Hemolysis

    .

     

    General Approach

    • Increased destruction anemia.
    • Many patients with hereditary hemolysis have low-grade compensated hemolysis, and often decompensate when a production issue is introduced (i.e. Pavrovirus B19 infections).

     

    Etiology

    • Hereditary
      • Abnormal Membrane (Spherocytosis, elliptocytosis)
      • Abnormal Enzymes (Pyruvate kindase def, G6PD def)
      • Abnormal Hemoglobin (thalessemias, hemoglobinopathies, sickle cell)
    • Acquired
      • Immune
        • Hemolytic transfusion reaction (AHTR)
        • Autoimmune hemolytic anemia (AIHA)
          • Warm AIHA
          • Cold AIHA
        • Drugs (i.e. penicillin)
        • Cold agglutinins
      • Non-Immune
        • Microangiopathic HA (MAHA) (thrombus in blood vessel shears cell)
        • DIC, HUS/TTP, pre-eclampsia/HELLP, vasculitides, malignant HTN.
      • Others:
        • PNH, hypersplenism, etc… mechanical heart valves

     

    HemolyticAnemiaApproach2.png

    Diagnosis

    • Symptoms:
      • Anemia (Exertional dyspnea, fatigue, etc...)
      • Jaundice, scleral icterus, gall stones (usually chronic congenital), splenomegaly.
    • Suspect:
      • Rapid Hb drop, no bleeding, increased retics, Plasma free Hb incr, elevated bilirubin (unconj), incr urobilinogen, AST (and not ALT), LDH, low or absent haptoglobin, urinary hemosiderinuria, coombs test
    • Labs:
      • 4 Cardinal Labs:
        • 1. High LDH
        • 2. High Bilirubin (indirect)
        • 3. Low haptoglobin
          • NOTE: LDH + Haptoglobin are 90% sensitive for hemolysis
        • 4.  Morphologic Changes in Erythrocytes  on Peripheral Smear
      • DAT (Direct Antiglobulin Test)
        • Used to evaluate immune-mediated hemolysis (one of many). 
        • Often part of initial workup.
        • Includes Ig, and 3rd component complement on RBCs
        • Direct Coombs’ Test (aka DAT - Direct Antiglobulin Test
          • Detects antibodies or complement on the surface of RBCs
          • Indications: (Hemolytic Disease of Newborn, Warm AIHA, Hemolytic Tfsn Reaction)
        • Indirect Coombs' Test
          • Detects antibodies in patient's serum (mix patient's serum + donor RBCs, check with Coumbs' Anti-Ig Ab)
          • Indications: Crossmatching, Atypical Blood Groups, AIHA, Blood Antibodies in Pregnant Women.
      • (detects IgG or complement on surface of RBC)
      • High Reticulocytes

     

    •  

      Intravascular

      Extravascular

      Hemoglobinemia

      +

      - (+ in severe cases)

      Hemoglobinuria

      + (free Hb in blood)

      - (+ in severe cases)

      Haptoglobin

      Absent

      Reduced(absent if severe)

      Hemosiderinuria

      Present

      Absent

      LDH

      Grossly Elevated

      Elevated

      Jaundice

      Present

      Present

      Splenomegaly

      Absent

      Present

      Blood film

      SchIstocytes (helmets)

      SphErocytes

      DAT

      Usually -

      Often +

     

     

    Treatment

    • Based on underlying disorder.
    • All pts with Chronic Hemolysis
      • Folic Acid Supplementation (1mg/day).
      • Make patient aware their Hb can rapidly drop if get BM suppression (i.e. classically Pavrovirus B19 infection).

