About the Condition

Description/definition:

Cold autoimmune hemolytic anemia (AIHA) is a condition of acquired uncompensated destruction of red blood cells (RBCs) by autoantibodies to RBC antigens that bind optimally to RBCs at 0-4 degrees C (32-39.2 degrees F), but also react at temperatures above 30 degrees C (86 degrees F). 

Cold autoimmune hemolytic anemia (AIHA) includes:

• Cold agglutinin disease (CAD)
• Paroxysmal cold hemoglobinuria

CAD is traditionally classified as:

1. Primary or idiopathic
   • > 90% of patients with primary CAD are reported to have clonal expansion of kappa-positive B cells in the bone marrow and a monoclonal immunoglobulin M (IgM)-kappa paraprotein
2. Secondary or acquired, caused by
   • Infection
   • Malignancy, especially B cell lymphoproliferative disorders
   • Autoimmune disease

According to a recent international consensus, CAD is defined as “an AIHA with a monospecific direct antiglobulin test (DAT) strongly positive for C3d (and negative or weakly positive with IgG [immunoglobulin G]) and a cold agglutinin (CA) titer of 64 or greater at 4°C. We recognize that there may be occasional cases with CA titer<64. Patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no
clinical or radiological evidence of malignancy.”¹

CAD accounts for approximately 15–25% of autoimmune hemolytic anemias (AIHAs). Prevalence of 5 to 20 cases per million and an incidence of 0.5 to 1.9 cases per million per year.

Pathophysiology:

Cold agglutinin disease caused by complement-fixing antibody (monoclonal immunoglobulin M [IgM] in about 90% of cases) that typically binds to antigens of the I blood group system (rarely the Pr antigen) with maximal reactivity between 0 and 4 degrees C (32-39.2 degrees F), leading to complement-mediated extravascular (and to lesser extent intravascular) hemolysis. Approximately 90% of cold agglutinins have anti-I specificity, while the remaining usually have anti-i specificity.

In primary cold agglutinin disease (CAD):

• Bone marrow displays a characteristic histomorphologic, immune phenotypic, and molecular pattern that has been designated CA-associated LPD.
• > 90% of patients reported to have clonal expansion of kappa-positive B cells in bone marrow and a monoclonal IgM-kappa paraprotein
• Monoclonal cold autoantibody is often encoded by IGHV4-34 and targets I antigen

Clinical Presentation:

• Onset is usually gradual
• Patients may present with symptoms and signs of anemia, including
  • Fatigue (attribute to both anemia and complement activation)
  • Weakness
  • Dizziness
  • Dyspnea
  • Pallor
• Patients may present with symptoms and signs of hemolysis, including
  • Jaundice
  • Dark urine
  • Hepatosplenomegaly
  • Splenic fullness 
• Patients may also present with history of cold-induced symptoms, resulting from agglutination of erythrocytes in the acral circulation, including:
  • Episodic acute hemolysis; including dark colored urine after exposure to cold, febrile illness, or major trauma
  • Using warm clothing or staying indoors in cold weather
  • Seasonal variation in symptom severity in cool climates
  • Acrocyanosis – in 40-50% of patients
  • Raynaud’s phenomenon
  • Livedo reticularis
• Patients may present with additional symptoms of underlying disease
• Complement-driven exacerbation of hemolysis is common during febrile infections and other conditions with acute-phase reaction.
• Physical findings include:
  • Pallor
  • Jaundice
  • Splenomegaly (rare)
  • Acrocyanosis (bluish appearance of extremities such as toes, fingers, tip of nose, or ears)
• For further information about the physical diagnosis in cold agglutinin disease, click here.
• Labs show:
  • Anemia
    • About 25% found to have severe anemia, defined as hemoglobin (Hb) < 8.0 g/dL.
    • About 35% have moderate anemia, defined as Hb 8.0-10.0 g/dL).
    • About 25% have mild anemia (Hb > 10.0 g/dL).
    • About 10% have compensated hemolysis (no anemia).
  • Hemolysis
    • Blood tests
    • Urine tests – hemoglobinuria has been reported in at least 15% of the patients.
• Positive DAT (see next section)

Diagnosis:

Clinicopathological diagnosis based on demonstrating hemolytic anemia and serological evidence of ant-red blood cell autoantibodies by direct antiglobulin test (DAT).

