Skip to main content

Congenital Disorders of Fibrinogen: Clinical Presentations, Diagnosis and Management

  • Chapter
  • First Online:
  • 1618 Accesses

Abstract

Congenital fibrinogen disorders (CFD) include two subtypes of fibrinogen defects: quantitative disorders, defined by absent (afibrinogenaemia) or decreased (hypofibrinogenaemia) fibrinogen levels, and qualitative disorders characterised by a discrepancy between functional and antigenic values of fibrinogen (dysfibrinogenaemia and hypodysfibrinogenaemia) (de Moerloose et al. 2013).

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Aygoren-Pursun E, Martinez Saguer I, Rusicke E, Louwen F, Geka F, Ivaskevicius V, Oldenburg J, Klingebiel T, Kreuz W. Retrochorionic hematoma in congenital afibrinogenemia: resolution with fibrinogen concentrate infusions. Am J Hematol. 2007;82:317–20.

    Article  CAS  PubMed  Google Scholar 

  • Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet. 1993;3:252–5.

    Article  CAS  PubMed  Google Scholar 

  • Bevan DH. Cryoprecipitate: no longer the best therapeutic choice in congenital fibrinogen disorders? Thromb Res. 2009;124 Suppl 2:S12–6.

    Article  CAS  PubMed  Google Scholar 

  • Bolton-Maggs PH, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, Collins PW, Kitchen S, Dolan G, Mumford AD. The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia. 2004;10:593–628.

    Article  CAS  PubMed  Google Scholar 

  • Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost. 2011;9:1687–704.

    Article  CAS  PubMed  Google Scholar 

  • Brennan SO, Wyatt J, Medicina D, Callea F, George PM. Fibrinogen brescia: hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 Gly–> Arg mutation. Am J Pathol. 2000;157:189–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brennan SO, Mosesson MW, Lowen R, Frantz C. Dysfibrinogenemia (fibrinogen Wilmington) due to a novel Aalpha chain truncation causing decreased plasma expression and impaired fibrin polymerisation. Thromb Haemost. 2006;96:88–9.

    CAS  PubMed  Google Scholar 

  • Brennan SO, Davis RL, Chitlur M. New fibrinogen substitution (gammaSer313Arg) causes diminished gamma chain expression and hypodysfibrinogenaemia. Thromb Haemost. 2010a;103:478–9.

    Article  CAS  PubMed  Google Scholar 

  • Brennan SO, Davis RL, Conard K, Savo A, Furuya KN. Novel fibrinogen mutation gamma314Thr–>Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia. Liver Int. 2010b;30:1541–7.

    Article  CAS  PubMed  Google Scholar 

  • Casini A, Blondon M, Lebreton A, Koegel J, Tintillier V, DE Maistre E, Gautier P, Biron C, Neerman-Arbez M, DE Moerloose P. Natural history of patients with congenital dysfibrinogenemia. Blood. 2015;125:553–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chapin J, Desancho M. Pulmonary embolism in a patient with congenital afibrinogenemia. Haemophilia. 2013;19:e380–2.

    Article  CAS  PubMed  Google Scholar 

  • Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002;126:499–505.

    PubMed  Google Scholar 

  • 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;77:1272–7.

    Article  PubMed  PubMed Central  Google Scholar 

  • DE Moerloose P, Neerman-Arbez M. Treatment of congenital fibrinogen disorders. Expert Opin Biol Ther. 2008;8:979–92.

    Article  PubMed  Google Scholar 

  • DE Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost. 2010;36:7–17.

    Article  PubMed  Google Scholar 

  • DE Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013;39:585–95.

    Article  PubMed  Google Scholar 

  • DE Raucourt E, Fischer AM, Meyer G, DE Mazancourt P. A Bbeta 14 Arg–>Cys fibrinogen variant in a patient with thrombotic complications (fibrinogen St-Germain III). J Thromb Haemost. 2006;4:2722–3.

    Article  PubMed  Google Scholar 

  • Dear A, Daly J, Brennan SO, Tuckfield A, George PM. An intronic mutation within FGB (IVS1+2076 a–>g) is associated with afibrinogenemia and recurrent transient ischemic attacks. J Thromb Haemost. 2006;4:471–2.

    Article  CAS  PubMed  Google Scholar 

  • Dempfle CE, George PM, Borggrefe M, Neumaier M, Brennan SO. Demonstration of heterodimeric fibrinogen molecules partially conjugated with albumin in a novel dysfibrinogen: fibrinogen Mannheim V. Thromb Haemost. 2009;102:29–34.

