At a Glance

Vasculitis is an inflammation of the blood vessel wall. In some cases, the vasculitis may result from immune complex deposition along the vessel wall, leading to a proinflammatory response. Cryoglobulins are antibodies that precipitate from the serum at cold temperatures, then redissolve when the temperature of the serum increases. Cryoglobulins can cause vasculitis, referred to as cryglobulinemic vasculitis, that is immune-complex mediated.

There are three classes of cryoglobulins designated type I, type II, and type III. Type I cryoglobulins are monoclonal immunoglobulins and are generally associated with a hematopoietic malignancy. In contrast, type II and type III, also known as mixed cryoglobulins, result from a mixture of immunoglobulins. A type II cryoglobulin is a monoclonal IgG or IgM with a background of polyclonal immunoglobulin. A type III cryoglobulin is a mixture of polyclonal immunoglobulin in the absence of a monoclonal antibody.

Type II and type III cryoglobulins are associated with infection or autoimmune disease. It has been estimated that 80-90% of type II cryoglobulins result from hepatitis C infection, whereas type III cryoglobulins are more associated with autoimmune diseases. In addition, type II cryoglobulins, like type I cryoglobulins, have rheumatoid factor activity, whereas type III cryoglobulins do not. In most cases of cryogloublinemic vasculitis, the cryoglobulin is a type II or type III.

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Cryoglobulinemic vasculitis is generally considered a small-vessel vasculitis. The most commonly affected organs are the skin, peripheral nerves, and kidney. Patients with cryoglobulinemic vasculitis may present with palpable purpura, especially on the lower legs, which is the most frequent dermatologic manifestation. Patients may also show signs of mononeuritis multiplex, arthralgias, and glomerulonephritis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Patients with cryoglobulinemic vasculitis often have evidence of a systemic inflammatory response, which can be seen as an elevated erythrocyte sedimentation rate (ESR), an elevated C-reactive protein (CRP), and anemia. Additionally, most patients have substantially decreased concentrations of complement proteins C3 and C4 because of the consumption of complement that occurs after activation through the immune complex formation in the vessel wall. C4 is often substantially decreased and may even be undetectable. Measurement of rheumatoid factor may also be useful, since both type I and type II cryoglobulins have rheumatoid factor activity.

If cryoglobulinemic vasculitis is suspected, the diagnosis can be confirmed by assessment for cryoglobulins. This assessment involves incubating a serum sample at refrigerated temperatures for several days and then measuring the amount of precipitate formed. This is referred to as the cryocrit. If a cryoprecipitate forms, the particulate matter can be immunophenotyped to determine the specific classification of the cryoglobulin. (Table 1)

Table 1
Cryoglobulin analysis Complement C3 and C4
Measurement of cryocrit, which reflects amount of cryoglobulin, and immunophenotyping to characterize cryoglobulin as type I, type II, or type III Concentrations would be significantly decreased because of activation of the complement pathways following immune complex deposition in the vessel walls.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Cryoglobulin analysis is subject to significant preanalytical variables. Blood samples for cryoglobulin analysis must be collected in prewarmed tubes, and the sample must be maintained at 37°C until the blood clot has formed and the serum has been separated. If the sample cools below this temperature, it is possible that the cryoglobulin could begin to precipitate and would be lost when the serum is separated from the blood clot. False negative results are possible if blood collection and processing is not performed appropriately.

What Lab Results Are Absolutely Confirmatory?

In the context of compatible clinical symptoms, presence of a cryoglobulin is highly suggestive of cryoglobulinemic vasculitis. In addition, a biopsy of the affected organ, possibly skin or the kidney, may be useful in confirming diagnosis. In the skin, pathology usually shows evidence of leukocytoclastic vasculitis with immunoglobulin (IgG or IgM) and complement (CD and C4) deposition. In the kidney, there may be evidence of membranoproliferative glomerulonephritis, again with immunoglobulin and complement deposits.