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STANOZOLOL IN TREATMENT OF LEG ULCERS DUE TO CRYOFIBRINOGENAEMIA
Five consecutive patients with cryofibrinogenaemia in association with
painful leg ulcers and intravascular dermal thrombi were treated with
stanozolol, an androgenic steroid with fibrinolytic properties. In all
patients treatment was followed by rapid and striking pain relief and
healing of the ulcers. Cryofibrinogenaemia was not detected on
subsequent laboratory evaluation, and dermal intravascular thrombi had
resolved on repeat histological examination.
Lancet 1991; 338: 347 48.
Cryofibrinogen, a plasma complex of fibrin, fibrinogen, and
fibronectin, was originally described in 1955 by Korst and
Kratochivil, who showed that it would precipitate reversibly on
cooling and could be made to clot with thrombin.(n1)
Cryofibrinogenaemia occurs as a primary (idiopathic) event or in
association with an underlying disorder such as a neoplasm, acute
infection, collagen vascular disease, or thromboembolic disease.(n2)
Cryofibrinogenaemia is often associated with painful cutaneous
ulcerations, which are usually located on the leg or foot and are
unresponsive to treatment. Fibrin thrombi within superficial dermal
vessels are observed histologically in skin specimens taken from the
ulcerations, suggesting that fibrin formation plays a part in the
development of cutaneous necrosis.(n3) This report describes five
consecutive patients with cryofibrinogenaemia, all of whom were
successfully treated with stanozolol, an androgenic steroid with
fibrinolytic properties.(n3, n4)
All five patients had very painful ulcerations located on the leg or
foot, and in all cases the skin of the lower extremities showed
varying degrees of livedo and scarring. The livedo pattern was not
confined to the skin adjacent to the ulcers but was more prominent at
the ankles and on the dorsum of the feet. The ulcer bed itself had
poor granulation tissue and, in some patients, frank necrosis. The
table describes the salient clinical features and course of our
subjects. Especially noteworthy was the painful nature of the ulcers,
which in patient 2 had been present intermittently since age 18. Pain,
when present, was described by all patients as constant and
interfering with daily activities. The patients had consulted several
physicians and had used many topical treatments, including occlusive
dressing, to no avail.
Before treatment with stanozolol was started, the presence of plasma
cryofibrinogen was confirmed, on at least two occasions, with Miale's
method.(n5) In all patients, intravascular dermal thrombi were seen in
tissue taken from the edge of the ulceration. Results of laboratory
tests were either normal or negative. Such studies included complete
blood counts, liver and kidney function tests, antinuclear antibodies,
rheumatoid factor, cryoglobulins, rapid plasma reagin, partial
thromboplastin time, anticardiolipin antibodies, and urinalysis. Chest
radiographs were also normal. Treatment with stanozolol was started at
2 mg twice daily but had to be increased in patient 5 because of
unsatisfactory response. Improvement was striking in all five patients
and was evident in patients 1-4 when they resumed for follow-up 2-6
weeks after the start of treatment. At chat time, all subjects said
that the pain had gone and that they were able to resume normal daily
activities. On physical examination, erythema and livedo were greatly
diminished, and the ulcerations were either healed or smaller without
evidence of necrosis. Patient 5 responded similarly to 8 mg a day
within 4 weeks. In patient 1 the use and discontinuation of stanozolol
was associated repeatedly with ulcer healing and ulcer recurrence,
respectively. In patient 2 stanozolol use for only 3 weeks brought
dramatic improvement after years of pain, and the beneficial effect
has persisted after discontinuation of the drug. Possibly, lysis of
existing fibrin thrombi with stanozolol sets up a new equilibrium
between fibrin formation and resolution, which results in less net
fibrin accumulation.
Cryofibrinogenaemia refers to the presence in the blood of an abnormal
cold precipitable protein which characteristically dissolves when the
cooled plasma is warmed.(n4) Smith and Arkin(n2) found
cryofibrinogenaemia in 3% of 36 000 randomly tested inpatients and
noted that the short-term survival of patients with
cryofibrinogenaemia was only a quarter of that of patients without
cryofibrinogenaemia, because the disorder was associated with internal
malignant disease, collagen vascular disease, thromboembolic events,
or infections. Patients may present with purpura or ecchymoses, but
other cutaneous findings such as gangrene, Raynaud's phenomenon, and
ulcerations may occur.(n6) These abnormalities are presumably related
to occlusion of small blood vessels by the abnormal cold precipitate.