    CAS  PubMed  Google Scholar 

  • Dib N, Quelin F, Ternisien C, Hanss M, Michalak S, DE Mazancourt P, Rousselet MC, Cales P. Fibrinogen angers with a new deletion (gamma GVYYQ 346–350) causes hypofibrinogenemia with hepatic storage. J Thromb Haemost. 2007;5:1999–2005.

    Article  CAS  PubMed  Google Scholar 

  • Ebert RF. Index of variant human fibrinogens. Ann Arbor: Boca Raton; 1994.

    Google Scholar 

  • Evron S, Anteby SO, Brzezinsky A, Samueloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion: a case report. Eur J Obstet Gynecol Reprod Biol. 1985;19:307–11.

    Article  CAS  PubMed  Google Scholar 

  • Franchini M, Raffaelli R, Musola M, Memmo A, Poli G, Franchi M, Pizzolo G, Veneri D. Management of inherited dysfibrinogenemia during pregnancy: a description of four consecutive cases. Ann Hematol. 2007;86:693–4.

    Article  PubMed  Google Scholar 

  • Francis JL, Armstrong DJ. Acquired dysfibrinogenaemia in liver disease. J Clin Pathol. 1982;35:667–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol. 2009;20:444–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gralnick HR, Givelber H, Abrams E. Dysfibrinogenemia associated with hepatoma. Increased carbohydrate content of the fibrinogen molecule. N Engl J Med. 1978;299:221–6.

    Article  CAS  PubMed  Google Scholar 

  • Grech H, Majumdar G, Lawrie AS, Savidge GF. Pregnancy in congenital afibrinogenaemia: report of a successful case and review of the literature. Br J Haematol. 1991;78:571–2.

    Article  CAS  Google Scholar 

  • Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost. 1995;73:151–61.

    CAS  PubMed  Google Scholar 

  • Hill MB, Brennan SO, Dear A, Strong J, Nejim T, Dolan G. Fibrinogen Nottingham II: a novel Bbeta Arg264gly substitution causing hypofibrinogenaemia. Thromb Haemost. 2006;96:378–80.

    CAS  PubMed  Google Scholar 

  • Inamoto Y, Terao T. First report of case of congenital afibrinogenemia with successful delivery. Am J Obstet Gynecol. 1985;153:803–4.

    Article  CAS  PubMed  Google Scholar 

  • Iwaki T, Castellino FJ. Maternal fibrinogen is necessary for embryonic development. Curr Drug Targets. 2005;6:535–9.

    Article  CAS  PubMed  Google Scholar 

  • Iwaki T, Sandoval-Cooper MJ, Paiva M, Kobayashi T, Ploplis VA, Castellino FJ. Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse. Am J Pathol. 2002;160:1021–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi T, Asahina T, Maehara K, Itoh M, Kanayama N, Terao T. Congenital afibrinogenemia with successful delivery. Gynecol Obstet Invest. 1996;42:66–9.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Kanayama N, Tokunaga N, Asahina T, Terao T. Prenatal and peripartum management of congenital afibrinogenaemia. Br J Haematol. 2000;109:364–6.

    Article  CAS  PubMed  Google Scholar 

  • Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461–610 (Lys 461 AAA–>stop TAA). Blood. 1992;80:1972–9.

    CAS  PubMed  Google Scholar 

  • Kotlin R, Zichova K, Suttnar J, Reicheltova Z, Salaj P, Hrachovinova I, Dyr JE. Congenital dysfibrinogenemia Aalpha Gly13Glu associated with bleeding during pregnancy. Thromb Res. 2011;127:277–8.

    Article  CAS  PubMed  Google Scholar 

  • Kotlin R, Suttnar J, Capova I, Hrachovinova I, Urbankova M, Dyr JE. Fibrinogen Sumperk II: dysfibrinogenemia in an individual with two coding mutations. Am J Hematol. 2012;87:555–7.

    Article  CAS  PubMed  Google Scholar 

  • Krammer B, Anders O, Nagel HR, Burstein C, Steiner M. Screening of dysfibrinogenaemia using the fibrinogen function versus antigen concentration ratio. Thromb Res. 1994;76:577–9.

    Article  CAS  PubMed  Google Scholar 

  • Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO, McCracken AA. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol. 2006;168:1299–308; quiz 1404–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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:e108–10.

    Article  CAS  PubMed  Google Scholar 

  • Lee CA, Chi C, Pavord SR, Bolton-Maggs PH, Pollard D, Hinchcliffe-Wood A, Kadir RA, Organization UKHCD. The obstetric and gynaecological management of women with inherited bleeding disorders – review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors’ Organization. Haemophilia. 2006;12:301–36.

    Article  CAS  PubMed  Google Scholar 

  • 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;53:699.

