دانلود کتاب Blood and Bone Marrow Pathology

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Front Сover
Title Page
Copyright Page
Preface
Contributors
Dedication to Sunitha N. Wickramasinghe
Contents
Section A: Normal blood and bone marrow cells
1 Normal blood cells
Erythrocytes
Morphology
Red cell parameters
Red cell life span
Functions of red cells
Reticulocytes
Granulocytes (polymorphonuclear leukocytes)
Neutrophil granulocytes
Morphology and composition
Number and life span
Functions
Eosinophil granulocytes
Morphology and composition
Number and life span
Functions
Basophil granulocytes
Functions
Monocytes
Lymphocytes
Platelets
Morphology and composition
Number and life span
Functions
Alterations in the blood in pregnancy
References
2 Normal bone marrow cells: development and cytology
Hemopoietic cells
Embryonic hemopoiesis
Postnatal changes in the distribution of hemopoietic marrow
General characteristics of hemopoiesis
Hemopoietic stem cells and progenitor cells
Erythropoiesis
Regulation of erythropoiesis
Light microscope cytology
Cytochemistry
Antigen expression
Ultrastructure
Megakaryopoiesis
Light microscope cytology
Antigen expression
Ultrastructure
Emperipolesis
Granulopoiesis and monocytopoiesis
Neutrophil granulopoiesis
Light microscope cytology
Cytochemistry
Antigen expression
Granule composition and ultrastructure
Eosinophil granulopoiesis
Light microscope cytology
Cytochemistry
Antigen expression
Eosinophil granules and ultrastructure
Basophil granulopoiesis
Monocytopoiesis: the mononuclear phagocyte system
Light microscope cytology
Cytochemistry
Antigen expression
Lymphopoiesis
Light microscope cytology
Antigen expression
Plasma cells
Bone marrow stromal cells
Bone marrow sinusoids
Bone marrow macrophages
Light microscope cytology, cytochemistry and antigen expression
Dendritic cells
Mast cells
Light microscope cytology
Antigen expression
Osteoblasts
Osteoclasts
Mesenchymal stem cells
Adipocytes
Assessment of marrow hemopoietic activity
Morphological assessment
Phenotypic assessment
References
3 Normal bone marrow histology
Normal bone marrow – generalities and function
Bone marrow structure
Bone marrow trephine biopsy
Processing and stains
Marrow cellularity
Marrow architecture
Hemopoiesis
Erythropoiesis
Granulopoiesis
Myeloid : erythroid ratio
Megakaryopoiesis
Macrophages, monocytes and dendritic cells
Mast cells
Lymphocytes
Plasma cells
Hemopoietic stem cells and early precursor cells
The bone marrow stroma
Stromal cells
The extracellular matrix
Reticulin
Collagen
Reticulin and collagen grading
Blood vessels
Nerves
Bone
References
4 Regulation of hematopoiesis
Introduction
Characteristics of hematopoietic stem and progenitor cells
Phenotypic characterization
Functional characterization
Hematopoietic stem cell fate decisions: symmetrical vs. asymmetrical
The hematopoietic stem cell niche
Osteoblastic niche
Vascular niche
Intrinsic regulation of hematopoiesis
Hematopoietic stem and progenitor cell specific genes
Homeobox genes
Polycomb genes
Cell cycle regulators
Extrinsic regulation of hematopoiesis
Classical cytokines
Morphogens
Hedgehog signaling
Wnt signaling
TGFβ superfamily
Notch pathway
Angiopoietin-like proteins
Insulin-like growth factors
Conclusions
References
Section B: Pathology of the marrow
5 Pathology of the marrow: general considerations and infections/reactive conditions
Principles of bone marrow examination
Alterations of the marrow in disease
Alterations in cellularity
Alterations in the frequency and morphology of various types of bone marrow cells
Erythroblasts and neutrophil precursors
Myeloid : erythroid ratio
Morphologic changes in erythroblasts
Morphologic changes in the neutrophil series
Eosinophil series
Basophils
Mast cells
Megakaryocytes
Lymphocytes
Plasma cells
Macrophages (histiocytes)
Hemophagocytic syndromes
Osteoblasts and osteoclasts
Changes in iron stores and intraerythroblastic iron
Iron stores
Alterations in stainable non-hemoglobin iron within erythroblasts
Infections and the bone marrow
HIV infection
Changes in the peripheral blood
Changes in the bone marrow
Bone marrow granulomas
Metastatic tumors in bone marrow
Bone marrow fibrosis
Storage cells in lysosomal storage diseases
Sphingolipidoses
Gaucher disease
Sea-blue histiocyte syndrome
Niemann–Pick disease
Fabry disease
Mucopolysaccharidoses
Other storage diseases and hyperlipidemias
Bone marrow necrosis
Gelatinous transformation
Amyloidosis
Vascular and embolic lesions
Aluminum deposition
Post-mortem bone marrow changes
References
Recommended reading
Section C: Disorders affecting erythroid cells
6 Investigation and classification of anemia
Definition and causes of anemia
Clinical features of anemia
The blood count and red cell indices in anemia
Red cell morphology in anemia
Investigation of the cause of anemia
Microcytic anemias
Macrocytic anemias
Normocytic anemias
Assessment of the erythropoietic response to anemia
The classification of anemia
References
7 Abnormalities of the red cell membrane
Hereditary spherocytosis
ANK1 gene mutations
SLC4A1 gene mutations
SPTB gene mutations
EPB42 gene mutations
SPTA1 gene mutations
RHAG gene mutations
Hereditary elliptocytosis and poikilocytosis
SPTA1 gene mutations
SPTB gene mutations
EPB41 gene mutations
Genetic disorders of the monovalent cation leak across the membrane
A pleiotropic syndrome revolving around dehydrated hereditary stomatocytosis
Overhydrated hereditary stomatocytosis
Hereditary cryohydrocytosis
