Patients: general RBD's Info
Blood coagulation is a process that stops bleeding thanks to the action of several coagulation proteins.
Partial or total deficiency of one of these proteins may lead to bleeding symptoms.
The severity of bleeding manifestations can be classified from mild (e.g. epistaxis, hematuria, gum bleeding and bleeding after surgery) to severe (e.g. life- threatening hemorrages such as central nervous system, gastrointestinal and umbilical cord bleeding. Disabling bleeding such as deep muscle and joint bleedings can also occur.
Among inherited bleeding disorders, haemophila A and B (i.e. deficiency of coagulation factors VIII and IX), along with the von Willebrand disease, represent 95-97% of bleeding disorders.
Deficiency of the remaining coagulation factors, fibrinogen, factor II, V, V+VIII, VII, X, XI and XIII are classified as Rare Bleeding Disorders (RBDs).
They affect one person out of 500,000-2 million, depending on the deficient factor and are inherited in an autosomal recessive fashion (i.e. both men and women can be similarly affected because the deficiency is not linked to the X chromosome). Heterozygous carriers may present with a less severe phenotype. Very few clinical centres have the opportunity to follow- up significant numbers of patients because of the rarity of these conditions; consequently the amount of information available on diagnosis and treatment is limited. Even though RBDs have a limited impact on the national health systems, their impact at a global level is significant as they illustrate the challenges in providing high quality, evidence based care for all rare disease populations.
Deficiency of the remaining coagulation factors, fibrinogen, factor II, V, V+VIII, VII, X, XI and XIII are classified as Rare Bleeding Disorders (RBDs).
They affect one person out of 500,000-2 million, depending on the deficient factor and are inherited in an autosomal recessive fashion (i.e. both men and women can be similarly affected because the deficiency is not linked to the X chromosome). Heterozygous carriers may present with a less severe phenotype. Very few clinical centres have the opportunity to follow- up significant numbers of patients because of the rarity of these conditions; consequently the amount of information available on diagnosis and treatment is limited. Even though RBDs have a limited impact on the national health systems, their impact at a global level is significant as they illustrate the challenges in providing high quality, evidence based care for all rare disease populations.
To this purpose, a European study has been designed in order to collect data on patients affected with RBDs. This project entitled “Establishment of a European Network of Rare Bleeding Disorders (EN-RBD)”
obtained funding in 2007 from European Commission (European Community Action Programme for Public Health, EAHC-DG SANCO) with the following aims:
develop a network of European centres treating patients affected with RBDs;
harmonize RBDs data by collecting patient information using of a web-based database;
make the network accessible to all Centres initially with the ultimate goal of a single worldwide database when the instrument is fully operational;
prepare guidelines for the diagnosis and treatment of RBDs based on the experience obtained with the EN-RBD project;
encourage pharmaceutical industries to develop new products to treat these patients.
The most common symptoms reported in all the deficiencies of any severity are mucocutaneous bleeding (e.g. nose bleeding, mouth and gums bleeding, presence of blood in urine, ecchymosis) and bleeding during/after surgery. Gastrointestinal bleedings have been observed in all deficiency types, with the exception of factor XIII deficiency. Disabling bleeding are more frequent in some specific deficiencies: deep muscle and joint bleedings are present in all severe and moderate deficiencies, with the exception of ractor XI deficiency;
umbilical cord and central nervous system bleedings occurred in severe fibrinogen, factor X and factor XIII deficiencies.
Severe deficiencies of fibrinogen, factor X and factor XIII are among the most disabling due to the early onset of severe bleeding episodes. They usually become manifest before the third year of life. Conversely, deficiency of factor XI, even in its severe form, remains asymptomatic in about 40% of all patients. However these patients may bleed during or after surgery. In all other RBD’s bleeding
manifestations were very heterogeneous with no obvious pattern. The symptoms were also analysed in relation to the functional activity of the deficient factor. The prevalence of the most severe symptoms, such as deep muscle and joint, central nervous system, gastrointestinal tract and umbilical cord bleedings was significantly reduced when the deficient factor levels were greater than 10% (or above 20mg/dl of fibrinogen in the case of afibrinogenemia). These results can help physicians to better identify those patients who need prophylaxis and preventative treatments.
Women
Excessive bleeding during the menstrual period and miscarriage has been reported in women with any factor deficiency regardless of severity. Such bleeding may in fact occur during/after delivery unless adequate treatment is administered. Since these symptoms can be found also in the healthy population, it is necessary to carry out comparative studies in order to verify the relative contribution of the RBDs in women with these symptoms.Heterozygous patients
Heterozygous patients (patients with a functional activity of the factor higher than 30%) rarely bleed spontaneously and bleeding typically occurs after surgery, tooth extraction, trauma and childbirth. However, 10-30 % of patients in our registry had spontaneous mucocutaneous bleeding.Available Treatments
The personal and family history of bleeding should always be considered when deciding if treatment is required. The dosage and frequency of the treatment depends on the minimum level of the deficient factor required to secure haemostasis. The half-life of the deficient factor and the type and severity of the bleeding episodes or surgical procedure should also be taken into account. Available treatments include:fresh frozen plasma, preferably virus inactivated (not always available);
prothrombin complex concentrate (containing different amount of factors II, VII, IX, X);
Individual plasma concentrates (fibrinogen, factor VII, factor XI and factor XIII);
recombinant factor VII concentrate;
anti-fibrinolytic agents.
Clinical studies are currently under way on plasma-derived FX concentrate and on recombinant FXIII concentrate.
Conclusions
The EN-RBD database has proved to be an effective and efficient tool for the collection of patient data in an anonymous and comprehensive manner. It allows effective analysis of the data by means of database interrogation. The data collected is secure. The constant development of the EN-RBD database is a fundamental step to reach new challenging goals. The improvements will enable us to:continue evaluating RBDs prevalence in a larger population as well as in populations with a high rate of consanguinity;
determine the efficacy of treatment protocols and monitor the natural history of the disease with and without treatment;
help establish appropriate use of the available resources;
plan clinical audit programmes as well as research projects to assess sub-groups (women, children, etc);
effectively inform patients about their disease in order to improve their awareness;
identify the weaknesses of the health care systems in the field of RBDs. We strongly encourage the creation of National Registries and the sharing of data with the EN-RBD database in order to expand everyone’s knowledge.
Is you centre already involved in the EN-RBD network?
If not ask them to contact us at This e-mail address is being protected from spambots. You need JavaScript enabled to view it or visitwww.rbdd.eu
