Pathophysiology of Blood Disorders

ISBN-10: 0071713786
ISBN-13: 9780071713788
Edition: 2011
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Book details

List price: $64.95
Copyright year: 2011
Publisher: McGraw-Hill Medical Publishing Division
Publication date: 12/27/2010
Binding: Paperback
Pages: 352
Size: 7.00" wide x 9.00" long x 0.75" tall
Weight: 1.408
Language: English

Author Profiles Dr. Bunn and Dr. Aster are outstanding educators in blood diseases at Harvard Medical School. Dr Bunn is a former president of the American Society of Hematology, and has a great reputation among leading experts in hematology.

Overview of Blood and Hematopoietic Tissues (Aster and Bunn)
Impact of blood in health and disease
Red blood cell
White blood cells
Platelets
Blood clotting proteins
The bone marrow
The spleen
The thymus
Lymph nodes
Hematopoiesis and the Bone Marrow (Scadden)
Hematopoietic cell diffrerentiation
Myeloid lineage
Erythroid lineage
Megakaryocyte-platelet lineage
Lymphoid lineages - B, T, and NK cells
The biology of the stem cell
Self-renewal
Stem cell ontogeny
Stem cell trafficking
The regulation of blood cell formation
The bone marrow niche and cell-cell interactions
Cytokines in early hematopoietic differentiation
Lineage specific cytokines
Cytokine therapy
Stem cell therapy
Anemias and Disorders of the Red Blood Cell
Overview of the Anemias (Bunn) (See full sample chapter)
Definition of anemia
Adaptations to anemia
Alterations in blood flow
Changes in oxygen unloading
Stimulation of erythropoiesis
Signs and symptoms of anemia
Pathophysiology of anemia
Anemia due to blood loss
Anemia due to decreased red cell production
Microcytic
Macrocytic
Normocytic
Anemia due to increased red cell destruction
Anemias due to Bone Marrow Failure or Infiltration (Bunn)
Congenital causes of bone marrow failure
Acquired aplastic anemia and pure red cell aplasia
Myelophthisis
Myelodysplasia
Leukemias (Myelodysplasia and the leukemias will be covered in detail in Chapters 21 and 22)
Iron Homeostasis: Deficiency and Overload (Heeney)
Normal iron homeostasis
Iron binding proteins: transferrin; ferritin
The iron cycle
Role of hepcidin in iron regulation
Iron utilization in erythropoiesis
Laboratory evaluation of iron status
Serum iron and transferrin saturation
Serum ferritin
Bone marrow and liver iron stores
Serum transferrin receptor
Iron deficiency
Etiology
Clinical features - signs and symptoms
Hematological features
Treatment
Iron overload
Primary - inherited mutations in proteins regulating iron homeostasis
Secondary - transfusional hemosiderosis
Megaloblastic Anemias (Heeney)
Biochemistry of vitamin B12 and folate
Pathophysiology
Megaloblastic marrow and peripheral blood morphology
Vitamin B12 and folate absorption
B12 deficiency
Etiology
Clinical presentation (signs and symptoms)
Laboratory evaluation
Treatment
Folate deficiency
Etiology
Clinical presentation (signs and symptoms)
Laboratory evaluation
Treatment
Anemias associated with Chronic Disease (Heeney and Bunn)
Anemia of chronic inflammation
Infection
Cancer
Connective tissue disorders
Pathophysiology - role of hepcidin
Lab features
Treatment
Anemia of renal insufficiency
Cause
Erythropoietin levels
Treatment with erythropoietin and iron
Anemia of chronic liver disease
Anemia of endocrine hypofunction
Thalassemia (Nathan)
Ontogeny of globin gene expression
Organization of alpha and beta globin genes
Definition and classification of the thalassemias
Mutations responsible for the thalassemias
Beta thalassemia
Beta+ versus beta0
Beta thal major
Cellular pathogenesis
Clinical presentation
Laboratory evaluation
Complications
Treatment
Red cell transfusion
Iron chelation
Stem cell transplant
Prevention - prenatal diagnosis
Beta thal intermedia
Beta thal minor
Interacting beta thalassemias - Hb S and Hb E
Alpha thalassemia
Four degrees of gene deletion - correlate with clinical presentation
Three alpha gene deletion - Hb H disease
Four alpha gene deletion - Hydrops fetalis
Prevention - prenatal diagnosis
Sickle Cell Disease and other Disorders of Hemoglobin Structure (Bunn)
