Centre for Rheumatic Diseases, University Department of Medicine, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER and
1 Biochemistry Department, Wishaw General Hospital, 50 Netherton Street, Wishaw ML2 0DP, UK
SIR, Cryofibrinogen was first described in 1955 by Korst and Kratochvil [1]. It refers to a plasma complex of fibrin, fibrinogen and fibronectin that precipitates in plasma cooled to 4°C and may dissolve upon warming to 37°C. Cryofibrinogenaemia may occur as a primary event or secondarily to a wide range of diseases, including carcinoma, acute and chronic inflammatory processes, collagen vascular diseases and thromboembolic disorders, but the aetiology of this condition remains obscure.
We report a patient with cryofibrinogenaemia who initially responded to stanozolol and then developed significant proteinuria. This case illustrates that the cryofibrinogen level can fall concomitant with stanozolol therapy, confirming its efficacy, but this is also the first report of amyloidosis in cryofibrinogenaemia.
A 72-yr-old female had attended a dermatology out-patient clinic intermittently for 10 yr, with biopsy-confirmed leucocytoclastic vasculitis of unknown aetiology. Treatment with dapsone gave a good clinical response in the initial phase. However, frequent recurrence of vasculitis occurred despite an increased dose of dapsone. In May 2000, she developed florid vasculitic lesions and was commenced on prednisolone 30 mg per day to achieve disease control. However, a week later she developed breathing difficulty that required admission to the ENT (ear, nose and throat) unit. She was noted to have intra-oral lesions compatible with vasculitis; direct laryngoscopy failed to show glottic oedema but did show vasculitic lesions on each of the aryepiglottic folds.
Because of the lack of symptom control, she was referred by the dermatologists. Investigation revealed normal full blood count and elevated erythrocyte sedimentation rate (39 mm/h) and C-reactive protein (29 mg/l; normal range 010 mg/l), normal renal function and urinalysis, and normal liver function tests. There were no monoclonal antibodies detected on protein electrophoresis and no cryoglobulins were present. Immunology results were negative for antinuclear antibodies and antineutrophil cytoplasmic antibodies, with normal C3 and C4 levels and slightly elevated C3d. Azathioprine 50 mg/day was added for its steroid-sparing effect and prednisolone was reduced to 25 mg/day.
Four months later, a raised plasma cryofibrinogen level (384 mg/l) was detected and stanozolol 2.5 mg/day was introduced to treat cryofibrinogenaemia. Over the subsequent 4 months, the dose of stanozolol was increased to 10 mg with a gradual reduction of daily oral prednisolone to 10 mg, while azathioprine was increased to 100 mg/day.
Five months later, the patient was admitted as an emergency with vomiting and diarrhoea with pyrexia and a widespread purpuric rash. However, on this occasion she was noted to have blood and protein detected on analysis. Stanozolol was stopped, but 1 day after admission she sustained a myocardial infarction (confirmed on thallium scan) complicated by pulmonary oedema, which responded to diuretics and ACE (angiotensin-converting enzyme) inhibitors. It remains uncertain whether this was a consequence of vasculitis.
The proteinuria was quantified at 3.5 g/24 h, with reduced creatinine clearance (38 ml/min; normal range 80140 ml/min). Myeloma screening was again negative and cryofibrinogen was undetectable at the time of renal biopsy despite the presence of the vasculitic rash. Renal size was normal by ultrasound. Biopsy showed no evidence of vasculitis, but was positive for amyloid by Congo red staining and confirmed to be AA amyloid by immunostaining. The prednisolone dosage was subsequently increased and she has subsequently received six courses of intravenous cyclophosphamide. The proteinuria has decreased to 1.3 g/24 h, but the low creatinine clearance remains and is under regular review.
Cryofibrinogenaemia commonly presents as purpuric lesions on the arms and legs, which have a vasculitic pathology, as seen in our patient. Symptomatic cases of cryofibrinogenaemia have been treated successfully with various therapies, including fibrinolytic drugs such as the combination of streptodornase and/or urokinase, and plasmapheresis [2]. In 1991, Falanga et al. [3] reported promising results with stanozolol in the treatment of leg ulcers due to cryofibrinogenaemia. Stanozolol is an androgenic steroid that facilitates fibrinolysis, thus supporting its use in the treatment of cryofibrinogenaemia. This case shows that the level of cryofibrinogen does indeed fall after treatment with stanozolol, as would be expected with the reported clinical improvement.
The development of amyloid in our patient could represent two unrelated diseases in one patient. Alternatively, it could be that the amyloid was present before the cryofibrinogenaemia without any clinical features of amyloidosis at presentation. However, given that the history, clinical examination and investigations in this case suggest chronic inflammation, it may well be that the cryofibrinogenaemia preceded and resulted in the amyloidosis. It is well recognized that AA amyloid occurs most commonly in the renal tissues, in association with other chronic inflammatory disorders, chronic microbial infections and malignant neoplasms, and it was AA amyloid that was identified in the renal biopsy. Congo red staining is the pathognomonic histochemical test for amyloidosis, but immunostaining using specific antibodies is diagnostic for AA amyloid [4]. We hypothesize that cryofibrinogen is more likely to have resulted in the formation of ß pleated sheets and therefore amyloid (SAA) formation. This process, possibly mediated by the complement cascade, may have resulted in changes to hydrogen bonds and the secondary structure of the cryofibrinogen, resulting in polymerization of the polypeptides. A similar process is thought to give rise to amyloidogenic amylin in type 2 diabetes [5].
To date there has been no report describing an association between cryofibrinogenaemia and amyloidosis. Given this, we postulate thatalbeit rarelycryofibrinogenaemia may lead to secondary amyloidosis, as illustrated in our case, and that cryofibrinogenaemia should be added to the list of causes of amyloid and excluded in suspected cases.
Notes
Correspondence to: M. Field. E-mail: mf4a{at}clinmed.gla.ac.uk
References