Pathophysiology of Blood Disorders

Pathophysiology of Blood Disorders
By:Aster, Jon C.; Bunn, Howard Franklin;
Pub Date:January 17th 2011
Format:Paperback 352 pages
eBook Available: View eBook Details
ISBN:0071713786 / 9780071713788
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Main description

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!


"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.



  • 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

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


Blood clotting proteins

The bone marrow

The spleen

The thymus

Lymph nodes

Chapter 2 - Hematopoiesis and the Bone Marrow


Hematopoietic cell diffrerentiation

Myeloid lineage

Erythroid lineage

Megakaryocyte-platelet lineage

Lymphoid lineages - B, T, and NK cells

The biology of the stem cell


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


(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




Anemia due to increased red cell destruction

Chapter 4 - Anemias due to Bone Marrow Failure or Infiltration


Congenital causes of bone marrow failure

Acquired aplastic anemia and pure red cell aplasia




(Myelodysplasia and the leukemias will be covered in detail in Chapters 21 and 22).

Chapter 5 - Iron Homeostasis: Deficiency and Overload


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


Clinical features - signs and symptoms

Hematological features


Iron overload

Primary - inherited mutations in proteins regulating iron homeostasis

Secondary - transfusional hemosiderosis

Chapter 6 - Megaloblastic Anemias


Biochemistry of vitamin B12 and folate


Megaloblastic marrow and peripheral blood morphology

Vitamin B12 and folate absorption

B12 deficiency


Clinical presentation (signs and symptoms)

Laboratory evaluation


Folate deficiency


Clinical presentation (signs and symptoms)

Laboratory evaluation


Chapter 7 - Anemias associated with Chronic Disease

(Heeney and Bunn)

Anemia of chronic inflammation



Connective tissue disorders

Pathophysiology - role of hepcidin

Lab features


Anemia of renal insufficiency


Erythropoietin levels

Treatment with erythropoietin and iron

Anemia of chronic liver disease

Anemia of endocrine hypofunction

Chapter 8 - Thalassemia


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



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


Inheritance - beta globin structural mutation: b6 Glu ® Val

The sickling disorders: SS, Sb0Thal, 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


Acute pain crises

Acute chest syndrome

Chronic organ damage


Bone - aseptic necrosis

Renal: impaired concentrating ability; impaired glomerular function

Pulmonary hypertension


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


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


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


Chapter 12 - Erythrocytosis (Polycythemia)


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


Phases of clot formation and dissolution

Platelet plug



Molecules that participate in clot formation and clot lysis

Platelet activation




Laboratory evaluation of platelet function

Platelet aggregation

Bleeding time

Blood Coagulation

In vitro coagulation cascade

Laboratory evaluation

Partial thromboplastin time

Prothrombin time

Thrombin time


Factor assays

Factor VIII panel: activity, antigen, ristocetin cofactor, multimer assay

D-dimer assay

Mixing studies - identification of circulating anticoagulant

Anticoagulent/fibrinolytic drugs


Heparin and heparin mimetics (see Chapter 17)

Fibrinolytic agents

Chapter 14 - Platelet Disorders


Acquired Platelet Disorders


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


Clinical presentation and course


Thrombotic thrombocytopenic purpura

Molecular pathogenesis

Diagnostic criteria

Clinical presentation and course


Acquired qualitative platelet disorders

Drug induced defects in platelet secretion: aspirin, NSAID


Hereditary Platelet Disorders

Defective adhesion: Bernard-Soulier

Defects of release and of storage pools

Defective aggregation: Glanzmann's thrombesthenia

Chapter 15 - Inherited Coagulation Disorders


Factor VIII deficiency (hemophilia A, classic hemophilia)



mutations responsible for hemophilia A

Clinical manifestions of disease

Laboratory monitoring


Factor VIII infusion

Supportive care

Complication of therapy

HIV, viral hepatitis

Acquired inhibitors (inducible and uninducible)

Factor IX deficiency (hemophilia B, Christmas disease)



mutations responsible for hemophilia B

Clinical manifestions of disease

Laboratory monitoring


Factor IX concentrate infusion

Supportive care

Complication of therapy: HIV, viral hepatitis

Chapter 16 - Acquired Coagulation Disorders


Impaired synthesis of coagulation factors

Liver disease


Vitamin K deficiency

Usual clinical setting

Hemorrhagic disease of the newborn

Factitious or accidental warfarin ingestion

Disseminated intravascular coagulation


Lab diagnosis


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


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


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


Heparin-induced thrombocytopenia

Pathogenetic mechanism

Clinical presentation

Laboratory diagnosis


Section III - Disorders of Leukocytes

Chapter 18 - Leukocyte Function and Non-malignant Leukocyte Disorders


Distribution of cells within the myeloid/neutrophil compartment

Marrow compartment

Peripheral compartment



Determinants of peripheral neutrophil count





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



Drug induces

Chronic inflammation


Approach to patient with neutrophilia

Evaluation of neutropenia


Constitutional, benign

Severe congenital neutropenia

Neutrophil elastase mutations

Kostmann's syndrome

Cyclic neutropenia


Acquired neutropenia



Vitamin B12, folate deficiency


Immune related


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


Reactive lymphocytosis; cytomegalovirus, HIV, toxoplasmosis

Infectious mononucleosis

Lymphopenia: steroid therapy, immunodeficiency syndromes

Histiocytic disorders - hemophagocytic lymphohistiocytosis

Chapter 19 - Introduction to Hematologic Malignancy


Classes of hematologic malignancies

Acute leukemias

Myelodysplastic syndromes

Chronic myeloproloferative disorders


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


Chronic myeloproliferative disorders: tumors caused by m


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