ARTHRITIS & RHEUMATISM Volume 37 Number 12, December 1994, pp 1812-1815 0 1994, American College of Rheumatology 1812 DERMATOLOGIC VIGNETTE PAINFUL ACRAL PURPURIC NODULES JYOTI B . BURRUSS, VILMA C . FABRE, and JEFFREY P. CALLEN A 67-year-old woman presented with a history of intermittent, painful lesions on her feet. These lesions had been present for 2-3 years, with an associated burning sensation. She denied the presence of any known exacerbating factors including cooling of her extremities, or a seasonal association. She had not noted similar lesions on her fingertips. Her earlier medical history was significant for hyperlipidemia, osteoarthritis, and a malignant melanoma excised in 1981. She had not recently undergone any invasive procedures. A presumed diagnosis of vasculitis had been made, and she was being followed up by a local dermatologist. No biopsy had been performed. Laboratory evaluation had included serum multiphasic analysis, complete blood cell count (CBC), and cryoglobulin measurements, all of which were normal. Medication included buffered aspirin 325 mg 3 times per day for her arthritis. Physical examination revealed erythematous to violaceous papules and small nodules on the tips of her toes (Figure 1). Both feet were warm. The dorsalis pedis and posterior tibia1 pulses were normal bilaterally. Upon referral to us, a biopsy was performed (Figures 2 A and B). This revealed epidermal ischemia and eosinophilic globular masses within numerous deep dermal blood vessels, consistent with fibrin thrombi. Further laboratory evaluations revealed normal or negative findings on the following studies: serum multiphasic analysis, serum viscosity, antineutrophil cytoplasmic antibody (classic and perinuclear), antinuclear antibody, VDRL, rapid plasma reagin, cold agglutinins, anticardiolipin antibody, total hemolytic complement, erythrocyte sedimentation rate, cryoglobulins, urinalysis, and CBC. Serum protein electrophoresis revealed a mildly elevated q-globulin fraction consistent with an acute-phase reaction pattern. An electrocardiogram (EKG), echocardiogram, and carotid ultrasound were obtained to rule out an embolic etiology. The echocardiogram revealed a mild mitral regurgitation. The carotid study showed small plaques in the carotid arteries without significant stenosis and normal vertebral arteries. Results of the EKG and chest radiography were normal. Cryofibrinogens were positive. A complete physical examination revealed no other abnormalities including no detectable primary malignancy or evidence of metastatic disease. Treatment with oral stanozolol 2 mg twice daily was initiated, and the aspirin was continued for her arthritis. She had marked improvement within 8 weeks of the What is your diagnosis? (a) Erythromelalgia (b) Cholesterol emboli (c) Cryofibrinogenemia (d) Cryoglobulinemia (e) Cutaneous vasculitis Diagnosis: Cryofibrinogenemia Jyoti B. Burruss, MD, University of Louisville, Louisville, Kentucky; ViIma C. Fabr.6, MD: University of Louisville; Jeffrey P. Callen, MD: University of Louisville. Address reprint requests to Jeffrey P. Callen, MD, 310 East Broadway #200, Louisville, KY 40202. Submitted for oublication December 27. 1993: acceoted in revised form January 29, 1994. Figure 1. Erythematous to violaceous nodule on the distal area of the patient’s toe. DERMATOLOGIC VIGNETTE A 1813 B Figure 2. A and B, Biopsy specimens revealing marked pallor of the keratinocytes with pyknosis of the nuclei. A moderate perivascular lymphocytic infiltrate is present in the superficial and deep zones of the dermis. Eosinophilic globular masses within numerous deep dermal blood vessels consistent with fibrin thrombi, as well as focal extravasation of red blood cells, are present. No neutrophils, nuclear dust, or fibrinous degeneration of the blood vessel walls are noted (hematoxylin and eosin stained, original magnification X 4 in A and x 40 in B). initiation therapy, with resolution of the pain and cutaneous lesions (Figure 3). Discussion The patient’s initial symptoms on presentation suggested a diagnosis of erythromelalgia. The lack of improvement with aspirin as well as the severity of her symptoms resulted in the full laboratory evaluation for other etiologies. Cryofibrinogens are cold-precipitated Figure 3. The patient’s toes after 8 