Inheritance - beta globin structural mutation: 6 Glu
The sickling disorders: SS, S b 0 Thal, S b+Thal, SC, AS
Molecular pathogenesis
Structure of the sickle fiber
Kinetics of fiber formation
In vivo significance of polymer formation
Cellular aspects of in vivo sickling and vaso-occlusion
Contribution of Hb F
Sickle cell - endothelial cell adhesion
Clinical manifestations
Constitutional: growth, development and susceptibility to infections
Hemolytic anemia
Vaso-occlusion
Acute pain crises
Acute chest syndrome
Chronic organ damage
Stroke
Bone - aseptic necrosis
Renal: impaired concentrating ability; impaired glomerular function
Pulmonary hypertension
Treatment
Supportive - analgesia, oxygen, fluid and pH balance
Prophylaxis: penicillin and vaccinations
Hydroxyurea - induction of Hb F
Novel therapeutic strategies
Other Inherited Hemolytic Anemias (Lux)
Disorders of the red cell membrane
Molecular anatomy of the red cell membrane
Hereditary spherocytosis - mutations in spectrin, band 4.1, band 3
Other inherited membrane disorders
Disorders of red cell metabolism
Hexose monophosphate shunt and G6PD deficiency
Glycolytic pathway - pyruvate kinase deficiency
Acquired Hemolytic Anemias (Bunn)
Acquired membrane disorders
Paroxysmal nocturnal hemoglobinuria
Spur cell anemia
Traumatic hemolytic disorders
Thrombotic thrombocytopenic purpura (Covered in detail in Chapter 14)
Hemolytic uremic syndrome
Disseminated intravascular coagulation (Covered in detail in Chapter 16)
Heart valve hemolysis
Immune hemolytic anemias
Pathophysiologic principles
Clinical presentation and course
Warm antibody hemolysis
Cold antibody hemolysis
Lab diagnosis
Treatment
Erythrocytosis (Polycythemia) (Bunn)
Pathophysiologic principles
Algorithm for evaluating patients with erythrocytosis
Primary erythrocytosis - polycythemia vera (See Chapter 20 for coverage of molecular pathogenesis, Chapter 22 for clinical presentation and course, diagnosis and treatment)
Secondary erythrocytosis
Appropriate erythropoietin production
High altitude hypoxemia
Pulmonary hypoxemia
Cardiac hypoxemia (right to left shunt)
Mutant hemoglobin with high oxygen affinity
Inapproriate erythropoietin production
Tumors: renal, hepatic
Von Hippel Lindau syndrome
Inherited disorders of oxygen sensing HIF pathway
Disorders of Hemostasis and Thrombosis
Overview of Hemostasis (Furie)
Phases of clot formation and dissolution
Platelet plug
Coagulation
Fibrinolysis
Molecules that participate in clot formation and clot lysis
Platelet activation
Adhesion
Aggregation
Secretion
Laboratory evaluation of platelet function
Platelet aggregation
Bleeding time
Blood Coagulation
In vitro coagulation cascade
Laboratory evaluation
Partial thromboplastin time
Prothrombin time
Thrombin time
Fibrinogen
Factor assays
Factor VIII panel: activity, antigen, ristocetin cofactor, multimer assay
D-dimer assay
Mixing studies - identification of circulating anticoagulant
Anticoagulent/fibrinolytic drugs
Warfarin
Heparin and heparin mimetics (see Chapter 17)
Fibrinolytic agents
Platelet Disorders (Furie)
Acquired Platelet Disorders
Thrombocytopenia
Decreased production
Drugs, toxins
Aplasia (Chap 4), myelodysplasia (Chap 22), PNH (Chap 11)
Sequestration (hypersplenism)
Increased consumption/destruction
Immune thrombocytopenia
Chronic ITP
Acute ITP
Drug induced
Alloimmune
Clinical presentation and course
Treatment
Thrombotic thrombocytopenic purpura
Molecular pathogenesis
Diagnostic criteria
Clinical presentation and course
Therapy
Acquired qualitative platelet disorders
Drug induced defects in platelet secretion: aspirin, NSAID
Uremia
Hereditary Platelet Disorders
Defective adhesion: Bernard-Soulier
Defects of release and of storage pools
Defective aggregation: Glanzmann's thrombesthenia
Inherited Coagulation Disorders (Furie)
Factor VIII deficiency (hemophilia A, classic hemophilia)
Genetics x-linked mutations responsible for hemophilia A
Clinical manifestions of disease
Laboratory monitoring
Therapy
Factor VIII infusion
Supportive care
Complication of therapy
HIV, viral hepatitis
Acquired inhibitors (inducible and uninducible)
