Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients may give a history of Raynaud’s phenomenon, arthralgia, myalgia, or signs of palpable purpura in the context of a connective tissue disease, lymphoproliferative disorders or infectious diseases. Thirty to fifty percent of cases occur without any systemic underlying condition and are termed “essential.”

Characteristic findings on physical examination

Palpable purpura typically on the lower extremities (Figure 1, Figure 2), which may be preceded by paresthesias or cold exposure (50% of cases), Raynaud’s phenomenon, acrocyanosis, livedo reticularis, peripheral gangrene (rare), ulcerations, and ecchymose

Figure 1

Figure 1

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Figure 2

Figure 2

Expected results of diagnostic studies

ü Cryocrit levels, or quantitation of cryoglobulin precipitate concentration, are used to make therapeutic decisions or assess the response to therapy

ü Cryoglobulin titer levels 1 to 5mg/dL (one may need to repeat this test up to 3 times to help exclude this condition)

ü Serum electrophoresis with subsequent immunofixation or immunodiffusion, which results in various findings for immunoglobulin light chains, immunoglobulin heavy chains, or even complement components

o Type I: Monoclonal immunoglobulin G, M or A (IgG, IgM, or IgA)

o Type II (mixed): A mixture of polyclonal immunoglobulin and monoclonal immunoglobulin

o Type III (mixed): A mixture of polyclonal immunoglobulins

ü Rheumatoid factor (RF) activity elevation (especially in types II and III)

ü Low complement components, such as C4, C2 and C1q levels

ü Skin biopsy will typically show leukocytoclastic vasculitis with immune complex deposition in small-sized vessels. Occasionally, medium-sized vasculitis may occur. Less commonly, there will be an inflammatory or non-inflammatory purpura, non-inflammatory hyaline thrombosis within blood vessels or post-inflammatory findings.

ü Kidney biopsy will show either a thrombotic or hypocellular lesion without evidence of vasculitis (type I) or membranoproliferative glomerulonephritis with intraluminal deposits of immune complexes (types II and III)

ü Imaging studies and bone marrow biopsies may lead to more information on the disease process

ü Acute phase reactants (ie, C-reactive protein and erythrocyte sedimentation rate (ESR) are elevated

ü Re-solubilization of cryoglobulin precipitate to confirm diagnosis is a diagnostic step

Diagnosis confirmation

To confirm the diagnosis of cryoglobulinemia one has to exclude as many diagnoses that mimic it by reviewing the patient’s history, by focusing on blood work that will narrow a differential diagnosis or by even repeating blood work and tissue biopsy. Several diseases can mimic cryoglobulinemia. It is important to consider conditions with similar presentation where microthrombi are found in dermal blood vessels. A number of diagnoses can mimic cryofibrinogenemia. It is always important to consider pathologies with similar presentations where microthrombi are seen in the dermis (small- to medium-size vasculopathy).

The best way to confirm the diagnosis of cryofibrinogenemia is to exclude diagnoses that mimic cryofibrinogenemia by reviewing the patient’s history. This involves blood work that will narrow a differential diagnosis or even repeat blood work studies. When indicated, performing a biopsy of other organs such as the muscle, lung and kidney can be helpful.

Among other diagnostic possibilities:

–Cryofibrinogenemian (+ plasma cryofribrinogen precipitate, exacerbation of lesions with cold exposure, microlivedo pattern, livedo reticularis, purpura, Raynaud’s phenomenon).

–Septic embolization (+ blood cultures, elevated white blood cell count/immature leukocytes, fever, multiple organ involvement, stroke-like symptoms, history of IV drug use/sepsis)

–Cholesterol embolization (+ history of invasive coronary procedures/recent anticoagulant or thrombolytic therapy/femoral fracture, acute multi-organ failure, purple/blue toes, livedo reticularis, intact peripheral pulses, eosinophilia, tissue biopsy of lesion shows crystallized cholesterol)

–Frostbite (clinical history of cold exposure with early symptoms of pain and burning that progressed to anesthesia; if superficial, frostbite skin will indent; if deep, frostbite skin hard to touch, + history ofperipheral vascular disease/ Raynaud’s phenomenon/peripheral neuropathy/alcohol use/high altitude/outdoor living in the context of cold exposure, white to yellow skin initially, then darkens/ulcerates/blisters/necrosis days later)

