Thrombosis Research 130S2 (2012) S7–S11

Original Article

Epidemiology and treatment of congenital fibrinogen deficiency

Flora Peyvandi *Hemophilia and Thrombosis Center, University of Milan, Italy

A R T I C L E I N F O A B S T R A C T

Keywords:Congenital fibrinogen deficiencyEpidemiologyAfibrinogenemiaHypofibrinogenemiaDysfibrinogenemiaSurgeryFibrinogen concentratePregnancyFibrinogen replacementHaemocomplettan® PRiaSTAP®

Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia,hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong associationbetween fibrinogen activity levels and clinical bleeding severity. Patients with afibrinogenemia experiencefrequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracra-nial hemorrhage. Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerableto bleeding after trauma. Dysfibrinogenemia is associated with both spontaneous bleeding and a relativelyhigh risk of thrombosis. Fibrinogen replacement therapy is effective in treating bleeding episodes in con-genital fibrinogen deficiency. Fibrinogen concentrates are the preferred treatment option and guidelines nowexist for their on-demand use and to manage surgery. Prophylaxis may benefit patients with afibrinogenemiaand others with a severe bleeding tendency. The dose and frequency of administration should be adjusted tomaintain a fibrinogen activity level >0.5–1.0 g/L. Pregnant women with afibrinogenemia require prophylac-tic factor replacement as early as possible during pregnancy, continuing throughout pregnancy, and after thebirth. Fibrinogen replacement should also be considered in pregnant women with other fibrinogen deficien-cies. The risk of thrombosis presents an additional management challenge in these patients, often necessi-tating the concurrent use of anticoagulants and fibrinogen. Although basic guidelines have been developed,further studies are needed to help optimize treatment in different patient groups under different clinicalcircumstances and to improve our understanding of thrombotic events.

© 2012 Elsevier Ltd. All rights reserved.

Fibrinogen, the soluble precursor of fibrin, is a key contributor toboth primary and secondary hemostasis, promoting clot formation,platelet aggregation, and fibrinolysis [1–3]. Fibrinogen is the mostabundant clotting factor in the human circulation, with normalconcentrations typically ranging from 2.0 to 4.5 g/L [4].

Congenital fibrinogen deficiencies can be either quantitative(afibrinogenemia and hypofibrinogenemia) or qualitative (dysfib-rinogenemia). Clinical manifestations vary according to the typeof deficiency: afibrinogenemia (a complete lack of fibrinogen) isassociated with a high frequency of bleeding, with 85% of pa-tients experiencing umbilical cord bleeding, 72% reporting musclehematomas, and 54% reporting hemarthrosis in one Iranian study[5]. Epistaxis, menorrhagia, and oral cavity bleeding were reportedby ≥70% of patients in this study; central nervous system (CNS)bleeds occurred in 10% of patients [5]. In dysfibrinogenemia, overhalf of patients experience no clinical complications; however,bleeding occurs in around 25%, and thrombosis (primarily deep vein

Abbreviations: aPTT, activated partial thromboplastin time; CNS, central nervoussystem; ELISA, enzyme-linked immunosorbent assay; EN-RBD, European Networkof Rare Bleeding Disorders; FFP, fresh frozen plasma; LMWH, low-molecular-weightheparin; PT, prothrombin time; TT, thrombin time; WFH, World Federation ofHemophilia.* Correspondence: Flora Peyvandi, Hemophilia and Thrombosis Center, Univer-sity of Milan, Via Pace, 9, 20122 Milan, Italy. Tel.: +39 0255035414; fax: +390254100125.E-mail address: flora.peyvandi@unimi.it (F. Peyvandi).

0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.

thrombosis, thrombophlebitis, and pulmonary embolism) has beenreported in approximately 20% of patients – often developing at ayoung age [1]. Patients with hypofibrinogenemia (characterized byfibrinogen levels <1.5 g/L) are usually asymptomatic, although theyhave a tendency to bleed when exposed to trauma or if they have asecond associated hemostatic abnormality [3].

Epidemiology of congenital fibrinogen deficiency

International registries suggest that congenital fibrinogen defi-ciency is one of the rarest of the rare bleeding disorders [6,7]. Theestimated prevalence of afibrinogenemia is approximately one inone million [8]. The most recent World Federation of Hemophilia(WFH) annual global survey, which was conducted in 2009, foundthat only 7% of rare bleeding disorders were due to congenitalfibrinogen deficiency [7]. We have recently reported data fromthe European Network of Rare Bleeding Disorders (EN-RBD), andfound a similar prevalence (8%) of congenital fibrinogen deficiencyamongst 592 patients included in the database [6]. The prevalenceof fibrinogen deficiency was similar in men (46%) and women (54%),and below the age of 60 years, the prevalence was similar amongstall age groups (Fig. 1).

