Pathophysiology of Blood Disorders

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:: 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

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:: Glanzmanns 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

Virchows 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. Downs 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

Kostmanns 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