    PubMed  Google Scholar 

  • Makris M, Calizzani G, Fischer K, Gilman EA, Hay CR, Lassila R, Lambert T, Ludlam CA, Mannucci PM. EUHASS: the European haemophilia safety surveillance system. Thromb Res. 2011;127 Suppl 2:S22–5.

    Article  CAS  PubMed  Google Scholar 

  • Mensah PK, Oppenheimer C, Watson C, Pavord S. Congenital afibrinogenaemia in pregnancy. Haemophilia. 2011;17:167–8.

    Article  CAS  PubMed  Google Scholar 

  • Miesbach W, Galanakis D, Scharrer I. Treatment of patients with dysfibrinogenemia and a history of abortions during pregnancy. Blood Coagul Fibrinolysis. 2009;20:366–70.

    Article  CAS  PubMed  Google Scholar 

  • Miesbach W, Schenk J, Alesci S, Lindhoff-Last E. Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. Thromb Res. 2010;126:e428–33.

    Article  CAS  PubMed  Google Scholar 

  • Mosesson MW. Update on antithrombin I (fibrin). Thromb Haemost. 2007;98:105–8.

    CAS  PubMed  Google Scholar 

  • Mumford AD, Ackroyd S, Alikhan R, Bowles L, Chowdary P, Grainger J, Mainwaring J, Mathias M, O’Connell N, Committee, B. 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;167:304–26.

    Article  CAS  PubMed  Google Scholar 

  • Neerman-Arbez M. To aggregate or not to aggregate. J Thromb Haemost. 2007;5:1997–8.

    Article  CAS  PubMed  Google Scholar 

  • Neerman-Arbez M, De Moerloose P. Hereditary fibrinogen abnormalities. In: Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U, editors. Williams hematology. 8th ed. New York: McGraw-Hill; 2010;2(2):p1–0.

    Google Scholar 

  • Neerman-Arbez M, Tirefort Y, De Moerloose P. Can mutations identified in congenital fibrinogen disorders explain the clinical manifestations? J Coagul Disord. 2010;2(2):1–9.

    Google Scholar 

  • Ness PM, Budzynski AZ, Olexa SA, Rodvien R. Congenital hypofibrinogenemia and recurrent placental abruption. Obstet Gynecol. 1983;61:519–23.

    CAS  PubMed  Google Scholar 

  • Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest. 2000;106:385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozdemir MA, Isik B, Patiroglu T, Karakukcu M, Mutlu FT, Yilmaz E, Unal E. A case of congenital afibrinogenemia complicated with thromboembolic events that required repeated amputations. Blood Coagul Fibrinolysis. 2015;26(3):354–6.

    Google Scholar 

  • 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;6:705–8.

    Article  CAS  PubMed  Google Scholar 

  • Peyvandi F. Epidemiology and treatment of congenital fibrinogen deficiency. Thromb Res. 2012;130 Suppl 2:S7–11.

    Article  CAS  PubMed  Google Scholar 

  • Peyvandi F, Palla R. Fibrinogen concentrates. Clin Adv Hematol Oncol. 2009;7:788–90.

    PubMed  Google Scholar 

  • Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost. 2006;4:1634–7.

    Article  CAS  PubMed  Google Scholar 

  • Peyvandi F, Bidlingmaier C, Garagiola I. Management of pregnancy and delivery in women with inherited bleeding disorders. Semin Fetal Neonatal Med. 2011;16:311–7.

    Article  PubMed  Google Scholar 

  • Peyvandi F, Palla R, Menegatti M, Siboni SM, Halimeh S, Faeser B, Pergantou H, Platokouki H, Giangrande P, Peerlinck K, Celkan T, Ozdemir N, Bidlingmaier C, Ingerslev J, Giansily-Blaizot M, Schved JF, Gilmore R, Gadisseur A, Benedik-Dolnicar M, Kitanovski L, Mikovic D, Musallam KM, Rosendaal FR. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012;10:615–21.

    Article  CAS  PubMed  Google Scholar 

  • Peyvandi F, Menegatti M, Palla R, Siboni SM, Boscarino M, Susan H, Borhany M, Naveena F, Pergantou H, Platokouki H, van Meegeren M, Brons P, Laros-Van Gorkom B, Heiman M, Shapiro AD, Bidlingmaier C, Casini A, Saracevic M, Danijela M, Ozdemir N, Mumford AD, Fraustina H, Chapin JC, Harvey A, Naderi M, Giansily M, Schved J-F, de Moerloose P. Prospective data collection on patients with fibrinogen and factor xiii deficiencies: prelimary results of the PRO-RBDD project. Blood 2014;124:2838–2839.

    Google Scholar 

  • Pike GN, Bolton-Maggs PH. Factor deficiencies in pregnancy. Hematol Oncol Clin N Am. 2011;25:359–78. viii–ix.