Factor IX deficiency (hemophilia B, Christmas disease)
Genetics x-linked mutations responsible for hemophilia B
Clinical manifestions of disease
Laboratory monitoring
Therapy
Factor IX concentrate infusion
Supportive care
Complication of therapy: HIV, viral hepatitis
Acquired Coagulation Disorders (Furie)
Impaired synthesis of coagulation factors
Liver disease
Drugs
Vitamin K deficiency
Usual clinical setting
Hemorrhagic disease of the newborn
Factitious or accidental warfarin ingestion
Disseminated intravascular coagulation
Etiology
Lab diagnosis
Treatment
Factor X deficiency and amyloid
Coagulation factor deficiencies due to specific inhibitor
Acquired Factor VIII deficiency
Others: V, vWD, etc
Lupus anticoagulant/anti-cariolipin (see Chapter 17)
Thrombotic Disorders (Bauer)
Principles of thrombosis and thrombotic disorders
Nation-wide and world-wide impact
Virchow's triad
Inhibitors/regulators of coagulation
Anti-thrombin III - effect of heparin
Protein S, activated protein C cleavage of Va and VIIIa
Tissue factor protein inhibitor
Fibrinolysis
Risk factors for venous thrombosis
Inherited thrombotic disorders
Assay measurements
Protein C deficiency - warfarin skin necrosis
Protein S deficiency
Factor V Leiden
Prothrombin gene mutation: 20210 G-> A
Impact of inherited defects on thrombotic risk
Acquired thrombotic disorders
Antiphospholipid antibody syndrome (lupus anticoagulant; anti-cardiolipin antibody)
Clinical presentation
Laboratory diagnosis
Treatment
Heparin-induced thrombocytopenia
Pathogenetic mechanism
Clinical presentation
Laboratory diagnosis
Treatment
Disorders of Leukocytes
Leukocyte Function and Non-malignant Leukocyte Disorders (Berliner)
Distribution of cells within the myeloid/neutrophil compartment
Marrow compartment
Peripheral compartment
Circulating
Marginating
Determinants of peripheral neutrophil count
Production
Margination
Sequestration
Destruction
Evaluation of neutrophilia
Primary hematologic disorders
Congenital - e.g. Down's syndrome, inherited defects in leukocyte adhesion
Acquired - e.g. chronic myeloid leukemia
Secondary to other disorders
Infection
Stress
Drug induces
Chronic inflammation
Post-splenectomy
Approach to patient with neutrophilia
Evaluation of neutropenia
Congenital
Constitutional, benign
Severe congenital neutropenia
Neutrophil elastase mutations
Kostmann's syndrome
Cyclic neutropenia
Others
Acquired neutropenia
Post-infection
Drug-induced
Vitamin B12, folate deficiency
Hypersplenism
Immune related
Auto-immune
Isoimmune - newborns
Associated with immune disorders
Dignostic evaluation
Treatment of neutropenias
Depends on severity
Wide range of options: supportive, steroids, IgG, G-CSF, stem cell transplant
Qualitative abnormalities of neutrophil function
Disorders of respiratory burst: chronic granulomatous disease, myeloperoxidase def
Abnormalities of leukocyte adhesion and chemotaxis
Defects in structure and function of neutrophil granules
Non-malignant lymphocyte disorders
Lymphocytosis
Reactive lymphocytosis; cytomegalovirus, HIV, toxoplasmosis
Infectious mononucleosis
Lymphopenia: steroid therapy, immunodeficiency syndromes
Histiocytic disorders - hemophagocytic lymphohistiocytosis
Introduction to Hematologic Malignancy (Fleming)
Classes of hematologic malignancies
Acute leukemias
Myelodysplastic syndromes
Chronic myeloproloferative disorders
Lymphomas
Diagnostic criteria
Lineage of the malignant cell (cell of origin)
Molecular genetic features
Clinical features
Clinical subtypes of disease
Leukemia versus lymphoma
Acute versus chronic leukemia
Indolent versus aggressive lymphoma
Clonality in hematologic malignancies
Critical for distinguishing some neoplasms from reactive proliferations
Established by a number of techniques
X-chromosome inactivation (rarely used clinically)
Conventional and molecular cytogenetics
Acquired mutations of pathogenetic significance: e.g., JAK2 mutation in PCV
B cells: production of monoclonal immunoglobulin protein
B cells or T-cells: detection of monoclonal antigen receptor gene rearrangements
Molecular Mechanisms underlying Hematologic Malignancies (Aster)
