Advances in Hemophilia Treatment: From Genetics to Joint Health

Description

This book offers a comprehensive and state of the art overview of hemophilia management by reviewing all most recent advances and cutting edge information in this fast evolving field. As hemophilia patients are often affected by joint problems it also provides clear guidance on the surgical treatment of musculo-skeletal manifestations. The first part is devoted to the disease’s pathophysiology (differentiating hemophilia A and B), genetics, pharmacotherapy – including replacement and non-replacement therapy – and gene therapy, as well as quality of life issues – also related to hemophilia carriers. The second part is then focused on joint problems, ranging from joint health assessment and pain control to surgical treatment of acute hemarthrosis and hemophilic arthropathy, i.e. radiosynovectomy, total joint arthroplasty and arthroscopic joint debridement. Written by experts drawn from leading institutions involved in treatment of hemophilia and related joint problems, this book offers a valuable resource to hematologists, orthopedic surgeons, rehabilitation physicians, radiologists, and pharmacy researchers. Preface Contents 1: Pathophysiology of Hemophilia 1.1 Introduction 1.2 Pathophysiology of Hemophilia 1.3 Pathophysiology of Hemophilic Arthropathy 1.3.1 Joint Bleeding 1.3.2 Synovitis 1.3.3 Cartilage Degeneration 1.3.4 Bone Damage 1.3.5 Vascular Development and Angiogenesis 1.4 Conclusions References 2: Genetics of Hemophilia A and B 2.1 Introduction 2.2 History of Hemophilia 2.3 Types of Hemophilia 2.4 Inheritance of Hemophilia 2.5 Molecular Genetics of Hemophilia A 2.6 Molecular Genetics of Hemophilia B 2.7 Conclusions References 3: Inhibitors in Hemophilia A 3.1 Introduction 3.2 Concept of Inhibitor 3.3 Etiopathogenesis of Inhibitors 3.4 Laboratory Diagnosis of Inhibitors 3.5 Management 3.5.1 Prophylaxis in Inhibitor Patients 3.5.2 Treatment of Bleeding Episodes 3.5.2.1 Activated Prothrombin Complex Concentrate (aPCC, FEIBA™) Mechanism of Action of FEIBA Clinical Efficacy of FEIBA 3.5.2.2 Recombinant Factor VII Activated (rFVIIa) Background Mechanism of Action Clinical Efficacy of rFVIIa 3.5.2.3 Effectiveness Comparison: FEIBA Versus rFVIIa 3.6 Future 3.7 Conclusions References 4: Immune Tolerance Induction in Patients with Hemophilia A 4.1 Introduction 4.2 Immune Tolerance Induction (ITI) in Patients with Severe Hemophilia A 4.2.1 Definition and Objective of ITI 4.2.2 Prognostic Factors to Achieve Immune Tolerance 4.2.3 Immune Tolerance Regimen 4.2.4 Immune Tolerance in Patients on Prophylaxis Regimen with Emicizumab 4.3 Immune Tolerance in Patients with Mild or Moderate Hemophilia 4.4 Conclusions References 5: Hemophilia A: New Drugs 5.1 Introduction 5.2 Extended Half-Life Factor VIII Products 5.2.1 Efmoroctocog Alfa, rFVIIIFc 5.2.2 Rurioctocog Alfa Pegol, BAX 855 5.2.3 Damoctocog Alfa Pegol, BAY94–9027 5.2.4 Turoctocog Alfa Pegol, N8GP 5.2.5 FVIII-VWF-XTEN, BIVV001 5.3 Non-replacement Therapy 5.3.1 Emicizumab 5.3.2 Concizumab 5.3.3 Fitusiran 5.4 Conclusions References 6: Inhibitors in Hemophilia B 6.1 Introduction 6.2 Epidemiology 6.3 Pathophysiology 6.4 Allergic and Anaphylactic Reactions 6.5 Clinical and Laboratory Follow-Up 6.6 Treatment 6.7 New Therapeutic Approaches 6.7.1 Gene Therapy (GT) 6.7.2 Other Molecules 6.8 Conclusions References 7: Immune Tolerance Induction in Hemophilia B 7.1 Introduction 7.2 Epidemiology 7.3 Immunology of FIX Inhibitors 7.4 Allergic Reactions, Anaphylactic Reactions, and Nephrotic Syndrome 7.5 Management of Patients with Hemophilia B with Inhibitors 7.5.1 Treatment and Prevention of Bleedings 7.5.2 Immune Tolerance Induction Treatment 7.5.2.1 Outcome of Immune Tolerance Induction 7.5.2.2 Predictors of Outcome of Immune Tolerance Induction 7.6 Future Directions 7.7 Conclusions References 8: Hemophilia B: New Drugs 8.1 Introduction 8.2 Extended Half-life (EHL) Factor IX Products 8.2.1 Albutrepenonacog Alfa, rFIX-FP 8.2.2 Nonacog Beta Pegol, N9-GP 8.2.3 Eftrenonacog Alfa, rFIXFc 8.3 Conclusions References 9: Management of Hemophilia Carriers 9.1 Introduction and Epidemiology 9.1.1 Definition of a “Carrier” 9.2 Symptoms 9.2.1 Surgeries 9.2.2 Pregnancy 9.2.3 Other Types of Bleeding 9.3 Diagnosis 9.4 Bleeding Tools: The International Society on Thrombosis and Hemostasis (ISTH)-Bleeding Assessment Tool (BAT) 9.5 Treatment 9.6 Conclusion References Suggested Reading 10: Pharmacoeconomic Aspects in Hemophilia 10.1 Introduction 10.2 Economic Evaluations in Healthcare 10.3 