Clinical Features and Management of Congenital Fibrinogen Deficiencies

Abstract

Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account.

Keywords

congenital fibrinogen disorders - afibrinogenemia - hypofibrinogenemia - dysfibrinogenemia - hypodysfibrinogenemia - bleeding - thrombosis - fibrinogen concentrate

• References

• 1 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39 (6) 585-595
• 2 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
• 3 Peyvandi F, Menegatti M, Palla R. Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management. Semin Thromb Hemost 2013; 39 (6) 579-584
• 4 Mumford AD, Ackroyd S, Alikhan R , et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (3) 304-326
• 5 Peyvandi F. Epidemiology and treatment of congenital fibrinogen deficiency. Thromb Res 2012; 130 (Suppl. 02) S7-S11
• 6 Neerman-Arbez, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost 2016; 42 (4) 344-355
• 7 Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4 (7) 1634-1637
• 8 Vakalopoulou S, Rizopoulou D, Zafiriadou E , et al. Management of acute bleeding in a patient with congenital afibrinogenaemia. Haemophilia 2006; 12 (6) 676-678
• 9 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107 (1) 204-206
• 10 Reidy K, Brand B, Jost B. Severe elbow arthropathy in a patient with congenital afibrinogenemia: a case report. J Bone Joint Surg Am 2010; 92 (2) 456-458
• 11 Parameswaran R, Dickinson JP, de Lord S, Keeling DM, Colvin BT. Spontaneous intracranial bleeding in two patients with congenital afibrinogenaemia and the role of replacement therapy. Haemophilia 2000; 6 (6) 705-708
• 12 Polack B, Pouzol P, de Mazancourt P, Gay V, Hanss M. Is primary prophylaxis required in afibrinogenemia?. Transfusion 2010; 50 (6) 1401-1403
• 13 Arcagök BC, Özdemir N, Tekin A , et al. Spontaneous splenic rupture in a patient with congenital afibrinogenemia. Turk Pediatri Ars 2014; 49 (3) 247-249
• 14 Rodriguez-Merchan EC. Surgical wound healing in bleeding disorders. Haemophilia 2012; 18 (4) 487-490
• 15 van Meegeren ME, de Rooy JW, Schreuder HW, Brons PP. Bone cysts in patients with afibrinogenaemia: a literature review and two new cases. Haemophilia 2014; 20 (2) 244-248
• 16 Lagier R, Bouvier CA, Van Strijthem N. Skeletal changes in congenital fibrinogen abnormalities. Skeletal Radiol 1980; 5 (4) 233-239
• 17 Brennan SO, Laurie A, Smith M. Novel FGG variant (γ339C→S) confirms importance of the γ326-339 disulphide bond for plasma expression of newly synthesised fibrinogen. Thromb Haemost 2015; 113 (4) 903-905
• 18 Bay A, Coskun E, Leblebisatan G, Sivasli E. Epidural hematoma and cephalohematoma with congenital hypofibrinogenemia. Blood Coagul Fibrinolysis 2012; 23 (3) 229-231
• 19 Peyvandi F, Palla R, Menegatti M , et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (4) 615-621
• 20 Peyvandi F, Menegatti M, Palla R , et al. Fibrinogen deficiency: preliminary results of the PRORBDD project. In: XXV Congress of the International Society on Thrombosis and Haemostasis. Toronto, Canada; 2015
• 21 Asselta R, Robusto M, Braidotti P , et al. Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen γ-module. J Thromb Haemost 2015; 13 (8) 1459-1467
• 22 Casini A, Sokollik C, Lukowski SW , et al. Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature. Haemophilia 2015; 21 (6) 820-827 [Epub ahead of print]
• 23 Maggiore G, Nastasio S, Sciveres M. Long-term outcome of liver disease-related fibrinogen Aguadilla storage disease in a child. J Pediatr Gastroenterol Nutr 2011; 53 (6) 699
• 24 Puls F, Goldschmidt I, Bantel H , et al. Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease. J Hepatol 2013; 59 (3) 626-630
• 25 de Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost 2010; 36 (1) 7-17
• 26 De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986; 77 (4) 1272-1277
• 27 Mosesson MW. Update on antithrombin I (fibrin). Thromb Haemost 2007; 98 (1) 105-108
