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XXIX International Congress Buenos Aires Argentina 10-14 July 2010 Mild hemophilia A Management of patient remain a major Challenge: Diagnosis in 40% of patient , discrepant factor VIII level are measured when a one-stage clotting assay is used as compared with a two-stage (chromogenic) assay. – FVIII levels are reduced by 50% when mesured by a two stage assay, leading to missing the diagnosis when a one stage assay is used. – The reverse situation is less frequent • Mutation and molecular mechanisms of many of these discrepant cases have been resolved – FVIII reduced in a two stage/one stage: Nbs of missence mutation clustered within the A domains that lead to defective stability of FVIIIa – Mutation imparing FVIII activation by thrombin result in higher activity in a two stage Treatment Desmopressin 2-6 fold increase of FVIII level over baseline Prior to therapeutic use the magnitude and the half life of the FVIII response to desmopressin should be obtained Predictors of the magnitude of response to Desmopressin not well studied but the inderlying molecular defect seems to be important as The response tend to be similar within families There is reproductive pattern of response in patient with the same mutation Antifibrinolytic agent Inhibitor development Prevalence : 3-13% Missence mutation located in the region encoding light chain contribute to an unexpected high incidence of inhibitors. Arg2150 His, Arg593Cys, intensive perioperative factor VIII administration seems to be risk factor Inhibitor development Overall success of immune tolerance seems lower than the reported success in severe hemophilia A Available data are not sufficient to offer evidence based advice on the optimal treatment Maximal use of desmopressin, avoidance of intensive courses of treatment with FVIII concentrate hase to be considered Issues in the Aging person with hemophilia Cardiovascular disease: • Arteriosclerotic vascular disease similar to general population – Probably decreased risk of death from cardiovascular disease – Risk increased with high blood pressure, hepatitis C, HIV, Highly Active Anti Retroviral therapy • The hemophilia provider is challenged to balance the bleeding and clotting risk in individual patients when providing treatment Issues in the Aging person with hemophilia Cardiovascular disease: • Concensus Guidelines: – Avoidance of thrombolytic therapy – Use of bare metal stents for percutanous coronary intervention – Use of prophylaxis during dual antiplatelets therapy Issues in the Aging person with hemophilia Joint disease • Increased disability • Pain control issues • Osteoporosis – Role of secondary prophylaxis – Targeted physiotherapy – Reducing risk of fall Issues in the Aging person with hemophilia Joint disease • Joint replacement -Optimal timming? -Optimal factor replacement therapy? -Role of VTE prophylaxis? Renal disease Cancer Update on pathogenesis of the bleeding joint Recently it has been demonstrated that induced joint bleeds in haemophilic mice lead to elevation of pro-inflammatory cytokines (IL-1b, IL-6, KC and MCP-1) in the synovial fluid supporting the existence of an inflammatory synovial component in pathogenesis of haemophilic arthropathy. These released cytokines will have repercussions on cartilage integrity. Update on pathogenesis of the bleeding joint The devastating effects of joint bleeding are also evident independent of synovial inflammation. Exposure of cartilage tissue in vitro to whole blood (50% volume/volume) for 4 days leads to disturbance of cartilage matrix turnover. Even after a follow up period of 10 weeks matrix synthesis is still inhibited However, finally repair activity prevailed and cartilage damage vanished. Update on pathogenesis of the bleeding joint Preliminary results of recent studies demonstrated that sufficient repeated joint bleeds finally lead to persisting cartilage damage Disturbance of matrix turnover in the long-term is considered to be caused by apoptosis of the chondrocyte. Apoptosis of chondrocytes can be inhibited by addition of IL-10. Most recently it appeared that IL-4 has even more protective effects on blood induced cartilage damage than IL-10 Middle genicular artery embolisation in hemophilic children and adolescents A new treatment option for children with recurrent bleeding in the knee joint Methodology: occluding the single artery that goes intra-articular and nourishes the synovial membrane Relapses after embolisation were 60% from 1 month to 1.5 years. In 40% the amount of bleeding was much less and the frequency was reduced from 1 episode after 4 years to 2.2 episodes per year. Twenty percent of cases failed.