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Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia

2006; Elsevier BV; Volume: 4; Issue: 7 Linguagem: Inglês

10.1111/j.1538-7836.2006.02014.x

1538-7933

Flora Peyvandi, Sabine Haertel, Sigurd Knaub, Pier Mannuccio Mannucci,

Hemoglobinopathies and Related Disorders

Journal of Thrombosis and HaemostasisVolume 4, Issue 7 p. 1634-1637 Free Access Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia F. PEYVANDI, F. PEYVANDI Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Luigi Villa Foundation, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, ItalySearch for more papers by this authorS. HAERTEL, S. HAERTEL ZLB Behring GmbH, Clinical Research and Development Department, Marburg, GermanySearch for more papers by this authorS. KNAUB, S. KNAUB ZLB Behring GmbH, Clinical Research and Development Department, Marburg, GermanySearch for more papers by this authorP. M. MANNUCCI, P. M. MANNUCCI Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Luigi Villa Foundation, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, ItalySearch for more papers by this author F. PEYVANDI, F. PEYVANDI Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Luigi Villa Foundation, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, ItalySearch for more papers by this authorS. HAERTEL, S. HAERTEL ZLB Behring GmbH, Clinical Research and Development Department, Marburg, GermanySearch for more papers by this authorS. KNAUB, S. KNAUB ZLB Behring GmbH, Clinical Research and Development Department, Marburg, GermanySearch for more papers by this authorP. M. MANNUCCI, P. M. MANNUCCI Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Luigi Villa Foundation, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, ItalySearch for more papers by this author First published: 20 June 2006 https://doi.org/10.1111/j.1538-7836.2006.02014.xCitations: 97 Flora Peyvandi, A. Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione Luigi Villa, University of Milan and IRCCS Maggiore Hospital Milan, Milan, Italy.Tel.: +39 02 54125707; fax: +39 02 54100125; e-mail: flora.peyvandi@unimi.it AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Congenital deficiency of plasma fibrinogen is a hereditary bleeding disorder with an autosomal recessive pattern of inheritance [1] and an estimated incidence of 1–2 per million in the general population [1]. Due to the rarity of the disorder, the available data on the incidence of bleeding episodes, prevalent clinical manifestations and treatment modalities are scarce [2-7]. Afibrinogenemia is sometimes associated with symptoms that are unusual in patients with defects of coagulation factors, such as thrombotic complications and miscarriages [8-12]. However, knowledge on the incidence and significance of these unusual symptoms is influenced by publication bias. Fresh frozen plasma, cryoprecipitate (cryo) and lyophilized fibrinogen concentrates are the main sources of fibrinogen for replacement therapy, but there is limited knowledge on optimal dosages and target plasma levels. Finally, there is little experience on the use of prophylactic replacement therapy. In order to fill these gaps of knowledge, we report here on the results of a questionnaire survey based upon the data obtained in 100 a- or hypofibrinogenemic patients. In Europe and Canada the questionnaire was sent to 14 physicians known to treat patients with fibrinogen deficiency from their publications, from marketing information (use of the fibrinogen concentrate manufactured by ZLB Behring, Marburg, Germany) or from asking hemophilia centers. In the USA, the questionnaire was sent to 97 hemophilia centers from the national registry. This survey and its design were agreed upon by the Food and Drug Administration, because there is no fibrinogen concentrate in the USA and little is known about the incidence of bleeding and treatment practice in patients with fibrinogen deficiency. The general part of the questionnaire (available upon request) was meant to gather information on the number of patients under the care of each physician, the peak levels of plasma fibrinogen considered necessary for hemostasis, the