Southeast Asian ovalo-stomatocytosis
Paroxysmal exertion-induced dyskinesia
Conclusion
References
8 Erythroenzyme disorders
Introduction
Clinical features
Blood cell morphology
Biochemical investigation of erythroenzyme disorders
Molecular basis of erythroenzyme disorders
References
9 Abnormalities of the structure and synthesis of hemoglobin
Introduction
Normal human hemoglobin: structure and synthesis
Inherited disorders of hemoglobin
Thalassemias
Background
β Thalassemias
Genetic basis of disease
Pathophysiology
Genotype-phenotype correlation
Diagnosis
Clinical features and management
β Thalassemia in association with other hemoglobin variants
HbE/β thalassemia
HbS/β thalassemia
HbC/β thalassemia
The δβ-, γδβ-thalassemias and HPFH syndromes
εγδβ Thalassemia
α Thalassemias
Genetic basis of disease
Pathophysiology
Genotype-phenotype correlation
Diagnosis
Bart’s hydrops fetalis
HbH disease
Carriers
Clinical features
α Thalassemia with mental retardation (ATR) syndromes
Acquired α thalassemia
Structural hemoglobin variants
Sickle cell disease
Background
Genetic basis and pathophysiology
Diagnosis
Clinical features
Management
Other sickling disorders
Other hemoglobin variants
Unstable hemoglobin disorders
Hemoglobin variants with abnormal oxygen binding
Hemoglobins M
Thalassemic hemoglobinopathies
Acknowledgment
References
10 Acquired hemolytic anemia
Introduction
Clinical and laboratory features of hemolytic anemia
Mechanisms of hemolysis
FcR-mediated red cell clearance
Complement-mediated red cell destruction
Complement regulation
Examples of complement-mediated hemolytic anemia
Immune hemolytic anemia
Warm autoimmune hemolytic anemia (AIHA)
Specificity of IgG autoantibodies in AIHA
Diagnostic evaluation of a patient with suspected AIHA
Management of patients with warm AIHA
Cold autoimmune hemolytic anemia
Paroxysmal cold hemoglobinuria
Alloimmune hemolytic anemia
Transfusion reactions due to immune-mediated hemolysis
Hemolytic disease of the newborn
Drug-induced immune hemolytic anemia
Drug-independent antibodies
Drug-dependent antibody
Oxidative injury to red cells
Non-immune hemolytic anemia
Infection-induced hemolytic anemia
Mechanical injury to red cells
Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome
Cardiac valve hemolysis
External impact on red cells
Other causes of hemolytic anemia
Acknowledgments
References
11 Iron deficiency anemia, anemia of chronic disorders and iron overload
Introduction
Spectrum of pathology related to disorders of iron metabolism
Iron deficiency
Iron maldistribution
Iron overload
Major pathways of iron exchange
Molecular mechanisms in iron metabolism
Cellular uptake of iron from transferrin
Regulation of cellular iron homeostasis
Regulation of iron uptake in specific tissues
Developmental (transcriptional) regulation of iron uptake in the erythron
Hepatocyte iron uptake
Macrophage iron uptake
Uptake of iron by duodenal mucosal cells
Iron release from ‘donor’ cells
Regulation of iron absorption and internal iron exchange
Iron absorption in health and disease
Role of hepcidin
Regulation of hepcidin production
Assessment of iron status
Serum transferrin receptors
Serum ferritin
Tissue biopsy
Potential clinical use of hepcidin assay
Iron deficiency
Causes of iron deficiency
Clinical features of iron deficiency anemia
Development and pathological effects of iron deficiency
Exhaustion of iron stores
Iron-deficient erythropoiesis
Iron deficiency anemia
Mechanism of iron deficiency anemia
Non-hematological effects of iron deficiency
Diagnosis of iron deficiency
Treatment of iron deficiency
Functional iron deficiency
Pathophysiology
Treatment
Anemia of chronic disorders
Pathogenesis
Impaired production of erythropoietin
Inhibition of erythropoiesis
Decreased red cell survival
Reduction in iron supply to the erythroid marrow
Diagnosis
Treatment
Iron overload
Iron overload disorders – definitions and pathophysiology
Primary iron overload
HFE-related (Type 1) hereditary hemochromatosis
Non HFE-related hereditary hemochromatosis
Iron loading in other inherited disorders of iron metabolism
Neonatal hemochromatosis
Secondary iron overload
Parenteral iron loading
Increased dietary iron intake
Increased iron absorption
Pathogenesis of iron-induced damage
Treatment
References
12 Macrocytic anemia
Megaloblastic hemopoiesis
Vitamin B12-related and folate-related causes of megaloblastic anemia
Vitamin B12
Causes of vitamin B12 deficiency (Box 12.1)
Folates
Folate and neural tube defects
Causes of folate deficiency (Box 12.1)
Vitamin B12-independent and folate-independent causes of megaloblastic erythropoiesis (Box 12.2)
Abnormalities of nucleic acid synthesis
Drug-induced impairment of DNA synthesis78
Orotic aciduria85,86
Lesch–Nyhan syndrome87
Uncertain etiology
Anti-convulsant therapy3
Chronic alcoholism3
Myelodysplastic syndromes and erythroleukemia
Thiamine-responsive anemia89,90
Macrocytosis with normoblastic erythropoiesis3
References
Recommended reading
13 Aplastic anemia and pure red cell aplasia
Acquired aplastic anemia
Definition and differential diagnosis
Etiology
Drugs
Industrial/domestic chemicals
Viruses
Pathophysiology
The stem cell in aplastic anemia
The microenvironment in aplastic anemia
Autoimmune basis of aplastic anemia
Hematology
Clinical presentation
Classification of aplastic anemia
Clinical course
Clonal evolution in aquired aplastic anemia
Treatment of aplastic anemia
Immunosuppression
Growth factors
Cyclophosphamide
