[Haemophilia].
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Haemophilia is an X-linked inherited clotting disorder with a prevalence of 1 per 5000 men. A deficiency of clotting factor VIII (FVIII; haemophilia A) or IX (FIX; haemophilia B) causes haemophilia patients to suffer from spontaneous bleeding and excessive blood-loss following surgery or trauma. Prophylactic administration of a factor VIII- or factor IX-concentrate is the standard treatment for children with severe haemophilia. Women who are carriers of the F8 or F9 gene mutation can have a lowered plasma concentration of factor VIII or IX, and thus suffer from a mild form of haemophilia. Drugs that have a negative influence on blood clotting, such as NSAIDs, can lead to life-threatening bleeding in haemophilia patients. One of the main complications of haemophilia treatment is the formation of inhibiting antibodies that inactivate FVIII or FIX. Haemophilia patients should be treated by a multidisciplinary team in a hospital with a haemophilia treatment centre.Keywords:
Haemophilia B
Clotting factor
Factor IX
Blood clotting
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Summary In haemophilia patients, a relationship is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX (FVIII/FIX) activity. However, it is known from clinical experience, that some haemophilia patients, despite similar FVIII/FIX plasma levels, could exhibit different bleeding phenotype. After determining preanalytical test conditions, we evaluated the thrombin generation capacity from haemophilia plasma samples in various conditions and the potential usefulness of thrombin generation test (TGT) in haemophilia patients. In a series of 46 haemophilia patients (34 haemophilia A and 12 haemophilia B patients), we found a significant correlation between plasmatic FVIII/FIX levels and endogenous thrombin potential (ETP), peak and time to peak obtained by thrombin generation measurement. In addition, a correlation was found between severe clinical bleeding phenotype and ETP. Our results suggest that TGT could be a promising tool to evaluate haemostasis capacity in patients with haemophilia. Our ex vivo results, obtained 24 hours after FVIII concentrate administration, showed that in patients presenting similar plasmatic FVIIII levels, thrombin generation capacity may be significantly different. These results suggest that in patients with haemophilia, TGT could be useful for individually tailoring prophylactic regimens as well as for adapting clotting factors infusions in surgical situations, in addition to FVIII/FIX plasma clotting activities.
Haemophilia B
Clotting factor
Factor IX
Thrombin Generation
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Carriers of haemophilia are known to have a wide range of clotting factor levels and bleeding symptoms. This study aimed at investigating whether carriers of severe and moderate haemophilia had an increased bleeding tendency, compared with a control group, using a condensed version of a bleeding assessment tool developed by the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD study group (MCMDM-1VWD). One hundred and twenty-six genetically verified carriers of severe and moderate haemophilia and 90 controls were interviewed regarding bleeding symptoms. A bleeding score of at least 4 was considered positive, indicating a significant bleeding tendency. Clotting factor levels were tested in the carriers.Nineteen of the women were carriers of haemophilia B, with a mean factor (F)IX:C level of 0.54 (± 0.27) kIU/l, and 107 were carriers of haemophilia A, with a mean FVIII:C level of 0.74 (± 0.32) kIU/l. The median bleeding score was 2 (-3-12) among carriers and -1 (-3-8) among controls (P < 0.001). The bleeding score was weakly correlated to clotting factor levels in carriers of haemophilia A (rs = -0.36, P < 0.001). We conclude that the bleeding tendency in our cohort of carriers differed significantly from that in the controls and that clotting factor levels might not be sufficient to predict the bleeding tendency.
Clotting factor
Factor IX
Haemophilia B
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Haemophilia is the most common congenital disorder of coagulation and affects approximately 1 in 10,000 males around the world. Haemophilia A is due to a deficiency of factor VIII in the circulating blood whilst haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by factor IX deficiency. It is less common than haemophilia A and affects 1 in about 30,000 males. Both factors VIII and IX are essential glycoproteins in the clotting cascade [1] (Fig. 1). The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis, typically affecting the hinge joints such as the ankle, knee and elbow. The severity of bleeding depends upon the level of factor in the blood.
Clotting factor
Factor IX
Haemophilia B
PROTHROMBIN COMPLEX
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Inherited bleeding disorders are a group of congenital coagulopathies resulting when deficiencies of the proteins responsible for coagulation, platelet function or fibrinolysis occur. Haemophilia A (HA, deficiency of factor VIII), Haemophilia B (HB, deficiency of factor IX) and von Willebrand Disease (vWD) are the most frequent, being >90% of all inherited bleeding disorders with a prevalence of 0.5, 0.1 and 1–5/10,000 respectively1–3. Other rare inherited bleeding disorders are represented by deficiencies of factor I, II, V, VII, X, XI, XII, XIII, combined V+VIII, combined vitamin K-dependent factors, with a general population prevalence between 1/500,000 and 1/2,000,0004. Inherited bleeding disorders require wide-ranging care and effective management within a multidisciplinary team setting. The modern treatments of inherited bleeding disorders are now remarkably effective, although expensive.
In Italy the epidemiological data on inherited bleeding disorders derive from three registries:
The Italian National Registry for Rare Diseases (RNMR);
The National Registry of Congenital Coagulopathies (RNCC);
The Haemophilia Database of the Italian Association of Haemophilia Centres (AICE).
These registries differ in terms of organisation, purpose and data collection process. A general description and results for each registry is reported as follow.