laboratory assay used to measure plasma fibrinogen, and the types of products used for treatment. A part specific for each patient collected demographic variables and the protocol adopted for prophylactic or on-demand treatment of spontaneous, post-traumatic or surgical bleeding episodes categorized according to location. The incidence of bleeding episodes was calculated for each patient starting from the time period when she/he started to be followed up regularly at the treatment center. Analysis was done separately for patients on prophylaxis or on-demand treatment, and for each of the main replacement products. Thirty-four physicians from 10 different countries [USA (11), Italy (9), Canada (3), Austria (2) Iran (2), Germany (2), Spain (2), Switzerland (1), Turkey (1) and UK (1)] responded to the questionnaire because they followed at least one patient with a- or hypofibrinogenemia. Data from 100 patients (53 males and 47 females, median age 20.5 years, range 7 months to 75 years) were obtained. The most common method used for plasma fibrinogen determination was the Clauss fibrin polymerization assay. Patients’ fibrinogen levels ranged from 0 to 116 mg dL−1, with a median level of 6 mg dL−1. Seventy-two patients had levels of < 10 mg dL−1, 26 between 10 and 50 mg dL−1, and one more than 50 mg dL−1 (1 missing). The only patient with relatively high fibrinogen value (116 mg dL−1) was reported to be a bleeder and not to have dysfibrinogenemia (values of immunoreactive fibrinogen were similar to those of functional fibrinogen). A total of 517 bleeding episodes (322 spontaneous, 100 trauma-related, 79 surgery-related and 16 ‘other’ or ‘unspecified’) were reported. The mean annual incidence of bleeding episodes was 0.5 for patients on prophylactic replacement therapy (range 0–2.6) and 0.7 for patients on on-demand therapy (range 0–16.5). Although the incidence of bleeding appears to be low, there were 15 patients treated on demand who had an annual incidence equal or greater than one per year (Table 1). Of these 15 more frequent bleeders (13 had fibrinogen levels of < 10 mg dL−1), some had been followed at the hemophilia centers for < 12 months, so their reported incidence of bleeding may be somewhat inaccurate (Table 1). Of the reported bleeding episodes, 40% were of mucosal type, 54% non-mucosal, and 6% unspecified. Among the 72 patients with severe fibrinogen deficiency (< 10 mg dL−1), the most frequent hemorrhages were hemarthrosis (25%), muscle hematoma (17%), gastrointestinal (GI) bleeding (17%), epistaxis (10%) and menorrhagia (7%). Central nervous system (CNS) and intra-retroperitoneal bleeding were reported rarely (4% each). Two patients had a thrombotic episode (see below) and four of 30 women of childbearing age had a miscarriage. Among the 26 patients with milder fibrinogen deficiency (10 mg dL−1 or more) the most frequent hemorrhagic symptom was menorrhagia (in 46% of patients), whereas hemarthrosis (14%), muscle hematoma (12%), GI bleeding (5%) and epistaxis (6%) were less frequent than in patients with severe deficiency. There was no case of CNS and intra-retroperitoneal bleeding, thrombosis and miscarriage. Table 1. Details of patients treated on demand with at least one bleeding episode per year Patients code Plasma fibrinogen levels (mg dL−1) Duration of follow-up (years) Number of events* Incidence per year Treatment products 2001 <10 8.0 11 1.4 Concentrate† 2002 <10 0.3 3 9.0 Mixed 2003 <10 6.9 15 2.1 Mixed 7001 <10 0.8 2 2.6 Mixed 7002 <10 5.0 18 3.6 Concentrate 12001 <10 23.6 61 2.6 Mixed 15001 <10 2.8 46 16.5 Mixed 18002 <10 0.1 1 7.6 Mixed 19002 <10 1.0 1 1.0 Cryoprecipitate 20001 <10 0.5 1 2.1 Mixed 20002 32 0.5 1 1.8 Other 21001 <10 0.2 1 4.2 Concentrate 21002 <10 0.9 1 1.0 Concentrate 26001 90%). Nineteen patients were on regular prophylaxis (17 with fibrinogen concentrates and two with cryo). Typical reasons for this mode of treatment delivery were previous CNS bleeding and frequent spontaneous bleeding. Daily doses of fibrinogen ranged from 18 to 120 mg kg−1, with a median of 53 mg kg−1. Most patients (59%) received weekly doses, the remaining patients were treated every 2 weeks or once a