• 28 Dupuy E, Soria C, Molho P , et al. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001; 102 (3) 211-219
• 29 Sartori MT, Milan M, de Bon E, Fadin M, Pesavento R, Zanon E. Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature. Haemophilia 2015; 21 (1) 88-94
• 30 Remijn JA, Wu YP, Ijsseldijk MJ, Zwaginga JJ, Sixma JJ, de Groot PG. Absence of fibrinogen in afibrinogenemia results in large but loosely packed thrombi under flow conditions. Thromb Haemost 2001; 85 (4) 736-742
• 31 Ni H, Denis CV, Subbarao S , et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 2000; 106 (3) 385-392
• 32 Ozdemir MA, Işik B, Patiroglu T , et al. A case of congenital afibrinogenemia complicated with thromboembolic events that required repeated amputations. Blood Coagul Fibrinolysis 2015; 26 (3) 354-356
• 33 Chapin J, DeSancho M. Pulmonary embolism in a patient with congenital afibrinogenemia. Haemophilia 2013; 19 (6) e380-e382
• 34 MacKinnon HH, Fekete JF. Congenital afibrinogenemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971; 104 (7) 597-599
• 35 Miljić P, Nedeljkov-Jančić R, Zuvela M, Subota V, Dorđević V. Coexistence of hypofibrinogenemia and factor V Leiden mutation: is the balance shifted to thrombosis?. Blood Coagul Fibrinolysis 2014; 25 (6) 628-630
• 36 Marchi R, Walton BL, McGary CS , et al. Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: implications for identifying coagulopathic mechanisms in humans. Thromb Haemost 2012; 108 (3) 516-526
• 37 Chevalier Y, Dargaud Y, Argaud L, Ninet J, Jouanneau E, Négrier C. Successive bleeding and thrombotic complications in a patient with afibrinogenemia: a case report. Thromb Res 2011; 128 (3) 296-298
• 38 Mukaddam A, Patil R, Jadli A, Chandrakala S, Ghosh K, Shetty S. Paradoxical bleeding and thrombosis in a patient with afibrinogenemia and fibrinogen Mumbai mutation. Am J Clin Pathol 2015; 143 (5) 755-757
• 39 Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (6) 909-919
• 40 Shapiro SE, Phillips E, Manning RA , et al. Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia. Br J Haematol 2013; 160 (2) 220-227
• 41 Casini A, Blondon M, Lebreton A , et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (3) 553-561
• 42 Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol 2001; 114 (2) 249-257
• 43 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73 (1) 151-161
• 44 Shen YM, Trang V, Sarode R, Brennan S. Fibrinogen Dusart presenting as recurrent thromboses in the hepatic portal system. Blood Coagul Fibrinolysis 2014; 25 (4) 392-394
• 45 Sugo T, Endo H, Matsuda M , et al. A classification of the fibrin network structures formed from the hereditary dysfibrinogens. J Thromb Haemost 2006; 4 (8) 1738-1746
• 46 Collet JP, Soria J, Mirshahi M , et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82 (8) 2462-2469
• 47 Travlou A, Gialeraki A, Merkouri E, Politou M, Sfyridaki A, Neerman-Arbez M. Coexisting dysfibrinogenemia (gamma Arg275His) and FV Leiden associated with thrombosis (Fibrinogen Crete). Thromb Res 2010; 126 (2) e162-e164
• 48 Morris TA, Marsh JJ, Chiles PG , et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009; 114 (9) 1929-1936
• 49 Marsh JJ, Chiles PG, Liang NC, Morris TA. Chronic thromboembolic pulmonary hypertension-associated dysfibrinogenemias exhibit disorganized fibrin structure. Thromb Res 2013; 132 (6) 729-734
• 50 Gillmore JD, Lachmann HJ, Wechalekar A, Hawkins PN. Hereditary fibrinogen A alpha-chain amyloidosis: clinical phenotype and role of liver transplantation. Blood 2010; 115 (21) 4313 , author reply 4314–4315
• 51 Guglielmone HA, Sánchez MC, Quiñonez M, Fernández E. Fibrinogen Córdoba: biochemical characterization of a new congenital hypodysfibrinogenemia. Clin Chim Acta 2002; 317 (1–2) 239-240
• 52 Keller MA, Martinez J, Baradet TC , et al. Fibrinogen Philadelphia, a hypodysfibrinogenemia characterized by abnormal polymerization and fibrinogen hypercatabolism due to gamma S378P mutation. Blood 2005; 105 (8) 3162-3168