Anabolic steroids
Stem cell transplantation
HLA matched sibling transplants
Matched unrelated donor and cord blood transplants
Conclusion: Aplastic anemia
Pure red cell aplasia
Acquired PRCA
Transient erythroblastopenia of childhood
Parvovirus B19 infection
Chronic, acquired PRCA
Primary PRCA
Secondary PRCA
Viruses and PRCA
PRCA and lymphoproliferative disease
Treatment of pure red cell aplasia
References
14 Sideroblastic anemia
Hereditary sideroblastic anemia
X-linked inheritance
ALA synthase 2 defect
ABCB7 defect
Autosomal recessive sideroblastic anemia
Putative deficit of mitochondrial glycine import
Glutaredoxin 5 defect
Pseudouridine synthase 1 defect
Mitochondrial tyrosyl-tRNA synthetase defect
Defective high-affinity thiamine transporter THTR-1
Additional modes of inheritance not yet explained
Mitochondrial inheritance
Acquired sideroblastic anemia
Secondary acquired sideroblastic anemia
Primary acquired sideroblastic anemia
Differential diagnosis of primary sideroblastic anemia
Acknowledgments
References
15 Congenital dyserythropoietic anemias
Congenital dyserythropoietic anemia, type 1 (CDA-1)
Congenital dyserythropoietic anemia, type 2 (CDA-2)
Congenital dyserythropoietic anemia, type 3 (CDA-3)
Other types of congenital dyserythropoietic anemia
Diagnosis of congenital dyserythropoietic anemia
References
Section D: Disorders affecting the leukocyte lineages
16 Abnormalities in leukocyte morphology and number
Neutrophils
Neutropenia
Congenital and idiopathic neutropenias
Benign chronic neutropenias
Neutropenia in patients with congenital immune defects
Neutropenia in patients with congenital chromosomal abnormalities
Other rare conditions
Acquired neutropenias
Infections associated with neutropenia.
Drug-induced neutropenia.
Miscellaneous neutropenias
Neutrophilia
Neutrophilia in acute infection or inflammation
Neutrophilia and cancer
Miscellaneous neutrophilias
Qualitative and morphological abnormalities
Inherited abnormalities
Acquired abnormalities
Eosinophils
Eosinopenia
Drug-induced eosinopenia
Eosinopenia of acute infection or inflammation
Eosinophilia
Eosinophilia and asthma
Eosinophilic gastrointestinal disorders
Eosinophils and parasitic infestations
Eosinophilia in tumors
Miscellaneous
Qualitative and morphological abnormalities
Basophils
Basopenia
Basophilia
Monocytes
Monocytopenia
Monocytosis
Lymphocytes
Lymphopenia
Congenital lymphopenias
Acquired lymphopenias
Miscellaneous lymphopenias
Lymphocytosis
Lymphocytosis and infections
References
17 Disorders of phagocyte function
Introduction
Disorders of phagocyte maturation
Deficiencies of adhesion and migration
Phagocyte signaling abnormalities
Deficiencies of the phagocyte respiratory burst
Extrinsic disorders of phagocytosis
References
18 Acute myeloid leukemias
Introduction
Classification systems
Methods for diagnosis and classification
Clinical history
Peripheral blood and bone marrow cell count and morphology
Immunophenotyping
Cytochemistry
Cytogenetics and molecular testing
Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); (RUNX1-RUNX1T1)
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); (CBFB-MYH11)
Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); (PML-RARA)
AML with t(9;11)(p22;q23); (MLLT3-MLL)
AML with t(6;9)(p23;q34); (DEK-NUP214)
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.1); (RPN1-EVI1)
AML (megakaryoblastic) with t(1;22)(p13;q13); (RBM15-MKL1)
Acute myeloid leukemia with gene mutations
AML with mutated NPM1
AML with mutated CEBPA
Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC)
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified (AML, NOS)
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia (AMML)
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis (APMF)
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis (TAM)
Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell (BPDC) neoplasm
References
19 Acute lymphoblastic leukemia/lymphoma and mixed phenotype acute leukemias
Introduction
Acute lymphoblastic leukemia/lymphoma
Clinical presentation
Classification
Cytology, cytochemistry and histopathology
Immunophenotypic diagnosis
B-cell lymphoblastic leukemia/ lymphoma (B-LBL)
T-cell lymphoblastic leukemia/ lymphoma (T-LBL)
Cytogenetic abnormalities
Molecular genetics
Minimal residual disease monitoring
Mixed phenotype acute leukemias
Clinical presentation
Classification
Cytology and histopathology
Immunophenotypic diagnosis of MPAL
Cytogenetics and molecular genetics of MPAL
References
20 Myelodysplastic syndromes
Definition
Epidemiology
Classification
Diagnosis
Blood film examination
Erythrocytes
Leukocytes
Platelets
Bone marrow examination
Bone marrow aspirate
Erythropoiesis
Granulopoiesis
Thrombopoiesis
Bone marrow trephine
General histologic features of myelodysplastic syndromes
Assessment of spatial distribution of hemopoiesis in MDS
Cytologic features in trephine biopsy sections in MDS
Characteristic features of MDS subtypes
Myelodysplasia in hypoplastic bone marrow
Histologic features of secondary myelodysplasia
Use of immunohistochemistry and fluorescent in situ hybridization (FISH) in trephine biopsy sections in myelodysplasia
Flow cytometry in diagnosis of MDS
Genetics
Pathogenesis
Clinical course and management
References
21 Molecular studies in myeloproliferative and myelodysplastic/myeloproliferative neoplasms
Introduction
The Philadelphia chromosome and BCR-ABL in chronic myelogenous leukemia
The Janus kinase 2 in MPN
JAK2V617F