month. The two patients on cryo received weekly doses of 10 and 18 bags of cryo, respectively. Nine of the 19 patients treated prophylactically had no breakthrough bleeding, five of 19 suffered from 1–2 episodes per year, two from two to four episodes, and two patients experienced CNS bleeding during prophylaxis (on weekly treatment, one with cryo, one with fibrinogen). No information was provided on the fibrinogen levels attained at the time of these breakthrough bleeding episodes. Ischemic stroke occurred in a patient treated bi-weekly with 63 mg kg−1, which was changed to the same dosage every 3 weeks but with this schedule a CNS bleeding occurred. With 42 mg kg−1 no event occurred in the last 3 years. For another patient on prophylaxis with cryo the dose was changed due to ‘thrombosis’, but the type of the thrombosis was not specified. This survey is retrospective and based upon a questionnaire, and has therefore all the limits and biases of this type of analysis. According to previous reports [1-6], bleeding manifestations are highly heterogeneous in fibrinogen-deficient patients, ranging from mild to catastrophic in severity. This survey is the first that attempts to provide data on the incidence of bleeding episodes in these patients. The mean annual incidence in patients treated on-demand was 0.7 (0–16.5). These wide ranges confirm the heterogeneity of the disease: some patients do not bleed at all, others bleed more frequently, for example, 15 patients had more than one bleeding event per year (Table 1). A few patients among the frequent bleeders had been followed up for < 12 months, so that their reported incidence of bleeding may be inaccurate. However, even if the calculated incidences were doubled, the mean number of bleeding episodes per year would still be close to one per year, which is unexpectedly low. In hemophilia A and B, for instance, the average frequency of bleeding is no < 10–15 episodes per year [13]. This survey also indicates that the therapeutic approaches of the participating physicians were variable. The peak fibrinogen level most often recommended for on-demand treatment of minor bleeding was approximately 100 mg dL−1, but the target level for major episodes such as CNS bleeding was higher (150 mg dL−1). Minor episodes, like epistaxis, were usually treated with target peaks of 50–70 mg dL−1. Duration of treatment ranged from 1 to 2 weeks for major events, from 1 to 7 days for minor events. The main types of replacement material used (fibrinogen concentrates and cryo) seem to be equally effective, but fibrinogen concentrates have a better safety profile because they are virus-inactivated. The volume of infusion required for adequate hemostasis is much larger for cryo and high amounts of unnecessary proteins such as factor VIII and von Willebrand factor are infused with this blood product. Finally, more precise dosing can be accomplished with fibrinogen concentrates in order to achieve the desired target plasma levels, because their potency is known, in contrast to cryo. There were only few data to compare bleeding events before and after the start of prophylaxis, so that it is difficult to assess the efficacy of this mode of treatment delivery. Surprisingly, the mean incidence of bleeding episodes in patients on prophylaxis was not much lower than that in patients treated on demand. A severe manifestation such as intracranial bleeding occurred in two patients on prophylaxis. Unfortunately, there were no data about the plasma levels of fibrinogen at the time of the events. As the pharmacokinetics of fibrinogen after replacement therapy show a large between-patients variability [14], adjustment of the prophylactic schedule to the pharmacokinetic data of the individual patient might be an option. Four of 30 women in the fertile age had a miscarriage, so that this complication appears frequently in this series as in others [3, 5]. Two patients experienced thrombotic events under prophylactic treatment. Occurrence of thrombosis in patients with fibrinogen deficiency has been repeatedly described [3, 5-12]. The prevailing hypothesis on the mechanism of this complication is that thrombin