Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients may give a history of a painful, necrotic ulcer(s) located on the extremities, acral surfaces and ears, which appear after cold exposure and are refractory to care with standard therapy. Also, there may be a history of cold urticaria, cold sensitivity/intolerance, reticulated rash, purpura, bruising, painful nodules, joint pain, muscle pain, Raynaud’s phenomenon, with possible systemic manifestations such as renal disease, pulmonary insufficiency and fever. Interestingly, symptoms are not uniformly related to cold exposure.

Characteristic findings on physical examination:

Characteristic findings include painful, necrotic and gangrenous ulceration(s) on the extremities, acral surfaces refractory to standard therapy, acral purpura, microlivedo/livedo reticularis, cold urticaria, Raynaud’s phenomenon, segmental swelling, thrombotic or hemorrhagic phenomenon, and/or ecchymosis (Figure 1, Figure 2, Figure 3). Patients are commonly observed rubbing the skin around ulcers; apparently this provides some relief.

Expected results of diagnostic studies

-Cryofibrinogen titer level present in plasma

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-Skin biopsy histology showing small-vessel microthrombi, generally consisting of some evidence for characteristic cylindrical configuration in the vessel wall

– Immunofluorescence, direct and indirect, and periodic acid Schiff (PAS) may identify the components of vascular deposits, such as immunoglobulin (Ig) G, IgM, C3, C5-9, and fibrinogen

-Gel electrophoresis with subsequent immunofixation or immunodiffusion demonstrates a monoclonal paraprotein of IgM subtype

-Peripheral smear may show a characteristic “rouleaux formation” and deposits of cryoprecipitate

-Imaging studies may provide evidence of thrombosing vasculopathy, even in the medium-sized vessels, especially the arteries.

There are a number of diagnoses that 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.

Cryofibrinogenemia should be differentiated from the following:

Septic embolization (+ blood cultures, elevated white blood cell count/immature leukocytes, fever, multiple organ involvement, stroke-like symptoms, history of intravenous [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)

Cryoglobulinemia (+ history of an infectious process/ lymphoproliferative or autoimmune disorders, purpura found mostly on the extremities, +/- ANA , +RH factor, + serum immune elecrophoresis, + serum and plasma levels of cryoglobulin)

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 of peripheral 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)

Protein C deficiency (personal or family history of recurrent/late pregnancy loss/myocardial infarcation/stroke/deep vein thrombosis, lesions on extremities/torso/penis/breast)

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)

Cocaine- levamisole toxicity (painful purpura on external ears and cheeks, irregularly shaped purpuric lesions on the trunk and extremities, history of cocaine use, neutropenia, mouth pain, fever)

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

Purpura fulminans (severe/acutely life-threatening condition that follows bacterial or viral 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/parathyroiectomy with normalized phosphate and calcium, tissue biopsy results showing calcium deposition).

–Elevated alpha-1 antitrypsin and alpha-2 macroglobulin levels

Who is at Risk for Developing this Disease?

This is typically a disease of adults with predominance among patients aged 50 to 60 years and in women (ratio 1.6:1). There is insufficient information on the incidence of cryofibrinogenemia. According to various publications, the prevalence of individuals with cryofibrinogenemia with no symptoms is anywhere from 2.8% to 3% of the population. The asymptomatic presence of increased plasma cryofibrinogen in hospitalized patients reaches 3%. An asymptomatic individual can have a cryofibrinogen level up to 0.49 + 0.5g/L. Those who are symptomatic usually have a level of 1.02 ± 1.2g/L.

What is the Cause of the Disease?

The pathophysiology is unclear. There are two types of cryofibrinogenemia; essential/primary and secondary. Essential cryofibrinogenemia is idiopathic and can present in someone otherwise healthy. There are also rare familial forms (autosomal dominant phenotype, which have been described in medical literature, but many questions remain regarding this classification of cryofibrinogenemia.)

Most cases are secondary to an autoimmune connective tissue disease, collagen vascular disease, infection (streptococcal, chronic hepatitis), malignancy (multiple myeloma, lymphoma, carcinoma, leukemia, fibrosarcoma), thromboembolic disease, medication (oral contraceptives), hyperglycemia, diabetes, pregnancy, or pseudotumor cerebri. The presence of secondary cryofibrinogenemia is considered to indicate a poorer prognosis and more resistance to therapy.

Systemic Implications and Complications

These findings are related to the severity of the disease and the possible underlying entity. There have been cases of pulmonary, renal and musculoskeletal manifestations. In each patient, a thorough history and physical examination are needed to gain insight into the extent of the disease.

