Gao Qingping

1
General Hematology
Gao Qingping Department of Hematology
Renmin Hospital of Wuhan University
2

• ??Overview

3

• (?)Definition

4

• 1? Hematopoietic system

5
Components and functions of blood
Hematopoietic system is composed of the
blood and the hemopoietic organ
6

• (1)Blood

7
WBC
PLASMA
HAMOCYTE
PLT
RBC
Blood is composed of the plasma and the
hematocytes
8
PLASMA
PLT
WBC
RBC
Blood is about 7 percent of body weight,
blood volume 5 L. joining a small amount of
anticoagulant (such as heparin or sodium
citrate), the visible elements by natural
settlement or centrifugal precipitation can tell
the three-tier the yellow plasma in the upper,
the WBC and platelet middle and lower the red
blood cell
9
Two major components blood cells (cellular
fraction) plasma (non-cellular fraction)
10
Primary functions-1 RBC(red blood cell)
to transport O2 and CO2 Neutrophils
to destruct microorganism Lymphocyte to
mediate immune reaction Platelets to
promote hemostasis and coagulation
11
Primary functions-2 T cell
cell- mediated immune B cell
humoral-mediated immune Monocytes to
phagocytize and modulate immune Eosinophils
to be involved in IgE immune
reaction Basophils to be involved in
type I hypersensitivity
12

• Primary functions-3
• Plasma
• coagulation factors coagulation
• Immunoglobulins immune
• Complements immune

13

• (2)Hematopoietic organ

14
Yolk sac
bone marrow
liver
hematopoiesis in liver
hematopoiesis in bone marrow
hematopoiesis in Yolk sac
Hematopoietic cells occur in mesoderm(???)
in embryo. with the embryonic development, the
hematopoietic center transfer. the hematopoiesis
is divided into three phases prior to birth
spleen
lymphoid tissue
m
Hematopoiesis prior to birth
15
Yolk sac
bone marrow
liver
hematopoiesis in liver
hematopoiesis in bone marrow
hematopoiesis in Yolk sac
During embryogenesis, hematopoiesis occurs
in spatially(??) and temporally(??) distinct
sites, including the extraembryonic yolk sac, the
fetal liver, and the preterm(??) bone marrow
spleen
lymphoid tissue
m
Hematopoiesis prior to birth
16

• A? prior to birth

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• a?yolk sac

18
villus
amniotic sac
amnion
cardiac tube
Allantois ??
Cardiac cavity
body stalk ??
chorion???
Yalk sac
blood island
blood island
the embryo(19th day)
19
Yolk sac
The hematopoiesis in Yolk sac began in
embryonic in the 3rd week, and stop in the 9th
week The hematopoietic island of Yolk
sac walls is the 1st hematopoietic center
hematopoiesis in Yolk sac
m
Hematopoiesis prior to birth
20
Yolk sac
The development of primitive erythroblasts
in the yolk sac is critical for embryonic
survival Primitive erythroblasts
differentiate within the vascular network rather
than in the extravascular space and circulate as
nucleated cells
hematopoiesis in Yolk sac
m
Hematopoiesis prior to birth
21
Yolk sac
While it is widely assumed that primitive
red cells remain nucleated throughout their life
span, it is likely that many ultimately enucleate
upon terminal differentiation
hematopoiesis in Yolk sac
m
Hematopoiesis prior to birth
22

• b?liver

23
Mesencephl ??
blood stream in brain
medulla oblongata ??
nerve ending
eye
heart
umbilical cord
liver
hand
coccygeal vertebra ??
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liver
hematopoiesis in liver
The hematopoiesis in liver began in
liver in the 6rd week, reach the peak in
16th-20th weeks, and stop in the 24th week .
Liver generated mainly white and red blood cells,
no lymphocytes. Spleen, kidneys, thymus and lymph
node take part in hematopoiesis
hematopoiesis in Yolk sac
spleen
lymphoid node
m
Hematopoiesis prior to birth
25
liver
hematopoiesis in liver
Like primitive erythropoiesis in the
yolk sac, definitive erythropoiesis in the fetal
liver is necessary for continued survival of the
embryo
hematopoiesis in Yolk sac
spleen
lymphoid node
m
Hematopoiesis prior to birth
26
liver
hematopoiesis in liver
In contrast to the yolk sac, where
hematopoiesis is restricted to maturing primitive
erythroid, macrophage, and megakaryocytic cells,
hematopoiesis in the fetal liver consists of
definitive erythroid, megakaryocyte, and multiple
myeloid
hematopoiesis in Yolk sac
spleen
lymphoid node
m
Hematopoiesis prior to birth
27

