2.13.08 cold agglutinin rogers
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Cold Agglutinins
Jennifer L. Rogers, MD
2/13/08UNC Internal Medicine
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Overview
Introduction
Cold Agglutinin Disease
• Pathophysiology
• Clinical presentation
• Diagnosis
• Differential
• Treatment
Summary
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Autoimmune Hemolytic Anemia
Immunologic destruction of RBCsmediated by autoantibodies againstantigens on the RBC surface
Classified by isotype (IgG, IgM, IgA) andthe temperature at which they maximallyreact
In general, cold-reacting antibodies areIgM and warm-reacting antibodies are IgGcausing extravascular hemolysis
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What does cold and warmagglutinin mean?
Based on immunology of cold agglutinins
Cold AIHA IgM-RBC agglutination occursat 4
o
C without the use of antiglobulin
Warm AIHA IgG-RBC agglutination occurswhen RBCs are incubated withantiglobulin antisera at 37
o
C for 2 hrs
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Cold-Induced Hemolysis
Two different clinical entities due to cold-reacting antibodies:
• Cold Agglutinin disease
• Paroxysmal cold hemoglobinuria
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Cold Agglutinin Disease
Characterized by IgM antibodies (rarely IgA orIgG) directed against polysaccharide antigens(anti-I or i) on the RBC surface
Cold agglutinins found frequently in normaladults at low titers
Pathology results with high titer antibodyproduction:
• Oligoclonal antibodies due to infection• Monoclonal antibodies due to paraneoplastic or
or neoplastic process
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Postinfectious
Oligoclonal antibody usually with a kappalight chain
Commonly moderate titer cold agglutinin
Titer peaks 2-3 weeks after the onset ofinfection and can persist for 2-3 months
Hemolysis usually mild lasting for 2-4weeks
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Associated Infections
Mycoplasma pneumoniae (anti-I) 50-75%
Infectious mononucleosis (anti-i) 60%
Other viruses: CMV, Varicella, Rubella,Parvovirus B19, Hepatitis B, HIV, Influenza B
Listeria monocytogenes (anti-I)
Other bacteria: Legionella pneumophila,Chlamydia psittacosis
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Monoclonal Cold Agglutinins
Paraneoplastic or neoplastic growth of animmunocyte clone
Kappa light chain anti-I antibodies Spectrum from benign chronic cold agglutinins
to high-grade malignant lymphoma• CLL, Waldenstrom’s macroglobulinemia, lymphocytic
lymphoma
5-10% patients with chronic cold agglutinins
develop a malignant clone• Trisomy 3 Titer can be used as a tumor marker
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Epidemiology
Cold-agglutinin disease constitutes 7-25%of AIHA cases
Incidence is roughly 1 in 300,000
Average age is >60 and peaks in 70s-80s
No racial predilection
More common in women 1.5:1
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Pathophysiology of Hemolysis
RBC destruction occurs mainly byimmunoadherence mediatedindirect lysis resulting inextravascular hemolysis by
phagocytic cells in liver(spherocytes, elevated LDH/bili)
Can also occur by complement-mediated direct lysis if sufficient
polymers are produced resulting inintravascular hemolysis(hemoglobinemia, hemoglobinuria,hemosiderinuria)
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Immunoadherence
IgM antibody fixation to antigen occurs at peripheralareas where temperature is low enough to bind
Complement is then activated resulting in C3 and C4binding
Phagocytosis then occurs (phagocytes do not have IgMreceptors unlike IgG, IgA)
Hemolysis limited by enzymes that inactivate C3 and C4resulting in C3d
IgM dissociates from antigen when blood returns to thecore of the body thus also limiting hemolysis
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Severity of hemolysis
Amount of hemolysis depends upon:
• Antibody titer ( the higher the titer, themore hemolysis)
• Thermal amplitude (the higher the temp,the more hemolysis)
• Degree of antibody inhibition by C3d
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Clinical Presentation
Signs and Symptoms
Related to anemia and hemolysis
• Dyspnea, fatigue, tachycardia• Scleral icterus, splenomegaly