JAK2 (K539L and other aberrations in exon 12)
The JAK2V617F mutation in de novo acute leukemia and in MPN transformed to acute leukemia
Myeloproliferative leukemia virus oncogene (MPL) mutations in MPN
TET2 mutations in MPN and other myeloid malignancies
JAK2V617F, MPLW515L/K, BCR-ABL, KITD816V: molecular markers may be combined in an individual patient
The casitas B-lineage lymphoma gene (CBL) aberrancies in MPN and other myeloid malignancies
Summary and future perspectives
References
22 Erythrocytosis and polycythemia
Introduction
The pathology of erythrocytosis
Congenital erythrocytosis
Associated with reduced P50
High-oxygen-affinity hemoglobinopathy
2,3-Bisphosphoglycerate mutase (BPGM) deficiency
Methemoglobinemia
Associated with normal P50
VHL mutations including Chuvash erythrocytosis (frequently termed Chuvash polycythemia)
Prolyl hydroxlase domain 2 (PHD2) mutations
Hypoxia inducible factor alpha (HIF2α) mutations
Epo receptor (Epo-R) mutations
Acquired erythrocytosis
Erythrocytosis secondary to hypoxia
Erythrocytosis independent of hypoxia
Erythropoietin and related agents
Post-renal transplant erythrocytosis
Erythrocytosis secondary to tumors
Bone marrow biopsy in erythrocytosis
Polycythemia vera (PV)
Clinical features
Laboratory features
World Health Organization 2008 criteria for the diagnosis of PV
Pre-polycythemic PV
Post-polycythemic PV
Genetics in PV
The bone marrow biopsy in PV
Familial PV
Unclassifiable erythrocytosis
References
23 Essential thrombocythemia and primary myelofibrosis
Introduction
Essential thrombocythemia (ET)
Clinical features
Molecular data
Blood and bone marrow findings
Primary myelofibrosis (PMF)
Clinical features
Molecular data
Blood and bone marrow findings
References
24 Chronic myelogenous leukemia
Introduction
Clinical features and course of disease
Diagnostic procedures
Genetics
Morphology
At diagnosis
Phases of disease
Chronic phase (CP)
Early CP
Late chronic phase (lCP)
Accelerated phase (AP)
Acute phase, blast crisis (BC)
Prognostic factors in CML
Differential diagnoses
Non-neoplastic changes
Neoplastic disorders
Atypical CML
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia
Chronic myelomonocytic leukemia
Primary myelofibrosis
Polycythemia vera (PV)
Essential thrombocythemia
Myelodysplastic syndromes
Acute leukemia
Coincidence of other myeloid neoplasms
References
25 Myeloproliferative neoplasms with eosinophilia
Myeloid and lymphoid neoplasms with PDGFRA rearrangement
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Supplementary investigations
Myeloid neoplasms with PDGFRB rearrangement
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Supplementary investigations
Myeloid and lymphoid neoplasms with FGFR1 rearrangement
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Supplementary investigations
Chronic eosinophilic leukemia, not otherwise specified
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Supplementary investigations
Eosinophilia in other myeloproliferative neoplasms
Chronic myelogenous leukemia
Primary myelofibrosis
Systemic mastocytosis
Eosinophilic transformation of other myeloid neoplasms
Conclusions
References
26 Systemic mastocytosis
Definition
Introduction
Molecular genetics aspects
Important messages
Routine work-up of cases with suspected systemic mastocytosis
Bone marrow trephine biopsy
General morphological aspects of SM
Bone marrow smears
Blood smears
Morphology of the various defined subtypes of SM in the bone marrow
Main subtypes of SM
Provisional entities
Differential diagnosis
References
27 Myelodysplastic/myeloproliferative neoplasms
Introduction
Chronic myelomonocytic leukemia
Definition and diagnostic criteria
Epidemiology, clinical and laboratory features
Morphology and immunophenotypic features
Prognosis
Special considerations
Chronic myelomonocytic leukemia developing in a course of myelodysplastic syndrome
Therapy-related CMML
Atypical chronic myeloid leukemia, BCR-ABL1 negative
Definition and diagnostic criteria
Epidemiology, clinical and laboratory features
Morphology and immunophenotypic features
Prognosis
Special considerations
Syndrome of abnormal chromatin clumping
Atypical chronic myeloid leukemia with t(8;9)(p22;p24)/PCM1-JAK2
Juvenile myelomonocytic leukemia (JMML)
Definition and diagnostic criteria
Epidemiology, clinical and laboratory features
Morphology and immunophenotypic features
Prognosis
Special considerations
Differential diagnosis between JMML and viral infection
JMML and transient polyclonal myeloproliferation of Noonan syndrome
Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Definition and diagnostic criteria
Epidemiology, clinical and laboratory features
Morphology and immunophenotypic features
Provisional entity in myelodysplastic/myeloproliferative neoplasm, unclassifiable: refractory anemia with ring sideroblasts associated with marked thrombocytosis
Definition and diagnostic criteria
Epidemiology, clinical and laboratory features
Morphology and immunophenotypic features
Prognosis
Special considerations
Differentiation of RARS-T from myeloproliferative neoplasms with thrombocytosis and ring sideroblasts
RARS and RARS-T, distinct entities or clinical continuum
Miscellaneous myeloid neoplasms with myelodysplastic and myeloproliferative features
Myelodysplastic syndrome with isolated del(5q) and JAK2V617F mutation
Myelodysplastic/myeloproliferative neoplasm with isolated isochromosome 17q
Concluding remarks
References
28 The chronic lymphoid leukemias