• c?bone marrow and lymphoid tissue

28
The hematopoiesis in bone marrow began
in 4th month, bone marrow turned into
hematopoietic center in 5th month. Multipotent
stem cells came from embryonic liver and bone
marrow, lymphatic stem cells from the thymus
bone marrow
hematopoiesis in bone marrow
lymphoid tissue
spleen
m
Hematopoiesis prior to birth
29
bone marrow
hematopoiesis in bone marrow
lymphoid tissue
m
Hematopoiesis in adult
30

• A? adult

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• a?Bone marrow

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bone marrow
The marrow, located in the medullary cavity
of bone, is the sole site of effective
hematopoiesis in humans
m
Hematopoiesis in adult
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bone marrow
The marrow produces approximately six
billion cells per kilogram of body weight per day
m
Hematopoiesis in adult
34
bone marrow
Hematopoietically active (red) marrow
regresses after birth until late adolescence,
after which it is focused in the skull,
vertebrae, shoulder and pelvis, ribs, and sternum
m
Hematopoiesis in adult
35
bone marrow
Fat cells replace hematopoietic cells in
the bones of the hands, feet, legs, and arms
(yellow marrow). Fat occupies approximately 50
percent of the space of red marrow in the adult.
In very old individuals, a gelatinous(??? )
transformation of fat to a mucoid material may
occur (white marrow)
m
Hematopoiesis in adult
36
bone marrow
Yellow marrow can revert to
hematopoietically active marrow if prolonged
demand is present, as in chronic hemolytic
anemia. Thus, hematopoiesis can be expanded by
increasing the volume of red marrow and
decreasing the development time from progenitor
to mature cell
m
37

• b?lymphoid tissue

38
The lymphoid tissues can be divided
into primary and secondary lymphoid organs
lymphoid tissue
m
Hematopoiesis in adult
39
Primary lymphoid tissues are sites where
lymphocytes develop from progenitor cells into
functional and mature lymphocytes The
major primary lymphoid tissue is the marrow, the
site where all lymphocyte progenitor cells reside
and initially differentiate
lymphoid tissue
m
Hematopoiesis in adult
40
The other primary lymphoid tissue is
the thymus, the site where progenitor cells from
the marrow differentiate into mature
thymus-derived (T) cells
lymphoid tissue
m
Hematopoiesis in adult
41
Secondary lymphoid tissues are sites
where lymphocytes interact with each other and
nonlymphoid cells to generate immune responses to
antigens These include the spleen, lymph
nodes, and mucosa-associated lymphoid tissues
(MALT)
lymphoid tissue
m
Hematopoiesis in adult
42
The structure of these tissues provides
insight into how the immune system discriminates
between self antigens and foreign antigens and
develops the capacity to orchestrate a variety of
specific and nonspecific defenses against
invading pathogens
lymphoid tissue
m
Hematopoiesis in adult
43

• ?? Hematopoietic system disease

44
Diseases of red blood cells (RBC) Diseases
of white blood cells (WBC) Diseases of bleeding
and thrombosis
45

Multipotential stem cell
Multipotential stem cell
Myeloid progenitor
lymphoid progenitor
megakaryocytic progenitor
Myeloid-monocytic progenitor
erythroid progenitor
megakaryoblast
plasmoblast
myeloblast
monoblast
myeloblast
pronormoblast
lymphoblast
promyelocyte
promegakaryocyte
Basophilic nor
promonocyte
prolymphocyte
myelocyte
Polychromatic nor
Granular Meg
proplasmocyte
monocyte
orthochromatic nor
lymphocyte
metamyelocyte
Thrombocytogenous Meg
bang granulocyte
reticulocyte
lymphocyte
BM PB
monocyte
plasmocyte
Naked nucleus Meg
Segmentai granulocyte
macrophage
platelet
T cells
B cells
nutrophil
RBC
eosinophil
basophil
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• (?) Diseases of red blood cells