The EN-RBD database offers important new insights intothe variety of bleeding phenotypes and the association be-tween fibrinogen activity and bleeding severity in patients withcongenital fibrinogen deficiency. Over 40% (42.3%) of individ-

S8 F. Peyvandi / Thrombosis Research 130S2 (2012) S7–S11

Fig. 1. Epidemiology of congenital fibrinogen deficiency: results from the European Network of Rare Bleeding Disorders (EN-RDB) [6].

uals in the EN-RBD database with afibrinogenemia or hy-pofibrinogenemia had a history of Grade III bleeding (definedas spontaneous major bleeding including hematomas, hemarthrosis,CNS, gastrointestinal, and umbilical cord bleeding); 3.8% had expe-rienced Grade II bleeding (defined as spontaneous minor bleeding,such as bruising, ecchymosis, oral cavity bleeding, epistaxis, andmenorrhagia) and 19.2% had experienced Grade I bleeding (bleedingthat occurred after trauma or drug ingestion) [6]. A linear regressionanalysis, adjusted for age, gender, and center where the diagnosiswas made, found a strong association between fibrinogen activitylevel and bleeding severity (Fig. 2): patients with a mean fibrinogen

Linear regression analysis: adjusted for age, gender and country

Beta Factor activity for Factor activity for Factor activity for Factor activity for(95% CI) asymptomatic patients Grade I bleeding Grade II bleeding Grade III bleeding

(95% CI) (95% CI) (95% CI) (95% CI)

−40.22 113.4 73.19 32.97 0(−54.24, −26.19) (22.8, 204.01) (0, 164.14) (0, 126.39) (0, 90.61)

Fig. 2. Linear regression analysis of the association between fibrinogen activity level and bleeding severity: results from the European Network of Rare Bleeding Disorders(EN-RDB) [6]. CI, confidence interval.

activity level of at least 0.7 g/L appeared to be protected fromspontaneous bleeds, while a level >1.0 g/L completely protectedthe individual from bleeding symptoms [6]. This suggests that afibrinogen activity level of approximately 1.0 g/L would be anappropriate target for prophylactic treatment.

Diagnosing congenital fibrinogen deficiency

Establishing a diagnosis of congenital fibrinogen deficiency anddistinguishing between the different phenotypes requires a combi-nation of standard coagulation tests and antigenic and functional

F. Peyvandi / Thrombosis Research 130S2 (2012) S7–S11 S9

Fig. 3. Laboratory diagnosis of congenital fibrinogen deficiencies: differentiating between the phenotypes. aPTT, activated partial thromboplastin time; ELISA, enzyme-linkedimmunosorbent assay; PT, prothrombin time; TT, thrombin time.

assays. A definitive diagnosis may be established by demonstratinga relevant molecular defect.

Laboratory analysis

Afibrinogenemia is characterized by the complete absence orreduced amounts of immunoreactive fibrinogen, as measured byantigenic and functional assays. All coagulation tests that rely onfibrin as the endpoint (e.g. prothrombin time [PT], activated partialthromboplastin time [aPTT], thrombin time [TT] and reptilase time)are infinitely prolonged, and fibrinogen is undetectable by bothfunctional (Clauss method) and antigenic assays (enzyme-linkedimmunosorbent assay [ELISA]) (Fig. 3).

Hypofibrinogenemia is characterized by variably prolongedfibrin-based coagulation tests and a proportional decrease in func-tional and immunoreactive fibrinogen (Fig. 3). Dysfibrinogenemiais associated with variably or infinitely prolonged coagulation testsand a normal or increased antigen level, with a lower functionalfibrinogen level resulting in a low functional activity to antigenratio (most commonly 1:2).

Molecular analysis

Fibrinogen circulates in the blood as a disulfide-linked hexamercomposed of two identical heterotrimers, each consisting of oneAα chain, one Bβ chain and one γ chain. The three chains areencoded by different genes (FGA, FGB and FGG, coding for Aα, Bβ,and γ chains, respectively), clustered on chromosome 4 (q28–30)[9]. More than 80 distinct mutations in the genes encoding fibrino-gen have already been identified in patients with afibrinogenemiaor hypofibrinogenemia [10] – the majority (∼70%) are missensemutations (data from www.geht.org). Several specific mutationsappear to be associated with different types of congenital fibrino-gen deficiency: the majority of mutations causing afibrinogenemiaand hypofibrinogenemia are in the FGA gene [1], with two spe-cific mutations found frequently in Europeans (FGA IVS4+1G>T(c.510+1G>T) and FGA 11-kb deletion) (data from www.geht.org).