Chronic myeloproliferative disorders: tumors caused by mutations in tyrosine kinases
Pathophysiology: hyperproliferation of hematopoietic progenitors with preserved differentiation
Chronic myeloid leukemia: BCR-ABL fusion oncoproteins
Polycythemia vera: gain of function JAK2 mutations
Chronic eosinophilic leukemia: gain of function FGFR1 or PDGFR mutations
Targeted therapies with kinase inhibitors
Acute leukemias: tumors caused by complementary mutations in critical transcription factors and tyrosine kinases
Pathophysiology: hyperproliferation of blasts and arrested development leading to bone marrow failure
Acute promyelocytic leukemia
Molecular pathogenesis: PML/RARa fusion proteins + tyrosine kinase mutations
Targeted therapy - all-trans retinoic acid
BCR-ABL+ acute lymphoblastic leukemia
Molecular pathogenesis: Ikaros mutations + BCR-ABL fusion genes
Targeted therapy - ABL kinase inhibitors
Myelodysplasia
Pathophysiology: acquired mutations that lead to apoptosis of hematopoietic progenitors (ineffective hematopoiesis) and disordered (dysplastic) maturation
Genetic and cytogenetics
Lymphomas: mainly tumors of mature lymphocytes
Germinal center B cells - most common origin for human lymphomas
Role of genomic instability in germinal center B cell lymphomas
Recurrent genetic abnormalities: translocations involving BCL2, BCL6, and C-MYC
Other contributors to B cell lymphomagenesis
Chronic immune stimulation
Chronic immune dysregulation
Oncogenic viruses (EBV)
T/NK cell lymphomas - rare, usually extranodal, diverse clinicopathologic features
EBV-related (subset)
ALK tyrosine kinase fusion protein-related (subset)
Plasma cell neoplasms and related disorders
Pathophysiology
Abnormal immunoglobulins
Bone resorption
Suppression of B cell function
Diminished hematopoiesis
Genetics: diverse chromosomal translocations involving the IgH locus
Acute Leukemias (DeAngelo)
Impact relative to cancer in general
Clinical presentation
Laboratory diagnosis
Blood and marrow morphology
Cell surface markers
Karyotype
Acute myeloid leukemia
Etiology
Principles of treatment
Induction
Post remission consolidation
Stem cell transplantation in selected patients
Factors influencing outcome
Age
Karyotype
WBC at presentation
Rapidity of response to induction therapy
Targeted therapy (APML and all-trans retinoic acid)
Acute lymphoblastic leukemia
Age-dependent incidence
Prognostic factors
Treatment
Induction
CNS prophylaxis
Consolidation
Maintenance
Treatment issues
Toxicity: myelosuppression, liver, CNS, pancreas
Infections
Complications of steroid therapy
Sites of relapse
Chronic lymphocytic leukemia
Clinical presentation
Staging
Prognostic factors
Treatment
Patients with early stage and/or minimal symptoms require no treatment
Chemotherapy
Anti-CD20 monoclonal antibody
The Myeloproliferative Disorders and Myelodysplasia (DeAngelo)
Clonal disorders arising from mutated hematopoietic stem cells
Chronic myeloid leukemia
Molecular pathogenesis: BCR-ABL fusion protein
Natural history
Laboratory diagnosis
Treatment
Targeted drug therapy: imatinib and newer tyrosine kinase inhibitors
Conventional chemotherapy
Stem cell transplantation
Polycythemia vera
Molecular pathogenesis: JAK2 kinase mutations
Clinical presentation and course
Laboratory diagnosis
Treatment: phlebotomy versus hydroxyurea
Essential Thrombocytosis
Molecular pathogenesis: majority of patients have JAK2 mutation
Clinical presentation and course
Laboratory diagnosis
Treatment
Primary myelofibrosis
Molecular pathogenesis: JAK2 mutations (50%), rarely MPL mutations
Clinical presentation and course
Laboratory diagnosis
Treatment
Myelodysplastic Syndromes
Clonal disorders arising from mutated myeloid stem cell
Morphologic feature: trilineage dysplasia
Clinical presentation
Elderly patient develops anemia, pancytopenia
Highly variable course
Classification - presence of blasts, cytogenetic abnormalities worsen outcome
Treatment - supportive, growth factors, chemotherapy, revlimid, stem cell transplant
Hodgkin Lymphoma, Non-Hodgkin Lymphoma and Plasma Cell Disorders (Freedman)
