2.13.08 Cold Agglutinin Rogers

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Cold Agglutinins

Jennifer L. Rogers, MD

2/13/08UNC Internal Medicine



Overview

Introduction

Cold Agglutinin Disease

• Pathophysiology

• Clinical presentation

• Diagnosis

• Differential

• Treatment

Summary



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



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



Cold-Induced Hemolysis

Two different clinical entities due to cold-reacting antibodies:

• Cold Agglutinin disease

• Paroxysmal cold hemoglobinuria



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



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



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



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



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



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)



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



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



Clinical Presentation

Signs and Symptoms

Related to anemia and hemolysis

• Dyspnea, fatigue, tachycardia• Scleral icterus, splenomegaly

Related to cold exposure• Acrocyanosis





Diagnosis

Hemolytic anemia

• Elevated LDH, indirect bilirubin, reticulocytecount

• Decreased haptoglobin

Spurious macrocytosis

• RBC agglutination due to cooling during

automated counting

Agglutination on peripheral smear



Peripheral Smear



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



Direct Coombs’ Test



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



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



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



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



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



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



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



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

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2.13.08 Cold Agglutinin Rogers