     

    Hereditary Hemolytic Anemia

    Hereditary Spherocytosis

    • Most common congenital chronic hemolytic anemia (1 in 2000 in North European descent).
    • Pathology:
      • Autosomal dominant, but can be sporatic with variable penetrance.
      • Unstable membrane due to mutations (i.e. Ankyrin and other ankoring proteins lead to spectrin deficiency --> results in cytoskeleton dysfunction and loss of erythrocyte area).
        • Destabilizes the erythrocyte membrane/structure --> spherocytic shape.
        • Reduced deformibility --> trapping and destruction in the spleen.
    • Symptoms:
      • Hemolysis symptoms (anemia, jaundice, splenomegaly, gall stones).
        • Suspect if relatives also have this history.
      • Range from severe neonatal jaundice to aplastic crisis from Pavrovirus B19 infection.
      • Many diagnosed in late adulthood with enlarged spleen (mildly anemic and asymptomatic).
    • Labs:
      • Classically Osmotic Fragility Testing --> only tells you there are spherocytes (does not help with cause)
        • Put RBCs into hypotonic solutions, as water rushes in, biconcave shapes can sustain more water influx, and spherocytosis already inflated can burst.
      • MCH (Mean Cellular Hemoglobin Concentration)
        • Goes up with spherocytosis, sometimes used to help diagnosis.
      • Need to have negative DAT.
      • Peripheral Blood Smear:  See spherocytes (loss of biconcave shape).
        • Can also get this with warm hemolytic anemia
        • spherocytosis.jpg
    • Treatment:
      • If asymptomatic:
        • No treatment.
        • Sometimes replace folic acid, and counsel on looking out for pigment gallstones.
      • If symptomatic:
        • Indications for Treatment of Hereditary Spherocytosis:

           1.  Symptomatic anemia

           2.  Painful splenomegaly

           3.  Recurrent billiary stones

           4.  Failure to thrive

        • Require treatment.
        • Laparoscopic splenectomy
          • Then VACCINATE gainst encapsulated organisms including pneumococcus, H.influenzae, Meningogoccus, etc.. !!!

    G6PD Deficiency

    • G6PD is an enzyme, and most common RBC enzyme defect --> affecting >200 million people worldwide.
      • Glucose-6-phosphate dehydrogenase.
    • X-linked (see almost exclusively in men)
    • Disease caused by various G6PD mutations on the X-chromosome
      • Different mutations = different G6PD activity.
      • X-linked, so more common in males. 
      • More often african american descent.
      • Mutations thought to protect against Plasmodium falciparum (malaria).
        • RBC cannot generate NADPH and maintain glutathione in reduced state --> causes hemolytic anemia.
    • Two main variants:
      • African American Variant (more common)
        • causes episodic hemolysis in response to oxidant stressors (drugs!).
          • Big Three that trigger hemolytic anemias:
            • Dapsone
            • Trimethoprim Sulfa
            • Nitrofurantoin
            • Others (less common)
              • Phenazopyridine - used as urinary anesthetic
              • Rasburicase - metabolizes uric acid.
      • Mediterranian Variant (less common)
        • Leads to chronic hemolysis.
        • Worsens after ingestion of fava beans (can be fatal hemolytic anemia).
    • Labs:
      • Can measure G6PD level (elevated?).
        • In African American (AA) variant, elevated levels of G6PD found in young reticulocytes --> hence can be falsely normal during hemolytic episode.
        • When hemolyzing will destroy older cells, so will measure normal levels.
        • Hence: In AA variant wait several months after a hemolytic event before measuring G6PD.
      • **Peripheral Smear**:
        • See bite cells! aka helmet cells DURING ACUTE HEMOLYTIC EPISODE.
        • Brilliant cresyl blue stain reveals heinz bodies (denatured oxidized hemoglobin)
          (Brillian cresyl blue generally used for counting erythrocytes).
          • biteCells.jpg
    • Treatment:
      • Once diagnosed:
        • Counsel not to receive drugs that cause oxidative hemolysis (Big Three):
          • Dapsone
          • Trimethoprim Sulfamethoxazole
          • Nitrofurantoin
      • During hemolytic crisis:
        • Supportive (avoid/withdraw from responsible drug)
        • Treat underlying infection (oxidative stress).
      • NOTE: when AA variant has hemolytic episode, begins to retic.  AA variant retics have high G6PD levels --> improves hemolysis even if offending drug is continued.

    Acquired Hemolytic Anemias

    • Must do family history and personal history to avoid missing a hemolytic anemia. 

    Intro Autoimmune Hemolytic Anemia (AIHA)

    • Most common is IgG (80%) and IgM (20%)
    • Causes:
      • Idiopathic
      • Autoimmune
      • Lymphoproliferative
      • Malignant
      • Infectious
      • Drug-Related.
    • Classified by the temperature at which autoantibodies bind RBCs.