Types of Economic Evaluations 10.4 Costs of Prophylaxis in Hemophilia 10.5 Costs of Orthopedic Surgery in Patients with Hemophilia 10.6 Quality and Cost of Drug Replacement Therapy Used During Orthopedic Surgeries in Patients with Hemophilia 10.7 Economic Evaluations as a Tool in Decision-Making 10.8 Pharmacoeconomy and Health Management in the Pharmacological Treatment of Hemophilia 10.9 Conclusions References 11: Assessment of Joint Health and Outcome Measures in Hemophilia 11.1 Introduction 11.2 Joint Health and Outcome Assessment Tools in Hemophilia 11.2.1 Body Structure and Function 11.2.1.1 Annual Joint Bleeding Rate (AJBR) 11.2.1.2 Pain Assessment in Hemophilia 11.2.1.3 Physical Examination Measurements 11.2.1.4 Imaging Tests Ultrasound Radiology Magnetic Resonance Imaging (MRI) 11.2.2 Activities and Participation 11.2.3 Health-Related Quality of Life (HRQoL) 11.2.4 Patient-Reported Outcomes 11.2.5 Economic Factors 11.2.6 Other Measures 11.3 Which Tools to Choose? 11.4 Future Perspectives 11.5 Conclusions References 12: Musculoskeletal Medicine in Hemophilia (Including Pain Control) 12.1 Introduction 12.2 Musculoskeletal (MSK) Clinical Manifestations 12.2.1 Hemarthrosis 12.2.2 Chronic Synovitis 12.2.3 Osteochondral Damage: Hemophilic Arthropathy 12.2.4 Muscle Hematomas 12.2.5 Hemophilic Pseudotumor 12.2.6 Pain Management 12.2.6.1 Painkillers 12.2.6.2 Minimally Invasive Interventional Procedures 12.2.6.3 Physical Exercise 12.2.6.4 External Devices 12.2.6.5 Other Modalities 12.2.7 Osteoporosis 12.2.8 Age-Related Musculoskeletal (MSK) Comorbidities 12.3 Conclusions References 13: Management of Acute Hemarthrosis in Hemophilia (Including Joint Aspiration) 13.1 Introduction 13.2 Clinical Manifestations of Acute Bleeding 13.3 Treatment of Acute Hemarthrosis 13.3.1 Hematologic Treatment 13.3.2 Rest and Splinting 13.3.3 Ice 13.3.4 Analgesia 13.3.5 Joint Aspiration (Arthrocentesis) 13.3.6 Arterial Embolization 13.4 Conclusions References 14: Hemophilic Arthropathy: Radiosynovectomy 14.1 Introduction 14.2 Indications for Radiosynovectomy 14.3 Radiosynovectomy in Patients with Inhibitors 14.4 Technique of Radiosynovectomy 14.5 Effect of the Radioactive Material on the Synovium 14.6 Efficacy of Radiosynovectomy 14.7 Complications of Radiosynovectomy 14.8 Safety of Radiosynovectomy 14.9 Conclusions References 15: Hemophilic Arthropathy: Arthroscopic Joint Debridement 15.1 Introduction 15.2 Arthroscopic Knee Debridement 15.3 Arthroscopic Ankle Debridement 15.4 Conclusions References 16: Hemophilic Arthropathy: Total Joint Arthroplasty 16.1 Introduction 16.2 Total Knee Arthroplasty 16.3 Total Hip Arthroplasty 16.4 Total Elbow Arthroplasty 16.5 Total Ankle Arthroplasty 16.6 Conclusions References 17: Hemophilic Arthropathy: Other Orthopedic Procedures 17.1 Introduction 17.2 Orthopedic Surgery of Complications of Intra-Articular Bleeds 17.2.1 Excision of the Radial Head and Partial Open Synovectomy 17.2.2 Surgical Ulnar Nerve Release 17.2.3 Ankle Distraction 17.2.4 Ankle Fusion 17.2.5 Surgical Lenghtening of the Achilles Tendon Associated with a Posterior Open Capsulotomy 17.3 Orthopedic Surgery of Complications of Intramuscular Bleeds 17.3.1 Compartment Syndromes 17.3.2 Hemophilic Pseudotumors 17.4 Fractures 17.5 Conclusions References 18: Gene Therapy in Hemophilia: Latest Developments 18.1 Introduction 18.1.1 History of Gene Therapy 18.1.2 Gene Editing 18.1.3 Gene Transfer 18.1.4 Immunogenicity 18.1.5 History of Gene Therapy in Hemophilia 18.2 Genetic Therapy in Hemophilia A 18.3 Genetic Therapy in Hemophilia B 18.4 Risks to Genetic Therapy 18.5 Ethics in Gene Therapy 18.5.1 Expecting the Unexpected 18.5.2 Cost/Genomic Justice 18.6 CRISPR + Somatic vs. Germline Mutations 18.7 Conclusions References 19: A Summary of the Recent Recommendations of the World Federation of Hemophilia 19.1 Introduction 19.2 Fundamentals of Management 19.3 Hemostatic Products 19.4 Acute and Emergency Management of Bleeds 19.5 Prophylaxis (Regular Replacement Therapy) 19.6 Management of PWH with Inhibitors 19.7 Treatment of Musculoskeletal Adverse Events 19.8 Management of Specific Problems and Comorbidities 19.8.1 Carriers of Hemophilia 19.8.2 Surgery and Other Invasive Techniques 19.8.3 Treatment of Comorbidities 19.8.4 Medical Problems with Aging 19.8.5 Management of Transfusion-Transmitted Infections 19.9 Central Venous Access Devices 19.10 Pain Management 19.11 Dental Care 19.12 Genetic Counseling 19.13 Circumcision 19.14 Vaccination 19.15 Psychosocial Matters 19.16 Outcome Evaluation 19.17 Conclusions Reference