Rare bleeding disorders (RBDs), accounting for the 3% to 5% of patients with abnormal hemostasis, include the inherited deficiencies of coagulation factor II (prothrombin), factor V, combined factor V/VIII, factor VII, factor X, factor XI, factor XIII, and fibrinogen. The prevalence of RBDs is variable, both the relative frequency among the different factors and frequency in different regions of the world. The genetic transmission of these disorders is usually autosomal recessive. Bleeding manifestations caused by these inherited deficiencies are of variable severity and usually related to the extent of the decreased activity of the particular coagulation factor. Usually, only homozygous and compound heterozygous patients are symptomatic, although occasionally heterozygotes display a bleeding tendency. On the whole, the most typical symptom, common to all RBDs, is the occurrence of mucosal bleeding, whereas life-endangering bleeding, such as CNS or umbilical cord bleeding, is more frequent only in some deficiencies, such as afibrinogenemia, severe factor XIII and factor X deficiencies, characterized by very low or undetectable coagulant activity. Treatment of patients affected with the various coagulation factor deficiencies could be (a) on demand for spontaneous bleeding episodes, (b) during the management of surgical procedures, and (c) for prevention of bleeding by prophylaxis. Because of the rarity of these disorders and the technical limitations of laboratory testing and the lack of specific concentrates, a unified, evidence-based therapeutic approach for each RBD is not always available. To overcome these limitations, global partnerships and networking between treatment centers have been developed to increase our knowledge and create platforms for researchers and clinicians to exchange information.
Acronyms and Abbreviations
aPTT, activated partial thromboplastin time; COPII, coat protein complex II; EGF, epidermal growth factor; ELISA, enzyme-linked immunosorbent assay; ERGIC, endoplasmic reticulum–Golgi intermediate compartment; FFP, fresh-frozen plasma; GGCX, γ-glutamyl carboxylase; Gla, γ-carboxyglutamic acid; LMAN, mannose-binding lectin; MCFD, multiple combined-factor deficiency; PAR, protease-activated receptor; PCC, prothrombin complex concentrate; PPH, postpartum hemorrhage; PT, prothrombin time; RBDs, rare bleeding disorders; SD, standard deviation TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor; TT, thrombin time; VKORC1, vitamin K epoxide reductase–oxidase complex.
Rare congenital deficiencies of plasma proteins involved in blood coagulation, such as fibrinogen, prothrombin (factor II), and factors V, V+VIII, VII, X, XI, and XIII, generally lead to lifelong bleeding diseases called rare bleeding disorders (RBDs). These disorders have been described in most populations with an incidence varying from one case in 500,000 for factor VII deficiency, to one case in 2 to 3 million for prothrombin and factor XIII deficiency.1,2 However, their relative frequency varies among populations, being higher in regions where consanguineous or endogamous marriages are common, partly as a result of increased high frequencies of specific mutant genes in these inbred populations.3–8 Two large surveys were made by the World Federation of Hemophilia (WFH; www.wfh.org) and the European Network of the Rare Bleeding Disorders (EN-RBD; www.rbdd.eu), with the aim of collecting better organized and harmonized data ...