Molecular analysis may be particularly valuable as a tool toidentify individuals with dysfibrinogenemia, since some mutationsare predictive of the clinical bleeding phenotype, while others maypredispose the individual to developing thrombotic complications[3]. Most patients with dysfibrinogenemia are heterozygous formissense mutations; the majority of which are in the FGA gene [1].Two mutation “hot spots” have been identified for dysfibrinogene-mia: FGA residue Arg35His and Arg35Cys (Arg16), and FGG residueArg301His and Arg301Cys (Arg275) (data from www.geht.org). Twomutations associated with a predisposition to thrombosis (FGAArg573Cys [Arg554Cys] and FGG Arg301His [Arg275His]) have also

been reported [11,12]. It is possible that, in the future, treatmentdecisions may be influenced by the results of mutation analysis,especially if a predisposition to thrombosis can be identified.

Treatment of congenital fibrinogen deficiency

The treatment of congenital fibrinogen deficiency depends pri-marily on the severity and location of the bleeding and on theurgency of the situation. Non-transfusional treatments should beconsidered for initial use, where appropriate, with fibrinogen re-placement therapy administered if bleeding continues.

Non-transfusional treatments

Antifibrinolytic amino acids (e.g. ε-aminocaproic acid, tranex-amic acid) may be useful alone or in combination with replacementtherapy for the treatment of less severe forms of mucosal tracthemorrhages, although these agents should be used with cautionin patients with a history or family history of thrombosis andother thrombotic risk factors, such as pregnancy, surgery, and/orimmobilization [1]. Recommended doses are 50–60 mg/kg every4–6 hours for ε-aminocaproic acid and 25 mg/kg every 6–8 hoursfor tranexamic acid [13]. Fibrin glue may be effective in facilitatinglocal hemostasis [14]. Estrogen–progestogen preparations may helpto reduce menstrual blood loss in women with iron-deficiencyanemia due to menorrhagia [13].

Fibrinogen replacement therapy

Fibrinogen replacement therapy is effective in treating bleedingepisodes in congenital fibrinogen disorders. Options for replacementinclude fresh frozen plasma (FFP), cryoprecipitate and fibrinogenconcentrates. The latter are generally considered the treatments ofchoice in congenital fibrinogen deficiency due to their improvedsafety [3,13,15], rapid onset of action, dosing flexibility, smallinfusion volume, and ease of administration relative to otheroptions [16].

Four plasma-derived fibrinogen concentrates are available:Clottagen®/Clottafact® (LFB, France), Fibrinogen HT (Benesis,Japan), FIBRORAAS (Shanghai RAAS, China) and Haemocomplettan®

P/RiaSTAP® (CSL Behring, Germany) [17]. Preparation of all of theseconcentrates incorporates a number of rigorous steps for the inac-tivation and/or removal of viruses, leading to an extremely low riskof pathogen transmission [15].

On-demand treatmentRecommendations for the use of FFP, cryoprecipitate, and

fibrinogen concentrates to treat spontaneous bleeds and during

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Table 1Recommended on-demand treatment schedules for fibrinogen replacement therapy in patients with congenital fibrinogen deficiency [13,14].

Factor deficient Major surgery Minor surgery Spontaneous bleeding Comments

Treatment with FFPFibrinogen FFP (15–20 mL/kg)

Target: >100 mg/dL until healingcomplete

FFP (15–20 mL/kgTarget: >50 mg/dL for 2–3 days

FFP (15–20 mL/kg)Target: >50 mg/dL until bleedingstops

Treatment with concentratesFibrinogen Concentrate (20–30 mg/kg)

Target: >100 mg/dL until healingcomplete

As for major surgeryTarget: >50 mg/dL until healingcomplete

As for major surgeryTarget: >50 mg/dL depending ontype of bleeding

Prophylaxis with weeklyconcentrate (20–30 mg/kg) ifspontaneous bleeding is frequentand severe. Patients withthrombotic phenotype should betreated with LMWH

Cryoprecipitate (1 bag/10 kg)Target: >100 mg/dL until healingcomplete

As for major surgery As for major surgery

LMWH, low molecular weight heparin; FFP, fresh frozen plasma.

surgery are shown in Table 1 [13,15]. A target fibrinogen level>0.5–1.0 g/L is generally recommended for on-demand treatment,depending on the clinical situation [13,14]. Pharmacokinetic studiesof fibrinogen concentrates involving patients with afibrinogene-mia or severe hypofibrinogenemia suggest a single dose of 60–70mg/kg achieves a fibrinogen activity level of 1.3–1.45 g/L within 40minutes to 1 hour, with a median half-life of 3–5 days [16,18,19].