–Vasculitis (+/- C- or P-ANCA, + multi-organ involvement, + history of rheumatic diseases/cancer/infection/substance abuse/chemical exposure, purpura, livedo reticularis, elevated ESR/CRP, eosinophilia, hematuria, anemia, tissue biospy of lesion shows vascular inflammation/destruction)

–Disseminated intravascular coagulation (possible history of trauma/ burns/severe infections/malignancies, or other mechanical tissue or endothelial injury that induces thombin dysregulation, mucosal bleeding, fever, bullae,extensive symmetric purpura/necrosis, frank bleeding, hypotension, hematuria, petechiae, hypotension, tachycardia)

–Inherited or acquired hypercoagulable state (family history and personal history of deep vein thrombosis/stroke/late pregnancy loss/pulmonary embolism, use of agents that induce hypercoagulable state, multi-organ system involvement, purpuric to necrotic lesions not confined to one area of the body)

–Ecythyma gangrenosum (immunosuppressed, typically secondary to Pseudomonas aeruginosa bacteremia, painless macules that become painful purpuric to black lesions within 24 hours, systemically ill with fever, chills and hypotension)

–Warfarin-induced skin necrosis (often a complication in patients with protein S or C deficiency, lesions on extremities/torso/breast/penis, dermal biopsy shows ischemic necrosis and thrombosis of cutaneous thrombosis/hemorrhage, history of warfarin use)

–Antiphospholipid syndrome (history of miscarriage/preterm delivery/late pregnancy loss, +antibodies against phosphlipid (anti-cardiolipin, anti-beta2 /glycoprotein I, history of deep vein thrombosis, livedo reticularis, thrombocytopenia)

–Purpura fulminans (severe/acutely life-threatening condition that follows bacterial infection (eg, Neisseria meningitidis, varicella zoster virus), acute illness with high fever and rapid deterioration, symmetrical progression from purpura on extremities to widespread necrosis/echymoses, not usually localized to fatty areas/mucous membranes/neck/head, + blood culture)

–Thrombocytopenic disorders (elevated/decreased/dysfunctional platelets often asymptomatic but can result in prolonged bleeding, multiple petechiae, mucosal bleeding, minor trauma-induced ecchymoses, blood studies indicating a platelet issue)

–Oxalosis (+ urine oxalic acid, +history of kidney stones/hematuria/progressive renal disease, +nephrocalcinosis, possible autosomal recessive inheritance)

–Calciphylaxis (+ history of calcium metabolism disorder (dystrophic, idiopathic, iatrogenic, metastatic)/renal disease/hyperparathyroidism/hemodialysis, livedo reticularis, refractory ulcers, elevated calcium-phosphate product/PTH, s/p renal malignancy/renal transplant/parathyroidectomy with normalized phosphate and calcium, tissue biopsy results showing calcium deposition)

–Atherosclerotic peripheral vascular disease (often in the advanced age, history of transient ischemic attack/myocardial infarction/angina/smoking/dyslipidemia/hypertension, loss of hair on affected skin, coldness of skin, weak pulses, claudication or pain at rest especially in the limbs, vascular studies demonstrating arterial disease)

Who is at Risk for Developing this Disease?

It has been estimated that clinically significant cryoglobulinemia has a prevalence of 1:100,000 patients, although detectable levels of circulating cryoglobulin have been found in a significant proportion of patients with secondary cryoglobulinemia.

What is the Cause of the Disease?

The etiology is unknown. Since a healthy individual may have minute levels of cryoglobulin, it is speculated that this finding may reflect a “physiological clearance of endogenous immune complexes by immunoglobulins with rheumatoid factor activity.” It is generally thought the underlying disease is involved in the pathogenesis of cryoglobulinemia. The pathogenesis is attributed to the production of immunoglobulin, antibodies, and immune complexes.

Systemic Implications and Complications

Systemic implications and complications vary on a case by case scenario, though type I has symptoms mainly related to hyperviscosity, and mixed cryoglobulinemia has manifestations generally mediated by immune complex deposition. There are a number of systemic manifestations that can be attributed to the immune complex deposition (ie, arthralgia, gomerulonephritis, peripheral neuropathy) and hyperviscosity (visual blurring, ischemia, sudden hearing loss). Overall, manifestations range from neurologic impairments (ie, due to retinal vasculitis), renal failure, arthritis/arthralgia, to bowel symptoms of ischemic colitis. Often, the underlying etiology of the disease plays a role in these systemic manifestations. For example, hepatitis C virus (HCV) can be found in 96% to 100% of cases of cryoglobulinemic hepatitis and glomerulonephritis. It is best to treat the underlying disease while directing management of any clinical presentation that involves systemic manifestations.

