Thromboembolism in patients with congenital afibrinogenaemia

Michael Nagler; Johanna A. Kremer Hovinga; Lorenzo Alberio; Kristiina Peter-Salonen; Hendrik von Tengg-Kobligk; Daniel Lottaz; Marguerite Neerman-Arbez; Bernhard Lämmle

doi:10.1160/TH16-02-0082

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 116(04): 722-732
DOI: 10.1160/TH16-02-0082

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Thromboembolism in patients with congenital afibrinogenaemia

Long-term observational data and systematic review

Michael Nagler

¹Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland

²Department of Clinical Research, University of Bern, Bern, Switzerland

,

Johanna A. Kremer Hovinga

¹Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland

²Department of Clinical Research, University of Bern, Bern, Switzerland

,

Lorenzo Alberio

¹Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland

³Service of Hematology and Central Hematology Laboratory, CHUV, University of Lausanne, Lausanne, Switzerland

,

Kristiina Peter-Salonen

¹Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland

,

Hendrik von Tengg-Kobligk

⁴Institute for Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, Bern, Switzerland

,

Daniel Lottaz

²Department of Clinical Research, University of Bern, Bern, Switzerland

,

Marguerite Neerman-Arbez

⁵Department of Genetic Medicine and Development, University Medical Center, Geneva, Switzerland

,

Bernhard Lämmle

¹Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland

⁶Center for Thrombosis and Hemostasis, University Medical Center, Mainz, Germany

› Institutsangaben

Abstract

Summary

Frequent arterial and venous thromboembolism in patients with congenital afibrinogenaemia (CA) is neither understood nor is a safe and effective treatment established. It was our objective to report on the clinical observations and laboratory data contributing to the understanding of the frequency, physiopathology, prognosis and treatment of CA. We observed the long-term clinical course and laboratory data in a cohort of four patients with CA and thromboembolic complications, and conducted a systematic review retrieving all available data. Four patients with CA developed recurrent and extensive arterial and venous thromboembolism (TE) from an age of 25–51 years. In two patients, a treatment strategy targeting at maintaining constantly measurable fibrinogen (Fbg) levels (≥0.5 g/l) either by regular Fbg replacement or by orthotopic liver transplantation resulted in long-term remissions. Radiological imaging documented resolved arterial thrombi after 6–12 months. In contrast, recurrent thromboembolic events were observed in two other patients with infrequent Fbg replacement. A systematic review of the literature revealed 48 reports of TE in patients with CA (median age at first event 31 years), and a favourable outcome in most patients with frequent application of Fbg, aimed at constantly measurable trough levels. Present data suggests that patients with CA are at high risk of arterial and venous thromboembolic events, probably caused by thrombin excess owing to lack of thrombin scavenging by Fbg/fibrin. Regular low-dose Fbg replacement might be a safe and effective treatment option in patients with CA and thromboembolic complications.

Note: Preliminary data of this report were presented as oral presentation at the XXV Congress of the International Society on Thrombosis and Haemostasis, June 20^th to 25^th, Toronto, Canada.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Afibrinogenaemia - venous thromboembolism - thrombosis - aortic disease - arterial occlusive disease - peripheral vascular disease - fibrinogen

