Hemolytic Anemia

Anemia due to shortened survival of RBCs due to premature destruction; numerous cause including inherited and acquired conditions, acuity ranges from hyperacute to chronic, and severity runs from mild to fatal.

  • Key finding: increased reticulocyte count not explained by recent bleeding or correction of nutrient deficiency (n.b.: when assessing an anemic patient, always send reticulocyte count prior to transfusion – reticulocyte count is the most important laboratory test in differentiating etiologies of anemia)
  • Other suggestive findings of RBC destruction are elevated LDH and bilirubin, decreased haptoglobin and spherocytes on peripheral smear
  • Major forms: Warm Autoimmune Hemolytic Anemia (WAIHA), Cold Agglutinin Syndrome (CAS), Paroxsymal Cold Hemoglobinuria (PCH), Drug-induced Hemolytic Anemia, DIC, Hemoglobinopathies, RBC membrane/enzymatic defects, Microangiopathic Hemolytic Anemias (MAHA), Post-transfusion Hemolysis (AHTR, DHTR), Paroxysmal Nocturnal Hemoglobinuria (PNH), RBC parasitic infection (malaria, Babesia), mechanical hemolysis (aortic stenosis or prosthetic heart valves), osmotic hemolysis from hypotonic fluid infusion, snake envenomation
  • Many classification systems, including by cellular site of defect/activity, immune versus non-immune mediated destruction, site of RBC destruction (intravascular versus extravascular), acuity/duration (acute versus chronic)
    • Immune hemolysis is RBC destruction by antibodies and/or complement bound to RBC surface
      • Characterized by positive direct antiglobulin test (DAT, or in antiquated medicine parlance, “direct Coombs test”) and/or positive indirect antiglobulin test (“indirect Coombs test”)
      • g.: AIHAs, drug-induced hemolysis, hemolytic transfusion reactions, PCH, CAS

 

  • General Approach:
    • If initial evaluation suggests presence of potentially life-threatening hemolytic process (e.g.: MAHA, DIC, acute transfusion reaction or fulminant AIHA, contact specialists immediately (Hematology and Transfusion Medicine)
      • Life-saving interventions should not be delayed while waiting for results of diagnostic tests!
    • Obtain peripheral blood smear and DAT (“direct Coombs” – though the lab never refers to this test by that name) ASAP
      • If peripheral smear suggests hereditary hemolytic anemia due to hemiglobinopathy, metabolic defect or membrane defect, then more specific testing should be pursued; spherocytes or schistocytes support active hemolytic process
      • If DAT is positive, immune-mediated hemolysis is most likely etiology, and specific additional testing may be warranted (see table below)
      • If DAT is negative, immune-mediated process is less likely, and specific additional testing as suggested by H&P should be considered
      • b.: DAT testing performed in Blood Bank, not Core Lab; results can often be obtained in <30 minutes if you ask nicely
    • There is no specific diagnostic test for hemolytic anemia, but increased LDH, low haptoglobin and elevated unconjugated bilirubin supports the Dx, as does an elevated reticulocyte count
    • “Classic” presentations:
      • Anemia with TCP and numerous schistocytes = Thrombotic microangiopathy (TMA)/MAHA (e.g.: TTP, HUS, drug-induced TMA)
      • Rapid onset of fever, back pain, dark urine, pink plasma post-transfusion = AHTR
      • Life-long anemia, splenomegaly, abnormal RBC morphology = inherited spherocytosis, elliptocytosis, stomatocytosis
      • Rapid hemoglobin drop after drug exposure, blister or “bite” cells on smear = G6PD deficiency

 

