Cold Agglutinin Disease

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Cold Agglutinin Disease

• Daniel K. Noland MD
• January 28, 2005

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Case History

• 64 year old biology professor who sought medical
  attention because of feeling weak and having
  dark colored urine and stool
• Past Medical History Idiopathic Thrombocytopenic
  Purpura 15 years ago, Hypercholesterolemia
• Past Surgical History hernia repair, vasectomy,
  and appendectomy

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Physical Exam

• General Lethargic and confused
• Vitals Pulse-100, respirations-25-30, Temp 37 C,
  BP 124/67
• Abdomen soft, n-t, no organomegaly
• Skin reticular mottling of legs and hands,
  acrocyanosis resolving in warmer temperatures

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Hospital Course

• Transferred to MCG ICU with a Hemoglobin around
  3
• Transfused multiple units of O negative blood and
  plasmapheresis begun HD 1
• Mental status improved, skin discoloration
  resolved, and Hemoglobin reached 7 HD 2
• Attempted to continue plasmapheresis, but machine
  kept clotting off

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Hospital Course continued

• Mental status began declining again
• Transfused multiple units of Packed Red Blood
  Cells, this time A because he had been
  successfully typed
• HD 3 the patient started having kidney failure
  (creatinine went from normal to 2 to 4 and urine
  output greatly decreased)

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Hospital Course continued

• Fluid then began to back up into his lungs
• When resp reach 40/min he was intubated
• Plasmapheresis was attempted on HD 3 with
  continued clotting off of machine
• HD 4 oxygen requirement increased, Levophed
  needed to maintain BP
• Patient went into Disseminated Intravascular
  Coagulation

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Final Hospital Course

• INR reached 4 despite FFP transfusion
• Dialysis attempted, but cathedor became blocked
  after only 2 hours
• Despite addition of Vasopressin BP decreased and
  patient went into Pulseless Electrical Activity
• Multiple medications were given via ACLS protocol
  before the code was called HD 4

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Cold Agglutinin Disease

• 16-22 of immune hemolysis
• incidence of 1/80k to 1/30k
• can be primary(idiopathic) or secondary
• can be acute(which usually means self-limited) or
  chronic
• Primary is usually chronic and secondary is
  usually transient and caused by infection

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Demographics

• Primary cold agglutinin disease usually occurs
  after the fifth decade of life
• There is no race or sex predisposition
• In 78 people with persistent disease
• 31 had lymphoma
• 13 had Waldenstrom Syndrome
• 6 had CLL
• 24 had chronic idiopathic CAD

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Secondary, Acute CAD

• Usually acute, transient and infectious occurring
  in children and young adults
• Can be more severe in newborns (
• Commonly associated with Mycoplasma pneumoniae,
  mononucleosis(EBV or CMV), other viruses and
  bacteria
• Usually polyclonal(vs mono in primary or
  secondary to neoplasm)

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Pathophysiology

• Usually IgM(sometimes IgG, rarely IgA) with
  specificity for the I (or rarely neonatal i)
  precursor of the ABH and Lewis blood groups
• Binds to RBCs in colder areas of the body
  (extremities, ears, etc.)and fixes compliment
• If sufficient compliment to for MAC activation
  get intravascular hemolysis

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Pathophysiology 2

• Otherwise C3b and C4b cause RBCs to be
  phagocytosed in the lungs, spleen and especially
  liver
• Many unaffected people are walking with titers of
  164 at 4 C, and none at inc temp
• CAD occurs with titers over 11000 and the
  antibodies may react at 28-31 or even 37 C

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Clinical Presentation

• Acrocyanosis(purplish discoloration of digits,
  ears, nose) as well as pain can occur due to
  intra-arteriolar agglutination
• Anemia- the associated anemia is usually mild but
  may result in pallor, fatigue, dyspnea, etc.
• Anemia/pain worse with exposure to cold
• Hemolysis can result in jaundice, splenomegaly,
  and sometimes fever

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Clinical Presentation 2

• MCV increased due to agglutination and
  reticulocytosis
• Smear shows spherocytosis, polychromatophilia,
  and RBC agglutination
• DAT usually for anti-C3 but IgG neg
• Eluate testing is negative
• Urinalysis shows hemoglobinuria, hemosiderinuria
  and elevated urobilinogen
• indirect bili, plasma Hgb, and LDH are inc.

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Prognosis and Treatment

• Most cases are mild and self-limited
• For secondary chronic, treat underlying disease
• For idiopathic, chronic avoid cold (sufficient
  clothing/move to warmer climate) and strenuous
  exercise
• For severe cases hospitalize in high ambient
  temperature room/- heating blanket

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Prognosis and Treatment

• RBC transfusion is indicated in acute, severe
  disease but crossmatching is difficult even if
  reactions are done at 37 C
• Prednisone appears only to be effective in a
  subset with more severe disease, low cold
  agglutinin titer, and high thermal amplitude
• Plasmapheresis may cause temporary dec in titers
  , but antibody production continues...

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Prognosis and Treatment 3

• Chlorambucil has been used successfully in CAD as
  have cyclophosphamide, vincristine and
  fludarabine
• There are no randomized controlled trials and the
  latter three were all used as part of a treatment
  regimen for underlying cancers

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Reasons to Suspect Cold Agglutinins in the Lab

• Listed on requisition
• Hgb and Hct do not match/-3
• MCHC 37
• Will also cause Decreased RBC, Increased MCV and
  MCH
• Can affect WBC and Hgb to a lesser extent

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Solutions for CAD specimens in the Hematology Lab

• When it first doesnt pass Coulter-heated water
  bath then immediately run in secondary mode
• Consider manual hematocrit if above fails
• Severe cases may require washing prior to red
  cell lysis

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Paroxysmal Cold Hemoglobinuria

• Rarest form of DAT positive AutoImmune Hemolytic
  Anemia
• Historically associated with syphilis
• Currently usually acute transient condition
  secondary to viral infections especially in
  children
• Also, idiopathic chronic disorder in older
  patients

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PCH2

• In one study, 0/531 adults with well defined
  hemolytic disease had PCH, compared with 22/68
  kids
• Antibody is IgG which usually binds in colder
  areas of body and then lyze when returned to 37
  C(Donath-Landsteiner test)
• Antibody is polyspecific, reacts with most red
  cells
• transfusion is more often needed in kids

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Cryoglobulinemia

• Cryoglobulins are antibodies that undergo
  reversible precipitation at low temperatures
• Type I(mult. myeloma and Waldenstrom), Type
  II/III(CLL, liver dz, infxns, autoimmune dz) and
  essential (idiopathic)
• Can cause end organ damage(esp renal),
  vasculitis, hyperviscosity, and gangrene
• Morbidity mortality related to underlying dz, but
  always worse w/ renal involvement

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Paroxysmal Nocturnal Hemoglobinuria

• Inability to synthesize GPI (protein anchor)
  leads to hemolysis
• Dark color in am due to urine concentration o/n,
  really breakdown occurs 24 hrs/day
• presents as 1)hemolytic anemia due to compliment
  2) Large vessel thrombosis or 3) dec
  hematopoiesis (mild to aplastic)
• Rare, X(but not linked), insidious and chronic
  (median survival 10.3 years)