     

    Warm AIHA

    • Caused by IgG antibodies
      • Bind RBC Rh antigens close to body temperature.
    • Antibody-coated RBCs are bound to Fc receptors in splenic macrophages, which causes partial phagocytosis of RBCs creating spherocytes.
      • Warm AIHA --> See spherocytes (NOT schistocytes).
      • Looks identical to hereditary spherocytosis, but not congenital. 
    • Clinical Features
      • Jaundice, mild splenomegaly.
      • Peripheral smear: spherocytes.
      • Diagnosis: DAT  (aka Direct Coombs Test) is positive for IgG on RBC surface.
        • 10% negative, if still suspect do a more sensitive Coombs ("super coombs").
        • (negative or weakly positve for complement)
        • Peripheral Smear: Spherocytes (extravascular hemolysis)
        • Coombs Test (DAT) --> Positive for IgG, +/- complement
    • Treatment
      • Corticosteroids
        • Interfere with antibody production and macrophage clearance.
        • Prednisone usually 1mg/kg/day + prolonged 2-4w taper. 
        • 2/3 respond. 
      • Splenectomy
        • Indications: non-responders, or relapse or chronic steroids. 
        • 1/3 develop normal Hb, 1/3 have acceptable Hb, and 1/3 don't respond.
      • Others:
        • Rituximab (Monoclonal CD-20 antibody)
          • Beneficial in non-randomized trials for refractory Warm AIHA. 
        • Danazol (Synthetic androgen - immunedeficient).

     

    Cold AIHA

    • Caused by IgM antibodies
      • Usually binds I or i antigen (big I, little i)
    • Bind occurs at temperatures <37°C, with max activity ~4°C
    • Pathology:
      • When exposed to cold - tip of nose/finger --> causes cold agglutinin disease.
      • Efficiently fix complement --> RBC clearance by direct intravascular hemolysis or binding macrophages in liver (Kupffer Cells)
      • Reverses with rewarming.
    • Clinical Features:
      • Anemia --> mild-to-mod, chronic, worse in cold temperatures.
      • EBV and mycoplasma can trigger.
        • Peripheral Smear: clumping/agglutination of RBC's
          (... as slides are kept at low temperature.)
          • Clumping = astronomically high MCV.
        • Coombs Test (DAT) --> Negative for IgG, positive for complement.
          • (IgM doesn't stay on RBCs very long, so instead of IgM,  just look for complement)

         
      • Most have clonality, and have underlying lymphoma.
    • Treatment:
      • Avoid cold temperature.
        • When infusing blood products or fluids (use warm solutions)
        • Wear gloves, mittens, etc..
        • Move to warm environments 
      • Other:
        • Chlorambucil, cyclophosphamide, rituximab
      • If severe, use plasmapheresis to clear IgM (large, stays in blood stream, does not diffuse out)
      • NOTE: corticosteroids and splenectomy are ineffective (complement mediated hemolysis, in liver)
      • Transfusion:
        • Challenging, difficult to cross-match.  Only transfuse when necessary
        • But do not hold back for angina and CNS symptoms.
        • High risk of acute or delayed hemolytic transfusion reaction.
          • Communicate with blood bank, use blood warmer, most compatible
          • NOTE: even patient's own blood won't be compatible.

     

    Drug-Induced Hemolytic Anemia

    • Caused by drug or drug metabolite or induced antibody interaction with RBC membrane.
    • Typically days or weeks after drug initiation.
    • Identify causative agent difficult (drugs, herbals etc..)
    • Many drugs can cause this:
      • 2nd + 3rd gen cephalosporins (MOST COMMON)
      • chemo drugs
      • MANY kinds
    • Clinical Features:
      • Testing for drug-induced antibodies is suboptimal
      • Sometimes DAT positive for IgG, C3, both or neither. (positive DAT in 1-2% of hospitalized pts)
    • Treatment:
      • Stop the drug
        • Usually hemolysis resolves after stopping drug, but can prolong with certain agents like fludarabine.

     

    Microangiopathic Hemolytic Anemia (MAHA)

     

     

     

    Paroxysmal Nocturnal Hemoglobinuria (PNH)

     

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