Cryoglobulinemia (kry-o-glob-u-lih-NEE-me-uh) is a rare condition in which atypical blood proteins called cryoglobulins clump together when they get cold. This may happen at body temperatures below 98.6 Fahrenheit (37 Celsius).

These clumps can block blood flow. They also can cause inflammation. This can damage the skin, joints, nerves, kidneys and other organs.

Some people have cryoglobulins in their blood but no symptoms. When cryoglobulins cause inflammation of the blood vessels, it's called cryoglobulinemic vasculitis or cryoglobulin-associated vasculitis. This inflammation can damage tissues and organs.

Treatment for cryoglobulinemia depends on the type and what's causing it.

There are three main types of cryoglobulinemia. Types 2 and 3 together are called mixed cryoglobulinemia because the cryoglobulins contain a mixture of proteins.

• Type 1. This type has one kind of atypical protein, called monoclonal. Type 1 most often is linked to certain blood conditions and cancers.
• Type 2. This type has two types of atypical protein, both monoclonal and polyclonal. Type 2 most often is linked to hepatitis C virus infection.
• Type 3. This type has a mix of polyclonal proteins. Type 3 most often is linked to autoimmune diseases such as rheumatoid arthritis.

Mixed cryoglobulinemia that has no known cause may be called essential mixed cryoglobulinemia. When mixed cryoglobulinemia causes inflammation of the blood vessels and related symptoms or organ damage, it may be called mixed cryoglobulinemia syndrome.

Some people have no symptoms of cryoglobulinemia. For people who have symptoms, the symptoms may come and go.

Symptoms depend on the type of cryoglobulinemia and how it affects the body. When cryoglobulinemic vasculitis develops, it often affects the skin, joints, nerves and kidneys.

Cryoglobulinemia symptoms can include:

• Skin changes. Purple or red-purple spots called purpura often appear on the legs. The spots may look different depending on your skin color. Cryoglobulinemia also can cause a purplish, netlike skin pattern called livedo reticularis and open sores called ulcers.
• Joint and muscle pain. Joint pain is especially common with mixed cryoglobulinemia. Muscle pain also can occur.
• Peripheral neuropathy. Cryoglobulinemia can damage nerves, especially in the hands and feet. This nerve damage is called peripheral neuropathy. It can cause numbness, tingling, pain or weakness.
• Raynaud's disease. The fingers or toes may change color and feel numb or painful when they get cold. This can happen with cryoglobulinemia, particularly type 1.
• Kidney issues. Cryoglobulinemia can cause blood or protein in the urine, high blood pressure and reduced kidney function.

When to seek care

Make an appointment with a healthcare professional if you have symptoms that concern you. This is especially true if you have unexplained purple skin spots, skin sores, numbness or tingling, joint pain, or symptoms that happen again and again when you're exposed to cold temperatures.

When to seek emergency care

Some complications of cryoglobulinemia need emergency care. Type 1 cryoglobulinemia can make the blood too thick or block blood flow. Seek emergency medical care for sudden confusion, vision changes or stroke symptoms. Also seek emergency care if you have signs of severely reduced blood flow to a finger or toe, such as terrible pain or darkening of the skin.

Cryoglobulinemia can be linked to infections, certain blood conditions and cancers, and autoimmune diseases. The conditions linked to cryoglobulinemia vary by type.

• Infections. Hepatitis C is an important cause of mixed cryoglobulinemia. Other infections linked to cryoglobulinemia include hepatitis B and HIV.
• Blood conditions and cancers. Type 1 cryoglobulinemia most often is linked to certain blood conditions and cancers, including multiple myeloma, Waldenstrom macroglobulinemia, non-Hodgkin lymphoma and chronic lymphocytic leukemia.
• Autoimmune diseases. These are diseases in which the immune system attacks healthy tissue by mistake. Examples linked to cryoglobulinemia include Sjogren disease, lupus and rheumatoid arthritis.

Sometimes no cause is found.

Factors that increase the risk of cryoglobulinemia include having a condition linked to the production of cryoglobulins, the blood proteins that clump together when they get cold. These conditions include chronic hepatitis C infection, some autoimmune diseases, and certain blood conditions and cancers.

Cryoglobulinemia is rare. The age and sex of people who have it vary depending on the type of cryoglobulinemia and what's causing it.

Diagnosis of cryoglobulinemia involves a blood test to check for cryoglobulins.

Cryoglobulin blood test

The blood sample for this test needs special handling because cryoglobulins can clump together if the sample gets cold too soon. The sample is kept at about body temperature — 98.6 Fahrenheit (37 Celsius) — while the blood clots. Then the serum is separated from the blood cells. Serum is the liquid that remains after blood has clotted. The serum is then cooled before the lab checks for cryoglobulins.

What do cryoglobulin test results mean?

A positive cryoglobulin test result means that cryoglobulins were found in the blood sample. Further testing can show whether the cryoglobulins are monoclonal, polyclonal or a mixture of both. This information can help find out the type of cryoglobulinemia.

A negative test result doesn't always rule out cryoglobulinemia. If the blood sample isn't handled correctly, the test can have a false-negative result. This means the test says you do not have cryoglobulinemia when you do have it. The test may need to be repeated if your healthcare professional strongly suspects cryoglobulinemia.

What is a cryocrit?