Volltext

Referenzen

References
1 Borissoff JI, Spronk HM, Heeneman S. et al. Is thrombin a key player in the 'coagulation-atherogenesis' maze?. Cardiovasc Res 2009; 82: 392-403.
2 Mosesson MW.. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 03: 1894-1904.
3 Bolton-Maggs PHB, 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: 593-628.
4 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Haemost 2013; 39: 585-595.
5 Lak M, Keihani M, Elahi F. et al. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107: 204-206.
6 Clauss A.. Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol 1957; 17: 237-246.
7 Neerman-Arbez M, de Moerloose P, Bridel C. et al Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenaemia. Blood 2000; 96: 149-152.
8 Stroka D, Keogh A, Vu D. et al. In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenaemic patient's hepatocytes. J Thromb Haemost 2014; 12: 1874-1879.
9 Neerman-Arbez M, Honsberger A, Antonarakis SE. et al Deletion of the fibrinogen (correction of fibrogen) alpha-chain gene (FGA) causes congenital afibrogenaemia. J Clin Invest 1999; 103: 215-218.
10 Neerman-Arbez M, de Moerloose P, Honsberger A. et al Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenaemia: novel truncating mutations in the FGA and FGG genes. Human Genet 2001; 108: 237-240.
11 Peter K, Furlan M, Lämmle B.. Life-long haemorrhagic diathesis in a young man with unclottable global coagulation tests--congenital afibrinogenaemia. Ther Umschau 1999; 56: 516-518.
12 Castaman G, Lunardi M, Rigo L. et al. Severe spontaneous arterial thrombotic manifestations in patients with inherited hypo- and afibrinogenaemia. Haemophilia 2009; 15: 533-537.
13 Chapin J, De Sancho M.. Pulmonary embolism in a patient with congenital afibrinogenemia. Haemophilia 2013; 19: e358-e396.
14 Chun R, Poon MC, Haigh J. et al. Case 1–2005: cardiac surgery in congenital afibrinogenaemia with thrombo-occlusive disease. J Cardiothor Vasc Anesth 2005; 19: 109-117.
15 Erlacher M, Heiss J, Hainmann I. et al. Novel findings in two patients with late-diagnosed afibrinogenaemia: intraosseous haemorrhage and fingertip necrosis. Haemophilia 2009; 15: 980-982.
16 Karim S, Parsi M.. Fibrinogen concentrate use in a neonate with afibrinogenaemia. Transfusion 2011; 51: 115A.
17 Kinebuchi A, Ohtsuka T, Ishida S. et al. Leg ulcer presenting in a patient with congenital afibrinogenaemia. Eur J Dermatol 2002; 12: 70-72.
18 Laufs H, Weidauer S, Heller C. et al. Hemi-spinal cord infarction due to vertebral artery dissection in congenital afibrinogenaemia. Neurology 2004; 63: 1522-1523.
19 Matsumoto T, Wada H, Tamaru S. et al. Central venous catheter-related thrombosis after replacement therapy for intracranial bleeding in a patient with afibrinogenaemia. Haemophilia 2008; 14: 153-156.
20 Sartori M, Campello E, Barbar S. et al. Thrombosis of the abdominal aorta in congenital afibrinogenaemia. Haemophilia 2012; 18: 188.
21 Taslimi R, Golshani K.. Thrombotic and haemorrhagic presentation of congenital hypo/afibrinogenaemia. Am J Emerg Med 2011; 29: 573 e3-5.
22 Teresa SM, Marta M, Emiliano DB. et al. Thrombosis of abdominal aorta in congenital afibrinogenaemia: Case report and review of literature. Haemophilia 2015; 21: 88-94.
23 Bas DF, Oguz KK, Yavuz K. et al. Spinal cord infarction in congenital afibrinogenaemia: a case report and review of the literature. J Stroke Cerebrovasc Dis 2009; 18: 298-303.
24 Berkouk-Redjimi Y, Belhani MF. Rare congenital coagulation factor deficiencies: Clinical manifestations. Open J Hematol 2014; 5.
25 Bornikova L, Brodsky G, Manco-Johnson MJ. et al. Identification and expression of fibrinogen gene mutations and genotype/phenotype correlation studies in patients with inherited disorders of fibrinogen. Haemophilia 2011; 17: 564.
26 Boukhris I, Cherif E, Kechaou I. et al. Finger emergency in internal medicine. Thrombosis Res 2014; 133: S53.
27 Chevalier Y, Dargaud Y, Argaud L. et al. Successive bleeding and thrombotic complications in a patient with afibrinogenaemia: a case report. Thrombosis Res 2011; 128: 296-298.
28 De Mattia D, Regina G, Giordano P. et al Association of congenital afibrinogenaemia and K–dependent protein C deficiency--a case report. Angiology 1993; 44: 745-749.
29 Dear A, Daly J, Brennan SO. et al. An intronic mutation within FGB (IVS1+2076 a -> g) is associated with afibrinogenaemia and reccurrent transient ischaemic attacks (2). J Thromb Haemost 2006; 04: 471-472.
30 Drai E, Taillan B, Schneider S. et al. Portal vein thrombosis revealing congenital afibrinogenaemia [Thrombose portale revelatrice d'une afibrinogenaemie congenitale]. Presse Med 1992; 21: 1820-1821.
31 Dupuy E, Soria C, Molho P. et al. Embolized ischaemic lesions of toes in an afibrinogenaemic patient: possible relevance to in vivo circulating thrombin. Thrombosis Res 2001; 102: 211-219.
32 Falsoleiman H, Daloee MH, Dehghani M. et al. Percutaneous coronary intervention in a case of afibrinogenaemia. Asian Cardiovasc Thoracic Ann 2013; 21: 358-359.
33 Fuchs RJ, Levin J, Tadel M. et al. Perioperative coagulation management in a patient with afibrinogenaemia undergoing liver transplantation. Liver Transplant 2007; 13: 752-756.
34 Garcia-Monco JC, Fernandez Canton G, Gomez Beldarrain M. Bilateral vertebral artery dissection in a patient with afibrinogenaemia. Stroke 1996; 27: 2325-2327.