  • Warm Autoimmune Hemolytic Anemia (WAIHA)
    • Most common immune hemolytic anemia
    • Hemolysis is primarily extravascular, and usually mediated by pan-reactive IgG autoantibodies; On blood bank compatibility testing, autoantibodies typically demonstrate reactivity versus ALL RBC units tested (i.e.: no “fully compatible” units can be found)
    • Etiologies: Idiopathic or secondary to underlying malignancy (e.g.: CLL, lymphoma) or autoimmune disease (e.g.: SLE)
    • Associated conditions include development of lymphoproliferative disorders or venous thromboembolism
    • Diagnosis made when the 3 following are present:
      1. Hemolytic anemia
      2. Spherocytes on peripheral blood smear
      3. Positive DAT (IgG and/or C3d)
  • 20% have IgG alone, 13% C3d alone, 67% positive for both
    • After Dx of WAIHA made, assessments and testing for underlying associated conditions is appropriate
      • e.: serological testing for autoimmune diseases, particularly SLE, imaging and peripheral blood smear for malignancies and lymphoproliferative disorders
    • Treatment:
      • Corticosteroids are first-line therapy: 1-1.5 mg/kg/day prednisone or equivalent
        • Response usually seen in 24-72 hours
        • May require high doses for 10-14 days
      • Search for, and address, secondary causes, especially potentially causative drugs
      • Secondary treatment options (consider if no response to steroids or persistent dependence on high doses): splenectomy, rituximab
      • Third-line agents (for resistant disease only): Bortezomib, IVIG, danazol, azathioprine, cyclophosphamide, cyclosporine, mycophenolate, alemtuzumab, PLEX (?)
      • If anemia is symptomatic or accelerating, consider supplemental oxygen to maintain DO2 (dissolved oxygen in blood stream may be physiologically important and prevent organ injury under these conditions)
      • Supplementation with low dose folate has been suggested while hemolysis is ongoing
    • Transfusion Support:
      • Transfusion should only be performed in close consultation with Transfusion Medicine/Blood Bank; contact Blood Bank Medical Director early, particularly if transfusion support is considered possible
      • Consideration of transfusion should be a careful decision based upon considerations of cardiopulmonary reserve, magnitude of anemia, pace of hemolysis, and anemia-attributable organ injury/symptoms
        • Transfusion should NOT be based upon hemoglobin threshold alone, even if level is <7 g/dL!
      • Transfusion carries significant risks: can trigger alloimmune hemolysis, intensify the autoantibody production (inducing or increasing hemolysis), depress compensatory RBC production, or rarely, promote hypercoagulability and DIC
      • Finding optimal RBCs for transfusion may be very challenging for the Blood Bank, so provide as much lead-time as possible if transfusion is being considered
      • In the setting of life-threatening anemia, transfusion should not be withheld solely because of lack of compatible RBCs – “no patient should be allowed to die out of fear of a transfusion reaction”
        • May require use of “Emergency Release” RBC units – RBCs where serological compatibility cannot be guaranteed by Blood Bank
          • Must be requested, and signed for, by physician on treating service, preferably attending
        • Differential Diagnosis:
          • Evans Syndrome – combination of DAT+ WAIHA and immune thrombocytopenia (ITP)
            • Antibodies versus base protein of Rh blood group and GP IIb/IIIa
            • ~50% of cases are idiopathic in origin, but remainder have been associated with HIV, HCV, SLE, lymphoproliferative disorders, CVID, post-HSCT
            • Often resistant to steroid-based treatments for AIHA or ITP; frequently requires second- or even third-line treatments
          • IgM WAIHA – aggressive, severe hemolysis with IgM-type agglutinins that are active at 37C
            • DAT testing often challenging due to spontaneous agglutination, but usually strongly positive for C3d
          • Mixed-type AIHA
            • AIHA with features of both WAIHA and CAS
            • May be more severe and chronic than WAIHA alone
          • AIHA due to drugs
          • Cold Agglutinin Syndrome
          • PCH
          • Hereditary spherocytosis
          • Post-allogenic HSCT AIHA
            • High mortality Cx of HSCT
            • First line therapy fails frequently

 

  • Cold Agglutinin Syndrome (CAS)
    • 16-32% of all immune hemolytic anemias
    • Can be idiopathic or secondary, acute or chronic
      • Acute CAS: usually associated with EBV or Mycoplasma pneumonia infection, with a polyclonal IgM autoantibody
      • Chronic CAS: most often seen in the elderly; associated with Waldenstrom’s macroglobulinemia, CLL, lymphomas, other lymphoproliferative diseases; monoclonal IgM autoantibody.
    • Frequently complicates ABO/Rh typing in Blood Bank
    • Pathophysiology: IgM cold agglutinins bind to RBCs in cooler temperatures of the peripheral circulation, initiate complement fixation, then dissociate when RBCs return to warmer core; residual complement acts as an opsonin or can even activate complement cascade and cause hemolysis
    • DAT: positive for C3d only in >99% of cases
    • Treatment:
      • Avoid cold exposure (including while hospitalized – warm IVFs and blood products)
      • Corticosteroids are rarely effective
      • Immunosuppressive treatment if CAS is severe: rituximab and/or cytotoxic agents
      • Transfusion support:
        • Similar principles to transfusing for WAIHA as above
        • Limit transfusions strictly to those who develop severe anemia of rapid onset and who face cardiopulmonary complications
        • Obtaining “fully compatible” RBC units may be challenging – close consultation with Blood Bank/Transfusion Medicine services essential

 

