Abstract
Rare bleeding disorders (RBDs) comprise inherited deficiencies of factors I (fibrinogen),
II (prothrombin), V, VII, X, XI, and XIII as well as combined factor V + VIII and
vitamin K-dependent factors. They represent 3–5% of all congenital bleeding disorders
and are usually transmitted as autosomal recessive traits. These disorders often manifest
during childhood and have varied clinical presentations from mucocutaneous bleeding
to life-threatening symptoms such as central nervous system and gastrointestinal bleeding.
Bleeding manifestations generally vary within the same RBD and may also vary from
1 RBD to the other. Laboratory diagnosis is based on coagulation screening tests and
specific factor assays, with molecular techniques providing diagnostic accuracy and
enabling prenatal counseling. The approach to treatment of bleeding episodes and invasive
procedures needs to be individualized and depends on the severity, frequency and procedure-related
risk of bleeding. The first line of treatment of RBDs is replacement of the deficient
factor, using specific plasma-derived or recombinant products and using fresh frozen
plasma or cryoprecipitate when specific products are not available or in resource-limited
countries. Prophylaxis may be considered in individuals with recurrent serious bleeding
and especially after life-threatening bleeding episodes. Novel no-replacement strategies
promoting hemostasis by through different mechanisms need to be studied in RBDs as
alternative therapeutic options.
Keywords
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References
- Genetic diagnosis of haemophilia and other inherited bleeding disorders.Haemophilia. 2006; 12: 82-89
- Rare bleeding disorders: diagnosis and treatment.Blood. 2015; 125: 2052-2061
- World federation of hemophilia report on the annual global survey 2016.2017
- Introduction. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management.Semin Thromb Hemost. 2009; 35: 349-355
- North American Rare Bleeding Disorder Study G. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.J Thromb Haemost. 2004; 2: 248-256
- Consanguineous marriages in a Saudi population and the effect of inbreeding on prenatal and postnatal mortality.Ann Trop Paediatr. 1997; 17: 155-160
- Consanguineous marriages in the United Arab Emirates.J Biosoc Sci. 1997; 29: 491-497
- Bleeding disorders in the tribe: result of consanguineous in breeding.Orphanet J Rare Dis. 2010; 5: 23
- Consanguineous matings in the Egyptian population.J Med Genet. 1983; 20: 58-60
- Consanguineous marriages in Morocco and the consequence for the incidence of autosomal recessive disorders.J Biosoc Sci. 2009; 41: 575-581
- The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin.Blood. 1997; 90: 2654-2659
- Consanguineous marriage in Iran.Ann Hum Biol. 2004; 31: 263-269
- Descriptive epidemiology of hemophilia and other coagulation disorders in mansoura, egypt: retrospective analysis.Mediterr J Hematol Infect Dis. 2010; 2 (e2010025)
- Correlating clinical manifestations with factor levels in rare bleeding disorders: a report from Southern India.Haemophilia. 2012; 18: e195-200
Scully M-F. 2018.
- Inherited bleeding disorders: results from the Italian Regional Haemophilia Centre of Pescara.Blood Transfus. 2008; 6: 136-142
- 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: 615-621
- A web-based registry of inherited bleeding disorders in the region of Emilia-Romagna: results at three and a half years.Haemophilia. 2008; 14: 343-354
- Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management.Semin Thromb Hemost. 2013; 39: 579-584
- International Registry on Congenital Factor VIID. Factor VII deficiency: defining the clinical picture and optimizing therapeutic options.Haemophilia. 2008; 14: 1170-1175
- Familial deficiency of vitamin K-dependent clotting factors.Haemophilia. 2008; 14: 1209-1213
- Diagnosis and treatment of von willebrand disease and rare bleeding disorders.J Clin Med. 2017; 6
- Factor XI deficiency in Ashkenazi Jews in Israel.N Engl J Med. 1991; 325: 153-158
- 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: 304-326
- Factor XI deficiency in humans.J Thromb Haemost. 2009; 7: 84-87
- Recessively inherited coagulation disorders.Blood. 2004; 104: 1243-1252
- Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity.J Thromb Haemost. 2012; 10: 1938-1943
- European Network of Rare Bleeding Disorders g. Establishment of a bleeding score as a diagnostic tool for patients with rare bleeding disorders.Thromb Res. 2016; 148: 128-134