weeks of treatment. plasma proteins, and cryofibrinogenemia is often, but not exclusively, exacerbated upon cooling of the skin. This patient’s disease was apparently not worsened upon skin cooling, despite the fact that her lesions were acral in location. Interestingly, she had a paradoxical burning sensation, which may have been attributable to reactive hyperemia. Histopathologic findings in both cryofibrinogenemia and cryoglobulinemia include eosinophilic fibrin thrombi within the superficial or deep dermal blood vessels. Vasculitis may or may not be present, although extravasation of erythrocytes often occurs. A mild perivascular neutrophilic infiltrate may be present but is not a consistent finding. The differential diagnosis of noninflammatory intravascular thrombotic phenomena includes cryofibrinogenemia,cryoglobulinemia, antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, emboli, purpura fulminans, coumarin skin necrosis, protein C deficiency, and cholesterol emboli (1). Cryofibrinogens are complex plasma proteins composed mostly of fibrin, fibrinogen, and fibronectin, as well as smaller amounts of albumin, immunoglobulins, and other plasma proteins. They precipitate upon cooling to 4°C and dissolve upon rewarming to 37°C. 1814 This cryoprecipitate must be tested for in plasma anticoagulated with oxalate, citrate, or EDTA. Cryoglobulins precipitate in cooled serum and plasma. In contrast, cryofibrinogens are consumed in the clotting process, and thus do not precipitate in cooled serum (1). Cryofibrinogenemia is rare and can be associated with cold sensitivity, cutaneous ulcerations, livedo reticularis, acral purpura, hemorrhagic necrosis, and gangrene (2). It has been associated with malignancies, thrombotic processes, and infections, or it may be idiopathic. The various neoplasms reported in association with this disease include multiple myeloma, solid tumors (including prostate, pulmonary, ovarian, and gastric carcinomas), chronic lymphocytic and acute leukemias, lymphomas, and fibrosarcomas (3,4). Malignancy-associated cryofibrinogenemia occurs in 25% of patients with metastatic disease (5). Thrombotic events that may occur include myocardial infarction, stroke, pulmonary emboli, thrombophlebitis, gangrene, and thrombosis of the aorta or other large vessels. Associated infections include subacute bacterial endocarditis and rheumatic fever, although the significance of the correlation of these infections with cryofibrinogenemia has been questioned (3). Other reported associations have included diabetes mellitus, pseudotumor cerebri, pregnancy, oral contraceptives, Henoch-Schonlein purpura, various connective tissue diseases, ulcerative colitis, and monoclonal gammopathies (3-7). Our patient had a history of a malignant melanoma but no evidence of metastatic or recurrent disease associated with the onset of cryofibrinogenemia. Interestingly, in the series described by Smith and Arkin (3), 8 of 1 1 randomly selected patients in whom a serum protein electrophoresis was performed showed elevation of the cu,-globulinfraction, and all 11 had elevated a,-antitrypsin levels. Both of these are proteinase inhibitors and are known to inhibit plasmin. This inhibition may be the reason for the accumulation of the cryofibrinogens. In this series (3), an elevation in plasma fibrinogen was also noted. The thromboembolic events were postulated to be related to the abnormal protein levels. Our patient also had an elevated level of a2-globulin; a,-antitrypsin was not measured. The reported incidence rates of cryoglobulinemia and cryofibrinogenemiavary depending upon the study and the population screened. The incidence of cryofibrinogenemia was found to be 3% of 36,000 randomly tested hospitalized patients in one study (3). The immediate prognosis for survival was one-fourth BURRUSS ET AL that of other hospitalized patients. This increased mortality was likely due to the presence of an associated malignancy or to the hypercoagulable state. In another study of 130 randomly screened dermatology patients, cryofibrinogens were found in 9 patients (6.9%) as compared with cryoglobulins, which were found in only 1 patient (0.8%) (8). When symptomatic patients were screened, mixed cryoglobulins (50% polyclonal and 18% monoclonal) and monoclonal cryoglobulins (25%) were