47

• 1?Anemia

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iron deficiecy anemia (IDA) aplastic anemia
(AA) pure red cell aplassia (PRCA) hemolytic
anemia (HA) megaloblastic anemia
(MA) Thalassemia anemia of chronic disease (ACD)
sideroblastic anemia (SA)
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iron deficiecy anemia (IDA) hypochromic
microcytic anemia Ferritin decreased(lt12µg) BM
iron stain absent siderocytes
lt15 FEP/HB gt4.5µg/gHb
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aplastic anemia (AA) peripheral
pancytopenia Reticulocytes decreased no
adenopathy or organomegaly Marrow
hypocellularity except PNH?MDS and leukemia
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• 2? Erythrocytosis

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Diseases of red blood cells Erythrocytosis Polycy
themia Vera (PV) Secondary Erythrocytosis
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Polycythemia Vera (PV) Major Criteria total
RBC vol mengt36mg/kgwomengt32mg/kg arterial
O2 saturationgt92 Splenomegaly Minor
Criteria Platelet countgt400x109/L
Leukocytosisgt12x109/L LAPgt100(no infection)
Serum B12gt900pg/ml
54

• (?) Diseases of white blood cells

55

• 1? leukopenia

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leukepeania neutropenia agranulocytosis
    

    

    
57
Leukepeania lt
4109/L Neutropenia Mlid
lt 2109/L Moderate
lt 1109/L severe
(agranulocytosis) lt.5109/L very severe
lt.2109/L
58

• 2? Leukocytosis

59
Leukecytosis Leukemia (AML, ALL, CML,
CLL) Lymphoma (HL,NHL) Multiple Myeloma
(MM) Myelodysplastic syndrome (MDS) Leukemoid
Reactions
60

• (?) Diseases of bleeding and thrombosis

61

• 1? abnormalities of platelet and vascular function

62

• (1) abnormalities of vascular function

63

• A?hereditary

Hereditary hemorrhagic telangiectasis Epistaxis(??
) Telangiectasia(??????) visceral
lesions(????) and an appropriate family
history(????)
64

• B?acquired

Pyemia(????) Allergic purpura Vitmine C
deficiency
65

• (2) abnormalities of platelet

66

• A?abnormalilties of platelet count

67
(No Transcript)
68

• a?thrombocytopenia

Increased platelet destruction Decreased platelet
production
69

• Increased platelet destrution

Immune destruction  Autoantibodies ITP
disease-associated IT (SLE,CLL)
Alloantibodies post-transfusion purpura
neonatal purpura
Drug-induced IT quinidine
quinine Infection
HIV hepatitis
cytomegalovirus, Epstein-Barr
70

• Increased platelet destrution

Nonimmune destruction Infection
(bacterial, viral, malarial) TTP/HUS
DIC
71

• Platelet loss

massive bleeding
72

• Platelet redistribution

enlarged splenic pool Congestive
splenomegaly Other (NHL, Gaucher's
disease, etc.
73

• Decreased platelet production

Myeloproliferative disorders leukemia,
MM, myelofibrosisLymphoproliferative disorders
non-Hodgkin's lymphoma, CLLAplasia or
hypoplasia idiopathic, drug induced,
radiationIneffective hematopoiesis
myelodysplasia, vit B12 or folate
deficiencyMyelophthisis(??? ) prostate,
lung, breast, gastrointestinal cancersDrugs
chemotherapy, thiazide(??), alcohol
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• b?thrombocythemia

Essential (primary) thrombocythemia Secondary
thrombocythemia infection
tumor acute bleeding
hemolysis response to surgery and
drug desmosis(?????)
75

