Pathophysiology of Blood Disorders / Edition 1

Pathophysiology of Blood Disorders / Edition 1

by Howard Franklin Bunn, Jon C. Aster
     
 

ISBN-10: 0071713786

ISBN-13: 9780071713788

Pub. Date: 01/14/2011

Publisher: McGraw-Hill Professional Publishing

A concise full-color review of the mechanisms of blood diseases and disorders – based on a Harvard Medical School hematology course

2015 Doody's Core Title!

4 STAR DOODY'S REVIEW!

"This is a superb book. Deceptively small, yet packs a wallop. The emphasis on principles instead of practice is welcome....The text is clear, concise,

Overview

A concise full-color review of the mechanisms of blood diseases and disorders – based on a Harvard Medical School hematology course

2015 Doody's Core Title!

4 STAR DOODY'S REVIEW!

"This is a superb book. Deceptively small, yet packs a wallop. The emphasis on principles instead of practice is welcome....The text is clear, concise, and surprisingly approachable for what could have been a very dense and dry discussion. I could not put this book down and read it entirely in one sitting. When was the last time anyone found a hematology textbook so riveting?"--Doody's Review Service

Hematological Pathophysiology is a well-illustrated, easy-to-absorb introduction to the physiological principles underlying the regulation and function of blood cells and hemostasis, as well as the pathophysiologic mechanisms responsible for the development of blood disorders. Featuring a strong emphasis on key principles, the book covers diagnosis and management primarily within a framework of pathogenesis.

Authored by world-renowned clinician/educators at Harvard Medical School, Hematological Pathophysiology features content and organization based on a hematology course offered to second year students at that school. The book is logically divided into four sections: Anemias and Disorders of the Red Blood Cell, Disorders of Hemostasis and Thrombosis, Disorders of Leukocytes, and Transfusion Medicine; it opens with an important overview of blood and hematopoietic tissues.

Features

  • Succinct, to-the-point coverage that reflects current medical education
  • More than 200 full-color photographs and renderings of disease mechanisms and blood diseases
  • Each chapter includes learning objectives and self-assessment questions
  • Numerous tables and diagrams encapsulate important information
  • Incorporates the feedback of 180 Harvard medical students who reviewed the first draft -- so you know you’re studying the most relevant material possible

Product Details

ISBN-13:
9780071713788
Publisher:
McGraw-Hill Professional Publishing
Publication date:
01/14/2011
Edition description:
New Edition
Pages:
352
Sales rank:
784,275
Product dimensions:
6.90(w) x 8.90(h) x 0.60(d)

Table of Contents

Table of Contents

Chapter 1 – 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

Chapter 2 – 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

Section I – Anemias and Disorders of the Red Blood Cell

Chapter 3 – 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

Chapter 4 - 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).

Chapter 5 – 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

Chapter 6 - 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

Chapter 7 - 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

Chapter 8 – 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

Chapter 9 – Sickle Cell Disease and other Disorders of Hemoglobin Structure

(Bunn)

Inheritance – beta globin structural mutation: b

6 Glu ®

Val

The sickling disorders: SS, Sb

0Thal, Sb

+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

Chapter 10 – 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

Chapter 11 – 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

Chapter 12 - 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

Section II – Disorders of Hemostasis and Thrombosis

Chapter 13 – 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

Chapter 14 – 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

Chapter 15 – 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

Chapter 16 – 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)

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

Section III – Disorders of Leukocytes

Chapter 18 – 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

Chapter 19 – 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

Chapter 20 – 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

Chapter 21 – 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

Chapter 22 – 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

Chapter 23 – 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

Section IV – Transfusion Medicine

Chapter 24 - 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

Chapter 25 – 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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