Related to cold exposure• Acrocyanosis
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Diagnosis
Hemolytic anemia
• Elevated LDH, indirect bilirubin, reticulocytecount
• Decreased haptoglobin
Spurious macrocytosis
• RBC agglutination due to cooling during
automated counting
Agglutination on peripheral smear
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Peripheral Smear
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Diagnosis
Direct antiglobulin test (Coombs’ test)
• Positive anti-C3d
• Negative anti-IgG
Cold agglutinins titer
• Upper limits of normal 1:40
• Hemolysis usually occurs at titers >1:500
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Direct Coombs’ Test
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Differential Diagnosis
1. Anti-IgG Positive + Anti-C3 Negative -
Idiopathic Warm AIHA, Drug induced warm AIHA
(penicillin, methyldopa)2. Anti-IgG Positive + Anti-C3 Positive +
SLE, idiopathic warm AIHA, rarely drug associated
3. Anti-IgG Negative - Anti-C3 Positive +
Cold agglutinin disease, Paroxysmal coldhemoglobinuria, rarely warm AIHA if low-affintiy IgG
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Treatment
Depends on underlying etiology
Treat the infection
Supportive care
Transfusion
• ABO typing can be difficult
• If unclear typing, use group O RBCs
Avoidance of cold
• Warm IVF, blood products
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Treatment cont.
Prednisone
Not useful for cold agglutinin disease
Can be used if IgG co-antibodies
Splenectomy
Not useful because the liver is the main site of
immune clearance
Can be used if IgG co-antibodies are present
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Rituximab
Rituximab anti-CD20 monoclonal antibody
Mostly case reports and small prospective trials
Prospective uncontrolled study of 27 patients
treated with Rituxan. (Berensten)
• 54% response rate with 1 complete remission,19 partial responses over 11 months.
Prospective study of 20 patient, phase II trial. 5doses over 22 days, followed 48 weeks. (Schollkopf)
• 45% response to treatment with 1 CR, 8 PR
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Plasmapheresis
Adjunctive treatment to remove IgMantibody
Effect is short lived with 5 day half life
Used for severe hemolysis in acuteinfection when thermal amplitude is high
Used in preparation for surgery Severe acrocyanosis
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Other Agents
Cyclophosphamide, azathioprine,interferon, and fludarabine have beenused to suppress IgM synthesis
Generally not useful, response rates <20%One on-going phase II trial using Rituxan
and fludarabine “preliminary results
encouraging” (Berensten)Chemotherapy should be used to treat
underlying lymphoma or malignancy
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Take Home Points
Cold agglutinin disease AIHA due to IgMantibodies
Infection (Mycoplasma or Infectious Mono)
Monoclonal antibodies as part of spectrum frombenign cold agglutinins to malignant lymphoma
Coombs test: Positive anti-C3, negative IgG
Treatment: Supportive, avoid cold, treatunderlying disease. ?Rituxan
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References
Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia.Hematology Am Soc Hematol Educ Program. 2004 (1) 48-62.
Gertz M.A. Cold Hemolytic Syndrome. Hematology Am Soc Hematol. 2006; 19-23. Berensten S et al. Rituximab for primary chronic cold agglutinin disease: a
prospective study of 37 courses of therapy in 27 patients. Blood. 2004 Apr15;103(8):2925-8.
Berensten S et al. Primary chronic cold agglutinin disease: an update on
pathogenesis, clinical features and therapy. Hematology. 2007 Oct; 12(5) 361-70. Schollkopf C et al. Rituximab in chronic cold agglutinin disease: a prospective study
of 20 patients. Leuk Lymphoma. 2006 Feb;47(2)253-60. Berensten S et al. B-lymphocytes as targets for therapy in chronic cold agglutinin
disease. Cardiovasc hematol Disord Drug Targets. 2007 Sep;7(3)219-27. Jacobs A. Cold agglutinin hemolysis responding to fludarabine therapy. Am J
Hematol. 1996 Dec 53(4):279-80.
Koppel A et al. Rituximab as successful therapy in a patient with refractoryparoxysymal cold hemoglobinuria. Transfusion. 2007 Oct;47(10): 1902-4. Uptodate.com