The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding.

SummaryWe investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation.Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was somewhat more sensitive to clotting factor decrease than the ETP was.In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time

Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A

International audienceBACKGROUND:Hemophilia A (HA) is a congenital bleeding disorder resulting from factor VIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision.OBJECTIVES:To identify predictive markers of ITI efficacy.METHODS:The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n = 7] and ITI failure [n = 8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis).RESULTS:Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P 0.875).CONCLUSION:Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA

Major differences in bleeding symptoms between factor VII deficiency and hemophilia B.

SUMMARY BACKGROUND: The autosomally-inherited factor VII (FVII) deficiency and X-linked hemophilia B offer an attractive model to investigate whether reduced levels of FVII and FIX, acting in the initiation and amplification of coagulation respectively, influence hemostasis to a different extent in relation to age and bleeding site. METHODS: Hemophilia B patients (n = 296) and FVII-deficient males (n = 109) were compared for FVII/FIX clotting activity, F7/F9 genotypes and clinical phenotypes in a retrospective, multi-centre, cohort study. RESULTS: Major clinical differences between diseases were observed. Bleeding occurred earlier in hemophilia B (median age 2.0 years, IR 0.9-5.0) than in FVII deficiency (5.2 years, IR 1.9-15.5) and the bleeding-free survival in FVII deficiency was similar to that observed in 'mild' hemophilia B (P = 0.96). The most frequent disease-presenting symptoms in hemophilia B (hematomas and oral bleeding) differed from those in FVII deficiency (epistaxis and central nervous system bleeding). Differences were confirmed by analysis of FVII-deficient women. CONCLUSIONS: Our data support the notion that low FVII levels sustain hemostasis better than similarly reduced FIX levels. On the other hand, minute amounts of FVII, differently to FIX, are needed to prevent fatal bleeding, as indicated by the rarity of null mutations and the associated life-threatening symptoms in FVII deficiency, which contributes towards shaping clinical differences between diseases in the lowest factor level range. Differences between diseases are only partially explained by mutational patterns and could pertain to the specific roles of FVII and FIX in coagulation phases and to vascular bed-specific components

Clinical phenotypes and factor VII genotype in congenital factor VII deficiency

To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficienc

Major differences in bleeding symptoms between factor VII deficiency and haemophilia B

SUMMARY BACKGROUND: The autosomally-inherited factor VII (FVII) deficiency and X-linked hemophilia B offer an attractive model to investigate whether reduced levels of FVII and FIX, acting in the initiation and amplification of coagulation respectively, influence hemostasis to a different extent in relation to age and bleeding site. METHODS: Hemophilia B patients (n = 296) and FVII-deficient males (n = 109) were compared for FVII/FIX clotting activity, F7/F9 genotypes and clinical phenotypes in a retrospective, multi-centre, cohort study. RESULTS: Major clinical differences between diseases were observed. Bleeding occurred earlier in hemophilia B (median age 2.0 years, IR 0.9-5.0) than in FVII deficiency (5.2 years, IR 1.9-15.5) and the bleeding-free survival in FVII deficiency was similar to that observed in 'mild' hemophilia B (P = 0.96). The most frequent disease-presenting symptoms in hemophilia B (hematomas and oral bleeding) differed from those in FVII deficiency (epistaxis and central nervous system bleeding). Differences were confirmed by analysis of FVII-deficient women. CONCLUSIONS: Our data support the notion that low FVII levels sustain hemostasis better than similarly reduced FIX levels. On the other hand, minute amounts of FVII, differently to FIX, are needed to prevent fatal bleeding, as indicated by the rarity of null mutations and the associated life-threatening symptoms in FVII deficiency, which contributes towards shaping clinical differences between diseases in the lowest factor level range. Differences between diseases are only partially explained by mutational patterns and could pertain to the specific roles of FVII and FIX in coagulation phases and to vascular bed-specific component

European Network of Rare Bleeding Disorders (EN-RBD)

Congenital deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency (less factor/more bleeding). Rare Bleeding Disorders (RBDs) such as afibrinogenemia, Factor (F)II, FV, FV+VIII, FVII, FX, FXI and FXIII deficiencies are autosomal recessive diseases and represent 3% to 5% of all inherited coagulation deficiencies. Their distribution is variable in the world with a prevalence ranging from approximately 1 in 2 million for FII and FXIII deficiency to 1 in 500,000 for FVII deficiency. Due to their rarity, RBDs are typically orphan diseases, relatively neglected by health care providers, advocacy organizations, and drug manufacturers. Treatment of patients with RBDs during bleeding episodes or surgery is a challenge because of the lack of experience, paucity of data, unavailability of factor concentrates for some deficiency states and the possible occurrence of severe complications, which can be minimized by assessment risks of bleeding and thrombosis, use of haemostatic means other than blood components or no therapy at all. Moreover, the establishment of the genotype-phenotype correlation for each deficiency and the study of the genetic origin of these disorders may lead to prevention through prenatal diagnosis and to the discovery of new treatment strategies. Unfortunately, no suitable clinical trials exist to supply good evidence on how these people should best be treated and this lack has to be taken into account in the production of a suitable guideline. The lacuna of adequate information on clinical manifestations, treatment and genetic basis of RBDs can be made up for by the collection and organization of data and by their accurate statistical analysis. With this aim in mind, we have already developed an International Database on RBDs called Rare Bleeding Disorders Database (RBDD) (www.rbdd.org), based on decade-long research and the analysis of more than 250 patients affected by RBDs and designed to report clinical, laboratory (specific and advanced coagulation tests), genetic (mutation detection, in vitro expression study, and requirements for prenatal diagnosis) and therapeutic information. This database arises from the project "Establishment of a European Network of Rare Bleeding Disorders (EN-RBD)" funding from the European Union, in the framework of the Public Health Programme Nonetheless, the data collected so far are not as yet sufficient to indicate which course of action is needed to improve both diagnosis and treatment of RBDs, or provide evidence-based diagnostic and therapeutic guidelines. Hence, the aim of this project is to set up a European network of Treatment Centres, using the existing RBDD as the starting point, in order to increase the collection of clinical, genetic, and treatment data, and to develop a computer tool with the purpose of managing, editing and viewing all inserted data and making them readily available through database queries. Data could be made available through the existing RBDD, which will be developed and implemented in an Internet-accessible database (www.rbdd.eu), consisting of the following elements: - a public section containing the results of the data collection - a protected access area for authorized Centres to insert new data, which will monitor, process, and manage stored data. Standardization in collecting and analysing data will allow, firstly, European countries (through the collaboration of Centres participating already), and subsequently, all Treatment Centres worldwide, to share their research results, with the final goal of filling the gap between clinical data and clinical practice. RBDD will also constitute a valid source of information for clinical surveys of National and Supranational Health Organizations wishing to take healthy action in the field of RBDs