Cold Agglutinin Disease



3 Types of Cold Sensitive Antibodies:

  1. Cold Agglutinins (CAD)

  2. Donath-Landsteiner Antibodies[PCH]

  3. Cryoglobulins (Vasculitic Picture)



Epidemiology:

 • 6-7th decade

 • May occur in 30's

 • Mostly women

 • 15% of AIHA



Primary Secondary Cold Agglutinin Disease (CAD): 

 - Idiopathic monoclonal IgM

 - Possibly originate from a low-grade lymphoproliferative disorder



Secondary Cold Agglutinin Syndrome (CAS):

 - Due to Viral infection, autoimmune disorder or lymphoid malignancy (CLL)

 - Monoclonal - Lymphoid Malignancy

 - Polyclonal - Viral Infection



Clinical Presentation - Cold-Induced Circulatory Symptoms:

 • Livedo reticularis

 • Raynaud disease

 • Agglutination in the nose, ears, or fingers

 • Acrocyanosis (Cold-induced symptoms - most common presentation)

 • Cutaneous necrosis

 • Hemoglobinuria

 • Symptoms of anemia include fatigue, pallor, dyspnea, and poor appetite.



Diagnosis:

 • hemolytic anemia

 • Cold agglutinin titer of ≥64 at 4°C 

 • Reticulocytosis 

 • Hyperbilirubinemia

 • Elevated lactate dehydrogenase

 • Positive Coombs testing for anti-C3d and negative anti-lgG 

 • Compensated hemolysis

 • C3↓ C4↓

 • +Immunoglobulin M (IgM)

 • Blood smear - RBC agglutination



After CAD Is Established Check For:

 • Infections: Polyclonal IgM post infectious setting

	- Mycoplasma, EBV, HIV, rubella legionella, varicella, Citrobacter and influenza (younger pts)

 • Underlying malignancies - B-cell malignancies -> CLL (older)

 • Autoimmune disease (younger pts)



Differential Diagnosis Monoclonal IgM Includes Disorders Such As:

 • IgM monoclonal gammopathy of undetermined significance (MGUS), CLL, Myeloma

 • Waldenström macroglobulinemia



Paroxysmal Cold Hemoglobinuria (PCH):

 • Donath-Landsteiner (IgG) antibodies sensitize red blood cells (RBCs) at cold temperatures by fixing complement to the RBCs causing intravascular hemolysis on rewarming

 • Symptoms: High fevers, chills, flank pain, hemoglobinemia and passage of red-brown urine

 • Diagnostic Test: Donath-Landsteiner test



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