Suspect diagnosis in patient with:

• Compatible history
• Unexplained chronic anemia (median hemoglobin of 9-10 g/dL in the US population)
• Chronic hemolysis

Confirm diagnosis if:

• DAT positive for complement with or without immunoglobulin (Ig) G – up to 22% of CAD cases may have a positive anti-IgG DAT, in addition to a positive anti-C3d DAT.
• High titer cold agglutinin
  • >1:64 or more.
  • Semi-quantitative assay based on ability of antibodies to agglutinate erythrocytes at 4°C).
• Note: most defining criteria of CAD do not require that anti-I/anti-i specificity be present.

Optional confirmatory tests:

• SPEP showing monoclonal IgM-kappa in serum.
• Cellular kappa to lambda ratio > 3.5 in B cells (fluorescence activated cell sorting [FACS]).
• Cold agglutinin-associated lymphoproliferative disorders on bone marrow histology.

Once diagnosis of CAD is established, evaluate for secondary conditions; tests may include:

• Serum Ig and electrophoresis with immunofixation to identify underlying clonal bone marrow lymphoproliferative disorder often associated with primary CAD.
• HIV, hepatitis B, and hepatitis C testing.
• Anti-double-stranded DNA and antinuclear antibody (ANA) testing to help diagnose autoimmune disorders such as systemic lupus erythematosus (SLE).
• Computed tomography (CT) scan of chest, abdomen, and pelvis to rule out malignant disease.

Treatment:

• Treat if symptomatic anemia, severe circulatory symptoms, transfusion dependence.
• > 70% of patients reported to require therapy.
• Treatment decisions are based on expert opinion; prospective studies to support benefit are lacking.
• Nonpharmacological measures (especially avoidance of cold) are cornerstone of management. Has been shown to alleviate symptoms and may prevent severe exacerbations of hemolytic anemia.
• Supportive transfusions may be required
  • Consider using blood warmer when transfusing RBCs.
  • Blood bank testing for underlying alloantibodies and crossmatch testing should be performed at 37°C.
  • If the cold agglutinin has a broad thermal amplitude, obtaining crossmatch compatible blood may be a clinical challenge.
• Therapies may be aimed to suppress production of aberrant IgM or to inhibit complement-mediated destruction of red blood cells (RBCs)
  • Consider corticosteroids (prednisolone 1 mg/kg/day) or plasmapheresis as a temporary measure to remove IgM autoantibodies, if anemia is severe or life-threatening.
  • Although corticosteroids are a rapid and effective treatment for warm AIHAs, they have not been shown to be as effective in CAD. Retrospective studies have found that <15% of patients respond to corticosteroids, and they require higher doses to maintain remission.
  • Typically treated with one of the following regiments:
    • Rituximab
    • Rituximab plus bendamustine
    • Rituximab plus fludarabine
  • Consider complement system-targeting monoclonal antibody:
    • Eculizumab
    • Sutimlimab-jome (Enjaymo), which has been FDA approved to decrease need for RBC transfusion due to hemolysis in adults with CAD.
  • Surgical intervention, including splenectomy, has been shown to be effective only in patients with IgG-mediated CAD, which represents only approximately 3.5% of patients.

Prognosis:

• The median overall survival of patients with CAD has been estimated to be 12.5 years, similar to that of a general age- and sex-matched population.
• Estimated risk of transformation of the lymphoproliferative bone marrow disorder to aggressive lymphoma is about 3% to 4%.
• Increased risk of venous thromboembolism.