Dermal intravascular thrombi are seen in a variety of other disorders,
such as cryoglobulinaemia, livedo vasculitis, the antiphospholipid
syndrome, disseminated intravascular coagulation, coumadin necrosis,
and sepsis. These conditions were excluded in the five patients in our
series.
The treatment of cryofibrinogenaemia has been for the most part
symptomatic or, as in secondary cryofibrinogenaemia, directed at the
underlying cause. Therapeutic attempts have also been directed at the
pathogenesis of the disorder. It has been noted that the in-vitro
splitting of the fibrinogen band in the oxalated cryoprecipitate is
probably due to plasmin activity.(n7) Because the underlying pathology
is thought to be the precipitation of the complex of fibrin,
fibrinogen, and fibronectin, leading to the formation of small-vessel
thrombi, Rachmilewitz et al(n8) treated two patients with
cryofibrinogenaemia and ulcerations with oral 'Varidase' (Lederle, a
mixture of streptokinase and streptodornase) and reported resolution
of their symptoms. Copeman(n9) reported the combination of varidase
with plasmapheresis in a patient with cryofibrinogenaemia but did not
mention the efficacy or side-effects of treatment.
Stanozolol has been found helpful in the treatment of Raynaud's
phenomenon, a condition manifested by vascular obstruction as well as
spasm. In patients with Raynaud's phenomenon treated with 5 mg
stanozolol twice daily, plasma fibrinogen fell and blood-flow
measurements improved, though blood viscosity was unchanged.(n10, n11)
The authors of these two reports postulated that the action of
stanozolol may have been due to vasodilatation or to possible lysis of
small vessel thrombi. Subsequent studies have supported stanozolol's
ability to facilitate fibrinolysis.(n4)
Our observations in five patients with cryofibrinogenaemia and skin
ulceration, in whom treatment with stanozolol was followed by striking
pain relief and healing of the ulcers, suggest that stanozolol may
help lyse dermal thrombi or prevent the formation of new thrombi, thus
leading to better tissue perfusion and healing.
Five consecutive patients with cryofibrinogenaemia in association with
painful leg ulcers and intravascular dermal thrombi were treated with
stanozolol, an androgenic steroid with fibrinolytic properties. In all
patients treatment was followed by rapid and striking pain relief and
healing of the ulcers. Cryofibrinogenaemia was not detected on
subsequent laboratory evaluation, and dermal intravascular thrombi had
resolved on repeat histological examination.
Lancet 1991; 338: 347 48.
Cryofibrinogen, a plasma complex of fibrin, fibrinogen, and
fibronectin, was originally described in 1955 by Korst and
Kratochivil, who showed that it would precipitate reversibly on
cooling and could be made to clot with thrombin.(n1)
Cryofibrinogenaemia occurs as a primary (idiopathic) event or in
association with an underlying disorder such as a neoplasm, acute
infection, collagen vascular disease, or thromboembolic disease.(n2)
Cryofibrinogenaemia is often associated with painful cutaneous
ulcerations, which are usually located on the leg or foot and are
unresponsive to treatment. Fibrin thrombi within superficial dermal
vessels are observed histologically in skin specimens taken from the
ulcerations, suggesting that fibrin formation plays a part in the
development of cutaneous necrosis.(n3) This report describes five
consecutive patients with cryofibrinogenaemia, all of whom were
successfully treated with stanozolol, an androgenic steroid with
fibrinolytic properties.(n3, n4)
All five patients had very painful ulcerations located on the leg or
foot, and in all cases the skin of the lower extremities showed
varying degrees of livedo and scarring. The livedo pattern was not
confined to the skin adjacent to the ulcers but was more prominent at
the ankles and on the dorsum of the feet. The ulcer bed itself had
poor granulation tissue and, in some patients, frank necrosis. The
table describes the salient clinical features and course of our
subjects. Especially noteworthy was the painful nature of the ulcers,
which in patient 2 had been present intermittently since age 18. Pain,
when present, was described by all patients as constant and
interfering with daily activities. The patients had consulted several
physicians and had used many topical treatments, including occlusive
dressing, to no avail.