Chronic lymphocytic leukemia
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
Leukemic presentations of other B-cell lymphomas
Prolymphocytic leukemias
B-lineage prolymphocytic leukemia
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
T-lineage prolymphocytic leukemia
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
T-cell large granular lymphocyte leukemia and lymphoproliferative disorders of NK cells
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
Sézary syndrome
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
Adult T-cell leukemia/lymphoma
Clinical features
Pathologic features
Peripheral blood
Bone marrow
Other tissues
Immunophenotype
Cytogenetics and molecular genetics
References
29 Lymphoma
Introduction
General comments on bone marrow (BM) examination in lymphoproliferative diseases
Differential diagnosis of reactive lymphoid aggregates vs lymphoma
Interpreting necrotic deposits of possible lymphoma
The laboratory investigation of blood and BM specimens suspected or known to have involvement by lymphoma
Blood
Bone marrow aspirate
Bone marrow trephine biopsy (BMTB)
The World Health Organization (WHO) classification of lymphomas
Blood and BM involvement of lymphoma entities according to WHO classification
Mature B-cell neoplasms
Lymphoplasmacytic lymphoma (LPL)
Clinical features, blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Hairy cell leukemia (HCL)
Clinical features and pathology in the spleen
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
HCL variant (HCLv)
Clinical features and pathology in the spleen
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Splenic marginal zone B-cell lymphoma (SMZL)
Clinical features and pathology in the spleen
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Splenic diffuse red pulp small B-cell lymphoma
Clinical features and pathology in the spleen
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type
Clinical features and pathology at presenting sites
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Nodal marginal zone lymphoma (+/− monocytoid B-cells)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Follicular lymphoma (FL)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Mantle cell lymphoma (MCL)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS)
Clinical features and pathology at presenting sites
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Other diffuse large B-cell lymphoma subtypes
Other lymphomas of large B cells
Burkitt lymphoma (BL)
Clinical features and pathology at presenting sites
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Mature T-cell and NK-cell neoplasms
Extranodal NK/T lymphoma, nasal type; enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma
Clinical features and pathology at presenting sites
Blood and bone marrow aspirate findings
Bone marrow trephine biopsy
Genetic studies
Hepatosplenic T-cell lymphoma
Clinical features, pathology, blood and bone marrow aspirate findings
Bone marrow trephine biopsy
Genetic studies
Anaplastic large cell lymphoma (ALCL), ALK-positive, and ALCL, ALK-negative
Clinical and pathologic features
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Angioimmunoblastic T-cell lymphoma (AIL-T NHL)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Hodgkin lymphoma (HL)
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Classical Hodgkin lymphoma
Clinical features and lymph node pathology
Blood and bone marrow aspiration
Bone marrow trephine biopsy
Genetic studies
Post-transplant lymphoproliferative disorders (PTLD) and other lymphoid proliferations associated with impaired immunity
Clinical and pathologic features
Blood and BM aspiration
Bone marrow trephine biopsy
Appearances of lymphoma infiltrates following therapy
BM hyperplastic, dysplastic and stromal reactions to lymphoma
Differential diagnosis and classification of lymphoma when bone marrow trephine biopsy provides the sole source of tissue for assessment
Conclusions
References
30 Abnormalities in immunoglobulin synthesizing cells
Multiple myeloma
Epidemiology and etiology
Biology
The cell of origin
Biology and growth signaling
Cytogenetic and molecular abnormalities
Bone disease
Diagnostic criteria
Clinical features
Bone disease
Hyperviscosity
Recurrent infections
Renal failure
Neurological features
Staging and prognostic factors
Pathology
Treatment
Monoclonal gammopathy of undetermined significance
Clinical features
Biology
Pathology
Treatment/management/disease progression
Plasma cell leukemia
Clinical features
Biology
Pathology
Treatment/management/disease progression
Solitary bone plasmacytoma
Clinical features
Pathology
Treatment/management/disease progression
Extramedullary plasmacytoma
Clinical features
Pathology
Treatment/management/disease progression
POEMS syndrome
Lymphoproliferative disorders associated with an IgM paraprotein
Biology
Clinical features
Treatment/management
Disease progression
Light-chain-associated amyloidosis
Biology
Clinical features
Pathology
Treatment/management
Disease progression
Heavy-chain disorders
α-Heavy-chain disease
Clinical features
Pathology
Treatment/management/disease progression
γ-Heavy-chain disease
Clinical features
Pathology
Treatment/management/disease progression
µ-Heavy-chain disease
Clinical features
Pathology
Treatment/management/disease progression
Cryoglobulinemia
Clinical features
Pathology
Treatment/management/disease progression
Acknowledgments
References
