Congenital Bleeding Disorders-Diagnosis and Management (Dec 28, 2023)_(3031431553)_(Springer)

This significantly updated new edition describes in detail the clinical presentations, diagnosis, and management of a wide range of congenital bleeding disorders. It will assist readers in overcoming the significant challenges involved in clinical and laboratory diagnosis and in providing effective clinical care that makes optimal use of new products, including recombinant factor concentrate. The coverage ranges from hemophilia A and B and von Willebrand disease to rare bleeding disorders such as congenital factor V, factor X, factor XI, and factor XIII deficiency and inherited platelet function disorders. The exceptional attention to rarer conditions is of particular importance given the considerable risk of overlooking them during diagnosis, with potential consequences for disease-related morbidity and mortality. The authors are acknowledged specialists in the field from across the world who have particular expertise in the disorder that they discuss. The book will be of value to hematologists, oncologists, pediatricians, laboratory specialists and technicians, general physicians, and trainees. Foreword to the 1st Edition Preface Contents Introduction to the 1st Edition Part I: An Overview of Hemostasis and Congenital Bleeding Disorders 1: An Overview of Hemostasis 1.1 Introduction 1.2 Platelets 1.3 Platelet Surface Glycoproteins 1.3.1 Integrin αIIbβ3 (Glycoprotein IIb/IIIa) (CD41/CD61) 1.3.2 Glycoprotein Ib/V/IX (CD42 a–d) 1.3.3 Integrin α2β1 (Glycoprotein Ia/IIa) (CD49b/CD29) 1.3.4 Glycoprotein VI 1.3.5 Integrin α5β1 (Glycoprotein Ic/IIa) 1.3.6 Integrin αVβ3 (CD51/CD61) 1.4 Platelet Granules and Secretion 1.5 Endothelium 1.6 Coagulation Factors 1.7 RBC Contribution in Hemostasis 1.8 Anticoagulation Mechanisms 1.9 Fibrinolysis System References 2: Congenital Bleeding Disorders: Diagnosis and Management 2.1 Congenital Bleeding Disorders 2.2 Clinical Manifestations 2.3 Molecular Basis 2.4 Diagnosis 2.5 Diagnosis of Inherited Platelet Function Disorders (IPFDs) 2.6 Diagnosis of Glanzmann Thrombasthenia 2.7 Diagnosis of Bernard-Soulier Syndrome 2.8 Diagnosis of Gray Platelet Syndrome 2.9 Diagnosis of Von Willebrand Disease 2.10 Diagnosis of Congenital Factor Deficiency 2.11 Diagnosis of Congenital Fibrinogen Deficiency 2.12 Diagnosis of Prothrombin Deficiency 2.13 Diagnosis of Factor V Deficiency 2.14 Diagnosis of Factor VII Deficiency 2.15 Diagnosis of Factor VIII and IX Deficiency 2.16 Diagnosis of Factor X Deficiency 2.17 Diagnosis of Factor XI Deficiency 2.18 Diagnosis of Contact Coagulation Factor Deficiency 2.19 Diagnosis of Factor XIII Deficiency 2.20 Treatment References Part II: Common Bleeding Disorders 3: von Willebrand Disease: An Update on Diagnosis and Treatment 3.1 Introduction 3.2 von Willebrand Factor Synthesis, Structure, and Function 3.2.1 von Willebrand Factor Biosynthesis 3.2.2 von Willebrand Factor Structure 3.2.3 Disulfide Bridging and Multimerization of von Willebrand Factor 3.2.4 Post translational Modifications of von Willebrand Factor 3.2.5 Intracellular Storage and Secretion of VWF 3.2.6 Biological Activities of von Willebrand Factor 3.2.6.1 Interaction of von Willebrand Factor with Extracellular Protein 3.2.7 Interaction of von Willebrand Factor with Glycoprotein Ibα 3.2.8 Stabilization and Transport of Coagulation Factor VIII 3.2.9 Interaction of von Willebrand Factor with Integrin αIIbβ3 (GPIIb/IIIa) 3.3 von Willebrand Disease 3.3.1 Type 1 von Willebrand Disease 3.3.2 Type 2 von Willebrand Disease 3.3.2.1 Type 2A von Willebrand Disease 3.3.2.2 Type 2B von Willebrand Disease 3.3.2.3 Type 2M von Willebrand Disease 3.3.2.4 Type 2N von Willebrand Disease 3.3.2.5 Type 