• 53 Santoro R, Iannaccaro P, Sottilotta G. Congenital hypodysfibrinogenemia and abruptio placentae in a woman with history of cerebral thrombosis. Acta Obstet Gynecol Scand 2007; 86 (2) 247-248
• 54 Rea C, Hunt BJ. Novel management of anticoagulant resistant thrombotic hypodysfibrinogenaemia. Thromb Res 2012; 130 (5) 785-787
• 55 Cetinkaya SE, Pabuccu EG, Ozmen B, Dokmeci F. Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia. Acta Obstet Gynecol Scand 2011; 90 (2) 192-194
• 56 Peyvandi F, Bidlingmaier C, Garagiola I. Management of pregnancy and delivery in women with inherited bleeding disorders. Semin Fetal Neonatal Med 2011; 16 (6) 311-317
• 57 Snir A, Brenner B, Paz B, Ohel G, Lanir N. The role of fibrin matrices and tissue factor in early-term trophoblast proliferation and spreading. Thromb Res 2013; 132 (4) 477-483
• 58 Iwaki T, Castellino FJ. Maternal fibrinogen is necessary for embryonic development. Curr Drug Targets 2005; 6 (5) 535-539
• 59 Lebreton A, Casini A, Alhayek R, Kouteich KL, Neerman-Arbez M, de Moerloose P. Successful pregnancy under fibrinogen substitution in a woman with congenital afibrinogenaemia complicated by a postpartum venous thrombosis. Haemophilia 2015; 21 (1) e108-e110
• 60 Ness PM, Budzynski AZ, Olexa SA, Rodvien R. Congenital hypofibrinogenemia and recurrent placental abruption. Obstet Gynecol 1983; 61 (4) 519-523
• 61 Roqué H, Stephenson C, Lee MJ , et al. Pregnancy-related thrombosis in a woman with congenital afibrinogenemia: a report of two successful pregnancies. Am J Hematol 2004; 76 (3) 267-270
• 62 Aygören-Pürsün E, Martinez Saguer I, Rusicke E , et al. Retrochorionic hematoma in congenital afibrinogenemia: resolution with fibrinogen concentrate infusions. Am J Hematol 2007; 82 (4) 317-320
• 63 Inamoto Y, Terao T. First report of case of congenital afibrinogenemia with successful delivery. Am J Obstet Gynecol 1985; 153 (7) 803-804
• 64 Terasawa F, Hogan KA, Kani S , et al. Fibrinogen Otsu I: A gammaAsn319, Asp320 deletion dysfibrinogen identified in an asymptomatic pregnant woman. Thromb Haemost 2003; 90 (4) 757-758
• 65 Kadir R, Chi C, Bolton-Maggs P. Pregnancy and rare bleeding disorders. Haemophilia 2009; 15 (5) 990-1005
• 66 Yan J, Deng D, Luo M , et al. Dysfibrinogenemia in a patient undergoing artificial abortion after misdiagnosis and review of the literature. Clin Chim Acta 2015; 447 (X) 86-89
• 67 Gralnick HR, Coller BS, Fratantoni JC, Martinez J. Fibrinogen Bethesda III: a hypodysfibrinogenemia. Blood 1979; 53 (1) 28-46
• 68 de Moerloose P, Neerman-Arbez M. Treatment of congenital fibrinogen disorders. Expert Opin Biol Ther 2008; 8 (7) 979-992
• 69 Bevan DH. Cryoprecipitate: no longer the best therapeutic choice in congenital fibrinogen disorders?. Thromb Res 2009; 124 (Suppl. 02) S12-S16
• 70 Peyvandi F, Palla R. Fibrinogen concentrates. Clin Adv Hematol Oncol 2009; 7 (12) 788-790
• 71 Peyvandi F. Results of an international, multicentre pharmacokinetic trial in congenital fibrinogen deficiency. Thromb Res 2009; 124 (Suppl. 02) S9-S11
• 72 Manco-Johnson MJ, Dimichele D, Castaman G , et al; FIBRINOGEN CONCENTRATE STUDY GROUP. Pharmacokinetics and safety of fibrinogen concentrate. J Thromb Haemost 2009; 7 (12) 2064-2069
• 73 Négrier C, Rothschild C, Goudemand J , et al. Pharmacokinetics and pharmacodynamics of a new highly secured fibrinogen concentrate. J Thromb Haemost 2008; 6 (9) 1494-1499
• 74 Kreuz W, Meili E, Peter-Salonen K , et al. Efficacy and tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency. Transfus Apheresis Sci 2005; 32 (3) 247-253
• 75 Khayat C, El Khorassani M, Lambert T , et al. Pharmacokinetic and pharmacodynamic results of a multicenter, open-label, single arm study with a fibrinogen concentrate (FGTW) in subjects with afibrinogenemia. In: XXV Congress of the International Society on Thrombosis and Haemostasis. Toronto, Canada; 2015