35 Girard C, Guillot B, Biron C. et al. Digital skin necrosis in congenital afibrinogenaemia associated with hepatitis C virus infection, mixed cryoglobulinaemia and anticardiolipin antibodies. Acta Dermat Venereol 2005; 85: 56-59.
36 Goudier E, Ben Salah N, Aissaoui L.. Afibrinogenaemia and gangrene, a case report. JIM Sfax 2007; 13/14: 44-45.
37 Grandone E, Tiscia G, Cappucci F. et al. Clinical histories and molecular characterisation of two afibrinogenaemic patients: insights into clinical management. Haemophilia 2012; 18: e16-18.
38 Haberer JP, Obstler C, Samama CM. et al. Postoperative deep venous thrombosis in a woman with congenital afibrinogenaemia treated with fibrinogen concentrates. Eur J Anaesthesiol 2008; 25: 519-521.
39 Hanano M, Takahashi H, Itoh M. et al. Coexistence of congenital afibrinogenaemia and protein C deficiency in a patient. Am J Hematol 1992; 41: 57-60.
40 Jimenez Caballero PE, Servia Candela M, Marsal Alonso C. Afibrinogenaemia: description of a case with recurrent intracranial bleeding. Neurologia 2006; 21: 323-326.
41 Katsinelos P, Vasiliadis T, Soufleris K. et al. Capsule endoscopy findings in congenital afibrinogenaemia-associated angiopathy. VASA 2008; 37: 383-385.
42 Kumar N, Padma Kumar R, Ramesh B. et al. Afibrinogenaemia: a rare cause of young myocardial infarct. Singapore Med J 2008; 49: e104-106.
43 Lebreton A, Casini A, Alhayek R. et al. Successful pregnancy under fibrinogen substitution in a woman with congenital afibrinogenaemia complicated by a postpartum venous thrombosis. Haemophilia 2015; 21: e108-e110.
44 MacKinnon HH, Fekete JF.. Congenital afibrinogenaemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Canad Med Assoc J 1971; 104: 597-599.
45 Molho-Sabatier P, Soria C, Legrand C. et al Artery thrombosis in an afibrinogenaemic patient: The role of platelet aggregation independent of fibrinogen [Thrombose Arterielle Chez Un Sujet Afibrinogenaemique: Role De L'agregation Plaquettaire Independante Du Fibrinogene]. Rev Med Intern 1991; 12: S109.
46 Moscardo A, Cid A, Haya S. et al. Patient with congenital afibrinogenaemia and peripheral arterial thrombosis. Therapeutic antithrombotic management based on monitoring. Thrombosis Res 2014; 133: S117-S118.
47 Oruc N, Tokat Y, Killi R. et al. Budd-Chiari syndrome in an afibrinogenaemic patient: a paradoxical complication. Digest Dis Sci 2006; 51: 378-380.
48 Pati S, Kombogiorgas D, Anwar A. et al. Spontaneous extra-axial intracranial haemorrhage followed by thrombosis in congenital afibrinogenaemia: perioperative management of this rare combination. Surg Neurol 2009; 71: 689-692.
49 Roque H, Stephenson C, Lee MJ. et al. Pregnancy-related thrombosis in a woman with congenital afibrinogenaemia: a report of two successful pregnancies. Am J Hematol 2004; 76: 267-270.
50 Rupec RA, Kind P, Ruzicka T.. Cutaneous manifestations of congenital afibrinogenaemia. Br J Dermatol 1996; 134: 548-550.
51 Sakai N, Akamine S, Tokuyama T. et al. Chronic subdural hematoma in a patient with congenital afibrinogenaemia successfully treated with fibrinogen replacement. Neurol Med Chirurg 2011; 51: 780-783.
52 Santoro C, Fulvio M, Capria V. et al. A case of thrombosis in congenital afibrinogenaemia: A physiopathologic and management dilemma. Haemophilia 2015; 21: 75-76.
53 Schuepbach RA, Meili EO, Schneider E. et al. Lepirudin therapy for thrombotic complications in congenital afibrinogenaemia. Thromb Haemost 2004; 91: 1044-1046.
54 Simsek I, de Mazancourt P, Horellou MH. et al. Afibrinogenaemia resulting from homozygous nonsense mutation in A alpha chain gene associated with multiple thrombotic episodes. Blood Coagul Fibrinol 2008; 19: 247-253.
55 Takasugi Y, Shiokawa Y, Kajikawa R. et al. Mesenteric venous thrombosis in a patient with congenital afibrinogenaemia and diffuse peritonitis. Ann Hematol 2005; 84: 129-130.
56 de Bosch NB, Mosesson MW, Ruiz-Saez A. et al Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost 2002; 88: 253-258.
57 Korte W, Feldges A.. Increased prothrombin activation in a patient with congenital afibrinogenaemia is reversible by fibrinogen substitution. Clin Invest 1994; 72: 396-398.
58 Mosesson MW.. Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation. Thromb Haemost 2003; 89: 9-12.
59 Rezaie AR.. Protease-activated receptor signalling by coagulation proteases in endothelial cells. Thromb Haemost 2014; 112: 876-882.
60 De Marco L, Girolami A, Zimmerman TS. et al von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenaemia. J Clin Invest 1986; 77: 1272-1277.
61 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: 385-392.
62 Remijn JA, Wu YP, Ijsseldijk MJW. et al. Absence of fibrinogen in afibrinogenaemia results in large but loosely packed thrombi under flow conditions. Thromb Haemost 2001; 85: 736-742.
63 Casini A, Lukowski S, Quintard VL. et al. FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations. Thrombosis Res 2014; 133: 868-874.
64 Ozdemir MA, Isik B, Patiroglu T. et al. A case of congenital afibrinogenaemia complicated with thromboembolic events that required repeated amputations. Blood Coagul Fibrinol 2015; 26: 354-356.
65 Vu D, Bolton-Maggs PH, Parr JR. et al. Congenital afibrinogenaemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion. Blood 2003; 102: 4413-4415.

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