3 von Willebrand Disease 3.4 Clinical Manifestations 3.5 Diagnosis of von Willebrand Disease 3.6 Molecular Basis of von Willebrand Disease 3.7 Treatment of von Willebrand Disease 3.7.1 Desmopressin 3.7.2 von Willebrand Factor Concentrates 3.7.3 Recombinant von Willebrand Factor 3.7.4 Prophylaxis 3.7.5 Surgery 3.7.6 Pregnancy and Delivery References 4: Hemophilia A: Diagnosis and Management 4.1 Introduction 4.2 Factor VIII Structure and Function 4.3 Hemophilia A 4.4 Clinical Manifestations 4.4.1 Molecular Basis 4.4.2 Factor VIII Gene Mutations 4.4.3 Intron 22 Inversion 4.4.4 Insertions and Deletions in the Factor VIII Gene 4.4.5 Diagnosis 4.4.6 Chromogenic Assay 4.5 One-Stage Assay 4.5.1 Benefits of the One-Stage Methodology 4.5.2 Limitations of the One-Stage Assay 4.5.3 Discrepancy Between Chromogenic and One-Stage Assays 4.5.4 Determination of Factor VIII Concentrates Potency 4.5.5 Treatment 4.5.6 Replacement Therapy 4.5.7 Treatment of Hemarthrosis 4.5.8 Management of Bleeding 4.5.9 Adjunctive Management 4.5.10 Anti-Inflammatory Treatment 4.5.11 Rest, Ice, Compression, and Elevation (RICE) 4.5.12 Physiotherapy 4.5.13 Joint Aspiration 4.5.14 Surgical Treatments 4.5.15 Joint Debridement 4.5.16 Joint Arthroplasty 4.5.17 Fusion (Arthrodesis) 4.5.18 Treatment in Hemophilia Carriers 4.5.19 Problems Related to Treatment of Hemophilia 4.5.20 Viral Infections 4.5.21 Inhibitor 4.5.22 Inhibitor Associated Risk Factors 4.6 Inhibitor Evaluation 4.6.1 Treatment in Patient with Inhibitor 4.6.2 The Treatment Lines 4.6.3 Treatment of Bleeding in the Presence of Inhibitor 4.6.4 Bypassing Therapy Products 4.6.5 Salvage Treatment 4.6.6 Mouth Care in Hemophilia 4.6.7 Bleeding Prevention Strategy 4.7 Gene Therapy 4.7.1 The Gene Replacement by an Ex Vivo or in Vivo Approach 4.7.2 Advantages of Lentivirus (LV) Transduction 4.8 Adeno Associated Virus Gene Therapy for Hemophilia A 4.8.1 Other Proposed Approaches References 5: Hemophilia B: Diagnosis and Management 5.1 Introduction 5.2 Factor IX Structure and Function 5.3 Hemophilia B 5.4 Molecular Basis 5.5 FIX Propeptide Mutation-Associated Hypersensitivity to Coumarin Therapy 5.6 Clinical Manifestations 5.7 Diagnosis 5.8 Treatment 5.9 Inhibitor Formation: A Challenge of Replacement Therapy 5.10 Gene Therapy References Part III: Rare Bleeding Disorders 6: Congenital Fibrinogen Disorders, Diagnosis, and Management 6.1 Introduction 6.2 Classification 6.3 Diagnosis 6.4 Genetics 6.5 Clinical Features 6.6 Management References 7: Congenital Prothrombin Deficiency: Diagnosis and Management 7.1 Introduction 7.2 Coagulation Factor II (Prothrombin) Structure 7.3 Synthesis of Prothrombin 7.4 Thrombin Generation 7.5 Hemostatic Roles of Thrombin 7.5.1 Fibrin Formation 7.5.2 Factor XIII Activation 7.5.3 Factor V and Factor VIII Activation 7.5.4 Thrombin-Activated Fibrinolysis Inhibitors 7.5.5 Platelet Activation 7.5.6 Protein C Activation 7.6 Congenital Factor II (Prothrombin) Deficiency 7.7 Acquired Prothrombin and Thrombin Deficiency 7.8 Clinical Manifestations 7.9 Molecular Basis of Congenital Prothrombin Deficiency 7.10 Laboratory Diagnosis 7.10.1 Measurement of Factor II Activity 7.10.1.1 PT- Based One-Stage Assay 7.10.1.2 Chromogenic Assay 7.11 Determination of Factor II Antigen Level 7.12 Factor II Inhibitor Assay 7.12.1 Bethesda Assay 7.13 Treatment References 8: Congenital Factor V Deficiency, Diagnosis, and Management 8.1 Introduction 8.2 Factor V Structure and Function 8.3 Factor V Activation and Inactivation 8.4 Role of Factor V in the Coagulation Cascade 8.5 Congenital Factor V Deficiency 8.6 Clinical Manifestations 8.7 Quebec Platelet Disorder 8.8 Acquired Factor V Deficiency 8.9 Molecular Basis of Congenital Factor V Deficiency 8.10 Diagnosis 8.10.1 Factor V