Section E: Abnormalities of Hemostasis
31 Hemostasis:
Introduction
Physiology of hemostasis applied to diagnosis
Primary hemostasis: formation of the platelet plug5 (Fig. 31.1)
Platelet adhesion
Platelet aggregation
Secondary hemostasis: generation of fibrin clot by the coagulation pathway (Fig. 31.2)
Clot initiation: the tissue factor/factor VIIa complex
Clot amplification: the ‘tenase’ complex
Clot propagation: the prothrombinase complex
Clot regulation and removal: the protein C and fibrinolytic pathways
Clot regulation: the protein C system6 and antithrombin
Fibrinolysis: the plasmin system8
The clinical approach to the patient with a possible hemostatic disorder
History
Key questions
Surgical challenges
Dental surgery
Other types of surgery
Epistaxis
Gastrointestinal or urogenital bleeding
Menstruation
Bruising
’Third space’ bleeds
Summation and duration of bleeding episodes
Pattern of bleeding
Drug history
Family history
Clinical examination
Skin
Mucosae
Musculoskeletal system
Nervous system
Active bleeding
On defining the pretest probability of a bleeding disorder
Screening tests of hemostasis: two warnings
On venipuncture
On screening tests
Laboratory investigation of hemostasis
Tests of primary hemostasis
Screening tests
The platelet count
Platelet function testing
The skin bleeding time (SBT)
Diagnostic tests
Classical platelet aggregometry
Investigations of platelet granule structure and function
Coagulation tests
Coagulation screening tests
Prothrombin time (PT) and the international normalized ratio
Activated partial thromboplastin time (APTT)
APTT correction tests
Classic mixing experiments
Diagnostically misleading APTT prolongation
Thrombin time (TT)
Heparin interference with coagulation screening tests: the reptilase time
Fibrinogen assay
Fibrin–fibrinogen degradation products (FDPs) and D-dimer assay
Logical use of the coagulation screen
Disorders of hemostasis that may not affect screening tests
Diagnostic coagulation tests
Specific assays of individual clotting factors
Functional bioassays
Immunoassays
Molecular diagnosis in disorders of hemostasis
The problem of testing the fibrinolytic system
Monitoring hemostasis using global tests
The ideal coagulation test
Calibrated automated thrombin generation measurement
Interpretation and clinical feasibility.
Whole blood thromboelastometry
Interpretation and clinical feasibility.
Minimizing error in hemostatic testing, interpretation and process
Maximizing the clinical utility of hemostatic testing
References
32 Disorders affecting megakaryocytes and platelets: inherited conditions
Introduction
Structure
Disorders of megakaryocytes
Congenital megakaryocyte hypoplasia
Thrombocytopenia and absent radii (TAR) syndrome16–18
Fanconi anemia
Disorders of platelets
Platelet organelle defects
Dense bodies – general aspects
Hermansky–Pudlak syndrome (HPS)
Storage pool deficiency (SPD)
Chediak–Higashi syndrome (CHS)
Alpha granules
Gray platelet syndrome
Alpha-granule, dense-body deficiency
Heterogeneous storage organelle deficiency
Enlarged alpha granules
Jacobsen–Paris–Trousseau syndrome
Lysosomes
Chediak–Higashi syndrome
Giant dense body disorder
Disorders of platelet membranes and membrane organization
Small platelets
Wiskott–Aldrich syndrome
Giant platelet disorders
Mediterranean macrothrombocytopenia
May–Hegglin anomaly (MHA)
Epstein’s syndrome (ES)
Hereditary nephritis associated with May–Hegglin syndrome
Gray platelet syndrome (GPS)
Montreal platelet syndrome (MPS)
Bernard–Soulier syndrome (BSS)
Membrane inclusion disorders
Enyeart anomaly (EA)
Medich giant inclusion disorder
Platelet microtubule disorders
Absence of circumferential microtubule coils in normal sized platelets
Summary
References
33 Acquired disorders affecting megakaryocytes and platelets
Introduction
Structure and function of megakaryocytes and platelets
Human platelets
Platelet structure and function
Platelet membrane constituents
The integrin family of proteins
Platelet integrins and related proteins
Platelet alloantigens
Cytoplasmic platelet constituents
Biological function of platelets
Platelet adhesion (Fig. 33.5A)
Platelet activation
Platelet shape change
Platelet aggregation (Fig. 33.5B)
Quantitative platelet abnormalities: thrombocytopenia
Pseudothrombocytopenia
Pooling of platelets in the spleen
Mechanism involved
Thrombocytopenia due to failure of platelet production
Acquired amegakaryocytic thrombocytopenia
Drug-induced megakaryocyte hypoplasia
Bone marrow failure syndromes
Aplastic anemia
Thrombocytopenia due to increased platelet destruction
Non-immunologic causes of thrombocytopenia
Disseminated intravascular coagulation (DIC)
Pathogenesis
Laboratory diagnosis
Management
Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome
Clinical features of TTP
Laboratory investigations
Pathogenesis
Diagnosis
Management
Hemolytic uremic syndrome
Pre-eclampsia and HELLP syndrome
HELLP syndrome
Thrombocytopenia caused by massive blood transfusion
Management
Liver disease
Thrombocytopenia secondary to alcohol
Thrombocytopenia in hepatocellular failure
Thrombocytopenia caused by infection
Mechanism of thrombocytopenia
Thrombocytopenia induced by HIV infection
Thrombocytopenia due to hematinic deficiencies
Immunologic causes of thrombocytopenia
Molecular basis of HPA antigens
Antibody response to non-self HPA antigens
Alloantibody-mediated thrombocytopenia
Neonatal alloimmune thrombocytopenia
Antigens involved in NAIT
Diagnosis of NAIT
Clinical features
Management
