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Continuing Education Activity

Cryoglobulins are proteins that precipitate from an individual’s serum or plasma at temperatures lower than 37°C. They can be a mixture of immunoglobulin (Ig) and complement components or immunoglobulins alone. These cryoglobulins deposit in medium and large-sized blood vessels throughout the body, causing endothelial injury and end-organ damage known as cryoglobulinemia. This activity describes the evaluation and management of cryoglobulinemia and highlights the role of the interprofessional team in improving care for patients with this condition.


  • Identify the etiology of cryoglobulinemia.
  • Review the appropriate evaluation of cryoglobulinemia.
  • Summarize the management options available for cryoglobulinemia.
  • Describe the interprofessional team strategies for improving care coordination and communication to advance cryoglobulinemia care and improve outcomes.


Cryoglobulins are proteins that precipitate from an individual’s serum or plasma at temperatures lower than 37°C. They can be a mixture of immunoglobulin (Ig) and complement components or immunoglobulins alone.[1] These cryoglobulins deposit in medium and large-sized blood vessels throughout the body, causing endothelial injury and end-organ damage known as cryoglobulinemia. Diagnosis of this entity should be suspected in patients presenting with skin ulcers, arthralgia, glomerulonephritis, neuropathy, and purpura.

Brouet criteria classify cryoglobulinemia into three subgroups based on their immunoglobulin (Ig) composition.[2]

Type I Cryoglobulinemia

It has monoclonal Igs, typically IgG or IgM, and develops in the setting of lymphoproliferative or hematologic disorders of B cell lineage (e.g., multiple myeloma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, or protein-secreting monoclonal gammopathies like monoclonal gammopathy of undetermined significance (MGUS).

Type II Cryoglobulinemia

Type I and II are mixed cryoglobulinemia and have polyclonal Igs associated with autoimmune diseases, malignancy, or infections, particularly hepatitis C virus (HCV) infection.[3] Their constituent Ig is not a single monoclonal Ig.

Cryoglobulins are composed of a mixture of a monoclonal IgM (or IgG or IgA) with rheumatoid factor (RF) activity and polyclonal Ig in type II cryoglobulinemia.

These are often associated with:

  • Hepatitis C virus (HCV) infection
  • Mixed cryoglobulinemia syndrome
  • Hepatitis B virus (HBV)
  • HIV
  • Autoimmune diseases (mainly systemic lupus erythematosus [SLE], and Sjögren's syndrome)
  • Lymphoproliferative disorders.

About 10 percent of cases have no identifiable disease association, and hence the cryoglobulinemia is called "essential."

Type III Cryoglobulinemia

Cryoglobulins are composed of a mixture of polyclonal IgG (all isotypes) and polyclonal IgM in type III cryoglobulinemia. These cases are often secondary to autoimmune disorders. Sometimes, they can also be associated with infections (HCV most of the time).


Cryoglobulin is normally present within healthy individuals at small levels. Academics theorize that these levels indicate the existence of immune complexes that actively work toward clearing this protein by immunoglobulins (Igs) with rheumatoid factor (RF) activity.[2][4]

The prime risk factor for cryoglobulinemia is drug use, as 90% of cases of cryoglobulinemic vasculitis are associated with Hepatitis C infections. The formation of hepatitis C IgG and IgM rheumatoid factor causes the immune complex formation and complement activation, which leads to inflammation of blood vessels. It is also associated with monoclonal gammopathy (e.g., multiple myeloma, Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance [MGUS]), monoclonal gammopathies of renal significance, or connective tissue disease (e.g., systemic lupus erythematosus [SLE], Sjögren syndrome).


Cryoglobulinemia is a rare condition and is clinically significant in about 1 in 100,000. Cryoglobulins have been identified in several situations, specifically, including 15% to 20% of HIV-infected individuals, 40 to 65 percent of Hepatitis C-infected patients, and approximately 64 percent of HIV/HepC coinfected individuals.[5][6][7][8][9]

Patients with type 1 cryoglobulin are anywhere from 5% to 25% of the cases based on the currently available case series.


Chronic immune stimulation and lymphoproliferation lead to increased production of higher levels of the mono-, oligo- or polyclonal immunoglobulins, leading to the formation of the cryoglobulins.

There is the formation of the antigen-antibody complexes. Insufficient or poor clearance of the formed immune complexes leads to accumulation.


Tissue biopsy shows small-vessel leukocytoclastic vasculitis, which is inflammation of the blood vessels. It is also known as hypersensitivity vasculitis/angiitis in 50% of cases, inflammatory or noninflammatory purpura in 15%, and noninflammatory hyaline thrombosis, which is more common in type I in 10% of cases.[10]

History and Physical

Documented history of different conditions could point toward identifying cryoglobulinemia. Some things commonly paired with this disease include clonal hematologic disease (myeloma, monoclonal gammopathy of unknown significance), autoimmune diseases, infection with Hepatitis B, C, or HIV, skin purpura on lower limbs, skin ulcers under cold conditions, and acute foot or wrist drop suggestive of neuropathy from ischemia.

The presentation of cryoglobulinemia can differ greatly, and a majority of cases can be asymptomatic. Depending on the case, there are multiple classifications that this disease can fall under:

Type I Cryoglobulinemia

It presents with vascular symptoms including ischemia, livedo reticularis (erythematous, reticulated pattern that appears as lace-like and blanches on pressure), and skin necrosis.[11][12][13][14] Most commonly, this type shows skin indications with frequency around 70 to 85 percent. Though caution must be given if this case is what has been diagnosed, the skin exhibition must be treated before the onset of digital gangrene.

During initial studies of this specific type of cryoglobulinemia, France underwent a nationwide study involving 64 patients with expressed symptoms over 15 years.[11] All patients exhibited cutaneous association and often resulted in ulcers and necrosis. Usual findings also include peripheral neuropathy, arthralgia, and arthritis. None of the participants in this study showed any central nervous system signs, pulmonary, cardiac, or gastrointestinal symptoms.

Type II/III (Mixed) Cryoglobulinemia

Presentation of mixed cryoglobulinemia is commonly associated with underlying symptoms such as arthralgia, fatigue, and/or myalgia. Also, palpable purpura related to vasculitis or sensory changes due to peripheral neuropathy is common with type II/III.[15] Symptoms usually seen are referred to as “Meltzer’s triad,”; consisting of purpura, arthralgias, and weakness in most patients. The most prevailing symptom by far for this type is purpura, typically seen on the legs and up to the torso/upper extremities.[13] Typical manifestation lasts approximately one to two weeks with intermittent appearance one to two times per month.


When diagnosing this disease, there are a number of broad manifestations that could occur. But to summarize, a set of features evident include arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Caution must be given if any of these previously mentioned symptoms arise in conjunction with a clonal hematologic disease.

By far, the most predictive measure for cryoglobulinemia is based on the measurement of cryoglobulin coupled with a low C4 complement level. This combination is typical of cryoglobulinemia syndromes.[16] 

In lab detection of cryoglobulins, approximately 10 to 20 mL of blood is collected and prepared at 37°C without the addition of anticoagulants. The serum is then centrifuged and then refrigerated to allow precipitation of cryoglobulin. Type I cryoglobulinemia presents as a precipitate within 24 hours with a 3 to 5-day window. Type II/III present with precipitation approximately 5 to 7 days after initial refrigeration.

As a general rule, the cryocrit in individuals without cryoglobulinemia is close to zero, and a cryocrit greater than 0.5 to 1 percent or concentration over 50 mcg/mL is significant.[16][17][18] In type II, cryocrit is between 2 to 7 percent, while type III holds to around 1 to 3 percent. It is important to clarify that there is no established link between cryocrit levels and clinical exhibitions.

Another common method of evaluation for cryoglobulinemia is through immunochemical analysis. Immunofixation is performed on dissolved cryoglobulin by antibodies with specified heavy/light chains. This test allows specified categorization of the type after initial diagnosis. Other lab testing techniques include urinalysis, complement serum analysis, rheumatoid factor levels, viral serologies, and analysis of acute-phase reactants.

In special cases, specific testing is performed for further evaluation. One such test is the biopsy of organs impacted by the disease that is used to acquire additional information. Type 1 is generally seen in the skin, kidney, and bone marrow with affiliation to thromboses. Type II/III presents itself within the skin, kidney, and peripheral nervous system. Another test used in situations where the neuromuscular disease is evident is electromyography (EMG). Lastly, imaging studies are also used for further confirmation of the presence of cryoglobulinemia. However, it is important not to use imaging information as the sole means of evaluation, and the specified clinical presentation should guide these tests.

Treatment / Management

The treatment depends on the underlying primary disorder, severity, and nature of organ involvement. In presentations with mixed cryoglobulinemia with symptoms, the treatment is directed at the underlying autoimmune or infectious disorders.

Treatment for cryoglobulinemia focuses on each independent case and includes plasmapheresis and immunosuppression (e.g., glucocorticoids, rituximab) for a patient with rapidly progressing or life-threatening outcomes. The treatment is directed towards the infection or autoimmune disorder existing with symptomatic patients due to cryoglobulinemia.

Hepatitis C infections most commonly cause mixed cryoglobulinemia. The connection between this syndrome and autoimmune/lymphoproliferative disorders is common. The general onset of this disease is slow-paced, but in some situations, rapid progression can occur. 

The apparent severity of the disease guides professionals on how best to treat the patient. Though there is no established outline on severity designations, the subsequent descriptions are used for direction:

Mild Disease

Presentation in mild cases includes petechial rash without lesions, arthralgia with no apparent organ damage, and mild sensory neuropathy.

Moderate to Severe Disease

In this classification, the presentation includes:

  1. Progressive neuropathy
  2. Pulmonary vasculitis
  3. CNS vasculitis presented as a stroke or cognitive impairment
  4. GI vasculitis associated with bleeding and abdominal pain
  5. Digital ischemia

The aforementioned clinical indicators do not comprise a complete list of manifestations.

Across the board, mixed cryoglobulinemia's general treatment includes pain control, care for wounds, and prophylactic measures against infections. With patients receiving steroids or immunosuppressive therapy, the appropriate prophylaxis is important. The therapeutic approach taken for treatment should revolve around the existing etiology of the disease.

In mild diseases, immunosuppressive therapy is not required. Treatment is focused on the underlying disease. In moderate to severe cases, the specialized focus is to correct the primary symptoms with immunosuppressive therapy. Typically, immunosuppressive therapy is initiated until a steady state is achieved and followed by the devised regimen. Important note, in patients with HIV or hepatitis B virus (HBV), therapeutic antivirals should be provided before or simultaneously with immunosuppressive therapy.

Treatment with highly concentrated glucocorticoids combined with rituximab is suggested as a baseline treatment for moderate to severe cryoglobulinemia. In cases with no rituximab or if there are no results from its administration, cyclophosphamide is substituted.

In severe conditions such as:

  • Hyperviscosity syndrome
  • Skin ulcers by cutaneous vasculitis
  • Elevated cryocrit concentration – Greater than or equal to 10 percent

The recommended course of action is plasmapheresis, combined with immunosuppressive therapy. Daily exchanges approximately three times per week for a couple of weeks is the recommended course of action.

Cryoglobulinemia undergoing immunosuppressive treatments require special observation with the scrutiny level dependent on severity. Physical examination should always include monitoring of skin involvement and digital ischemia. Kidney association in treatment requires keeping in view the blood pressure, creatinine, complement, rheumatoid factor levels, and urinalysis. Progressive glomerulonephritis should be observed weekly compared to conditions without rapid disease progression, which require monthly evaluation. The defined regimen and overall prognosis are influenced heavily by organ involvement. Outlooks are poor for individuals with intestinal vasculitis and acute gastrointestinal or pulmonary hemorrhage.

Differential Diagnosis

Diagnosis of this disease must be carefully made as its clinical presentation is similar to other vasculitides affecting small or medium-sized vessels and includes:

  • ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (e.g., granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), microscopic polyangiitis.
  • IgA vasculitis (Henoch-Schönlein purpura)
  • Cutaneous small-vessel vasculitis
  • Hypersensitivity vasculitis
  • Vasculitis associated with a connective tissue disorder (e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s syndrome) 

Including other thrombotic and embolic disorders (e.g., thrombotic thrombocytopenic purpura, hemolytic uremic syndrome) should be considered as well.

Patients affected with chronic hepatitis C virus infection may develop arthralgias membranoproliferative nephritis even without cryoglobulinemia. So further testing is required to reach a definitive diagnosis.


When understanding the prognosis of cryoglobulinemia, the patient's root state must be considered to understand the extent of the disease properly. Specifically, when considering type 1 cryoglobulinemia, hematologic diseases are often a pre-existing condition.[14] Studies have shown that cryoglobulins being present in the blood do not indicate a higher mortality rate.

Survival rates with cryoglobulinemia are 70 percent after 10 years of evident symptoms and approximately 50 percent after 10 years of post-diagnosis. Prognosis is usually dependent on the effectiveness of the treatment.

HCV (hepatitis C) cryoglobulinemia related vasculitis is also a significant disease with an approximate five-year death rate of 25 percent.[1][19] Prognosis, aside from liver fibrosis, usually depends on the kidney, CNS, heart, and gastrointestinal tract. The vascularity associated with these organs/processes is affected and contributes heavily to the prognosis. Renal failure is shown to be higher in those with Hepatitis C compared to mixed cryoglobulinemia.

However, recent trials with CD-20 antibody rituximab have shown some beneficial results and its use is being suggested.[20]


Complications with cryoglobulinemia typically affect the outcomes of prognoses. Studies have indicated that complications typically will result in lower chances of survival in a patient. Common complications that arise include renal failure and the underlying development of a lymphoproliferative cell disorder.


  • Nephrology
  • Hematology
  • Infectious disease

Deterrence and Patient Education

Patients should be informed about the symptoms of cryoglobulinemia so that medical therapy can be sought early to avoid potential organ damage. Patients with mild disease that manifests primarily as arthralgias and fatigue benefit from understanding and avoiding the precipitating factor (i.e., cold temperatures, trauma). Moreover, NSAIDs could be advised to reduce the symptoms acutely.

Enhancing Healthcare Team Outcomes

Although survival rates with cryoglobulinemia are 70 percent after 10 years of evident symptoms and approximately 50 percent after 10 years of post-diagnosis, it can lead to long-term renal and lymphoproliferative cell disorders. It is thus necessary to timely diagnose and manage appropriately those diagnosed with cryoglobulinemia. A high index of suspicion in-person presenting with symptoms related to cryoglobulinemia and appropriate investigations can lead to better patient outcomes. Nurses need to be vigilant about a drop in hemoglobin and platelet and monitor renal function tests also look for symptoms related to anemia, thrombocytopenia, and uremia. It may also be essential to coordinate with a nephrologist if the patient develops acute renal failure and needs dialysis. Thus, a good patient outcome requires proper communication among physicians, nurses, pharmacists, nephrologists, and their teamwork.

Article Details

Article Author

Jenish Bhandari

Article Author

Mashal Awais

Article Editor:

Narothama R. Aeddula


8/10/2022 10:12:30 PM



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