ProphylaxisThe plasma half-life of fibrinogen is relatively long, enabling

weekly prophylaxis with fibrinogen concentrate [13]. The frequencyand dose should be adjusted to maintain a level >0.5–1.0 g/L, bear-ing in mind the highly variable inter-individual pharmacokineticsof fibrinogen replacement therapy [18]. At our center, we usuallyinitiate prophylaxis at a dose of 20–30 mg/kg every 10–14 days,increasing the dosing frequency to every 7 days if necessary.

Prophylaxis may be used from an early age to prevent bleeding(primary prophylaxis) [3], and this approach should be consideredfor all individuals with afibrinogenemia. Prophylaxis can also beinitiated later in life in people with a severe bleeding tendencyto prevent recurrences (secondary prophylaxis) [14]. The latterapproach is recommended for those who bleed frequently andseverely into the muscles, joints, gastrointestinal tract, or CNS[13] or after a potentially life-threatening bleed (e.g. intracranialhemorrhage) [14]. Prophylaxis is also recommended as early aspossible during pregnancy to prevent fetal loss in women withafibrinogenemia, continuing throughout pregnancy and after thebirth [1].

Although prophylactic administration of fibrinogen concentrateis now recommended in a variety of clinical circumstances [13],treatment must be individualized and the potential risk of throm-bosis weighed against the likely benefits of treatment [3]. Throm-boembolic complications are difficult to prevent in these patients,especially as some individuals are naturally predisposed to de-veloping thromboses – even without fibrinogen treatment. Sincethe priority must be to avert potentially life-threatening bleedsin our patients, use of low-molecular-weight heparin (LMWH)may be considered in high-risk patients receiving fibrinogen re-placement, especially if surgery is required. Unlike in hemophilia,anti-fibrinogen antibodies do not appear to complicate the man-agement of fibrinogen deficiency, although two cases have beenreported in the literature [20,21].

Treatment issues in women

Women with congenital fibrinogen deficiencies experience diffi-culties throughout their adult life. Most women with afibrinogen-emia suffer severe menorrhagia [5] and there have been reports

of decreased fertility in these women [22]. Studies in animalmodels have demonstrated that fibrinogen plays a critical role inmaintaining pregnancy, both by supporting normal development offetal vascular communication and in stabilizing embryo implanta-tion [23]. Although normal embryonic development occurs in thefibrinogen-deficient mouse model, the pregnancy is frequently notsustained – often as a result of vaginal bleeding [24,25]. This mayhelp to explain the high rates of recurrent, spontaneous abortion(at around 5–8 weeks) observed in women with afibrinogenemia[5,26,27].

Recommendations for the management of pregnancy, labor, anddelivery in women with congenital fibrinogen deficiency have beenpublished by several groups in the UK [14,28,29] and Japan [26]. Toprevent early fetal loss and bleeding complications in the pregnantwoman with afibrinogenemia, it is recommended that fibrinogenlevels are maintained throughout pregnancy at a minimum of ≥0.6g/L, and ideally at >1.0 g/L, using fibrinogen concentrate [26,28].During labor, a fibrinogen level of ≥1.5 g/L (ideally >2.0 g/L) isrecommended to prevent placental abruption [26].

Women with hypofibrinogenemia may also have problems withpregnancy and post-partum hemorrhage [22]. Factor replacementshould be considered based on the fibrinogen level, bleedingtendency, and previous obstetric history [29]. Regular monitoring offibrinogen levels and ultrasound assessment for concealed placentalbleeding and to monitor fetal growth are also recommended [29].

The management of pregnancy in women with dysfibrinogen-emia must be individualized based on the fibrinogen level andpersonal and family history of bleeding and thrombosis [14]. Nospecific treatment is required in asymptomatic women, however,fibrinogen replacement therapy should be considered in those witha bleeding phenotype, especially if the bleeding is significant orthey are undergoing invasive procedures [28]. Concomitant throm-boprophylaxis with LMWH should be considered [14]. To avoidpostpartum hemorrhage in women with a significant bleeding ten-dency or those undergoing cesarean section, prophylactic fibrinogenreplacement therapy is recommended to increase fibrinogen levelsto >1 g/L and maintain them >0.5–1 g/L above baseline untilhealing has occurred [14]. Postpartum prophylaxis with LMWH isrecommended for those with a personal or family history of throm-bosis or following cesarean section performed under fibrinogenreplacement cover [14].