Future pregnancies
Post-transfusion purpura (PTP)
Pathogenetic basis
Clinical features
Laboratory features
Management
Autoantibody-mediated thrombocytopenia
Immune thrombocytopenic purpura (ITP)
Pathophysiology
Clinical features
Laboratory investigation
Bone marrow aspirates
Thrombopoietin (TPO) levels
Management
Chronic immune thrombocytopenic purpura (ITP)
Clinical features of ITP
Pathophysiology of ITP
Implicated epitopes
Antibody class
Diagnosis
Standard first-line therapy
Chronic ITP failing to respond to therapy
Experimental therapies
Thrombopoietin receptor agonists (TPO-mimetics)
Secondary immune thrombocytopenia
Drug-induced thrombocytopenia
Clinical features
Investigations
Management
Predictable (non-immune) thrombocytopenia
Drug-induced immune thrombocytopenia
Heparin-induced thrombocytopenia (HIT)
Pathogenesis
Clinical features
Diagnosis
Management
Other drugs causing immune-mediated platelet destruction
Acquired functional abnormalities of platelets
Uremia in renal failure
Pathogenesis
Management
Myeloproliferative disorders
Pathophysiology
Platelet abnormalities in the myeloproliferative disorders
Management
Platelet abnormalities in leukemia and myelodysplastic syndromes
Management
Drugs that interfere with platelet function
References
34 Inherited disorders of coagulation
Introduction
Hemophilia
Inheritance
The molecular basis of hemophilia A and B (FVIII and FIX genes)
Diagnosis of hemophilia carrier state
Incidence and clinical manifestations
Treatment of hemophilia
Plasma-derived and recombinant factor products
1-Deamino-8-D-arginine vasopressin (DDAVP) or desmopressin
Antifibrinolytic agents
Inhibitors
Management of inhibitors
Immune tolerance induction
Prophylaxis
von Willebrand disease
Screening tests
Platelet function analyzer (PFA-100™) closure time and bleeding time
vWF antigen
vWF activity (ristocetin co-factor activity)
vWF activity (collagen-binding activity)
Factor VIII activity (FVIII:C)
Ristocetin-induced platelet aggregation (RIPA)
vWF multimeric analysis
Factor VIII binding assay
The subtypes of vWD
Type 1 vWD
Type 2 vWD
Management of vWD
1-Deamino-8-D-arginine vasopressin (DDAVP) or desmopressin
Antifibrinolytics
Clotting factor concentrates
Estrogens
The molecular basis of vWD
Rare inherited bleeding disorders
Disorders of fibrinogen
Prothrombin deficiency
Factor V deficiency
Combined factor V and VIII deficiency
Factor VII deficiency
Factor X deficiency
Factor XI deficiency
Factor XIII deficiency
Vitamin K-dependent factor deficiencies
α2-Plasmin inhibitor deficiency (aka α2-antiplasmin deficiency)
References
35 Acquired bleeding disorders
Introduction
Physiological deficiencies
Neonates
Drug-induced bleeding disorders
Heparin
Laboratory monitoring8
Hirudin and bivalirudin
Newer anticoagulants
Laboratory monitoring
Warfarin and vitamin K antagonists
Laboratory monitoring
Thrombolytic agents
Laboratory monitoring
Anti-platelet drugs
Laboratory monitoring
Hemostatic defects associated with vitamin K deficiency
Vitamin K and vitamin K deficiency
Vitamin K deficiency in neonates and young infants
Vitamin K deficiency in adults
Laboratory findings
Management of vitamin K deficiency
Hemostatic defects in liver disease
Laboratory findings in liver disease
Management of the coagulopathy of liver disease
The INR in liver disease
Hemostatic defects associated with renal disease and uremia
Laboratory diagnosis
Treatment
Hemostatic defects associated with ‘massive’ blood transfusion
Laboratory diagnosis
Treatment
Hemostatic defects associated with the use of extracorporeal circuits
Quantitative platelet abnormalities
Qualitative platelet abnormalities
Clotting factor abnormalities and DIC
Fibrinolytic activity
Drugs
Acquired inhibitors
Laboratory monitoring
Treatment
Disseminated intravascular coagulation (DIC)
Laboratory diagnosis of DIC
Management of acute DIC
Chronic DIC
Acquired hyperfibrinolysis
Laboratory investigation of systemic hyperfibrinolysis
Management of systemic hyperfibrinolysis
Bleeding and malignancy
Acute leukemias
Myeloproliferative disorders
Paraproteinemias
Acquired inhibitors of coagulation
Laboratory findings in acquired inhibitors
Management of acquired inhibitors
Acquired von Willebrand syndrome
Snake venoms and other toxic coagulopathies
References
36 Natural anticoagulants and thrombophilia
Introduction
Coagulation
Classic cascade mechanism of coagulation vs. cell-based models of thrombin generation
Molecular mechanism
Vitamin K-dependent proteins and their binding to the membrane
Regulatory mechanisms
SERPINs: a family of coagulation inhibitors
Antithrombin
Protein C system
Protein C structure
Protein C activation complex
Protein C function
Protein S
Protein S function
Tissue factor pathway inhibitor TFPI
Protein Z-dependent protease inhibitor
Other inhibitors and co-factors
Thrombophilia
Hereditary deficiencies of natural anticoagulants
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Genetic polymorphisms causing abnormal function of coagulant factors
Activated protein C resistance and factor V Leiden
Prothrombin polymorphism
Dysfibrinogenemia
Alterations of fibrinolytic mechanisms
Excess of other procoagulant factors
Acquired thrombophilic states
Lupus anticoagulants and the antiphospholipid syndrome
Hyperhomocysteinemia
Malignancies and inflammatory conditions
Associations among congenital and/or acquired conditions
Evaluation, diagnosis and treatment
Evaluation and diagnosis: screening for thrombophilias?