• B?abnormalities of platelet function

76

• a?disorders of adhesion

77

• b?disorders of aggregation

78

• c? disorders of granule release

79

• (3) coagulation deficiencies

80
Coagulation Deficiency Inheritance Pattern Prevalence Minimum Hemostatic Level Replacement Sources
Factor I     50100 mg/dL Cryoprecipitate/FFP
Afibrinogenemia AR Rare (lt300 families)    
Dysfibrogenemia AD or R Rare (gt300 variants)    
Factor II AD or R Rare (25 kindreds) 30 of normal FFP, factor IX complex concentrates
Factor V AR 1 per 1 million births 25 of normal FFP
Factor VII AR 1 per 500,000 births 25 of normal Recombinant factor VIIa (2030 µg/kg), FFP, factor IX complex concentrates
Factor VIII XR 1 per 5000 male births 80100 for surgery/life-threatening bleeds, 50 for serious bleeds, 2530 for minor bleeds Factor VIII concentrates
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vWD 1 and 2 variants   AD   1 gt50 vWF antigen and ristocetin cofactor activity DDAVP cryoprecipitate and FFP factor VIII
vWD 3 AR 1 per 1 million births gt50 vWF antigen and ristocetin cofactor activity DDAVP cryoprecipitate and FFP factor VIII
Factor IX XR 1 per 30,000 male births 2550 FFP
Factor X AR 1 per 500,000 births 1025 FFP
Factor XI AD or AR 1 per 1 million population 2040 FFP
Factor XII AR Not available No treatment
Factor XIII AR 1 per 3 million births 5 FFP, cryoprecipitate
82

• (4) Coagulopathies Secondary to Anticoagulation

83

• Coagulopathies Secondary to Anticoagulation

The most common acquired clinical coagulopathies
occur secondary to anticoagulation with warfarin
and other coumarin analogues and to the use of
heparin
84

• ??clinical manifestation
• of hematopoietic system disease

85

• (?)anemia

86
Renmin Hospital of Wuhan University
87

• Anemia is a common blood disorder. Women and
  people with chronic diseases are at increased
  risk of the condition

88

• Common causes of anemia
• Iron deficiency anemia
• Vitamin deficiency anemias
• Anemia of chronic disease
• Aplastic anemia
• Anemias associated with bone marrow disease
• Hemolytic anemias
• Other anemias

89

• The main symptom of most types of anemia
  is fatigue
• Other anemia symptoms include
• weakness pale skin a fast or irregular
  heartbeat shortness of breath chest pain
  dizziness numbness or coldness in your
  extremities headache

90

• (?)hemorrhage

91

• Bleeding severity can range from mild
  local bleeding at a small injury to massive
  hemorrhage

92

• Internal bleeding may also show via blood
  in stool, blood in urine, or gastrointestinal
  bleeding
• Other common sites for bleeding symptoms
  include nosebleeds, digestive bleeding, vaginal
  bleeding, rectal bleeding, and bleeding gums
• Bruising is also related to bleeding

93

• Excessive unexplained bleeding or
  bleeding easily can be caused by numerous
  diseases including bleeding disorders and several
  severe diseases (e.g. Leukemia)
• Any type of bleeding is a severe symptom
  that needs prompt professional medical diagnosis

94

• (?)fever

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• Fever is a frequent medical sign that
  describes an increase in internal body
  temperature to levels above normal
• Fever is most accurately characterized as a
  temporary elevation in the body's
  thermoregulatory set-point

96

• Fever is a common symptom of many medical
  conditions

97

• Infectious
• Non- Infectious
• Drug fever
• Cancers

98

• (?)jaundice

99

• causes of Jaundice
• hemolytic jaundice (Hemolytic anemia)
• liver diseases Hepatitis (Viral Autoimmune)
• obstruction jaundice

100

• (?) ostealgia

101

• The cause of the bone pain may not be
  immediately apparent, and further testing is
  usually warranted (CBC, x-rays, etc)

102

• Diseases affecting bones
• Leukemia - present with bony tenderness
  due to blast cells that have surfaced to the top
  of the bone
• Sepsis/Bacteraemia - infection of the
  blood
• Neoplasm/Cancer - can be primary bone
  tumour or may be metastatic (spread from another
  neoplastic site)

103

• (?) splenomegaly

104

• Splenomegaly is an enlargement of the
  spleen, which usually lies in the left upper
  quadrant (LUQ) of the human abdomen

105

• Splenomegaly is one of the four cardinal
  signs of hypersplenism, the other three being
  cytopenia(s), normal or hyperplastic bone marrow,
  and a response to splenectomy

106
Splenomegaly grouped
Increased function Infiltration
Removal of defective RBCs spherocytosisthalassemiahemoglobinopathiessickle cell anemiaImmune hyperplasiaAutoimmune hemolytic anemiaImmune thrombocytopeniaMyelofibrosis Metabolic diseasesGauchers diseaseNiemann-Pick diseaseAmyloidosisinfiltrationsLeukemialymphoma myeloproliferative disorderseosinophilic granuloma
107