Treatment Options

Important Note: All doses depend on the clinical scenario and co-morbidities. Drug interactions vary and precautions should be taken when prescribing any medical therapy. The listed therapies are based off of published case reports and clinical trials.

Treatment focuses on eliminating or limiting the formation of cryoprecipitation, alleviating symptoms, and treating the underlying cause.


–Stay warm and avoid environmental triggers that involve cold temperatures

–When exposed to cold, ensure that the body is covered appropriately

–Avoid agents that exacerbate vasoconstriction or precipitate thrombus formation (ie, sympathomimetic agents and smoking)

–Low-antigen-content (LAC) diet


Asymptomatic disease usually does not warrant therapy.

Wound care

Antimicrobial agent for infection

Mild disease (fatigue, arthralgias, myalgias, recurrent purpura, no evidence of end-organ damage)

–Cold avoidance, analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)

–For symptoms of inflammation unresponsive to NSAIDs, give oral low-dose corticosteroids (0.1 to 0.3 mg/kg/day)

–Neuropathic pain: Oral duloxetine 60 to 120mg/day; oral pregabalin 300 to 600mg/day

Moderate to severe disease (end-organ-threatening vasculitis/thrombosis)

–Severe necrotizing vasculitis resistant to immunosuppression and corticosteroids: intravenous Iloprost

–Type I: Chemotherapy and/or radiation therapy for the underlying disorder. If no malignancy is related to the presentation, oral prednisone (1 to 2mg/kg/day) for inflammation + intravenous cyclophosphamide (0.5 to 1g/m² every 3 to 6 weeks or oral 2mg/kg/day for a few months until there is efficient control of disease)

–Types II and III: Induce immunosuppression (ie, oral prednisone) with a combination of plasmapheresis and anti-viral therapy (polyethylene glycol [PEG] alpha interferon + ribavarin)

–Hepatitis C virus (HCV): oral PEG alpha interferon (1 to 1.5μg/kg/wk) + oral ribavarin (800 to 1200mg/day)

–Dosing for PEG alpha interferon and ribavarin varies by kidney function. A 48-week course is recommended.

Alternate therapy:

–High dose corticosteroids (ie, oral prednisone 0.5 to 1.5mg/kg/day or intravenous pulsed methylprednisolone 0.5 to 1g/day x 3 days followed by oral prednisone and/or other immunosuppressive therapy (ie, cyclophosphamide)


–A combination therapy of oral prednisolone, plasmapheresis and intravenous cyclophosphamide pulsed therapy or rituximab (intravenous 375mg/m² body surface area) instead of cyclophosphamide


–Add colchicine 0.6 to 1.2mg/day for 6 to 48 months

Severe disease (type I: hyperviscosity syndrome or vasculitis, types II and III: life- or organ-threatening vasculitis)

–Plasmapheresis in combination with immunosuppressive therapy (ie, high-dose corticosteroids + cyclosporine or azathioprine, or cyclophosphamide)

–Add rituximab (intravenous 375mg/m² body surface area/week) in the setting of an underlying B-cell malignancy (the use of plasmapharesis alone places the patient at risk for rebound or worsening of the disease hence aggressive immune suppressants are commonly used together with plasmapharesis)

–Add oral lenalidomide 25mg daily, 3 weeks on and 1 week off when there is underlying multiple myeloma and undifferentiated spondyloarthropathy

If symptoms are still uncontrolled despite therapies used in moderate disease, add or consider: intravenous Infliximab; intravenous immunoglobulin 2g/kg (as sole therapy or adjuvant therapy); oral mycophenolate mofetil (1g twice daily).

–Refractory Type I: 6 cycle of intravenous bortezomib 1.3 mg/m² on days 1, 4, 8, 11 and 21

–Essential type livedoid vasculitis: IV lipo-prostaglandin E1 10μL 2 to 3 times per week x 10 weeks

Neonatal management with transplancental cryoglobulinemia: Pentoxifylline; Protective measures against cold.


–Maintain therapies that have placed the patient in remission

–Eventually decrease medication doses when possible while avoiding relapse


–Depending on the extent of ischemia and necrosis, these areas may need debridement. Any ulceration may need debridement as well.

