At a Glance

Why Get Tested?

To determine if symptoms, like sensitivity of extremities to cold, are due to the presence of abnormal proteins called cryoglobulins in the blood, which can be associated with a variety of diseases

When To Get Tested?

When you have symptoms such as a rash, bruising, pain, weakness, joint pain, and/or paleness and coolness of the extremities that occur at cold temperatures

Sample Required?

A blood sample is obtained by inserting a needle into a vein in the arm and collecting the blood in a pre-warmed tube. The sample is kept at or near body temperature during sample preparation.

Test Preparation Needed?

No test preparation is usually needed. An 8-hour fast before sample collection may be instructed to minimize the potential for turbidity (cloudiness) in the sample due to triglycerides.

What is being tested?

Cryoglobulins are circulating proteins, specifically immunoglobulins (i.e., IgG, IgM, IgA or light chains), that clump together (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 and a variety of diseases and conditions. This test detects and measures the relative quantity of cryoglobulins in the blood.

Precipitated cryoglobulins can slow the flow of blood and block small blood vessels. The presence of large amounts of cryoglobulins in the blood, called cryoglobulinemia, can cause symptoms such as bruising, rashes, joint pain, weakness, and Raynaud phenomenon – pain, paleness, bluing, numbness, tingling and coldness in the fingers and toes with exposure to cold. (These symptoms can also occur in people who do not have cryoglobulinemia.) Cryoglobulins can cause tissue damage that leads to skin ulcers and, in severe cases, to gangrene. They can activate the immune system, leading to the deposit of immune complexes in tissues, and cause inflammation, bleeding, and clotting that can affect circulation in organs such as the kidneys and liver.

There are three types of cryoglobulinemia:

  • Type I, which consists of a monoclonal immunoglobulin – a single type of protein that is produced by an abnormal cloned cell. This type is often seen in people with myeloma or lymphoma.
  • Type II, which consists of a mixture of monoclonal and polyclonal immunoglobulins. This type is often seen in people with hepatitis C or other viral infections.
  • Type III, which consists of polyclonal immunoglobulins. This type is often seen in people with autoimmune diseases.

Initial testing does not distinguish between these three types of cryoglobulins, but the proteins involved can be determined through subsequent protein electrophoresis testing.

Common Questions

How is it used?

A cryoglobulins test is used to help detect the presence and relative quantity of cryoglobulins in the blood. It may be ordered along with other tests to help determine or rule out potential causes of cryoglobulinemia. The tests ordered depend on what condition or disease is suspected.

The sample is kept at or near body temperature during sample preparation. The person’s serum is then refrigerated 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.

If the cryoglobulin test is positive, then it will be followed with protein electrophoresis and immunofixation electrophoresis (IFE) testing to determine which type(s) of protein are present as cryoglobulins and which type of cryoglobulinemia the person has.

When is it ordered?

The cryoglobulins test is ordered whenever a person has symptoms that may be associated with cryoglobulinemia. Some of these may include:

  • Bruising
  • Rashes, purpura (purple patches)
  • Joint, muscle pain
  • Weakness, fatigue
  • Raynaud phenomenon, which is characterized by pain, paleness, bluing, numbness, tingling and coldness in the fingers and toes with exposure to cold.
  • Skin ulcers
  • Skin death, gangrene

What does the test result mean?

The cryoglobulins test is negative (no cryoglobulins found) in most healthy people and is not routinely ordered for those without symptoms.

When the test is positive, it means that cryoglobulins are present and have the potential to precipitate upon exposure to cold. The symptoms experienced when this happens will vary from person to person, may be different with each exposure, and will not necessarily correlate with the quantity of cryoglobulins present.

A positive test for cryoglobulins may be seen in numerous conditions. Some examples include:

  • Infections such as Lyme disease, infectious mononucleosis (mono), hepatitis C and HIV/AIDS
  • Kidney disease
  • Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome
  • Diseases characterized by an increase in lymphocytes such as multiple myeloma, lymphoma and lymphoid leukemia
  • Disorders associated with inflammation of blood vessels (vasculitis)

The cryoglobulins test will not indicate which type of cryoglobulins are present and is not diagnostic of a specific underlying condition.

Is there anything else I should know?

Most people who have cryoglobulinemia are chronically infected with hepatitis C virus (HCV), although not everyone with HCV (fewer than 3%) will develop cryoglobulinemia.

Can someone prevent cryoglobulin-related symptoms?

Avoiding contact with cold objects and exposure to cold can help prevent or minimize symptoms.

Is there something I can do to get rid of my cryoglobulins?

In general, no. If they are due to a temporary condition, such as a bacterial infection, then they may go away when the infection resolves. If they are due to a chronic condition, such as an autoimmune disorder, then they are likely to persist. In some cases, apheresis may be performed to remove cryoglobulins from the blood and to relieve symptoms, but this may help only temporarily.

What are some other tests that may be done to determine the underlying cause of cryoglobulinemia?

In addition to protein electrophoresis and, depending on the suspected underlying condition, other tests that may be performed include hepatitis C, ANA, mono test and rheumatoid factor, to name a few.

How is cryoglobulinemia treated?

It is primarily treated by addressing the underlying condition. Drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and other immune suppressants may sometimes be needed to help relieve symptoms and minimize complications. If symptoms are severe, plasmapheresis may be performed to reduce the amount of cryoglobulins in the blood by exchanging blood plasma for donor plasma. There is no permanent treatment or specific cure for cryoglobulinemia.

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