Haemophilia B
Factor IX
von Willebrand Disease
Clotting factor
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Health care officials and legislators need accurate data on prevalence and numbers of individuals with bleeding disorders in order to plan and allot their budgets; the manufacturers of coagulation factors also need these data to estimate the amount of factors required to prevent scarcity of these products.We surveyed the prevalence of haemophilia A, haemophilia B, von Willebrand's disease and rare bleeding disorders in North-Eastern Iran. The survey was done in the period from September 2009 to March 2011. Information was collected from the medical records in three major hospitals and a haemophilia centre; the patients' updated data were obtained by telephone.Overall in the current survey 552 patients with inherited coagulation disorders were identified and their medical records obtained. Of these, 429 (77.5%) had common bleeding disorders (haemophilia A, haemophilia B, von Willebrand's disease), 85 (15.6%) had rare bleeding disorders (deficiency of coagulation factors V, VII, X, XIII, I, XI, combined factor V and VIII deficiency) and 38 (6.9%) had platelet disorders.The commonest bleeding disorders were haemophilia A (n=287, 51.9%), haemophilia B (n=92, 16.6%), von Willebrand's disease (n=50, 9%), factor V deficiency (n=21, 3.8%), factor VII deficiency (n=19, 3.4%), factor X deficiency (n=2, 0.36%), combined factor V and VIII deficiency (n=28, 5.8%), factor XIII deficiency (n=11, 1.99%), factor XI deficiency (n=2, 0.4%), afibrinogenaemia (n=2, 0.36%) and platelet disorders (n=38, 6.9%).There is notable population of individuals with bleeding disorders in North-Eastern Iran.
Haemophilia B
von Willebrand Disease
Coagulation Disorder
Platelet disorder
Clotting factor
Factor IX
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Haemophilia is an inherited bleeding disorder caused by deficiency of factors VIII or IX (FVIII/IX). Severe deficiency is associated with spontaneous bleeding into the joints and recurrent bleeding results in haemophilic arthropathy, disability and reduced quality of life. The bleeding is treated with intravenous FVIII/IX concentrate, which the majority of people with haemophilia self-administer at home. Although initially FVIII/IX was administered on demand once bleeding started, increasingly it is now being used prophylactically. In haemophilia, prophylaxis can be defined as the administration of clotting factor concentrate in anticipation of or to prevent bleeding.
Although prophylaxis is now considered the gold standard for the treatment of severe haemophilia in childhood and adolescence, its use in adulthood is more controversial but here I argue that prophylaxis should be the gold standard in haemophilia treatment for life.
Clotting factor
Haemophilia B
Arthropathy
Anticipation (artificial intelligence)
Factor IX
Gold standard (test)
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Summary In this paper, a five generation Greek family is described with haemophilia B. The disease is characterized by a normal ox-brain prothrombin time, normal levels of the vitamin-K dependent clotting factors VII and X and a proportional reduction of factor IX acttivity and antigen levels all of which is consistent with the cross-reacting material negative form of haemophilia B. However, in this family the factor IX levels in the three patients of generation V are around 1 U/dl while the three older patients in generation III have factor IX levels ranging from 28 to 44 U/dl. In the oldest patient of generation V we observed a rise of the factor IX level from 1 U/dl up to the age of 13 to 10 U/dl at age 14. In addition, the older patients have very mild bleeding symptoms or none at all, while the young ones have occasional spontaneous haemorrhages in muscles and joints, compatible with severe or moderately severe haemophilia. The disease appears to be similar to haemophilia B Leyden which has been described in a Dutch family.
Haemophilia B
Factor IX
Clotting factor
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The annual amount of clotting factor used by patients at the Royal Free Haemophilia Centre increased significantly from 4 million iu in 1980 to over 15 million iu by 1994 (P < 0.0001). In order to assess the reasons for this increase, data on concentrate usage over this period were retrospectively collected for patients who had haemophilia or von Willebrand's disease. Only patients who were registered exclusively at the Centre were included in the study. In total, 498 patients met the inclusion criterion. The median age of the cohort on 1 January 1980 was 21 (range < 1-69) years. During the period there were 88 births and 45 deaths. The majority of patients had haemophilia A (55%). The median follow-up period per patient was 2.1 (range 0-14.8) years. Despite adjusting for increases in the number of patients and changes in body weight, statistically significant increases in clotting factor usage were detected for some subgroups of patients, in particularly for those with severe haemophilia A and B and from the late 1980s onwards, for patients with von Willebrand's disease. Two reasons for this increase in clotting factor usage were identified as being the introduction of improved products and prophylaxis. However, the increased cost of clotting factor provision that has resulted from these changes in treatment policy should not be analysed in isolation but should be balanced off against cost decreases in other areas and against increases in the effectiveness of treatment.
Clotting factor
Haemophilia B
Factor IX
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Haemophilia is an inherited, x-linked bleeding disorder. Patients with haemophilia lack clotting factor VIII (FVIII) or factor IX (FIX) causing spontaneous or prolonged bleeding. The hallmark of severe haemophilia is recurrent joint bleeding, eventually leading to severe crippling arthropathy. Functional limitations and the need for lifelong treatment have a large impact on a patient’s daily life. Classification of haemophilia Haemophilia is classified into the types and quantity of clotting factor deficiency. Haemophilia A patients lack FVIII and haemophilia B patients lack FIX. In 1958 haemophilia was classified in three severities based on clinical observations; 3 IU/dl had less complications of haemophilia than patients with baseline levels
Clotting factor
Arthropathy
Haemophilia B
Factor IX
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