| | Paroxysmal cold hemoglobinuria | Cold agglutinin disease | Cryoglobulinemia |
| Presentation | - Typically in childhood, rarely adults
- Dark (red-brown) urine after cold exposure with fever, chills, back or leg pain
| - Typically in older women (over 70 years)
- Anemia symptoms, acrocyanosis
| - Typically in older individuals (over 60 years)
- Palpable purpura, arthralgias, myalgias, may be chronic for decades
|
| Associated diseases | - Secondary or tertiary syphilis
- Post-viral infection (eg, varicella, measles, mumps, EBV, CMV)
- Post-bacterial infection (eg, mycoplasma, Klebsiella, Escherichia coli, Haemophilus influenzae)
- Post-measles vaccine
- Autoimmune disorders
- Lymphoma or CLL
| - Lymphoma or other lymphoproliferative disorder
- Infection (eg, mycoplasma, infectious mononucleosis)
- Monoclonal IgM gammopathy
- Autoimmune disorders
| - Infections (eg, adenovirus, hepatitis viruses, HIV, bacteria, spirochetes, fungi, parasites)
- Autoimmune disorders
- Inflammatory bowel disease
- Neoplasms (various)
- Lymphoproliferative disorders
- Cirrhosis
- Vaccinations
- Familial syndromes
|
| Clinical findings | - Jaundice
- Hemoglobinemia, hemoglobinuria, and hemosiderinuria
- Raynaud phenomenon
- Urticaria
- Anemia
- Neutropenia (rare)
| - Anemia
- Livido reticularis
- Acrocyanosis or Raynaud phenomenon
- Fatigue, weakness, dyspnea
- Hemoglobinuria (less common)
- Dysphagia for cold foods/liquids
| - Small to medium vessel vasculitis
- Macules, papules
- Arthralgias/myalgias
- Peripheral neuropathy
- Raynaud phenomenon
|
| Characteristics of hemolysis | - Intravascular, biphasic
- DAT positive using anti-C3 and negative using IgG, may be negative between episodes
| - Mainly extravascular; possibly intravascular in massive hemolytic crisis
- DAT positive using anti-C3 and negative using IgG (unless patient has an IgG, which may be warm-reacting)
| - Not associated with hemolysis
|
| Characteristics of antibody | - Antigen = "P antigen"
- Cold-reacting IgG
- Polyclonal
- Does not cause RBC agglutination
- Moderate titer (eg, <1:160)
- Binds RBCs and fixes complement; causes hemolysis upon rewarming (Donath-Landsteiner antibody)
| - Antigen = "I" or "i" antigen
- Cold-reacting IgM (rarely IgG or IgA)
- Monoclonal or polyclonal
- Agglutinates RBCs
- High titer (eg, >1:2000)
- Binds RBCs and fixes complement
- Some cold agglutinins are also cryoglobulins
| - Mixture of antibodies and complement
- Cold-reacting IgM, IgG, IgA, or combinations; may be isolated light chains, may be rheumatoid factor positive
- Monoclonal, polyclonal, or both
- Concentration varies, measured in mg/dL
- Precipitates upon cooling of plasma or serum
- Complement may be consumed with immune complexes
- Does not interact with RBCs
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