Prevention and treatment
References
Section F: Immunohematology
37 Blood groups on red cells, platelets and neutrophils
Introduction
Red cell surface antigens
The ABO and H histo-blood-group systems and other carbohydrate antigens
ABO and H antigens
HDFN caused by ABO antibodies
Altered expression of ABO antigens in leukemia
Lewis antigens
ABH and Lewis antigens on tumors
The Rh blood-group system
Rh-deficiency syndrome, Rhnull and Rhmod
HDFN caused by Rh antibodies
The Kell system and Xk
Anti-K and HDFN
The Kell–Xk complex and McLeod syndrome
Blood groups on red cell transporters
Receptors and adhesion molecules
The Duffy antigen receptor for chemokines
Glycoproteins of the immunoglobulin superfamily
Raph blood group and CD151
Complement regulatory glycoproteins
Red cell glycoproteins that anchor the membrane to its skeleton
Associations with infectious disease
Platelet antigens
Glycoproteins expressing platelet antigens
Antigens on the GPIIb/IIIa (CD41/CD61 or αIIbβ3) complex
Antigens on the GPIa/IIa (CD49/CD29 or α2β1)complex
Antigens on the GPIb/IX/V (CD42) complex
Antigens on CD109
Fetal and neonatal alloimmune thrombocytopenia
Pathophysiology
Clinical features
Neutrophil antigens
Glycoproteins expressing neutrophil antigens
Antigens on Fcγ receptor III (FcγRIIIb, CD16)
Antigens on CD11/CD18
Neutrophil antigens on other glycoproteins
Clinical syndromes associated with neutrophil antibodies
Neonatal alloimmune neutropenia (NAIN)
Autoimmune neutropenia of infancy
Transfusion-related acute lung injury (TRALI)
References
38 Transfusion medicine for pathologists
Introduction
Blood supply systems throughout the world
Whole blood
Blood donor recruitment
Plasma
Whole blood
Medical history
Physical and laboratory examination of the blood donor
Collection of whole blood
Venipuncture and blood collection
Adverse reactions to blood donation
Special blood donations
Autologous blood donation
Directed donor blood
Therapeutic bleeding
Preparation, storage, and characteristics of blood components
Red blood cells
Fresh frozen plasma
Plasma and source plasma
Cryoprecipitate
Whole blood-derived platelet concentrates – platelet-rich plasma method
Whole blood-derived platelet concentrates – buffy coat method
Collection and production of blood components by apheresis
Platelet concentrates
Granulocyte concentrates
Mononuclear cell concentrates
Plasma
Peripheral blood stem cells
Selection of apheresis donors
Reactions in apheresis donors
Laboratory testing of donated blood
Compatibility testing (crossmatching)
Transfusion therapy
Transfusion of components containing red blood cells
Effects of red blood cell transfusion
Transfusion of products containing coagulation factors
Transfusion of platelets
Granulocyte transfusion
Blood derivatives
Transfusion of cytomegalovirus (CMV)-negative blood products
Irradiated blood components
Fibrin glue
Transfusion in special situations
Massive transfusion
Cardiovascular surgery
Transplantation
Neonates
Hemophilia
Provision of red cells in urgent situations
Exchange transfusion of the neonate
Autoimmune hemolytic anemia
Pregnant women
Autoimmune thrombocytopenia
Neonatal alloimmune thrombocytopenia
Neonatal alloimmune neutropenia
Rare blood types
Techniques of blood transfusion
Complications of transfusion: recognition and management
Transfusion reactions
Reactions to platelets
Graft-versus-host disease (GVHD)
Other complications of blood transfusion
Transfusion-transmitted diseases
Post-transfusion hepatitis
HIV infection and AIDS
Other transfusion-transmitted infectious diseases (Table 38.1)
Role of hematopoietic growth factors in transfusion medicine
Erythropoietin
Granulocyte-macrophage colony simulating factor (GM-CSF)
Platelet growth factor
Blood substitutes
References
39 Histocompatibility: HLA and other systems
Introduction
The human major histocompatibility complex
History
Genomic organization
The human leukocyte antigens
Genomic organization
Diversity
Expression
Structure of class I and class II molecules
Function
Peptide processing and binding
T lymphocyte recognition of HLA molecules
Allorecognition and transplantation
Non-classical MHC class I molecules
HLA-E
HLA-F
HLA-G
Other potential histocompatibility molecules
MHC class I chain-related molecules (MIC)
CD1 molecules
Minor histocompatibility antigens
Other immune system receptors that recognize histocompatibility molecules as their ligands
Killer cell immunoglobulin-like receptors
CD94 and NKG2
Leukocyte immunoglobulin-like receptors
Techniques for the identification of HLA polymorphism
Serologic detection of class I and class II allelic products
Cellular detection of HLA disparity
DNA-based identification of class I and class II alleles
Sequence specific priming (SSP)
Sequence-specific oligonucleotide probe hybridization (SSOPH)
Sequence-based typing (SBT) of genomic DNA
Measurement of sensitization to histocompatibility differences
HLA assignments
Serologic specificities
DNA-based allele designations
National Marrow Donor Program® (NMDP) DNA nomenclature
Limitations in the assignment of HLA alleles
Correlation between serologic specificities and DNA-based allele assignments
Identification of HLA in clinical situations
Autoimmunity
Drug hypersensitivity
Cell, tissue and organ transplantation
Solid organ transplantation
Platelets
HSC transplantation
Unrelated donor registries and umbilical cord blood banks
Search strategies for donor identification
Histocompatible matches for HSC transplantation
Summary
References
Subject Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z