Semin Thromb Hemost 2009; 35(4): 349-355
DOI: 10.1055/s-0029-1225757
© Thieme Medical Publishers

Introduction: Rare Bleeding Disorders: General Aspects of Clinical Features, Diagnosis, and Management

Flora Peyvandi1 , Roberta Palla1 , Marzia Menegatti1 , Pier Mannuccio Mannucci1
  • 1Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, University of Milan, Luigi Villa Foundation, Milan, Italy
Further Information

Publication History

Publication Date:
13 July 2009 (online)


Rare bleeding disorders (RBDs) are autosomal recessive diseases including the inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FV + FVIII, FVII, FX, FXI, FXIII, and multiple deficiency of vitamin K–dependent factors, with clinical manifestations ranging from mild to severe. They represent 3 to 5% of all the inherited coagulation deficiencies with a prevalence in the general population varying between 1 in 500,000 and 1 in 2 million, being higher in areas where consanguineous marriages are diffuse. Despite the progress made in past years, as a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, the actual management of bleeding episodes and particularly the prophylactic treatment in patients affected with RBDs are not well established. In this introductory article, the main features, diagnosis, available treatment options, and treatment complications of RBDs will be discussed.


  • 1 Tuddenham E GD, Cooper D N. The Molecular Genetics of Haemostasis and Its Inherited Disorders. Oxford, UK; Oxford Medical Publications 1994
  • 2 Peyvandi F, Kaufman R J, Seligsohn U et al.. Rare bleeding disorders.  Haemophilia. 2006;  12(Suppl 3) 137-142
  • 3 Mannucci P M, Duga S, Peyvandi F. Recessively inherited coagulation disorders.  Blood. 2004;  104 1243-1252
  • 4 Bolton-Maggs P H, Perry D J, Chalmers E A et al.. The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.  Haemophilia. 2004;  10 593-628
  • 5 Peyvandi F, Cattaneo M, Inbal A, De Moerloose P, Spreafico M. Rare bleeding disorders.  Haemophilia. 2008;  14(Suppl 3) 202-210
  • 6 Greer I A, Lowe G D, Walker J J, Forbes C D. Haemorrhagic problems in obstetrics and gynaecology in patients with congenital coagulopathies.  Br J Obstet Gynaecol. 1991;  98 909-918
  • 7 Lee C A, Chi C, Pavord S R UK Haemophilia Centre Doctors' Organization et al. 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;  12 301-336
  • 8 Kumar M, Mehta P. Congenital coagulopathies and pregnancy: report of four pregnancies in a factor X-deficient woman.  Am J Hematol. 1994;  46 241-244
  • 9 Kadir R A, Sabin C A, Pollard D, Lee C A, Economides D L. Quality of life during menstruation in patients with inherited bleeding disorders.  Haemophilia. 1998;  4 836-841
  • 10 Kouides P A, Phatak P D, Burkart P et al.. Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: results of a patient survey.  Haemophilia. 2000;  6 643-648
  • 11 Lindley C, Sawyer W, Haddon T et al.. Comparison of PT, aPTT, and factor VII values obtained by concurrent sample collection by direct venipuncture and peripheral venous catheters.  Pharmacotherapy. 1994;  14 224-228
  • 12 Almadrones L, Godbold J, Raaf J, Ennis J. Accuracy of activated partial thromboplastin time drawn through central venous catheters.  Oncol Nurs Forum. 1987;  14 15-18
  • 13 Adcock D M, Hoefner D M, Kottke-Marchant K, Marlar R A, Szamosi D I, Warunek D J. Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays and Molecular Hemostasis Assays: Approved Guideline–Fifth Edition. Wayne, PA; Clinical Laboratory Standards Institute 2008 CLSI document H21–A5