    Article  Google Scholar 

  • Polack B, Pouzol P, DE Mazancourt P, Gay V, Hanss M. Is primary prophylaxis required in afibrinogenemia? Transfusion. 2010;50:1401–3.

    Article  PubMed  Google Scholar 

  • Pretorius E, Bronkhorst P, Briedenhann S, Smit E, Franz RC. Comparisons of the fibrin networks during pregnancy, nonpregnancy and pregnancy during dysfibrinogenaemia using the scanning electron microscope. Blood Coagul Fibrinolysis. 2009;20:12–6.

    Article  PubMed  Google Scholar 

  • Puls F, Goldschmidt I, Bantel H, Agne C, Brocker V, Dammrich M, Lehmann U, Berrang J, Pfister ED, Kreipe HH, Baumann U. Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease. J Hepatol. 2013;59:626–30.

    Article  CAS  PubMed  Google Scholar 

  • Reganon E, Vila V, Aznar J, Garrido G, Estelles A, Berenguer J. Study of the formation of fibrin clot in cirrhotic patients. An approach to study of acquired dysfibrinogenemia. Thromb Res. 1987;46:705–14.

    Article  CAS  PubMed  Google Scholar 

  • 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;85:736–42.

    CAS  PubMed  Google Scholar 

  • Roque H, Stephenson C, Lee MJ, Funai EF, Popiolek D, Kim E, Hart D. Pregnancy-related thrombosis in a woman with congenital afibrinogenemia: a report of two successful pregnancies. Am J Hematol. 2004;76:267–70.

    Article  CAS  PubMed  Google Scholar 

  • Rubbia-Brandt L, Neerman-Arbez M, Rougemont AL, Male PJ, Spahr L. Fibrinogen gamma375 arg–> trp mutation (fibrinogen aguadilla) causes hereditary hypofibrinogenemia, hepatic endoplasmic reticulum storage disease and cirrhosis. Am J Surg Pathol. 2006;30:906–11.

    Article  PubMed  Google Scholar 

  • Schwartz BA, Rangarajan S, Peyvandi F, Karimi M, Knaub S. Pharmacokinetic (PK) comparison of two fibrinogen concentrates for the treatment of congenital fibrinogen deficiency. Blood 2014;124:2817.

    Google Scholar 

  • Shapiro SE, Phillips E, Manning RA, Morse CV, Murden SL, Laffan MA, Mumford AD. Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia. Br J Haematol. 2013;160:220–7.

    Article  CAS  PubMed  Google Scholar 

  • Siebenlist KR, Mosesson MW, Meh DA, Diorio JP, Albrecht RM, Olson JD. Coexisting dysfibrinogenemia (gammaR275C) and factor V Leiden deficiency associated with thromboembolic disease (fibrinogen Cedar Rapids). Blood Coagul Fibrinolysis. 2000;11:293–304.

    CAS  PubMed  Google Scholar 

  • 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;132:477–83.

    Article  CAS  PubMed  Google Scholar 

  • Spena S, Duga S, Asselta R, Malcovati M, Peyvandi F, Tenchini ML. Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood. 2002;100:4478–84.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi H, Wada K, Shibata A. Planned pregnancy and delivery in a patient with congenital afibrinogenaemia and heterozygous protein C deficiency. Blood Coagul Fibrinolysis. 1995;6:141–2.

    Article  CAS  PubMed  Google Scholar 

  • Thorsen LI, Brosstad F, Solum NO, Stormorken H. Increased binding to ADP-stimulated platelets and aggregation effect of the dysfibrinogen Oslo I as compared with normal fibrinogen. Scand J Haematol. 1986;36:203–10.

    Article  CAS  PubMed  Google Scholar 

  • Trehan AK, Fergusson IL. Congenital afibrinogenaemia and successful pregnancy outcome. Case report. Br J Obstet Gynaecol. 1991;98:722–4.

    Article  CAS  PubMed  Google Scholar 

  • Yamanaka Y, Takeuchi K, Sugimoto M, Sato A, Nakago S, Maruo T. Dysfibrinogenemia during pregnancy treated successfully with fibrinogen. Acta Obstet Gynecol Scand. 2003;82:972–3.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alessandro Casini .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Casini, A., de Moerloose, P. (2016). Congenital Disorders of Fibrinogen: Clinical Presentations, Diagnosis and Management. In: Abutalib, S., Connors, J., Ragni, M. (eds) Nonmalignant Hematology. Springer, Cham. https://doi.org/10.1007/978-3-319-30352-9_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-30352-9_22

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-30350-5

  • Online ISBN: 978-3-319-30352-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics