Hemostatic Management in an Infant With Neuroblastoma and Severe Hemophilia B With Extended Half-life Recombinant Factor IX Fusion Protein.

In the rare co-occurrence of childhood cancer and severe hemophilia, hemostatic management is of paramount therapeutic importance. We present the case of an 11-month-old boy with severe congenital hemophilia B, who was diagnosed with metastatic high-risk neuroblastoma. He consequently developed paraneoplastic coagulopathy with life-threatening tumor hemorrhage and intracranial hemorrhage, showing central nervous system relapse. Management consisted of factor IX replacement with extended half-life factor IX fusion protein, adjusted to bleeding risk. Additional interventions included factor XIII, fibrinogen, fresh frozen plasma, tranexamic acid, and platelet transfusions. The half-life of factor IX products was markedly reduced requiring close factor IX monitoring and adequate replacement. This intensified treatment allowed chemotherapy, autologous stem cell transplantation, and GD2 antibody immune therapy without bleeding or thrombosis.

Continuous infusion factor replacement in haemophilia B during and after cardiac surgery: the better choice?

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%-100% for post-op days (PODs) 0-3, and at 60%-80% for PODs 4-14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:Dosage needed=%(desired FIX level-current level of FIX)×weight (kg)×1.3.This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18-24 hours. The rFIX infusion was started intraoperatively and continued after surgery to maintain target FIX activity. He was discharged on POD 9 on rFIX bolus dosing of 5000 IU every 12 hours for an additional 5 days. Using continuous factor infusion, we managed to decrease the amount rFIX used by >60% while maintaining steady state FIX activity level.

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates.

Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.

Hemophilia in a Changing Treatment Landscape.

The mainstay of hemophilia management has been the regular, prophylactic infusion of missing coagulation factors VIII/IX. This approach is limited by the need for frequent intravenous infusions, high cost, limited availability, and the development of inhibitory antibodies to factors VIII/IX. Numerous recent breakthroughs are addressing many of these limitations. These include the development of extended half-life factors that require less frequent infusions and the development of various novel agents that can be given subcutaneously and infrequently, including FVIII-mimetic antibody and downregulators of natural anticoagulants. Finally, gene therapy is set to offer patients a possibility for a cure.

El trasplante de hígado es un procedimiento plausible, efectivo y seguro en pacientes con hemofilia: caso clínico / Liver transplantation in hemophilia A: report of one case

Due to blood derivative requirements, many patients with hemophilia were exposed to Hepatitis C virus infection (HCV) before the availability of HCV testing. We report a 46-year-old male with Hemophilia A with a hepatitis virus C infection since 2004 causing a cirrhosis. Due to a hepatopulmonary syndrome, he received a liver allograph using a factor VIII replacement protocol, after eradicating the virus C. He had a good postoperative evolution, and no more factor VIII was required after transplantation until his last assessment.

Hemophilic pseudotumor of the mandible in a patient with hemophilia B.

INTRODUCTION: Hemophilic pseudotumor is a rare complication occurring in patients with hemophilia, frequently seen in the femur, tibia, pelvic bones, iliac bones, or rarely in the maxillofacial region. CASE REPORT: A 7-year-old male reported with a spontaneous extra-oral swelling that was managed with pre-operative transfusion of factor IX along with curettage of the lesion. Our report presents only the fourth case in literature wherein this tumor presented in a patient with hemophilia B. FINDING: Hemophilic pseudotumor is a rare entity in the maxillofacial region. High degree of suspicion is required for diagnosis, and close coordination between the medical and surgical teams aids in management.

Alfanonacogue - Benefix® para hemofilia B em pacientes menores de 19 anos de idade / Alfanonacogue - Benefix® for hemophilia B in patients younger than 19 years of age

CONTEXTO: As coagulopatias hereditárias são doenças hemorrágicas resultantes da deficiência quantitativa e/ou qualitativa de um ou mais fatores da coagulação e se caracterizam pela ocorrência de hemorragias de gravidade variável, de forma espontânea e/ou pós-traumática. Segundo dados de 2014 do Sistema Hemovida Web ­ Coagulopatias do Ministério da Saúde, o número de pacientes com Hemofilia B era de 1.881 no Brasil. Como não há cura para as hemofilias, os objetivos de tratamento são prevenir e tratar hemorragias de modo a evitar artropatias incapacitantes e dano tecidual, e melhorar a qualidade de vida e a sobrevida. As modalidades de tratamento da hemofilia B são definidas pela periodicidade com que é realizada a reposição dos fatores de coagulação IX, podendo ser sob demanda (episódico) ou profilático. O fator IX de origem plasmática faz parte do rol de tecnologias ofertada pelo SUS para o tratamento de Hemofilia B. TECNOLOGIA: Alfanonacogue (Benefix®). INDICAÇÃO: Controle e prevenção de episódios hemorrágicos e para profilaxia de atividades rotineiras e cirúrgicas de pacientes com hemofilia B, menores de 19 anos de idade. PERGUNTA: O uso do Fator IX recombinante (BeneFIX®), além de tão eficaz quanto comparado às opções disponíveis atualmente no SUS, proporciona vantagens de segurança aos pacientes com Hemofilia B? EVIDÊNCIAS CIENTÍFICAS: Os estudos apresentados pelo demandante demonstram a eficácia do medicamento Benefix em aumentar a atividade de FIX e controlar sangramentos. Entretanto, não foi apresentado estudo de eficácia que comparasse os fatores IX plasmático e recombinante, o que impossibilita posicionar o fator IX recombinante como igual, melhor ou pior do que o fator IX plasmático ofertado pelo SUS. Apenas um estudo retrospectivo comparou o fator IX plasmático (medicamento atualmente ofertado pelo SUS) com o fator IX recombinante, e concluiu que a frequência de reações alérgicas e do desenvolvimento de inibidores entre os pacientes que receberam ambos os fatores IX foi bem similar (Recht et al., 2011). Na revisão sistemática incluída pelo DGITS sobre tipos e frequência das reações adversas - não trombóticas e não associadas a inibidor - relacionadas aos fatores de coagulação utilizados em pacientes com hemofilia A, hemofilia B e doença de von Willebrand, os autores concluíram que os dados por eles apresentados confirmam o elevado grau de segurança dos produtos atualmente utilizados para terapia de hemofilia A e B e doença da von Willebrand (Franchini et al., 2012). Assim, até o momento, não há comprovação de que os fatores IX de origem plasmática utilizados atualmente pelo SUS confiram algum risco conhecido e quantificável aos pacientes quando comparados ao Fator IX recombinante. AVALIAÇÃO ECONÔMICA: Na análise de custo-minimização, foram encontrados os seguintes custos incrementais: profilaxia primária - R$ 474.978,00; cirurgia de médio porte - R$ 27.802,00; tratamento de sangramentos espontâneos - R$ 5.014,00. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário de R$ 728 milhões a aproximadamente R$ 1,01 bilhão de reais considerando o horizonte de tempo de 5 anos possivelmente está subestimado e não se justifica frente falta de evidência de superioridade em termos de eficácia e segurança do Fator IX recombinante em relação ao Fator IX plasmático. RECOMENDAÇÃO INICIAL: Os membros presentes na reunião do plenário da Conitec realizada no dia 10 de novembro deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável a incorporação do alfanonacogue (fator IX recombinante) para o tratamento da Hemofilia B. Tal recomendação foi embasada na falta de evidências que demonstrem superioridade do medicamento Benefix frente à tecnologia já disponível no tratamento da hemofilia B, e assim, sendo, não se justificaria o impacto orçamentário apresentado. CONSULTA PÚBLICA: Foi recebido um total de 155 contribuições, sendo 146 contribuições provenientes do formulário de experiência/opinião e 9 do formulário técnico-científico. Nenhuma das contribuições apresentou evidências de superioridade do fator IX recombinante em relação ao plasmático. RECOMENDAÇÃO FINAL: Os membros presentes na reunião do plenário da Conitec realizada no dia 08 de março de 2017 mantiveram a recomendação desfavorável a incorporação do alfanonacogue (fator IX recombinante) para o tratamento da Hemofilia B. DECISÃO: Não incorporar o alfanonacogue para hemofilia B em pacientes menores de 19 anos de idade, no âmbito do Sistema Único de Saúde - SUS, dada pela Portaria nº 17, publicada no DOU nº 77, do dia 24 de abril de 2017, seção 2, pág. 57.(AU)

Biodegradable hydrophilic carriers for the oral delivery of hematological factor IX for hemophilia B treatment.

Current protein replacement therapies for hemophilia B, a genetic bleeding disorder caused by a deficiency in coagulation factor IX, rely on IV injections and infusions. Oral delivery of factor IX is a desirable needle-free option, especially for prophylaxis. We have developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)]. Incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine. P(MAA-g-EG) polymer was synthesized by UV polymerization, and then subsequently crosslinked with peptide crosslinking agent using EDC-NHS chemistry. Physical characterization included FTIR for determining the composition of the peptide crosslinked polymer and SEM for microparticle morphology. The pH-responsive swelling and enzyme-specific degradation were confirmed by bright-field microscopy and the corresponding kinetics were determined by turbidimetric measurements. Evaluating the drug delivery application of this degradable system, factor IX release studies showed site-specific release, and in vitro transport studies resulted in improved factor IX absorption. Incorporation of the degradable crosslinking agent significantly improved the delivery potential as compared to previously reported non-degradable drug delivery systems. Using this degradable P(MAA-g-EG) system as a delivery vehicle for factor IX can possibly lead to an orally administered prophylactic treatment for hemophilia B patients.

Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigm™4).

INTRODUCTION: Paradigm™4 was an international extension trial investigating the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in haemophilia B patients (FIX activity ≤2%; aged 13-70years) who had previously participated in phase III pivotal (paradigm™2) or surgery (paradigm™3) trials. METHODS: Patients chose to continue treatment with nonacog beta pegol in either one of two once-weekly prophylaxis arms (10IU/kg or 40IU/kg), or an on-demand arm (40IU/kg for mild/moderate bleeds; 80IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity; key secondary objectives included assessing safety and haemostatic efficacy in the treatment and prevention of bleeds. RESULTS: Seventy-one patients received prophylaxis or on-demand treatment. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The median annualised bleeding rate for patients on prophylaxis was 1.36 (interquartile range [IQR] 0.00-2.23) and 1.00 (IQR 0.00-2.03) for the 10 and 40IU/kg treatment arms, respectively. The mean FIX activity trough achieved for 10 and 40IU once weekly was 9.8% and 21.3%, respectively. Fourteen patients on prophylaxis underwent 23 minor surgical procedures; haemostatic perioperative outcomes for all of those evaluated were 'excellent' or 'good'. CONCLUSIONS: Nonacog beta pegol showed a favourable tolerability profile (with no safety issues identified) with good prophylactic protection and control of bleeding in previously treated adult and adolescent haemophilia B patients.

Thromboprophylaxis and Incidence of Venous Thromboembolism in Patients With Hemophilia A or B Who Underwent High-Risk Orthopedic Surgeries.

Total hip replacement (THR) and total knee arthroplasty (TKA) carry a high risk of postoperative venous thromboembolism (VTE); therefore, anticoagulation prophylaxis is recommended in these patients. Unfortunately, there are no guidelines about VTE prophylaxis in patients with hemophilia who underwent these high-risk surgeries. To determine whether these patients have high risk of VTE, we conducted a retrospective study on patients with hemophilia who underwent elective THR/TKA at our institute from 2004 to 2012. Postoperatively, we collected information on duration and method of factor VIII/IX infusion, VTE-prophylaxis, and complications. There were 23 patients with hemophilia, 18 (78%) with hemophilia A and 5 (22%) with hemophilia B, who underwent high-risk surgeries (39% THR and 61% TKA). The VTE prophylaxis included sequential compression device, 12 (52%), and prophylactic enoxaparin, 1 (4%). Ten (43%) patients did not receive VTE prophylaxis. At 1-year follow-up, we did not find any evidence of clinical VTE in our patients. Better risk stratification is needed to identify patients who would benefit from pharmacological prophylaxis.

Coronary artery bypass grafting in a patient with hemophilia B: continuous recombinant factor IX infusion as per the Japanese guidelines for replacement therapy.

We herein report our experience of successfully managing the hemostatic system by controlling serum factor IX levels throughout the perioperative period in a patient with hemophilia B. Coronary artery bypass grafting with cardiopulmonary bypass was planned for a 52-year-old man with moderate severity of hemophilia B. During surgery, recombinant factor IX (rFIX; BeneFIX(®) Pfizer Japan inc., Tokyo, Japan) was administered by bolus infusion followed by continuous infusion as per the guidelines of the Japanese Society on Thrombosis and Hemostasis. The operative course was uneventful without any considerable bleeding or complications.

Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.

BACKGROUND: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. OBJECTIVES: The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase and The Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 14 December 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardized forms. MAIN RESULTS: While there were no eligible trials in people with Von Willebrand disease identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of epsilon aminocaproic acid published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference of -0.64 (95% confidence interval -0.93 to - 0.36) and the EACA trial a risk difference of -0.50 (95% confidence interval 0.77 to -0.22). The combined risk difference of both trials was -0.57 (95% confidence interval -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping epsilon aminocaproic acid (combined risk difference of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the epsilon aminocaproic acid trial, but overall the risk of bias appeared to be low for both trials. AUTHORS' CONCLUSIONS: Despite the discovery of a beneficial effect of systemically administered tranexamic acid and epsilon aminocaproic acid in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with Von Willebrand disease.

Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-ß (TGF-ß) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses.

Long-acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B-LONG study.

In the phase 3 B-LONG (Recombinant Factor IX Fc Fusion Protein [rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half-life compared with recombinant factor IX (rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately-severe to severe haemophilia B. In this B-LONG sub-analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator-determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks-12 months). Investigators/surgeons rated haemostatic responses as excellent (n = 13) or good (n = 1). In most surgeries (85·7%), haemostasis from the pre-surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation (R(2) = 0·9586, P < 0·001) between observed and population pharmacokinetic model-predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics.

[CORRECTION OF HEMOSTASIS WITH BLOOD PRODUCTS IN THE SURGICAL TREATMENT OF CONGENITAL HEART DISEASE IN INFANTS AND YOUNG CHILDREN].

The article deals with the safety and efficiency of recombinant activated factor VII (Coagil VII, Russia) and prothrombin complex concentrate (protromplex-600, Baxter Austria) in the neonatal and pediatric cardiac surgery. The study included 56 children aged from 7 days to 5.5 years underwent surgery with cardiopulmonary bypass for congenital heart defects repair. Clinical and laboratory evidences suggest that Coagil VII and protromplex-600 effective for bleeding stop. The drugs have no negative impact on hemodynamics. We did not identify allergic reactions and thrombosis associated with the introduction of drugs in the pen operative period.

Current management of the hemophilic child: a demanding interlocutor. Quality of life and adequate cost-efficacy analysis.

Hemophilias are the most known inherited bleeding disorders. The challenges in the management of hemophilic children are different from those in adults: prophylaxis regimen removed the hallmark of crippling disease with lifelong disabilities; individualized regimens are being implemented in order to overcome venous access problems. Presently, at least in high-income countries, advances in treatment of hemophilia resulted in continuous improvement of the patients' quality of life and life expectancy. Inhibitors remain the most severe complication of hemophilia therapy. The treatment' compliance is the key to achieve a successful management. The patient, his family, the medical and psychological team are the players of a comprehensive care system. The current management of hemophilic children is the example of huge resource investments enabling long-term benefits in particular quality of life as a primary objective of the healthcare process.

Prophylaxis in real life scenarios.

Prophylaxis has become the standard mantra of care for those individuals with severe haemophilia A and B. Primary prophylaxis is advocated to prevent the occurrence of symptomatic acute spontaneous haemarthroses and to preserve joint structure and function. Typically, twice or thrice weekly infusions of factor VIII or IX concentrates are integral to this treatment approach. Secondary prophylaxis is initiated after the relentless cycle of progressive joint damage has been triggered by prior haemarthroses and is intended to preserve existing joint health by preventing additional spontaneous bleeding events. Event-driven prophylaxis involves the administration of clotting factor concentrates to prevent acute traumatic bleeds, which are anticipated to occur in association with surgical or physical trauma. This regimen enhances the effectiveness of primary or secondary prophylaxis protocols or on-demand approaches to replacement therapy. Besides the marked reduction in the so-called annual bleed rate, prophylaxis regimens frequently increase personal self-confidence to embark on a more active and physical lifestyle; however, in reality, prophylaxis must be individualized in accordance with bleeding phenotypes, with the unique pharmacokinetic profile of administered replacement clotting factor concentrates, with the specific clinical scenario, and with the degree of intensity anticipated for any physical activity. The introduction of extended half-life replacement products will also influence how these prophylaxis regimens will be accomplished. The following scenarios will discuss how prophylaxis regimens can be implemented to protect the individual from developing spontaneous and activity-induced acute bleeding complications and to maintain an improved quality of life.

[Prevention and treatment of major bleeding during anticoagulation].

To prevent major hemorrhage during anticoagulation, it is quite important to manage controllable risk factors such as hypertension, diabetes mellitus, smoking habit, and too much alcohol intake. It is also important to avoid dual antithrombotic therapy as long as possible, which increases severe bleeding events. For patients with major bleeding during anticoagulation, we should stop oral medication, stop bleeding by mechanical compression or surgical interventions, and maintain circulation blood volume and blood pressure by appropriate intravenous drip infusion. When intracranial hemorrhage happens, adequate treatment to suppress blood pressure should be provided. Administration of prothrombin complex concentrate (PCC) and vitamin K is effective for urgent reversal of anticoagulation by warfarin. The PCC may be also useful for that by novel oral anticoagulants.