Painful acral purpuric nodules.

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.
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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.
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