- Congenital bleeding disorders.Curr Probl Pediatr Adolesc Health Care. 2005; 35: 38-62
- National and international registries of rare bleeding disorders.Blood Transfus. 2008; 6: s45-8
- Symptoms of inherited factor V deficiency in 35 Iranian patients.Br J Haematol. 1998; 103: 1067-1069
- Factor XI deficiency–esolving the enigma?.Hematology Am Soc Hematol Educ Program. 2009; : 97-105
- Frequency and clinical spectrum of rare inherited coagulopathies–a tricenter study.J Pak Med Assoc. 2008; 58: 441-444
- Rare inherited disorders of fibrinogen.Haemophilia. 2008; 14: 1151-1158
- Hereditary prothrombin deficiency.J Pak Med Assoc. 2009; 59: 637-639
- Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature.Haemophilia. 2008; 14: 323-328
- Factor XI deficiency and its management.Haemophilia. 2000; 6: 100-109
- High levels of coagulation factor XI as a risk factor for venous thrombosis.N Engl J Med. 2000; 342: 696-701
- Inherited factor XI deficiency confers no protection against acute myocardial infarction.J Thromb Haemost. 2003; 1: 658-661
- Bleeding symptoms in 27 Iranian patients with the combined deficiency of factor V and factor VIII.Br J Haematol. 1998; 100: 773-776
- Vitamin K-dependent coagulation factors deficiency.Semin Thromb Hemost. 2009; 35: 439-446
- Hereditary combined deficiency of the vitamin K-dependent clotting factors.Orphanet J Rare Dis. 2010; 5: 21
- Women and bleeding disorders.Haemophilia. 2010; 16: 160-167
- 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
- Improving care and treatment options for women and girls with bleeding disorders.Eur J Haematol. 2015; 95: 2-10
- Factor deficiencies in pregnancy.Hematol Oncol Clin North Am. 2011; 25 (viii-ix.): 359-378
- Coagulation factor deficiencies and pregnancy loss.Semin Thromb Hemost. 2003; 29: 171-174
- Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia.Br J Haematol. 1999; 107: 204-206
- Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen.Thromb Haemost. 1995; 73: 151-161
- The relevance of developmental hemostasis to hemorrhagic disorders of newborns.Semin Perinatol. 1997; 21: 70-85
- Developmental haemostasis. Impact for clinical haemostasis laboratories.Thromb Haemost. 2006; 95: 362-372
- Semin Thromb Hemost. 2009; 35: 400-406
- Inhibitors in patients with congenital bleeding disorders other than hemophilia.Semin Thromb Hemost. 2017;
- Comparison of thrombin generation assay with conventional coagulation tests in evaluation of bleeding risk in patients with rare bleeding disorders.Clin Appl Thromb Hemost. 2014; 20: 637-644
- The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency.Thromb Res. 2015; 136: 465-473
- Recombinant factor VIIa treatment for asymptomatic factor VII deficient patients going through major surgery.Blood Coagul Fibrinolysis. 2012; 23: 379-387
- Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype.Haemophilia. 2015; 21: 124-132
- Thrombin generation in patients with factor XI deficiency and clinical bleeding risk.Haemophilia. 2010; 16: 771-777
- Whole blood rotation thromboelastometry (ROTEM((R))) in nine severe factor V deficient patients and evaluation of the role of intraplatelets factor V.Haemophilia. 2012; 18: 463-468
- Influence of factor V HR2 on thrombin generation and clinical manifestation in rare bleeding disorders.Pathophysiol Haemost Thromb. 2005; 34: 279-283
- Congenital fibrinogen disorders.Semin Thromb Hemost. 2009; 35: 356-366
- Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery.Thromb Haemost. 2011; 106: 521-527
- Blood product support for delivery in severe factor X deficiency: the use of thrombin generation to guide therapy.Blood Transfus. 2007; 5: 204-209
- Genetic sequence analysis of inherited bleeding diseases.Blood. 2013; 122: 3423-3431
- Prenatal diagnosis and preimplantation genetic diagnosis: novel technologies and state of the art of PGD in different regions of the world.Haemophilia. 2011; 17: 14-17
- Genetic diagnosis in Hemophilia A from southern China: five novel mutations and one preimplantation genetic analysis.Int J Lab Hematol. 2017; 39: 191-201
- Experience of preimplantation genetic diagnosis for hemophilia at the University Hospital Virgen Del Rocio in Spain: technical and clinical overview.Biomed Res Int. 2015; 2015406096
- Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.Blood. 2000; 96: 149-152
- FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations.Thromb Res. 2014; 133: 868-874
MASAC Recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders.: National Hemophilia Foundation; Revised August 2017.