Treatment Options

DISCLAIMER: All doses depend on the clinical scenario and comorbidities. Drug interactions vary and precautions should be taken when prescribing any medical therapy. The listed therapies are based on 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, although not all cases are made worse by cold exposure (unlike cryoglobulinemia)

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

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


Wound care: Antimicrobial agents for infection –>Oral prednisone (10 to 60mg/day, or 0.5-1mg/kg/day, or 10mg/day in combination with oral azathioprine 150mg/day, or 10mg/day in combination with oral chlorambucil 4mg/day)

Asymptomatic patients usually do not warrant therapy.

Mild to moderate disease

A combination of oral corticosteroids (ie, prednisone 10 to 60mg/day or prednisone 0.5 to 1mg/kg/day, tapered over several months) and oral aspirin (81mg/day)

Moderate to severe disease

A combination of oral corticosteroids (ie. prednisone 10 to 60mg/day or prednisone 0.5 to 1mg/kg/day, tapered over several months) and oral warfarin or intramuscular (IM) heparin or oral bishydroxycoumarin –Plasmapheresis can be used to quickly reduce clinical symptoms

Severe and life-threatening disease

Fibrinolytic therapy

-V alteplase (10mg/24 hours)

-Streptokinase (with lower dosing on initiation, intravenous 25,000 to 200,000 U/24h or oral 50,000 to 80,000 U/24h)



-Urokinase (IV)

Alternative fibrinolytic agents

-Oral stanozolol (4 to 8mg/day or 2 to 4mg twice daily for 2 to 6 weeks). This drug is no longer available. There is speculation (see below) that danazol may be effective.

-Oral oxandrolone (i2.5 to 20mg/day)

-Oral danazol (200mg twice or three times daily)

Other agents

-Oral pentoxifylline (initiate with 800mg/day and taper down in combination with oral colchicine)

Adjunctive therapy

-Oral colchicine (0.6mg twice daily) used in combination with oral pentoxifylline


-Plasmapheresis (daily, as needed, or as adjunctive therapy with immunosuppressive management)

-Glucocorticoid therapy

Methylprednisolone (intravenous 2mg/kg/day in combination with plasma exchange for 10 treatments over 2 weeks)

Cytotoxic therapy

-Oral azathioprine (150mg/day alone or in combination with oral prednisone 10mg/day [dosing of azathioprine may vary based on the thiopurine methyltransferase level])

-Oral chlorambucil (10mg/day alone or 4mg/day in combination with oral prednisone 10mg/day). One must recognize that chlorambucil is an alkylating agent and that it can lead to myeloproliferative disorders.


-Maintain therapies that have placed the patient in remission. Eventually decrease medication doses when possible while avoiding relapse.

Uncommon therapy

-Batroxobin/ancrod (subcutaneous injections over several weeks)

-Therapy in the presence of hepatitis C virus infection

-PEG-interferon alpha-2b (1 to 1.5μg/kg/week) or interferon alpha-2b (3 million IU 3 times/week) plus oral ribavirin (600 to 1200mg/day)

-Surgical: Depending on the extent of ischemia and necrosis, involved or necrotic areas may need debridement; any ulceration may need debridement as well.

Follow-up care for wounds

Optimal Therapeutic Approach for this Disease

There is no optimal therapy and it is often asymptomatic. Therapy invariably depends on whether symptoms are present. Once a determination is made on the underlying cause of cryofibrinogen formation, one can decide on appropriate therapy. If cryofibrinogen is formed secondary to some specific entity, treatment is focused on the underlying cause. If the cryofibrinogen formation is primary, often a strictly preventive and symptomatic approach is taken. A thorough evaluation of any underlying hematologic dyscrasia must be explored as there is a high correlation with cryofibrinogenemia.

The best preventive approach is to stay warm and avoid environmental triggers that involve cold temperatures. When exposed to the cold, assure that the body is covered appropriately. Agents that might exacerbate vasoconstriction or precipitate a thrombus, such as sympathomimetic agents and smoking, can be limited or avoided.

The therapies listed below are beneficial, but relapses can still occur. Most therapies are composed of fibrinolytic medication, corticosteroids, and anticoagulants.

In most cases of mild cryofibrinogenemia (sometimes with only arthralgia and purpura), there is response to a chronic regimen of oral corticosteroids and aspirin.

In mild to moderate cases, especially in venous thrombosis, anticoagulants such as heparin and warfarin are used.

In more severe cases (eg, kidney decompensation, cerebral embolus), a combination of plasmapheresis and fibrinolytic agents are typically used. These fibrinolytic agents include alteplase, streptokinase, streptodornase, and urokinase. Examples of dosing are intravenous (IV) alteplase 10mg/24 hours or IV streptokinase 25,000U/24 hours. On a long-term basis these approaches can be impractical and expensive, but can be critical in acute ischemia due to this disease. In the United States, streptokinase is only administered intravenously.