A lab also may report a cryocrit. This is the percentage of serum made up of cryoglobulins after the proteins have clumped together and collected at the bottom of the sample. The amount of cryoglobulins doesn't always match how severe the symptoms are.

What other tests might be needed?

Other tests can help find the cause of cryoglobulinemia and show whether it's affecting your organs. These tests may include:

• Urine tests.
• Blood tests to check kidney function.
• Tests for hepatitis B and C.
• A rheumatoid factor test.
• Tests for immune system proteins called complement. A complement protein called C4 often is low in mixed cryoglobulinemia, especially type 2.

How is cryoglobulinemia different from cryofibrinogenemia?

Cryoglobulins can be found in serum and plasma. Plasma is the liquid part of blood when clotting has been prevented. Cryofibrinogen is a group of blood proteins found in plasma but not serum. These proteins clump together when plasma gets cold. The presence of cryofibrinogen in plasma is called cryofibrinogenemia.

How is cryoglobulinemia different from cold agglutinin disease?

Cryoglobulinemia and cold agglutinin disease both involve blood proteins that react to cold temperatures. But they affect the blood in different ways. In cryoglobulinemia, proteins called cryoglobulins clump together when they get cold. In cold agglutinin disease, proteins called cold agglutinins attach to red blood cells and cause the cells to clump together. This can lead to the breakdown of red blood cells, called hemolysis.

Some people with cold agglutinin disease also have cryoglobulins. This may contribute to symptoms caused by reduced blood flow in cold parts of the body, such as the fingers and toes.

Treatment depends on the type of cryoglobulinemia you have, what's causing it and how bad your symptoms are.

If you don't have symptoms

People who have cryoglobulins in their blood but no symptoms may not need treatment right away. Instead, their healthcare professionals may watch them for symptoms or other changes.

Treating the cause

When another condition is causing cryoglobulinemia, treating that condition is an important part of therapy.

For type 1 cryoglobulinemia, treatment may focus on the underlying blood condition.

For mixed cryoglobulinemia caused by hepatitis C, treatment includes medicines called direct-acting antivirals. These medicines treat hepatitis C. People with severe symptoms or organ damage may need other treatment while hepatitis C is being treated.

Medicines that affect the immune system

People with symptoms of cryoglobulinemic vasculitis also may need medicines that lower the immune response. One of these medicines is called rituximab. It may be used to treat serious complications of mixed cryoglobulinemic vasculitis, including kidney disease, peripheral neuropathy and skin ulcers.

Other medicines, including corticosteroids, may be used depending on the type and severity of the disease.

Treatment for severe disease

For severe or life-threatening symptoms or complications, you may have plasma exchange. This treatment removes plasma containing cryoglobulins and other harmful substances from the blood and replaces it with another fluid.

Follow-up care

Follow-up care depends on the type of cryoglobulinemia, what's causing it and how it has affected your health. Your care team may watch the condition as well as any symptoms or organ issues.

Prognosis

The outlook for people with cryoglobulinemia varies. It depends on the type of cryoglobulinemia, what's causing it and whether it has damaged the kidneys or other organs.

For people with type 1 cryoglobulinemia, the outlook depends in part on the underlying blood condition and how cryoglobulinemia affects the body. Kidney disease can affect the outlook.

Many people with mixed cryoglobulinemia have mild disease. But the condition also can cause serious or life-threatening complications. Treatments for hepatitis C and cryoglobulinemic vasculitis have improved the outlook for many people.

Cryoglobulinemic vasculitis can sometimes continue or come back after treatment.

If you have cryoglobulinemia, limit exposure to cold temperatures. Protect your fingers and toes from the cold, including when handling items from a freezer or refrigerator.

Check your feet and other areas affected by poor circulation for sores or other skin changes. Tell your healthcare professional about sores that don't heal or other new symptoms.

You may start by seeing your primary healthcare professional. Depending on what's causing the cryoglobulinemia and which parts of your body are affected, you may be referred to specialists. These doctors might include a hematologist if you have a blood condition; a rheumatologist if you have an autoimmune disease; a kidney specialist called a nephrologist; or a liver specialist called a hepatologist.

What you can do

When you make the appointment, ask if there's anything you need to do in advance, such as fasting before having tests. Make a note of:

• Your symptoms, including any that do not seem linked to the reason for your appointment, and when they began.
• Whether cold temperatures trigger your symptoms or make them worse.
• Key personal information, including major stresses, recent life changes and family medical history.
• All medicines, vitamins and other supplements you take, including the doses.
• Questions to ask your care team.

Consider asking a family member or friend to come with you, if possible. This person can help you remember what your care team tells you.

For cryoglobulinemia, some basic questions to ask include:

• What's likely causing my symptoms?
• What type of cryoglobulinemia do I have?
• What does my cryoglobulinemia test result mean?
• Do I need tests to look for an underlying condition?
• Is cryoglobulinemia affecting my kidneys or other organs?
• What treatment do I need?
• How will you watch me for complications or a return of symptoms?
• I have other health conditions. How can I best manage them together?
• Should I see a specialist?
• Are there brochures or other printed pages I can have? What websites do you suggest?

What to expect from your doctor

Your healthcare professional is likely to ask you questions, such as:

• Do you have symptoms all the time, or do they come and go?
• Do cold temperatures bring on or worsen your symptoms?
• Have you noticed any skin changes, sores, numbness or tingling?
• How bad are your symptoms?
• What, if anything, seems to make your symptoms better?