• (?) lymphadenectasis

108

• Lymph nodes play a vital role in your
  body's ability to fight off viruses, bacteria and
  other causes of illnesses

109

• Some 600 lymph nodes are situated
  throughout your body, with the majority in your
  head and neck. The lymph nodes that most
  frequently swell are in your neck, under your
  chin, in your armpits and in your groin
• The site of the swollen lymph nodes may
  help identify the cause

110

• following signs and symptoms depended on the
  cause of your swollen lymph nodes

111

• General swelling of lymph nodes throughout your
  body, indicative of infections such as HIV or
  mononucleosis, an infection of the glands, or
  immune disorders, such as lupus or rheumatoid
  arthritis

112

• Red, inflamed skin over the swollen lymph
  node, Swollen limb, possibly indicating lymph
  system blockage caused by swelling in a lymph
  node too far under your skin to feel
• Hardened, fixed, rapidly growing nodes,
  possibly indicating a tumor (rare)

113

• cause of swollen lymph nodes
• Common infections (virus infection)
• Other infections (TB, Toxoplasmosis)
• Cancers (Lymphoma Leukemia)

114

• (?) characteristic of clinical
  manifestation

115

• 1?there is no specific manifestation

116

• Anemia is a common blood disorder.
• Aplastic anemia (blood disease)
• Anemias associated with bone marrow
  disease (carcinoma metastaticum )

117

• 2?secondary hematopoietic manifestations
  are common

118

• 3?it is important for laboratory tests to
  diagnose hematopoietic disease

119

• ?? Laboratory Tests

120

• (?)Examination of the blood

121

• Examination of the blood is central to
  the diagnosis and management of hematologic
  diseases
• Assessment of the prevalence of red
  cells, of the several types of leukocytes, and of
  platelets, usually from automated particle
  counters

122

• Examination of the blood film for
  qualitative changes in the appearance of red
  cells, leukocytes, and platelets,and the presence
  of marrow precursors, malignant cells, and
  intracellular parasites can be used to diagnose
  specific diseases
• Gain insight into pathophysiology, and
  measure the response to treatment

123

• 1?blood routine

124

• White blood cells (WBC) 4-10109/L
• Differential Counting (DC) (N.L.M.E.B)
• Red blood cells (RBC) 4-5.5 or 3.5-51012/L
• Hemoglobin (HB) 120-160 or 110-150 g/L
• Hematocrit (Hct)
• MCV (mean corpuscular volume ) 80-100fl
• MCH (mean corpuscular hemoglobin ) 27-34pg
• MCHC(MCH concentration)
  320-360g/L
• Platelet
  100-300109/L

125

• 2?Reticulocyte

126

• Reticulocyte 0.5-1.5
• 24-84109/L

127

• 3?blood film

128
1 RBC
5 lymphocyte
2 eosinophil
6 monoocyte
3 basophil
4 neutrophil
7 platelet
129

• (?)Examination of the Marrow

130
Aspirate of BM (puncture of anterior superior
iliac spine )
131
biopsy of BM (biopsy of anterior superior iliac
spine )
132

• Microscopic examination of the BM is a
  mainstay of hematologic diagnosis
• Even with the advent of specialized
  biochemical and molecular assays, the primary
  diagnosis of hematologic malignancies and many
  nonneoplastic hematologic disorders relies upon
  examination of the cells in the BM

133

• Aspirate and biopsy of BM can be obtained
  with minimal risk and only minor discomfort and
  are quickly and easily processed for examination
  

134

• The BM should be examined when the
  clinical history, blood cell counts, blood film,
  or laboratory test results suggest the
  possibility of a primary or secondary hematologic
  disorder for which morphologic analysis or
  special studies of the BM would aid in the
  diagnosis

135

• Leukopenia, thrombocytopenia,
  bicytopenia, or tricytopenia nearly always
  require a marrow examination for diagnosis

136

• Nonhemolytic anemia that is not readily
  diagnosed as iron deficiency, thalassemia,
  vitamin B12 deficiency, folate deficiency, or
  another type of anemia defined by blood cell
  examination and supporting laboratory tests often
  requires a BM examination