Another alternative fibrinolytic agent, available outside the United States, is oral stanozolol (4 to 8mg/day). Unfortunately, due to the rampant abuse of steroids, especially in sports, stanozolol is no longer available for use in the United States. There is a substantial number of references that have described the efficacy of the anabolic steroid stanozolol in terms of both pain and ulcer healing.

Other agents similar to stanozolol have been used. These include danazol and oxandrolone, which have fibrinolytic properties. Of importance are the complications of using corticosteroids, especially when a patient has diabetes mellitus or cardiovascular disease. Corticosteroids can cause sodium retention and worsening of congestive heart failure and hypertension. A high dose of oral pentoxifylline started at 800mg 3 times per day, then tapered to 400mg has been shown to be effective as a therapy. A combination of pentoxifylline with oral colchicines (0.6mg twice per day) has been effective.

Plasmapheresis is a quick and effective way to remove cryofibrinogen from the blood (by membrane plasma separation, cryofiltration apheresis, membrane fractionation). It is considered one of several immunomodulatory methods. Other immunomodulatory approaches include glucocorticoids and cytotoxic therapy as options; oral prednisone (10 to 60mg/day), oral azathioprine (150mg/day), oral chlorambucil (10mg/day).

An alternative therapy has been used with success in Germany. Six patients treated with subcutaneous injections of batroxobin/ancrod, a snake poison with thrombin-like properties, experienced significant benefit. This may be used as a last resort for therapy as there is little is known about this therapy. It probably works by interfering with fibrin formation.

Patient Management

Mild to moderate disease

Need close follow-up care every 2 to 3 months, unless there is an exacerbation of symptoms.

Moderate to severe disease

Need to be seen every 2 to 4 weeks.

Severe and life-threatening disease

Hospitalize for systemic involvement that needs daily evaluation.


At first there needs to be close follow-up care on a weekly basis. Then, if symptoms steadily improve, there can be follow-up care every 2 to 4 weeks to 2 to 3 months.

Screen for any underlying causative or associated disease. If therapy is effective, continue it but try to evaluate whether the doses could be reduced without relapse. When a therapy is working and suddenly there is a relapse, consider modification of therapy, either by increasing the dosage or adding other therapies. Key information for the patient is that this is a treatable disease. It is something that can be resolved, especially if secondary to another disease. Without therapy, it is likely that the vasculitic component of this disease will have a wide range of adverse effects on the body.

Unusual Clinical Scenarios to Consider in Patient Management

In managing these patients, it is important to understand that this disease is facilitated by cold environments and hypothermia. Care must be taken when these patients need surgery or some other procedure that may expose them to cold.

What is the Evidence?

Saadoun, D, Elalamy, I, Ghillani-Dalbin, P, Sene, D, Delluc, A, Cacoub, P. “Cryofibrinogenemia: new insights into clinical and pathogenic features”. Am J Med. vol. 122. 2009. pp. 1128-35. (A 10-year cohort study of 60 patients with symptomatic and persistent cryofibrinogenemia, without cryoglobulinemia, analyzed the prevalence, clinical features, treatment and outcome of the disease in a single university center. The essential/idiopathic and secondary cryofibrinogenemias are described.)

Nash, JW, Ross, P, Neil Crowson, A, Taylor, J, Morales, JE, Yunger, TM. “The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney”. Am J Clin Pathol. vol. 119. 2003. pp. 114-22. (A prospective study of 10 patients with cryofibrinogenemia in which the histologic manifestations of the disease are described in four organ systems: skin, skeletal muscle, lung and kidney. Regardless of anatomic location, there is a similarity in the histologic features; the hypereosinophilic crystallized cryofibrinogen occludes the vasculature. Histologically, cryofibrinogenemia can be distinguished from cryoglobulinemia by the evoked granulomatous response to cylindrical cryofibrinogen precipitate.)

Blain, H, Cacoub, P, Musset, L, Costedoat-Chalumeau, N, Silberstein, C, Chosidow, O. “Cryofibrinogenaemia: a study of 49 patients”. Clin Exp Immunol. vol. 120. 2000. pp. 253-60. (A retrospective study of 49 patients that characterizes the clinical features and components of 30 patients with isolated cryofibrinogenemia and 19 patients with both cryofibrinogenemia and cryoglobulinemia.)

Falanga, V, Kirsner, RS, Eaglstein, WH, Katz, MH, Kerdel, FA. “Stanozolol in treatment of leg ulcers due to cryofibrinogenaemia”. Lancet.. vol. 338. 1991. pp. 347-8.

Shimoni, A, Körbling, M, Champlin, R, Molldrem, J. “Cryofibrinogenemia and skin necrosis in a patient with diffuse large cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation”. Bone Marrow Transplant. vol. 26. 2000. pp. 1343-5. (A case report of a 61-year-old man with recurrent leg ulceration secondary to cryofibrinogenemia that healed rapidly and remained in remission with a combination of colchicine and high-dose pentoxifylline.)