  • 14 WHO .Use of Anticoagulants in Diagnostic Laboratory Investigations. Geneva, Switzerland; WHO 1999: 1 WHO/DIL/LAB/99.1
  • 15 CISMEL . Activated partial thromboplastin time: a multicentre evaluation of 11 reagents in the screening of mild haemophilia A.  Scand J Haematol. 1980;  25 308-317
  • 16 Hoffmann J J, Meulendijk P N. Comparison of reagents for determining the activated partial thromboplastin time.  Thromb Haemost. 1978;  39 640-645
  • 17 Lawrie A S, Kitchen S, Purdy G, Mackie I J, Preston F E, Machin S J. Assessment of Actin FS and Actin FSL sensitivity to specific clotting factor deficiencies.  Clin Lab Haematol. 1998;  20 179-186
  • 18 Turi D C, Peerschke E I. Sensitivity of three activated partial thromboplastin time reagents to coagulation factor deficiencies.  Am J Clin Pathol. 1986;  85 43-49
  • 19 Zhang B, Cunningham M A, Nichols W C et al.. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex.  Nat Genet. 2003;  34 220-225
  • 20 Sadler J E. Medicine: K is for koagulation.  Nature. 2004;  427 493-494
  • 21 Peyvandi F, Tagliabue L, Menegatti M et al.. Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency.  Hum Mutat. 2004;  23 98
  • 22 Cairo A, Menegatti M, Sprefico M, Garagiola I, Peyvandi F. Recurrent mutations identified on LMAN1 and coagulation factors VII, X, XIII genes [abstract].  Haematologica. 2008;  93(s3) 97
  • 23 Handyside A H, Kontogianni E H, Hardy K, Winston R M. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification.  Nature. 1990;  344 768-770
  • 24 Peyvandi F, Jayandharan G, Chandy M et al.. Genetic diagnosis of haemophilia and other inherited bleeding disorders.  Haemophilia. 2006;  12(Suppl 3) 82-89
  • 25 Kwiecien M, Edelman A, Nichols M D, Jensen J T. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial.  Contraception. 2003;  67 9-13
  • 26 Santagostino E, Mancuso M E, Morfini M et al.. Solvent/detergent plasma for prevention of bleeding in recessively inherited coagulation disorders: dosing, pharmacokinetics and clinical efficacy.  Haematologica. 2006;  91 634-639
  • 27 Brenner B, Wiis J. Experience with recombinant-activated factor VII in 30 patients with congenital factor VII deficiency.  Hematology. 2007;  12 55-62
  • 28 González-Boullosa R, Ocampo-Martínez R, Alarcón-Martín M J, Suárez-Rodríguez M, Domínguez-Viguera L, González-Fajo G. The use of activated recombinant coagulation factor VII during haemarthroses and synovectomy in a patient with congenital severe factor V deficiency.  Haemophilia. 2005;  11 167-170
  • 29 Divanon F, Hecquard C, Borel-Derlon A. Experience with use of recombinant activated factor VII.  J Clin Pharm Ther. 2002;  27 133-138
  • 30 Altisent C, Lozano M, Sol E et al.. Dental extraction using rFVIIa in a patient with severe FV deficiency.  Haemophilia. 2000;  6 408
  • 31 O'Connell N M. Factor XI deficiency—from molecular genetics to clinical management.  Blood Coagul Fibrinolysis. 2003;  14(Suppl 1) S59-S64
  • 32 O'Connell N M, Riddell A F, Pascoe G, Perry D J, Lee C A. Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency.  Haemophilia. 2008;  14 775-781
  • 33 Al Dieri R, Peyvandi F, Santagostino E et al.. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding.  Thromb Haemost. 2002;  88 576-582
  • 34 Hemker H C, Giesen P, AlDieri R et al.. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability.  Pathophysiol Haemost Thromb. 2002;  32 249-253

Flora PeyvandiM.D. Ph.D. 

Associate Professor of Internal Medicine, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation

University of Milan and Luigi Villa Foundation, Via Pace 9, 20122 Milan, Italy