Follow-up care in a setting familiar with wound care: Standard wound care

Optimal Therapeutic Approach for this Disease

Treat the underlying disease when possible while directing therapy to reduce immune complexes in the blood so that clinical manifestations of vasculitis diminish. In general, cryoglobulinemia responds to immunosuppressive or cytotoxic (antineoplastic) drugs, or some combination of these two. Cyclophosphamide, azathioprine, methotrexate or penicillamine may be used. An adjunct to therapy in severe or life threatening cases is apheresis (either plasma exchange or cryoglobulin filtration). It can temporarily remove the cryoglobulin (immune complexes) and reduce the hyperviscosity, which helps reduce morbidity. Often, apheresis is used in conjunction with immunosuppressive drugs, but plasma exchange is more accepted than cryofiltration. A rebound phenomenon or “hyperviscosity syndrome” can occur if plasmapharesis is used alone.

Regardless of therapy, it is critical to address the underlying disease. If the patient is deemed to have a case of essential cryoglobulinemia, therapy is directed toward reducing the level of immune complexes in the blood. There has been dramatic success with intravenous immunoglobulin and some success with high dose corticosteroids augmented with cyclophosphamide or azathioprine, especially in essential cryoglobulinemia.

One must bear in mind that therapies may lead to a negative outcome on cryoglobulin blood test, but studies do not take into account the gelled and oil-like cryoglobulin. Therefore, if symptoms persist or there are relapses in light of a negative blood study, this situation may be the reason for the apparent discrepancy.

In cases of cryoglobulinemia in the context of an identified underlying disease, the cryoglobulinemia may improve or resolve if the causative disease is treated. Type II and type III cryoglobulinemia with vasculitis are secondary to HCV in 90% of cases. Therefore, antiviral therapy results in clinical improvement, especially in the vasculitic component of the disease. Interferon-alpha or pegylated interferon-alpha in combination with ribavirin is the treatment of choice. There is an associated decline of cryocrit, immunoglobulin M and rheumatoid factor activity with a decrease in HCV-RNA. The symptoms may subside quickly despite the continued presence of cryoglobulinemia.

In cases of non-HCV-associated mixed cryoglobulinemia with symptomatic vasculitis, corticosteroids (ie, intravenous methylprednisolone or oral prednisone with taper) and immunosuppressive therapies (azathioprine or cyclophosphamide or mycophenolate mofetil) are used either alone or together. Depending on the severity of vasculitic manifestations, plasmapharesis and rituximab may be added to the treatment regimen. There have been severe cases in which rituximab has been used as a first-line intervention. One interesting approach to therapy may be to incorporate a low-antigen-content diet , which has proven to improve clinical manifestations. A low-antigen-content diet incorporates nutrition that avoids common allergens that compete with immune complexes for clearance. Examples are eggs, nuts, dairy foods, and shellfish.

Patient Management

A patient who develops this disease may need to be monitored closely, depending on the severity of the clinical presentation. Mild to moderate cases may need immunosuppressive and cytotoxic agents with close follow-up every 2 to 3 weeks. Severe cases may need hospitalization with emergency therapies to address the systemic manifestations of vasculitis.

Remission may benefit from prophylactic corticosteroid therapy with follow-up and laboratory studies every 2 to 3 months unless symptomatic.

Screen for the underlying causative disease. If therapy works, continue it but try to evaluate whether the doses could be reduced while avoiding relapse. When a therapy is working and suddenly there is a relapse, consider modification of therapy, either by increasing the dosage or changing to another medication. Key information for the patient is that this is a treatable disease. It is something that can be resolved, especially if secondary to another condition. With no therapeutic modalities, it is likely that the vasculitic component of cryoglobulinemia will have a wide range of adverse effects on the body.

Unusual Clinical Scenarios to Consider in Patient Management

In the past few years, clinicians have found success with the following:

–For a case of essential type II cryoglobulinemia resistant to high-dose corticosteroids and cyclophosphamide/azathioprine, there was successful treatment with intravenous Ig 2g/kg body weight) on a monthly basis. After 10 treatments, it was discontinued. One year after receiving the intravenous IG, the patient remained in remission while on prednisone (5mg on alternate days).

–For the cryoglobulinemia associated with B-cell malignancies, rituximab is a very valuable therapy that targets CD20.

–For type I cryoglobulinemia with HLA B27 spondyloarthropathy, there has been successful therapy with drugs known to interact with tumor necrosis factor (known as lenalidomide and which is related to thalidomide). Oral lenalidomide 25mg once a day for 3 weeks with 1 week off for four cycles in conjunction with pulsed oral dexamethasone (40mg weekly) successfully treated cutaneous and systemic symptoms.

–For type I cryoglobulinemia associated with multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS), there has been successful therapy with systemic corticosteroids with and without alkylating agents.

What is the Evidence?

Sargur, R, White, P, Egner, W. “Cryoglobulin evaluation: best practice?”. Ann Clin Biochem. vol. 47(Pt 1). 2010. pp. 8-16. (The classification, clinical features and standardization of cryoglobulin testing in cryoglobulinemia are reviewed. Suggestions are made about the best laboratory practices in the detection and identification of cryoprecipitate, specifically cryoglobulins. Figures, tables and boxes are provided to facilitate understanding.)

Iannuzzella, F, Vaglio, A, Garini, G. “Management of hepatitis C virus-related mixed cryoglobulinemia”. Am J Med. vol. 123. 2010. pp. 400-8. (The therapies used for HCV-related mixed cryoglobulinemia (types II and III) are summarized. Mixed cryoglobulinemia is reviewed including proposed criteria for diagnosis and classification. Therapies are grouped by etiologic therapy, pathogenetic therapy, symptomatic therapy, and severity. Figures and tables are provided to facilitate understanding.)

Almog, O, Berlin, T, Rotman-Pikielny, P, Levy, Y. “A dramatic response to intravenous immunoglobulin in a patient with mixed cryoglobulinemia”. Isr Med Assoc J. vol. 12. 2010. pp. 53-4. (A case report of a 34-year-old woman with mixed cryoglobulinemia and multi-organ system involvement who went into full remission after therapy with intravenous IG.)

Mohammed, K, Rehman, HU. “Cryoglobulinaemia”. Acta Med Austriaca. vol. 30. 2003. pp. 65-8. (A brief but inclusive review of cryoglobulinemia.)

Fohlen-Walter, A, Jacob, C, Lecompte, T, Lesesve, JF. “Laboratory identification of cryoglobulinemia from automated blood cell counts, fresh blood samples, and blood films”. Am J Clin Pathol. vol. 117. 2002. pp. 606-14. (Four hematology cases are reviewed that show different means to detect cryoglobulin. Images, figures, and tables are provided. A guide is included for screening and diagnosis of cryoglobulin.)

Lin, RJ, Curran, JJ, Zimmerman, TM, Song, J, Niewold, TB, Sweiss, NJ. “Lenalidomide for the treatment of cryoglobulinemia and undifferentiated spondyloarthropathy in a patient with multiple myeloma”. J Clin Rheumatol. vol. 16. 2010. pp. 90-1. (A case report of type I cryoglobulinemia in the presence of HLA B27 spondyloarthropathy and multiple myeloma that reported treatment success with lenalidomide, an inhibitor of the TNF-alpha pathway and derivative of thalidomide.)

Kawakami, T, Kawasaki, K, Mizoguchi, M, Soma, Y. “Therapeutic effect of lipoprostaglandin E1 on livedoid vasculitis associated with essential cryoglobulinaemia”. Br J Dermatol. vol. 157. 2007. pp. 1051-3. (A case report of a 51-year-old female with livedoid vasculitis with essential cryoglobulinemia who was safely and effectively treated with lipoprostaglandin E1 in combination with low-dose oral corticosteroid therapy.)

Laugel, V, Goetz, J, Wolff, S, Beladdale, J, Sibilia, J, Messer, J. “Neonatal management of symptomatic transplacental cryoglobulinaemia”. Acta Paediatr. vol. 93. 2004. pp. 556-8. (A case report of symptomatic placental transfer of cryoglobulins. The symptoms, outcome and management are discussed.)

Spizzo, G, Mitterer, M, Gunsilius, E. “Bortezomib for the treatment of refractory Type-1 cryoglobulinaemia”. Br J Haematol. vol. 150. 2010. pp. 235-7. (Bortezomib, a selective proteasome inhibitor, is discussed as a cycled treatment approach to severe vasculitis associated with type I cryoglobulinemia. Two patients achieved a dramatic clinical improvement with bortezomib.)