Antigen Assay 8.10.2 Factor V Activity Assay 8.10.3 One Stage PT-Based Assay 8.10.4 Factor V Inhibitor Assay 8.10.5 Mixing Study 8.10.6 Bethesda Assay 8.11 Treatment References 9: Combined Factor V and Factor VIII Deficiency, Diagnosis, and Management 9.1 Comparative Characteristics of Coagulation Factors V and VIII 9.2 Combined Factor V and Factor VIII Deficiency 9.3 Etiology and Pathogenesis 9.4 Clinical Manifestations 9.5 Diagnosis 9.6 Molecular Basis and Diagnosis 9.7 Genotype-Phenotype Correlation 9.8 Management 9.9 Family Planning, Pregnancy, Childbirth References 10: Vitamin K-Dependent Coagulation Factors Deficiency, Diagnosis, and Management 10.1 Introduction 10.2 Structure and Function of GGCX and VKOR 10.2.1 Vitamin K Cycle 10.3 Vitamin K-Dependent Coagulation Factors Deficiency 10.4 Clinical Manifestations 10.5 Molecular Basis 10.6 Diagnosis 10.7 Management References 11: Congenital Factor VII Deficiency, Diagnosis, and Management 11.1 Introduction 11.2 Factor VII Structure and Function 11.3 Congenital Factor VII Deficiency 11.4 Acquired Factor VII Deficiency 11.5 Clinical Manifestations 11.6 Laboratory Approach to Congenital Factor VII Deficiency 11.6.1 Primary Tests for Diagnosis of FVII Deficiency 11.7 Differential Diagnosis 11.8 Functional Assays of FVII 11.8.1 The One Stage PT-Based FVII Activity Assay 11.8.2 The Chromogenic Factor VII Assay 11.9 Activated Factor VII Assay 11.9.1 The Clotting-Based Activated Factor VII Assay 11.9.2 Chromogenic-Based Activated FVII Assays 11.10 Immunological Assay of Factor VII 11.11 Molecular Basis 11.12 Management References 12: Congenital Factor X Deficiency, Diagnosis, and Management 12.1 Introduction 12.2 Factor X Structure and Function 12.3 Factor X Activation 12.4 Regulation of Factor X Activity 12.4.1 Factor X Gene 12.5 Congenital Factor X Deficiency (FXD) 12.5.1 Prevalence/Inheritance 12.6 Classification 12.7 Clinical Manifestations 12.8 Diagnosis 12.8.1 History Taking and Clinical Evaluation 12.8.2 First-Line Screening Tests (Primary Assays) 12.8.2.1 Russell Viper Venom FX Assay 12.8.2.2 The Principle of the Russell Viper Venom FX Assay 12.8.3 Specific Coagulation Assays 12.8.3.1 Functional Assays 12.8.3.2 The Principle of the One Stage PT-Based FX Activity Assay 12.8.3.3 Chromogenic Assays 12.8.3.4 The Principle of the Chromogenic FX Assay 12.8.3.5 Immunological Assays 12.8.3.6 The Principle of the Enzyme-Linked Immunosorbent Assay (ELISA) 12.9 Important Points 12.9.1 Molecular Diagnosis 12.9.1.1 F10 Gene Mutations and Its Clinical Significance/Genotype Phenotype Correlation 12.10 Prenatal Diagnosis (PND) 12.11 Diagnosis of Acquired Factor X Deficiency 12.12 Treatment 12.12.1 Antifibrinolytic Agents 12.12.2 Blood-Derived Products 12.12.2.1 Nonspecific FX Replacement Therapy 12.12.3 Factor IX/X Products 12.12.3.1 Specific Factor X Products 12.12.3.2 TEN01 12.12.3.3 TEN02 12.12.3.4 TEN03 12.12.3.5 TEN05 12.13 Management of Factor X Deficiency in Surgery 12.14 Treatment in Women: Pregnancy, Delivery, and Menorrhagia 12.14.1 Factor X Deficiency in Pregnancy 12.14.2 Recommendation for Management of Women with FX Deficiency 12.15 Prophylaxis 12.16 Intracranial Hemorrhage (ICH) 12.17 Prognosis 12.18 Acquired Factor X Deficiency 12.19 Management of Acquired Factor X Deficiency 12.20 Autoimmune Factor X Deficiency and Factor X Inhibitors References 13: Congenital Factor XI Deficiency, Diagnosis and Management 13.1 Introduction 13.2 Factor XI Structure 13.3 Factor XI Activation and Function 13.4 Factor XI Deficiency 13.5 Molecular Basis 13.6 Clinical Manifestations 13.7 Laboratory Diagnosis of Factor XI Deficiency 13.7.1 Overview 13.7.1.1 Functional Assay The One-Stage APTT-Based FXI Activity Assay The Chromogenic Factor XI Assay Factor