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Outcome of essential cryofibrinogenaemia in a series of 61 patients
1Department of Internal Medicine, Rouen University Hospital, 2INSERM U644, Rouen Faculty of Medicine and Pharmacy, 3Immunology Department, 4Dermatology Department, 5Nephrology Department, Rouen University Hospital, Rouen, France and 6Department of Internal Medicine, Nantes University Hospital, Nantes, France.
Correspondence to: Dr C. Belizna, Department of Internal Medicine, Rouen University Hospital, 76031 Rouen Cedex, France. E-mail: cristina.belizna{at}wanadoo.fr
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Abstract |
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Objectives. The present study assessed the outcome of several cases of cryofibrinogenaemia detected in our hospitals during a 10-yr period (December 1996–April 2007), and also attempted to evaluate the clinical manifestations and associated diseases.
Methods. We performed a retrospective study in a series of 61 consecutive cryofibrinogenemia patients detected in our hospitals.
Results. In the 61 cryofibrinogenaemia patients, 18 had essential cryofibrinogenaemia and 43 secondary cryofibrinogaemia. Five out of the 18 patients with primary cryofibrinogaemia (27%) developed lymphoma after a 5-yr follow-up period. The main manifestations were cutaneous, and there were no differences in clinical presentation and disease severity in both types of cryofibrinogenaemia. A small number of patients (six) had cryofibrinogenaemia associated with cryoglobulinaemia, and in two cases, hepatitis C virus infection was detected; but no differences were observed between these two groups of patients.
Conclusion. Cryofibrinogenaemia was found in our study with a high prevalence, suggesting that this pathology is rather underestimated.
Our data further suggests that these patients should have a regular follow-up because of the high risk of symptom recurrence. We also hypothesize that in some cases essential cryofibrinogenaemia might be a prerequisite for a secondary disease.
KEY WORDS: Cryofibrinogenaemia, Essential cryofibrinogenaemia, Outcome
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Introduction |
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Cryofibrinogenaemia is a rare and potentially severe disease, described for the first time in 1955 by Korst and Kratochvil. Although cryofibrinogenaemia may often be clinically asymptomatic, there are also situations where thrombotic phenomena of skin and viscera are present and could be responsible for an extremely severe presentation. Cryofibrinogens are precipitants of protein complexes made up of fibronectin, fibrinogen and fibrin that are found in the plasma but not in the serum of some individuals. Cryofibrinogen precipitates in cooled plasma at 4°C, and dissolves at 37°C. Currently, cryofibrinogenaemia has been classified into an essential (primary) and a secondary form (associated with malignancies, collagen vascular diseases and thrombotic disorders).
The prevalence of cryofibrinogenaemia and especially of the essential form is not well known at present, due to the increased number of haematological diseases and the diminished number of infections, but this disorder seems however under-evaluated [1–4].
The present study attempted to assess the outcome of several cases of cryofibrinogenaemia detected in our hospital during a 10-yr period, and also to evaluate the clinical manifestations and associated diseases.
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Materials and methods |
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We performed a retrospective study (December 1996–April 2007) in a series of 61 consecutive cryofibrinogenaemia patients detected at our hospitals. Patients included in the last 36 months had follow-up every 6 months.
The diagnosis of cryofibrinogenaemia was mostly clinical (93% of cases) and cutaneous signs were suggestive in 80% of the cases.
The diagnosis was confirmed by cutaneous biopsy, cryofibrinogen detection and when the clinical signs were suggestive, by muscular and/or renal biopsy and tomodensitometry. Cryofibrinogenaemia and cryoglobulin detection conformed to standard procedures [2, 5].
Blood was collected in tubes containing oxalate or citrate as anticoagulant. The samples for the detection of cryofibrinogens were kept at 37°C in order to prevent auto-absorption of cryofibrinogens by red blood cells and centrifugation was performed in the following hour. After centrifugation, the plasma was stored at 4°C for 72 h and cryofibrinogens developed between 24 and 72 h after cooling.
Cryofibrinogens were quantitated as follows: ‘none’ represents no precipitate; ‘heavy’ indicates a precipitate >100 mg/100 ml; and ‘trace’ represents a precipitate <100 mg/100 ml. Another blood sample was collected in a tube free of anticoagulant, cooled in the same manner as for cryofibrinogens and centrifugation was performed. This sample was used for the detection of precipitable cryoglobulins [2, 5].
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Results |
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Sixty-one patients with a mean age of 62 yrs (35–78 yrs) were retrospectively included in the study. Sex ratio of male:female was 1.7 : 1.