• 76 Schwartz BA, Rangarajan S, Peyvandi F, Karimi M, Knaub S. Pharmacokinetic (PK) Comparison of Two Fibrinogen Concentrates for the Treatment of Congenital Fibrinogen Deficiency. In: 57th American Society of Haematology. Orlando, USA; 2014
• 77 Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011; 9 (9) 1687-1704
• 78 De Vries A, Rosenberg T, Kochwa S, Boss JH. Precipitating antifibrinogen antibody appearing after fibrinogen infusions in a patient with congenital afibrinogenemia. Am J Med 1961; 30: 486-494
• 79 Bolton-Maggs PH, Perry DJ, Chalmers EA , et al. The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia 2004; 10 (5) 593-628
• 80 Fuchs RJ, Levin J, Tadel M, Merritt W. Perioperative coagulation management in a patient with afibrinogenemia undergoing liver transplantation. Liver Transpl 2007; 13 (5) 752-756
• 81 Stroka D, Keogh A, Vu D , et al. In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes. J Thromb Haemost 2014; 12 (11) 1874-1879
• 82 Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig 1994; 72 (5) 396-398
• 83 de Bosch NB, Mosesson MW, Ruiz-Sáez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost 2002; 88 (2) 253-258
• 84 Nagler M, Kremer Hovinga J, Alberio L , et al. Hereditary afibrinogenemia: long term observation of a highly thrombogenic condition and its management. In: XXV Congress of the International Society on Thrombosis and Haemostasis. Toronto, Canada; 2015
• 85 Schuepbach RA, Meili EO, Schneider E, Peter U, Bachli EB. Lepirudin therapy for thrombotic complications in congenital afibrinogenaemia. Thromb Haemost 2004; 91 (5) 1044-1046
• 86 Margaglione M, Vecchione G, Cappucci F , et al. Venous thrombosis in afibrinogenemia: a successful use of rivaroxaban. Haemophilia 2015; 21 (5) e431-e433
• 87 Kumar N, Padma Kumar R, Ramesh B, Garg N. Afibrinogenaemia: a rare cause of young myocardial infarct. Singapore Med J 2008; 49 (4) e104-e106
• 88 Falsoleiman H, Daloee MH, Dehghani M, Rohani A, Bayani B. Percutaneous coronary intervention in a case of afibrinogenemia. Asian Cardiovasc Thorac Ann 2013; 21 (3) 358-359
• 89 Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia 2008; 14 (6) 1151-1158
• 90 Tarumi T, Martincic D, Thomas A , et al. Familial thrombophilia associated with fibrinogen paris V: Dusart syndrome. Blood 2000; 96 (3) 1191-1193
• 91 Lefebvre P, Velasco PT, Dear A , et al. Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk). Blood 2004; 103 (7) 2571-2576
• 92 Schreiber K, Sciascia S, Cohen AT, Hunt BJ. Secondary thromboprophylaxis with rivaroxaban in major inherited thrombophilias. In: XXV Congress on the International Society of Thrombosis and Haemostasis. Toronto, Canada; 2015
• 93 Weisel JW. Why dysfibrinogenaemias still matter. Thromb Haemost 2009; 102 (3) 426-427
• 94 Huq FY, Kadir RA. Management of pregnancy, labour and delivery in women with inherited bleeding disorders. Haemophilia 2011; 17 (Suppl. 01) 20-30
• 95 Miesbach W, Galanakis D, Scharrer I. Treatment of patients with dysfibrinogenemia and a history of abortions during pregnancy. Blood Coagul Fibrinolysis 2009; 20 (5) 366-370
• 96 Yamanaka Y, Takeuchi K, Sugimoto M, Sato A, Nakago S, Maruo T. Dysfibrinogenemia during pregnancy treated successfully with fibrinogen. Acta Obstet Gynecol Scand 2003; 82 (10) 972-973
• 97 Franchini M, Raffaelli R, Musola M , et al. Management of inherited dysfibrinogenemia during pregnancy: a description of four consecutive cases. Ann Hematol 2007; 86 (9) 693-694
• 98 Pike GN, Bolton-Maggs PH. Factor deficiencies in pregnancy. Hematol Oncol Clin North Am 2011; 25 (2) 359-378 , viii–ix
• 99 Miesbach W, Scharrer I, Henschen A, Neerman-Arbez M, Spitzer S, Galanakis D. Inherited dysfibrinogenemia: clinical phenotypes associated with five different fibrinogen structure defects. Blood Coagul Fibrinolysis 2010; 21 (1) 35-40
• 100 Santacroce R, Cappucci F, Pisanelli D , et al. Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group. Blood Coagul Fibrinolysis 2006; 17 (4) 235-240