XII-Inhibited Dilute Thromboplastin Time 13.7.1.2 Immunological Factor XI Assay 13.8 Global Hemostasis Assays 13.9 Molecular Diagnosis 13.10 Recommendations and Precautions in Laboratory Investigation 13.11 Treatment References 14: Congenital Factor XIII Deficiency, Diagnosis, and Management 14.1 Introduction 14.2 Classification 14.3 Clinical Manifestations 14.4 Molecular Basis 14.5 Diagnosis 14.6 Management References Part IV: Inherited Platelet Function Disorders 15: Glanzmann Thrombasthenia: Diagnosis and Management 15.1 Introduction 15.2 Integrin αIIbβ3 (GPIIb/IIIa) Structure and Function 15.2.1 Biosynthesis Pathway 15.2.1.1 Integrin αIIbβ3 (GPIIb/IIIa) Structure 15.2.1.2 αIIb (GPIIb) Subunit 15.2.1.3 β3 (GPIIIa) Subunit 15.2.1.4 Ligand Binding to αIIbβ3 15.2.1.5 Signaling Pathway for αIIbβ3 (GPIIb/IIIa) Activation 15.2.2 Integrin αIIbβ3 Antagonists 15.3 Glanzmann Thrombasthenia 15.3.1 General Overview 15.3.2 Clinical Manifestations 15.3.3 Molecular Basis 15.3.3.1 The ITGA2B and ITGB3 Genes Mutations Mutations Affecting the αIIb Subunit KW-Milwaukee Patient SK I and SK II Patient LM Patient UP Patient KJ Patient Iranian Patient Tunisian Patients Turkish Patients Swiss Patient Kosovo Patient Caucasian Patient Caucasian Patient Arabs and Caucasian Patients Mutations Affecting the β3 Subunit Strasbourg I Variant ET Variant Cam Variant German Patients German (Mother) Jugoslav (Father) Patient Caucasian Patient 15.4 Diagnosis of GT 15.4.1 General Overview 15.4.2 Laboratory Diagnosis 15.4.2.1 Primary Tests Platelet Count and Peripheral Blood Smear Routine Coagulation Tests (Activated Partial Thromboplastin Time, Prothrombin Time, Thrombin Time, Bleeding Time) Closure Time/PFA-100®/200® 15.4.2.2 Platelet Aggregation Studies General Overview Light Transmission Aggregometry (LTA) Platelet Concentration and Adjustment Concentration of Agonists Interfering Variables 15.4.2.3 Luminaggregometry and Whole Blood Aggregometry General Overview Multiple Electrode Aggregometry/Impedance Whole Blood Aggregometry Optimal 96-Well Plate-Based Aggregometry 15.4.2.4 Flow Cytometry Variant Glanzmann’s Thrombasthenia Detection by Flow Cytometry Advantages and Disadvantages of Flow Cytometry 15.4.2.5 Clot Retraction Assay Other Platelet Studies 15.4.2.6 Genetic Analysis 15.4.3 Differential Diagnosis 15.4.4 Treatment 15.4.4.1 Local Measures and/or Antifibrinolytic Drugs 15.4.4.2 Systemic Hemostatic Management Platelets Concentrate Platelet Refractory Activated Recombinant Factor VII Mechanism of Action of rFVIIa 15.4.4.3 Surgical Management Minor Surgery Major Surgery 15.4.4.4 Hematopoietic Stem Cell Transplantation 15.4.4.5 Gene Therapy References 16: Bernard-Soulier Syndrome: Diagnosis and Management 16.1 Introduction 16.2 Glycoprotein Ib-IX-V Complex 16.2.1 Structure and Function 16.3 Bernard–Soulier Syndrome 16.4 Molecular Basis 16.5 Clinical Manifestations 16.6 Diagnosis 16.7 Differential Diagnosis 16.8 Management References 17: Gray Platelet Syndrome: Diagnosis and Management 17.1 Introduction 17.2 Clinical Manifestations 17.3 Molecular Basis 17.4 Laboratory Diagnosis 17.4.1 Primary Tests 17.4.1.1 Platelet Count and Peripheral Blood Smear 17.4.1.2 Routine Coagulation Tests (Activated Partial Thromboplastin Time, Prothrombin Time, Thrombin Time, and Bleeding Time) 17.4.2 BM Analysis 17.4.3 Myelofibrosis 17.4.3.1 Emperipolesis 17.4.4 Electron Microscopy 17.4.5 Light Transmission Aggregometry 17.4.6 Analysis of Platelet Lysate 17.4.7 Platelet Secretion Assays 17.4.7.1 Laboratory Assays for α-Granule Release Measurement of PF4 and β-TG Assessment of Platelet Surface P-Selectin 17.4.8 Serum Vitamin B12 Assessment 17.4.9 Genetic Analysis 17.4.10 Management of Patients with GPS 17.5 Concluding Remarks References