Essential Cryoglobulinemia & Vasculitis

Cryoglobulins are single or mixed immunoglobulins which precipitate when they are exposed to cold and dissolve when warmed. They may be present in small quantities in the blood of some healthy people but are most frequently associated with abnormal protein production in a variety of diseases and conditions. Precipitated cryoglobulins can slow the flow of blood and block small blood vessels. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

Cryoglobulinemia is a medical condition in which the blood contains large amounts of cryoglobulins. Several types of cryoglobulins have been identified, and the potential clinical manifestations vary by cryoglobulin type.

The presence of cryoglobulins in the serum may result in a clinical syndrome of systemic inflammation (most commonly affecting the kidneys and skin) caused by cryoglobulin-containing immune complexes.


Cryoglobulinemia is classically grouped into three types according to the Brouet classification. Type I is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström’s macroglobulinemiaTypes II and III are strongly associated with infection by the hepatitis C virus. Type III is strongly associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.

Type I cryoglobulinemia, or simple cryoglobulinemia, is the result of a monoclonal immunoglobulin, usually immunoglobulin M (IgM) or, less frequently, immunoglobulin G (IgG), immunoglobulin A (IgA), or light chains.

Types II and III cryoglobulinemia (mixed cryoglobulinemia) contain rheumatoid factors (RFs), which are usually IgM and, rarely, IgG or IgA. Types II and III cryoglobulinemia represent 80% of all cryoglobulins.

Clinical features:


Raynaud’s Phenomenon

  • Raynaud’s phenomenon with digital ulceration
  • Acrocyanosis
  • Vascular purpura and cutaneous vasculitis
  • Livedo reticularis
  • Myalgias and joint pains
  • Peripheral neuropathy
  • Arterial thrombosis
  • Occasionally renal failure



Cryoprecipitate at cold temperature and after rewarming

  • FBC, ESR, and Blood Film
  • Renal profile
  • LFTs
  • Hepatitis profile and EBV serology
  • Protein electrophoresis
  • Rheumatoid factor, ANA, and Complement assay
  • Cryoglobulin test: The sample is kept at body temperature (at 37°C) during preparation. The person’s serum is then refrigerated (at 4° C) for 72 hours and examined daily (up to 7 days) for precipitates. If there are any present, then the quantity is estimated and the sample is warmed to determine whether the precipitates dissolve. If they do, then cryoglobulins are present.
  • Urinalysis
  • Chest x-ray
  • Skin biopsy
  • Angiogram
  • Nerve conduction studies


Asymptomatic cryoglobulinemia does not require treatment.

Avoidance of cold to treat mild cases.

Secondary cryoglobulinemia is best managed with treatment of the underlying malignancy or associated disease. Otherwise, cryoglobulinemia is treated simply with suppression of the immune response.

Hepatitis C and mild or moderate cryoglobulinemia are usually treated with standard hepatitis C treatments. Cryoglobulinemia may return back with the discontinuation of the treatment.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used in patients with arthralgia and fatigue.

Immunosuppressive medications (eg, corticosteroid therapy and/or cyclophosphamide or azathioprine) are indicated upon evidence of organ involvement such as vasculitis, renal disease, progressive neurologic findings, or disabling skin manifestations.


Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for reduction of immunoglobulin production.

Rituximab therapy has been used predominantly in HCV-related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral (IFN-alfa) therapy. Rituximab therapy is reportedly well tolerated in this patient population; however, treatment has resulted in increased titers of HCV RNA of undetermined significance.


Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2011 Aug 23.

Adam M Tritsch, MD. Cryoglobulinemia: Background, Pathophysiology, Epidemiology Accessed: June 2016.

Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974). “Biologic and clinical significance of cryoglobulins. A report of 86 cases”. Am. J. Med. 57 (5): 775–88.

Ferri C, Zignego AL, Pileri SA (2002). “Cryoglobulins”. J. Clin. Pathol. 55 (1): 4–13.

Iannuzzella F, Vaglio A, Garini G. Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med. 2010 May. 123(5):400-8.

Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood. 2003 May 15. 101(10):3818-26.

Pramod Kerkar, MD. cryoglobulinaemia: epidemiology, causes, treatment, investigations Accessed: June 2015.

De Vita S, Quartuccio L, Isola M, et al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis & Rheumatism, 64(3), 843–853. DOI: 10.1002/art.33354

Ramos-Casals M, Stone JH, Cid MC, et al. (2012). The cryoglobulinaemias. The Lancet, 379(9813), 348–360. DOI: 10.1016/S0140-6736(11)60242-0

Herrick AL. (2012). Pathogenesis of Raynaud’s phenomenon. Rheumatology, 51(3), 1157–1166. DOI: 10.1093/rheumatology/ker378


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  • Heather Errington

    If I have tested negative for lupus and RA antibodies on labs, is it possible to still have type I? I was unclear as to whether all three types are dependent upon the same rheumatoid immunoglobulins I would have been tested for by my rheumatologist (cardiolipin ab, IGG, IGM, IGA). All results were negative, non fasting, however these and other symptoms persist. I am hoping to determine what doctor to see next. Your website is extremely helpful in this. Thank you in advance!

    • Hi Heather,
      Thanks for your comment.
      You haven’t mentioned the clinical presentation in your case and what was your main presenting symptom?
      Type I cryoglobulinemia is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström’s macroglobulinemia. Have you had your serum immunoglobulins, serum protein electrophoresis, serum free light chains, and BJP in the urine checked?

  • Heather

    Hello again, and thank you for the reply. A neurologist referred me to a rheumatologist based on what he felt was lupus symptoms – raynauds, a rash, brain fog, pain, abdominal discomfort. He also referred me to a hematologist for bleeding (mainly gums), and also tiny under the skin red spots that break open and bleed (separate from the rash, which is red, raised, and itchy). Then, he referred me to a pain management doctor for my primary complaint of bone pain, mainly my spine, that left my feet numb and tingly as well as my hands. Hands go numb while using them and in the morning, feet are discolored purple and tingly most of the time. The back pain is severe, making it difficult to sleep, and has begun causing shoulder and leg pain as well as an expanding pressure type headache at the base of my skull that wraps towards my ear, ending behind my right eye.
    Everything seems to begin with my spine, or rather can be traced back to it. I am 36 with low vitamin D (13L), spinal stenosis, degenerative disc disease, calcified discs… however the only lab work that has been done was the CBC, and the lupus screening -bloodwork only, no urine. She ran sm /rnp antibody, C-reactive protein, cardiolipin ab (iga, igg, igm). Due to the bone pain and degree of stenosis/degeneration on my spine for my age, plus the CNS symptoms, my concern was myeloma of the spine. Naturally, with how rare it is, I was not sure if it was included in the panels she ran or would even show up as an abnormality in a CBC. The discoloration on my feet looks very similar to the cryoglobunemia pictures included in your article.

  • Hi Heather,
    Thanks for your comment and for sharing your experience with us.
    If you are concerened about myeloma, in addition to the investigations I suggested in my previous reply, you can ask your GP or your local Hematologist to arrange an MRI scan spine or better a whole-body FDG PET CT scan to screen your whole body.

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