  • Paroxsymal Cold Hemoglobinuria (PCH)
    • Rarest form of DAT-positive AIHA
    • A post-infectious hemolytic anemia
      • Historically associated with syphilis
      • Now more commonly presents after a viral infection, particularly in younger children
      • Infectious agent usually undetermined, but implicated organisms include: measles, mumps, varicella, coxsackie virus, parvovirus, CMV, EBV, adenovirus, influenza A, Haemophilus influenzae, Mycoplasma pneumoniae, Klebsiella pneumoniae
      • Hemolysis is predominantly intravascular, and due to IgG autoantibody against P antigen on RBCs
      • Antibody binds at cooler temperatures in peripheral circulation and fixes complement; upon returning to central circulation, RBCs are lysed by completion of complement cascade
    • Clinical presentation:
      • Acute onset of fever, malaise, jaundice, pallor, abdominal pain and hemoglobinuria (red, heme-positive urine) in a patient with a recent history of a URI
    • Laboratory findings:
      • As hemolysis is largely intravascular, LDH, bilirubin, haptoglobin not reliable for assessing active hemolysis
      • DAT usually positive for only C3d
      • Definitive test (“Donath-Landsteiner” assay) complex and not routinely performed; if PCH suspected, discuss testing options with Blood Bank
    • Treatment:
      • Usually PCH is a transient illness, so only supportive care is needed
      • Avoid cold exposure
      • Steroids and splenectomy are both ineffective
      • Severity and pace of hemolysis should dictate transfusion needs
        • Compatible RBCs much less challenging to find than for other forms of WAIHA

 

DDx of a positive DAT

With Hemolysis Without Hemolysis
Autoimmune Hemolytic Anemia

(WAIHA, CAS, PCH)

 Hypergammaglobulinemia

(chronic infection, multiple myeloma, IVIG infusion)
Hemolytic Transfusion Reactions

(AHTR, DHTR)

 Drug Effect

(more common presentation)
Drug-induced Hemolytic Anemia

(uncommon presentation)

 Autoimmune Disease

Delayed Serological Transfusion Reaction

Infusion of Antithymoglobulin


Hemolytic Anemia Due to Drugs and Toxins 

    • Can be due to both autoimmune (drug-induced AIHA) and non-autoimmune processes
    • Irrespective of mechanism, still usually results in increased indirect bilirubin and LDH, decreased haptoglobin
    • Drug-induced Oxidative Hemolysis:
      • Results from oxidative attack at both hemoglobin (leading to methemoglobinemia) and RBC membrane, via production of hydroxyl free radicals and superoxides; damage to membranes results in decreased deformability and other derangements leading to RBC trapping in sinusoids and increased phagocytosis
      • Rarely, oxidative damage can be severe enough to cause intravascular hemolysis
      • G6PD deficiency substantially increases the susceptibility to drug induced hemolysis
      • Drugs associated with oxidative hemolysis:
        • Primaquine (especially in those with G6PD deficiency)
        • Amyl/butyl nitrite
        • Benzocaine/lidocaine
        • Dapsone
        • Ribavirin
        • Rifampin
      • Treatment:
        • DISCONTINUE all potential causative drugs immediately!
        • Consider blood transfusion or RBC exchange if shock or severe symptomatic anemia are present
        • If symptomatic methemoglobinemia and patient is NOT G6PD deficient, give methylene blue 1-2 mg/kg IV over 5 minutes
        • Do not give methylene blue if patient is known/suspected to be G6PD deficient – may cause/accelerate hemolysis
      • Immune Drug-Induced Hemolysis
        • Several mechanisms: Hapten, Ternary Complex and Autoimmune processes
        • b.: DAT positivity more common than clinically relevant hemolysis
        • Hapten: drug binds to RBC membrane, antibody then generated against drug
          • DAT strongly positive for IgG, sometimes also positive for C3d
          • Associated with extravascular hemolysis
          • Hemolysis usually gradual, but can become severe if not recognized and drug exposure continues
          • Classically occurs with PCN (especially high doses for >1 week) and penicillin derivatives (e.g.: piperacillin); also described with cephalosporins and tetracycline, 6-mercaptopurine
        • Ternary complex: antibody formed versus neoantigen consisting of drug and RBC membrane
          • Antibody can be IgG, IgM or both; resulting DAT positive for C3d +/- IgG
          • Acute intravascular hemolysis with hemoglobinuria is typical presentation
          • Severe hemolytic episodes can develop with subsequent exposures to even very small amounts of causative drug
          • Many drugs implicated, including quinine, quinidine, rifampicin, amphotericin B, diclofenac, cephalosporins (especially 3rd generation, including ceftriaxone)
        • Autoimmune: drug induces autoantibody against RBC antigens (usually Rh group)
          • Serologically indistinguishable from WAIHA
          • Refer to section on WAIHA above
          • Implicated drugs include L-dopa, procainamide, diclofenac, fludarabine, IBUPROFEN, cephalosporins
        • Other Non-Autoimmune Hemolysis:
          • Lead toxicity
          • Copper toxicity
          • Wilson disease
          • Interferon alfa (usually DAT-positive)
          • IVIG (immune, but not autoimmune hemolysis; usually DAT-positive)
          • Rho(D) Immune globulin (RhIG, RhoGam, WinRho)
          • Insect, spider, snake envenomation
            • In US: Brown recluse spider, pit viper family most common
              • For the latter, obtain antivenom ASAP
            • Artesunate
              • Self-limited process that develops >1 week after treatment of high parasite burden malaria
            • Distilled water (or other very hypotonic solutions)
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