Before treatment with stanozolol was started, the presence of plasma
cryofibrinogen was confirmed, on at least two occasions, with Miale's
method.(n5) In all patients, intravascular dermal thrombi were seen in
tissue taken from the edge of the ulceration. Results of laboratory
tests were either normal or negative. Such studies included complete
blood counts, liver and kidney function tests, antinuclear antibodies,
rheumatoid factor, cryoglobulins, rapid plasma reagin, partial
thromboplastin time, anticardiolipin antibodies, and urinalysis. Chest
radiographs were also normal. Treatment with stanozolol was started at
2 mg twice daily but had to be increased in patient 5 because of
unsatisfactory response. Improvement was striking in all five patients
and was evident in patients 1-4 when they resumed for follow-up 2-6
weeks after the start of treatment. At chat time, all subjects said
that the pain had gone and that they were able to resume normal daily
activities. On physical examination, erythema and livedo were greatly
diminished, and the ulcerations were either healed or smaller without
evidence of necrosis. Patient 5 responded similarly to 8 mg a day
within 4 weeks. In patient 1 the use and discontinuation of stanozolol
was associated repeatedly with ulcer healing and ulcer recurrence,
respectively. In patient 2 stanozolol use for only 3 weeks brought
dramatic improvement after years of pain, and the beneficial effect
has persisted after discontinuation of the drug. Possibly, lysis of
existing fibrin thrombi with stanozolol sets up a new equilibrium
between fibrin formation and resolution, which results in less net
fibrin accumulation.
Cryofibrinogenaemia refers to the presence in the blood of an abnormal
cold precipitable protein which characteristically dissolves when the
cooled plasma is warmed.(n4) Smith and Arkin(n2) found
cryofibrinogenaemia in 3% of 36 000 randomly tested inpatients and
noted that the short-term survival of patients with
cryofibrinogenaemia was only a quarter of that of patients without
cryofibrinogenaemia, because the disorder was associated with internal
malignant disease, collagen vascular disease, thromboembolic events,
or infections. Patients may present with purpura or ecchymoses, but
other cutaneous findings such as gangrene, Raynaud's phenomenon, and
ulcerations may occur.(n6) These abnormalities are presumably related
to occlusion of small blood vessels by the abnormal cold precipitate.
Dermal intravascular thrombi are seen in a variety of other disorders,
such as cryoglobulinaemia, livedo vasculitis, the antiphospholipid
syndrome, disseminated intravascular coagulation, coumadin necrosis,
and sepsis. These conditions were excluded in the five patients in our
series.
The treatment of cryofibrinogenaemia has been for the most part
symptomatic or, as in secondary cryofibrinogenaemia, directed at the
underlying cause. Therapeutic attempts have also been directed at the
pathogenesis of the disorder. It has been noted that the in-vitro
splitting of the fibrinogen band in the oxalated cryoprecipitate is
probably due to plasmin activity.(n7) Because the underlying pathology
is thought to be the precipitation of the complex of fibrin,
fibrinogen, and fibronectin, leading to the formation of small-vessel
thrombi, Rachmilewitz et al(n8) treated two patients with
cryofibrinogenaemia and ulcerations with oral 'Varidase' (Lederle, a
mixture of streptokinase and streptodornase) and reported resolution
of their symptoms. Copeman(n9) reported the combination of varidase
with plasmapheresis in a patient with cryofibrinogenaemia but did not
mention the efficacy or side-effects of treatment.
Stanozolol has been found helpful in the treatment of Raynaud's
phenomenon, a condition manifested by vascular obstruction as well as
spasm. In patients with Raynaud's phenomenon treated with 5 mg
stanozolol twice daily, plasma fibrinogen fell and blood-flow
measurements improved, though blood viscosity was unchanged.(n10, n11)
The authors of these two reports postulated that the action of
stanozolol may have been due to vasodilatation or to possible lysis of
small vessel thrombi. Subsequent studies have supported stanozolol's
ability to facilitate fibrinolysis.(n4)
Our observations in five patients with cryofibrinogenaemia and skin
ulceration, in whom treatment with stanozolol was followed by striking
pain relief and healing of the ulcers, suggest that stanozolol may
help lyse dermal thrombi or prevent the formation of new thrombi, thus
leading to better tissue perfusion and healing.