In these patients, 18 had cryofibrinogenaemia considered as essential and 43 cryofibrinogenaemia secondary to an underlying disease. There were 16 cases (26%) associated with neoplasia, 14 cases (22%) with infectious disease (Klebsiella pneumoniae, Mycoplasma pneumoniae, Herpes zoster virus, Epstein–Barr virus, severe sepsis, erysipela), 7 (11%) with thrombotic disorder (recurrent idiopathic thrombosis) and 6 (9%) with collagen vascular disease (mixed connective tissue disease, Sjögren's syndrome and dermatomyositis).
The cases of cryofibrinogenaemia secondary to cancer (16) were represented by 10 non-Hodgkin lymphomas, two chronic myelomonocytic leucaemias, two multiple myelomas, three adenocarcinomas (gastric, liver and lung) (Table 1).
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Clinical signs were cutaneous (80%) (ischaemia, purpura, livedo reticularis, ecchymosis, ulcers, necrosis and gangrene). Other symptoms included arthralgia (38%), nephritic syndrome (20%), multinevritis (18%), myalgia and muscle weakness (12%), fever (6%), arterial and/or venous thrombosis (25%) (digital necrosis, distal venous thrombosis and thromboembolic disease) (Table 2).
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In the case of essential cryofibrinogenaemia, the initial clinical presentation was palpable purpura in 14 out of the 18 cases (77%), with underlying leucocytoclastic vasculitis.
Cryoglobulinaemia was associated in 6 cases (10%), and hepatitis C virus serology was positive in two of these patients. However, hepatitis C virus was searched for in all 61 patients. There were no differences in the mean age and sex ratio of patients with isolated cryofibrinogenaemia and cryofibrinogenaemia associated with cryoglobulinaemia (mean age 64 yrs, sex ratio 1.8/1).
All cases with combined cryofibrinogenaemia and cryoglobulinaemia had an underlying disease [neoplasia in four patients (67%) and hepatitis C infection in two (23%)]. Cutaneous signs were suggestive in all these six patients (100%), and there were no differences in disease severity and/or clinical outcome compared with patients with isolated cryofibrinogenaemia. Furthermore, no differences were found between patients with and without hepatitis C virus infection. Comparative clinico-serological and virological characteristics of both disorders (cryofibrinogenaemia and cryoglobulinaemia) are presented in Table 2.
The diagnosis was assessed by the detection of cryofibrinogenaemia in all cases (100%) and cutaneous biopsy in 89% of patients. In cases where the clinical picture was suggestive, renal biopsy was performed in 20%, muscular and nervous biopsy in 12 and 18% of situations, respectively.
No matter what the anatomic site, all lesions disclosed an occlusive thrombotic diathesis comprising eosinophilic refractile deposits within vessel lumina with extension into the intima, with or without an accompanying characteristic granulomatous vasculitic component. Skin biopsy revealed pauci-inflammatory thrombogenic vasculopathy associated in 50% of the cases with occlusion of capillaries by eosinophilc precipitates and/or ischaemic changes of epidermis. Ultrastructural examination of the renal deposits showed fibrillary material within glomerular capillaries, mesangium and/or renal tubules. Muscle biopsy revealed ischaemic myopathy and/or necrotizing vasculitis of small vessels and nerve biopsy showed vasculopathy (necrotizing in 30% of the cases).
In our series, clinical outcome was satisfactory with corticosteroid and/or other immunosuppressive therapy in 43 cases, and streptokinase in four patients.
Early death due to sepsis or terminal neoplasia occurred in six cases. In eight cases, there was a spontaneous regression of the symptoms only by cold avoidance. In secondary cryofibrinogenaemia, the treatment was directed against the underlying cause, for instance, antibiotics for infections or corticosteroids in collagen vascular disorders.
In the case of patients diagnosed with cryofibrinogenaemia in the last 36 months (16), eight of them were considered as essential. Regular follow-up of patients diagnosed with cryofibrinogenaemia in the last 36 months (16), with eight of them considered as having essential cryofibrinogenaemia, allowed us to conclude that five of these last ones (61%) developed T and B lymphomas.