Summary and conclusions

Congenital fibrinogen deficiency results in a diverse range ofbleeding phenotypes and clinical challenges. There is a clear as-sociation between fibrinogen activity level and clinical bleedingseverity. Afibrinogenemia is one of the most severe congenital

F. Peyvandi / Thrombosis Research 130S2 (2012) S7–S11 S11

bleeding disorders with a high frequency of spontaneous majorbleeding episodes, including umbilical cord bleeding, CNS bleed-ing, hemarthrosis, and hematoma. Patients with afibrinogenemiaand others with a severe bleeding tendency could benefit fromprophylactic use of fibrinogen concentrate; however, few data areavailable to guide clinical decisions or help build evidence-basedguidelines. The risk of thrombosis presents an additional manage-ment challenge in these patients, and although molecular analysismay eventually help to identify at-risk individuals, more work isneeded to understand this important issue.

A new prospective European project evaluating the intensityof bleeding episodes and frequency of treatment in patients withfibrinogen deficiency is currently underway. The project is part ofthe European Haemophilia Network (EUHANET) and is receivingfunding from the European Union (Public Health Programme).

Acknowledgements

The author would like to thank Marzia Menegatti and RobertaPalla (U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Co-agulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Univer-sità degli Studi di Milano and Luigi Villa Foundation, Milan, Italy)for performing the statistical analyses and for interpreting the datacollected by the EN-RBD network. All of the collaborating partnersinvolved in the EN-RBD project (www.rbdd.eu/partners.htm) aregratefully acknowledged: Hemofilie Centrum Leuven, KatholiekeUniversiteit, Leuven, Belgium (Dr. K. Peerlink); Antwerp UniversityHospital UZA, Edegem, Belgium (Prof. A. Gadisseur); Centre forHemophilia and Thrombosis, Department of Clinical Biochemistry,University Hospital Skejbi, Aarhus, Denmark (Prof J. Ingerslev);Hopital Saint Eloi, Montpellier, France (Prof. J.F. Schved and DrM. Giansily-Blaizot) and associated centres; Pediatric Hemophiliaand Thrombosis Centre, Dr. von Hauner‘s Children‘s UniversityHospital, Munich, Germany (Dr C. Bidlingmaier); MVZ Labor Duis-burg GmbH – Duisburg, Germany (Dr. S. Halimeh); HaemophilliaCenter, Haemostasis Unit, Agia Sofia Children’s Hospital, Athens,Greece (Prof. H. Platokouki, Dr. H. Pergantou); First Regional Trans-fusion and Haemophilia Center, Hippocration Hospital, Athens,Greece (Dr. G. Theodossiades); “Laiko” General Hospital - 2ndBlood Transfusion Center and Haemophilia Center, Athens, Greece(Dr. O. Katsarou); Hippoktrateion Hospital, Tessalonike, Greece (DrV. Economou); National Centre for Hereditary Coagulation Disor-ders, St James’s Hospital, Dublin, Ireland (Dr R. Gilmore); AngeloBianchi Bonomi Hemophilia and Thrombosis Center, Universitàdegli Studi di Milano, Milan, Italy (Dr S.M. Siboni); HaemostasisDepartment and Haemophilia Center, Blood Transfusion Instituteof Serbia, Belgrade, Serbia (Dr D. Mikovic); National HaemophiliaCenter, University Children’s Hospital, Ljubljiana, Slovenia (Dr M.Benedik-Dolnicar and Dr L. Kitanovski); Department of PediatricHematology-Oncology, Cerrahpasa Medical Faculty of Istanbul Uni-versity, Istanbul, Turkey (Prof T. Celkan and Dr N. Özdemir); OxfordHaemophilia & Thrombosis Centre, Nuffield Department of ClinicalMedicine, University of Oxford, Oxford, United Kingdom (Dr. P.Giangrande); Royal Free Hampstead NHS Trust, London, UnitedKingdom (Prof. E.G.D. Tuddenham and Dr. P. Morjaria).

Conflict of interest

F.P. received speaker fees from Baxter, CSL Behring andNovoNordisk.

Role of the funding source

CSL Behring sponsored the symposium.

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