activity, which forms at a normal rate in patients with fibrinogen deficiency, is poorly neutralized because the thrombin-neutralizing activity of fibrin is lacking (so called antithrombin VI) [7, 12]. This hypothesis, however, is not consistent with the observation that in this as well as in other reported cases, thrombosis developed not only in untreated patients but also in those receiving replacement therapy. More studies should be done to understand the mechanism of thrombosis but they are rendered difficult by the rarity of fibrinogen deficiency. Acknowledgements This study was jointly planned and written by the authors of the Hemophilia and Thrombosis Center and those of ZLB Behring that supported the study. The following participants in the study are acknowledged: S. A-Acharya, USA; J. A. Aznar, Spain; S. Bernasconi, Italy; L. Boggio, USA; H. Britton, USA; D. Brown, USA; E. Broxon, USA; G. Cantin, Canada; G. Castaman, Italy; J. Ducore, USA; G. Growe, Canada; J. Hambleton, USA; K. Hoots, USA; V. Jiménez-Yuste, Spain; M. Karimi, Iran; K. Kavakli, Turkey; D. Keeling, UK; C. Kessler, USA; W. Kreuz, Germany; P. A. Kyrle, Austria; M. Lak, Iran; P. Leblond, Canada; B. Lewis; USA; L. J. Logan, USA; G. Mancuso, Italy; P. M. Mannucci, Italy; P. Marks, USA; E. O. Meili, Switzerland; M. Morfini, Italy; G. Piseddu, Italy; H. Pollmann, Germany; G. Rivard, Canada; M. Schiavoni, Italy; R. Schwarz, Austria; A. D. Shapiro, USA; R. Targhetta, Italy; F. Tarin, Spain; A. R. Thompson, USA; E. Williams, USA; E. Zanon, Italy. References 1 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104: 1243– 52. CrossrefCASPubMedWeb of Science®Google Scholar 2 Fried K, Kaufman S. Congenital afibrinogenemia in 10 offsprings of uncle–niece marriages. Clin Genet 1980; 17: 223– 7. Wiley Online LibraryPubMedWeb of Science®Google Scholar 3 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107: 204– 6. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 4 Schneider D, Bukovsky I, Kaufman S, Sadovsky G, Caspi E. Severe ovarian hemorrage in congenital afibrinogenemia. Acta Obstet Gynecol Scand 1981; 60: 431. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 5 Al-Mondhiry H, Ehmann WC. Congenital afibrinogenemia. Am J Hematol 1994; 46: 343– 7. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 6 Peyvandi F, Duga S, Akhavan S, Mannucci PM. Rare coagulation deficiencies. Haemophilia 2002; 8: 308– 21. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 7 Mosesson MW. Hereditary abnormalities of fibrinogen. In: E Beutler, MA Lichtman, BS Coller, TJ Kipps, U Seligsohn, eds. Williams Hematology, 6th edn. New York: McGraw-Hill, 2001: 1659– 71. Google Scholar 8 MacKinnon HH, Fekete JF. Congenital afibrinogenemia: vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. CMAJ 1971; 104: 597– 9. CASPubMedWeb of Science®Google Scholar 9 Cronin C, Fitzpatrick D, Temperley I. Multiple pulmonary emboli in a patient with afibrinogenaemia. Acta Haematol 1988; 79: 53– 4. CrossrefCASPubMedWeb of Science®Google Scholar 10 Kinebuchi A, Ohtsuka T, Ishida S, Otsuka S, Abe T, Yamakage A, Yamazaki S, Nakamura Y, Hirota K. Leg ulcer presenting in a patient with congenital afibrinogenaemia. Eur J Dermatol 2002; 12: 70– 2. PubMedWeb of Science®Google Scholar 11 Garcia-Monco JC, Fernandez Canton G, Gomez Beldarrain M. Bilateral vertebral artery dissection in a patient with afibrinogenemia. Stroke 1996; 27: 2325– 7. CrossrefPubMedWeb of Science®Google Scholar 12 Dupuy E, Soria C, Molho P, Zini JM, Rosenstingl S, Laurian C, Bruneval P, Tobelem G. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001; 102: 211– 9. CrossrefCASPubMedWeb of Science®Google Scholar 13 Rainsford SG, Hall A. A three-year study of adolescent boys suffering from haemophilia and allied disorders. Br J Haematol 1973; 24: 539– 51. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 14 Kreuz W, Meili E, Peter-Salonen K, Dobrkovská A, Devay J, Haertel S, Krzensk U, Egbring R. Pharmacokinetic properties of a pasteurised fibrinogen concentrate. Transfus Apher Sci 2005; 32: 239– 46. CrossrefPubMedWeb of Science®Google Scholar Citing Literature Volume4, Issue7July 2006Pages 1634-1637 ReferencesRelatedInformation