test is (+)
  • Treatment – supportive; avoidance of cold. Transfusion

Warm-Reactive IHA (MC than Cold IHA)

  • Can be primary or idiopathic
  • Most cases are due to underlying conditions (see first diagram)

Pathophysiology

  • IgG Ab in most cases
  • Often react against Rhesus Ag
  • RBC destruction is primarily by splenic macrophages (extravascular hemolysis)
    • Hemolysis is partial, resulting in RBCs shaped like spherocytes
  • There can be some degree of intravascular hemolysis if there is sufficient comp activation

Clinical features

  • Insidious onset of fatigue, weakness and SOB on exertion. Jaundice
  • Fulminant (MC in children) – back, leg, abd pain; N, V; dark urine.

Diagnosis

  • High MCV (due to reticulocytosis)
  • Smear – microspherocytes and polychromasia (pic)
  • DAT is + for IgG
    • DAT- means hereditary spherocytosis

Treatment

  • Treat underlying disease
  • Corticosteroids – prednisolone [1mg/kg/d]
    • Block the M Fc receptors, so prevent phagocytosis
    • Decrease Ab production by the spleen
    • High rate of relapse
  • Splenectomy
  • Immunosuppressive – cyclophosphamide, azathioprine

Drug- Related IHA

  • Hemolysis is mostly of the warm-reactive type

3 mechanisms of drug-related IHA

  • Drug adsorption (penicillin) type
    • Drug binds tightly to RBC surface, and an anti-drug Ab reacts with the drug bound to the RBC
    • DAT is + for IgG
    • Mostly extravascular hemolysis by spleen
    • Subacute hemolysis is MC (severe hemolysis is rare)
    • Mostly seen with high doses of penicillin
  • Neoantigen (immune complex) type
    • Complex of drug and anti-drug Ab, which binds to an Ag on RBC
    • Ab can be IgG/IgM – often fixes complement
      • Then dissociates from cell surface
    • Hemolysis is intravascular, usually sudden and severe
      • Can be assoc with ARF
    • Can occur even with low doses of medication – e.g. cephalosporins, quinine
  • Autoimmune (α-methyl dopa) type
    • Ab is directed against an RBC Ag, not against the drug itself
    • Similar characteristics to idiopathic warm IHA
    • Seen in pts taking methyl dopa/levodopa/procainamide

Clinical features

  • Insidious fatigue, pallor, jaundice
  • Patients with neoantigen type – hemoglobinuria

https://upload.wikimedia.org/wikipedia/commons/thumb/1/1c/Coombs_test_schematic.png/800px-Coombs_test_schematic.pngTreatment

  • Discontinue possible medications
  • Transfusions for pts with severe hemolysis
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