found more frequently than cryofibrinogens (3%) (9). Testing for cryofibrinogensalso may yield falsepositive and false-negative results if standardized methods are not employed. Anticoagulated blood must be used. A cryoprecipitate from heparinized plasma may mimic cryofibrinogen and be the source of a false-positive result. The blood must immediately be centrifuged or kept warm (37°C) to prevent autoabsorption of the cryofibrinogen by the red blood cells. Failure to do this can result in a false-negative reading, with the cryofibrinogen being discarded with the red blood cells (4). There are a variety of treatments for patients with cryofibrinogenemia, including symptomatic management, treatment of the underlying cause in patients with secondary cryofibrinogenemia, and, more recently, fibrinolytic therapies. Fibrinolytic therapy is based on the hypothesis that the pathologic process results from vascular compromise secondary to the precipitation of fibrin thrombi. Fibrinolytic therapy with streptokinase or streptodornase has resulted in some success (10). Recent reports have documented the efficacy of stanozolol in the treatment of cryofibrinogenemia as well as Raynaud’s phenomenon (2,ll). The benefit observed is believed to be due to the fibrinolytic activity of this anabolic steroid. The use of immunosuppressive agents with some success has been reported, suggesting a possible immunologic abnormality.Theagentsused haveincluded oral corticosteroids, azathioprine,pulse cyclophosphamide, chlorambucil, and plasmapheresis (1 3). In the report by Kirsner et a1 (2), the dosage of stanozolol for patients with leg ulcerations due to cryofibrinogenemia was 2 mg orally twice daily, with 2 patients requiring total daily doses of up to 8 mg. Of the 8 patients treated, 7 had healing of their cutaneous ulcers in 2-12 weeks. The 1 patient in whom this therapy failed was treated with the higher dosage of 8 mg/day. No major side effects were experienced by these patients. Side effects that have been reported include sodium retention, hypertension, acne, hirsut- DERMATOLOGIC VIGNETTE ism, liver function and lipid abnormalities, and dysmenorrhea, all of which are reversible upon discontinuation of the medication (2). This medication is contraindicated in patients with prostate cancer, in pregnant women, in men with breast carcinoma, and in women with breast carcinoma with hypercalcemia. Cryofibrinogenemia should be considered in the differential diagnosis of cutaneous leg ulcers and acral purpura. Histopathologic studies demonstrate eosinophilic thrombi in the small dermal vessels. Testing of plasma is necessary to detect the cryofibrinogen, and special handling is required for blood sample collection. Fibrinolytic therapy is frequently useful in patients with this disease. REFERENCES 1 . Beightler E , Diven DG, Sanchez RL, Solomon AR: Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 24:342-345, 1991 2. Kirsner RS, Eaglstein WH, Katz MH, Kerdel FA, Falanga V: 1815 Stanozolol causes rapid pain relief and healing of cutaneous ulcers caused by cryofibrinogenemia. J Am Acad Dermatol 28~71-74, 1993 3. Smith SB, Arkin C: Cryofibrinogenemia aggravated during hypothermia. N Engl J Med 281:1291-1292, 1969 4. Martin S: Cryofibrinogenemia, monoclonal gammopathy , and purpura. Arch Dermatol 115:208-211, 1979 5. Waxman S, Dove JT: Cryofibrinogenemia: incidence, clinical correlations and a review of the literature. Am J Clin Pathol 58:524-530, 1972 6. Cwazka WF, Sprenger MJD, Naguwa MSN, Birnberg FA: Cryofibrinogenemia in Henoch-Schonlein purpura. Arch Intern Med 139592493, 1979 7. Ball GV, Goldman LN: Chronic ulcerative colitis, skin necrosis, and cryofibrinogenemia, Ann Intern Med 85:464466, 1976 8. Goring H-D, Gans U: Uber das Vorkommen der Kryoproteine Heparin-Precipitable-Fraction,Kryofibrinogen and Kryoglobulin in einem nicht usgewahlten dermatologischen Krankengut. Dermatol Montsschr 159:52&525, 1973 9. Hobbs JR: Cryoproteins. Ann Med Interne Paris 137:254259, 1986 10. Copeman PWN: Cryofibrinogenemia and skin ulcers: treatment with plasmapheresis. Br J Dermatol 101:57-58, 1979 11. Ayres ML, Jarrett PEM, Browse NL: Blood viscosity, Raynaud’s phenomenon and the effect of fibrinolytic enhancement. Br J Surg 6851-54, 1981
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