Introduction
Neoplastic transformation of normal lymphoid cells
Epidemiology
Approach to patient: evaluation, staging
Classification
Non-Hodgkin - indolent, aggressive, highly aggressive
Hodgkin - variable, usually moderately aggressive
Clinical presentation and course
Lymphadenopathy or extranodal mass
Diagnosis established by biopsy followed by staging
Treatment, clinical course and survival all depend on the precise diagnosis
Non-Hodgkin Lymphoma (NHL)
Indolent NHL
Usually follicular B cell lymphoma
Painless lymphadenopathy, extranodal sites uncommon
Survive for years without therapy
Not curable with current therapy
Treatment with radiation, chemotherapy and/or anti-CD20 indicated for
Bulky nodal disease
Compromised organ function
Symptomatic from fever and/or weight loss (B symptoms), effusions
Cytopenias
Aggressive NHL
Usually diffuse B cell
Rapidly enlarging symptomatic masses
B symptoms
Extranodal sites common
Transformation from indolent NHL
High cure rate with chemotherapy + anti-CD20
Hodgkin Lymphoma
Clinical presentation: painless adenopathy; B symptoms in 30%
Pathological classification
Orderly spread from one lymph node region to contiguous nodal sites
Importance of staging
Treatment
Chemotherapy +/- radiation: 80% cured
Complications of therapy: cardiac, pulmonary, thyroid, second cancers
Plasma Cell Disorders
Clonal lymphoid cell proliferation producing structurally unique immunoglobulin
Monoclonal gammopathy of uncertain significance (M-GUS)
Often incidental finding in an elderly patient
Converts to multiple myeloma at a rate of 1% per year
Multiple myeloma
Malignant and progressive plasma cell proliferation associated with: anemia lytic bone lesions - due to activation of osteoclasts renal insufficiency - usually due to immunoglobulin light chain nephropathy acquired hypogammaglobulinemia leading to bacterial infections hypercalcemia
Diagnosis serum electrophoresis -immunoglobulin M spike -associated hypogammaglobulinemia serum immunoelectrophoresis and immunofixation: IgG or IgA M spike urine immunoelectrophoresis: kappa or lambda light chains, bone marrow: increased plasma cells, often abnormal in appearance
Treatment: chemotherapy, thalidomide, revlimid, proteasome inhibitors, stem cell transplant
Waldenstroms Macroglobulinemia (Lymphoplasmacytic lymphoma)
Malignant proliferation of lymphoplasmacytic cells producing IgM macroglobulins
Associated with anemia, symptoms of plasma hyperviscosity
Transfusion Medicine
Blood Transfusion (Kaufman)
Blood components
Red cells
Platelets
Plasma
Blood group antigens
ABO system
Structure of A, B and O antigens
Immunological and clinical consequences
Rh system
Rh proteins
Rh antibodies - clinical consequences
Other blood group antigens and antibodies
Pretransfusion testing
ABO typing
Antibody screen
Crossmatch
Indications for transfusion
Red cells
Platelets
Plasma
Risks of transfusion
Febrile reactions
Hemolytic reactions acute delayed direct antiglobulin test
Transfusion associated lung injury
Transmission of infectious pathogens
Viral: HIV, hepatitis
Bacterial
Hemolytic disease of the fetus and newborn
Newer cellular therapies
Hematopoietic Stem Cell Transplantation (Antin)
Transplantation immunology
Major histocompatability antigens
Minor histocompatability antigens
Selection of donor
Auto-transplant
HLA-matched sibling donor
Matched unrelated donor
Source of donor stem cells
Bone marrow
Peripheral blood - isolated CD34+ cells
Umbilical cord blood
Preparation of recipient for stem cell transplant
Minimal - aplastic anemia
Full marrow ablation - necessary in hematologic malignancies
Partial ablation - may prove beneficial in non-malignant disorders (SS)
Clinical course and complications following transplant
Infection
Acute - bacterial
Delayed - opportunistic
Graft rejection
Graft versus host disease / graft versus leukemia
Impact of stem cell transplantation on
Aplastic anemia
Acute leukemias
Chronic myelocytic leukemias
Beta thalassemia major
Sickle cell anemia
Others Supplement: Tables of normal lab values
Index

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