In two cases, the initial symptom was isolated purpura, and in three cases purpura associated with arthralgia and myalgia. Cryofibrinogenaemia was found with no evidence of an underlying primary disease, and especially neoplasia. The clinical, radiological, histological, immunohistological and electron microscopical findings were in favour of essential cryofibrinogenaemia. After a follow-up period of several months, other signs and symptoms appeared such as anorexia, weight loss, fever (two cases) and palpable enlarged lymph nodes (two cases). The diagnosis was confirmed by biology (relevant in three cases) and bone marrow biopsy (five patients).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionAcknowledgementReferences |
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Our study showed a relatively high prevalence of cryofibrinogenaemia during a 10-yr period, suggesting an underestimated disease. The characteristics of our patient series were: the reduced number of cryofibrinogenaemia cases associated with cryoglobulinaemia in particular, the wide variety of clinical manifestations as well as a significant number of essential cryofibrinogenaemias. Moreover, cryofibrinogenaemia outcome towards a secondary cryofibrinogenaemia was related to neoplasia after a 36-month follow-up.
In the literature, the prevalence of cryofibrinogenaemia was estimated at 3.4–13% [1–4], but these data are likely to be modified at the present, considering the reduction in the number of severe infections, and the simultaneous increased incidence of disease able to induce an immunodepression.
The high prevalence of cryofibrinogenaemia during a 10-yr period might be explained either by the higher sensitivity and specificity of the techniques used for the detection of cryofibrinogenaemia or by the awareness of clinicians of this pathology.
Some improper technical details, such as blood collection on inadequate recipients, use of sera instead of plasma, blood conservation at <37°C until centrifugation and improper transportation could contribute to false negative results [2, 6].
Another characteristic of our series was the high prevalence of forms apparently essential, followed by cryofibrinogenaemia related to neoplasic disease (most of them haematological). In the majority of the cases the outcome was favourable.
According to the literature, clinical signs were mostly cutaneous (80%) (ischaemia, purpura, livedo reticularis, ecchymosis, ulcers, necrosis and gangrene), and represented by purpura in 77% of the cases in patients with essential cryofibrinogenaemia.
All the other symptoms recorded in our study, i.e. arthralgia, nephritic syndrome, multineuritis, myalgia and muscle weakness, fever, thrombosis, were found with the same prevalence as described in previous reports [2, 7] and listed in Table 2.
Our data are however different from the findings of Blain et al. [1], who reported a high prevalence of cases with cryofibrinogenaemia associated with cryoglobulinaemia.
In fact, we found only six cases with cryoglobulinaemia, and we were unable to show any differences in the mean age, sex ratio, disease severity and/or clinical outcome of patients with isolated cryofibrinogenaemia and cryofibrinogenaemia associated with cryoglobulinaemia.
Moreover, in the group of these last patients, no differences in clinical presentation and disease severity were found between patients with and those without hepatitis C, but the small number of cases excludes a formal conclusion.
Conventional treatments (stanazolol, streptokinase, steroids) were effective in most cases, both in essential and secondary cryofibrinogenaemia and also in cryofibrinogenaemia associated or not with cryoglobulinaemia, according to previous reports [2, 7].
These data are however in contrast with those reported by Blain et al. [1] who observed a resistance to treatments in patients with isolated cryofibrinogenaemia.
The focus point of our report is mainly related to the clinical outcome of cases initially considered such as essential cryofibrinogenaemia. Therefore, we observed that after a 36-month follow-up 5 of 16 patients (61%) developed T and B lymphoma.
Several other signs and symptoms appeared during the follow-up period and the diagnosis of a haematological malignancy was then performed, suggesting that cryofibrinogenaemia was in fact secondary to neoplasia, even though initially evaluated as essential.
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Conclusion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionAcknowledgementReferences |
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A high prevalence of cryofibrinogenaemia was found in our study, suggesting that this disease is rather underestimated in current clinical practice.
The most important finding of our report is related to the outcome of essential cryofibrinogenaemia diagnosed and followed up in the last 3 yrs. Although we could not draw a formal conclusion, our data suggest that in some cases cryofibrinogenaemia considered as essential might be a prerequisite for another pathology that will develop several months or years later. These data support the need for routine follow-up of these cases and further prospective studies are warranted in a larger patient population, in order to understand the actual prevalence of primary and secondary cryofibrinogenaemia, clinical and biological characteristics and especially clinical outcome.
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Acknowledgement |
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The authors are most grateful to Richard Medeiros, Rouen University Hospital Medical Editor, for his valuable advice in editing the manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
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References |
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- Blain H, Cacoub P, Musset L, et al. Cryofibrinogenaemia: a study of 49 patients. Clin Exp Immunol (2000) 120:253–60.[CrossRef][Web of Science][Medline]
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- Musset L, Diemert MC, Taibi F, et al. Characterization of cryoglobulins by immunoblotting. Clin Chem (1992) 38:798–802.
[Abstract/Free Full Text] - Beightler E, Diven DG, Sanchez RL, Solomon AR. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol (1991) 24:342–5.[Web of Science][Medline]
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