- Prothrombin complex concentrates in emergency bleeding disorders.Am J Hematol. 2012; 87: 898-902
- Combined Factor V and Factor VIII Deficiency.Semin Thromb Hemost. 2009; 35: 390-399
- Combined deficiency of coagulation factors V and VIII: an update.Semin Thromb Hemost. 2013; 39: 613-620
- Desmopressin acetate as a haemostatic elevator in individuals with combined deficiency of factors V and VIII: a clinical trial.J Thromb Haemost. 2016; 14: 336-339
- Efficacy and safety of prophylactic treatment with plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency.Haemophilia. 2015; 21: 102-108
- Pharmacokinetics and safety of plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency.Haemophilia. 2015; 21: 95-101
- Developing the first recombinant factor XIII for congenital factor XIII deficiency: clinical challenges and successes.Semin Thromb Hemost. 2017; 43: 59-68
- Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel.Eur J Obstet Gynecol Reprod Biol. 2011; 158: 124-134
- Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-544
- A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies.Haemophilia. 2010; 16: 569-583
- Primary prophylaxis for children with severe congenital factor VII deficiency – clinical and laboratory assessment.Blood Cells Mol Dis. 2017; 67: 86-90
- Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER).Haematologica. 2013; 98: 538-544
- Emicizumab Prophylaxis in Hemophilia A with Inhibitors.N Engl J Med. 2017; 377: 809-818
- Emicizumab-kxwh: first global approval.Drugs. 2018; 78: 269-274
- Targeting TFPI for hemophilia treatment.Thromb Res. 2016; 141: S28-30
- Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.N Engl J Med. 2017; 377: 819-828
- An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia.Nat Med. 2015; 21: 492-497
- Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.J Thromb Haemost. 2015; 13: 743-754
- Design and characterization of an APC-specific serpin for the treatment of hemophilia.Blood. 2017; 129: 105-113
- Improved hemostasis in hemophilia mice by means of an engineered factor Va mutant.J Thromb Haemost. 2014; 12: 363-372
- Successful treatment with thalidomide of a patient with congenital factor V deficiency and factor V inhibitor with recurrent gastrointestinal bleeding from small bowel arteriovenous malformations.Haemophilia. 2013; 19: e59-61
- Factor V inhibitor in neonatal intracranial hemorrhage secondary to severe congenital factor V deficiency.J Pediatr Hematol Oncol. 2001; 23: 244-246
- Severe factor V deficiency and neonatal intracranial haemorrhage: a case report.Haemophilia. 2000; 6: 44-46
- Inhibitor to factor V in severe factor V congenital deficiency. A case report.Nouv Rev Fr Hematol. 1985; 27: 303-305
- A new report of FVII-inhibitor in a patient suffering from severe congenital FVII deficiency.Haemophilia. 2015; 21: e336-8
- Inhibitors to factor VII in congenital factor VII deficiency.Haemophilia. 2014; 20: e188-91
- Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors.Haemophilia. 2009; 15: 1065-1073
- Recombinant activated factor VII and tranexamic acid are haemostatically effective during major surgery in factor XI-deficient patients with inhibitor antibodies.Thromb Haemost. 2009; 102: 487-492
- Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiency.Haemophilia. 2002; 8: 145-148
- [Factor XI inhibitors : clinical and biological features].Ann Biol Clin (Paris). 2001; 59: 183-186
- The use of recombinant factor VIIa (NovoSeven) in a patient with a factor XI deficiency and a circulating anticoagulant.Blood Coagul Fibrinolysis. 2001; 12: 551-553
- Inhibitors to Factor XI in patients with severe Factor XI deficiency.Semin Hematol. 2006; 43: S10-2
- Auto- and alloantibodies against factor XIII: laboratory diagnosis and clinical consequences.J Thromb Haemost. 2018;
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Publication history
Published online: October 30, 2018
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© 2018 Published by Elsevier Ltd.