137

• (?)The Cluster of Differentiation (CD) Antigens

138

• The cluster of differentiation (CD)
  antigens are cellular molecules that are each
  recognized by monoclonal antibodies (MAbs) that
  allow for the identification each molecule's
  biochemical properties and cellular distribution

139

• The CD number for each molecule is
  defined at international workshops that exchange
  such Mabs and compare their ability to react with
  human cells and/or human cell molecules

140

• This chapter provides an overview of the
  nearly 250 CD antigens defined as of the seventh
  international workshop, listing the other names
  for these CD antigens along with their
  biochemistry, membrane-orientation, genetics, and
  cellular distribution on hematopoietic cells

141

• (?)Hematopoietic Stem Cells, Progenitors, and
  Cytokines

142

• Blood cell production is an enormously
  complex process in which a small number of
  hematopoietic stem cells (HSCs) expand and
  differentiate into an excess of 1011 cells each
  day

143

• Based on a number of strategies available
  to the experimental hematologist a hierarchy of
  hematopoietic stem, progenitor, and mature blood
  cells is emerging in which each successive
  developmental stage loses the potential to
  differentiate into a specific type or class of
  cells

144

• The stem and progenitor cells give rise
  to the formed elements of the blood

145

• the roles played by transcription factors
  and external signals in lineage fate
  determination, the cytokines and cell adhesion
  molecules that support cell survival,
  self-renewal, expansion and differentiation, and
  the cell surface properties that allow for their
  purification, and biochemical and genetic
  characterization

146

• A thorough understanding of hematopoietic
  stem and progenitor cells and their supportive
  microenvironment can provide critical insights
  into developmental biology of multiple cell
  systems, favorably impact blood cell development
  for therapeutic

147

• (?)Genetic Principles and Molecular Biology

148

• The understanding of hematology is more
  than ever dependent upon an appreciation of
  genetic principles and the tools that can be used
  to study genetic variation

149

• All of the genetic information that makes
  up an organism is encoded in the DNA. This
  information is transcribed into RNA and then the
  triplet code of the RNA is translated into protein

150

• Changes that affect the DNA or RNA
  sequence, either in the germ line or acquired
  after birth, can cause many hematologic
  disorders. These may be mutations that change the
  DNA sequence, including single base changes,
  deletions, insertions, or duplications, or they
  may be epigenetic changes that affect gene
  expression without any change in the DNA sequence

151

• (?)Cytogenetics and Gene Rearrangement

152

• Cytogenetic analysis provides
  pathologists and clinicians with a powerful tool
  for the diagnosis and classification of
  hematologic malignant diseases

153

• The detection of an acquired, clonal,
  somatic mutation establishes the diagnosis of a
  neoplastic disorder and rules out hyperplasia,
  dysplasia, metaplasia, and aplasia, morphologic
  changes that may be a result of toxic injury,
  inflammation, degeneration, or vitamin deficiency

154

• A number of specific cytogenetic
  abnormalities have been identified that are very
  closely, and sometimes uniquely, associated with
  morphologically and clinically distinct subsets
  of leukemia or lymphoma, enabling clinicians to
  predict their clinical course and likelihood of
  responding to particular treatments

155

• The detection of one of these recurring
  abnormalities is helpful in establishing the
  diagnosis and adds information of prognostic
  importance

156

• In many cases, the prognostic information
  derived from cytogenetic analysis is independent
  of that provided by other clinical features.
  Patients with favorable prognostic features
  benefit from standard therapies with well-known
  spectra of toxicities

157

• (?) Apoptosis

158

• Apoptosis is a physiologic form of cell
  death that has evolved in multicellular organisms
  as a mechanism of eliminating unwanted cells

159

• Apoptosis is a cell-autonomous process
  that may be triggered through a receptor or
  through the detection of cellular damage

160

• It involves a coordinated series of
  enzymatic steps orchestrated by activation of a
  special class of proteases (caspases) and is
  controlled by inhibitors at each step, conferring
  tight control over this lethal process

161

• The cell destruction process is
  accompanied by alterations in most organelles,
  particularly mitochondria, as well as changes to
  the cytoskeleton, plasma membrane, and ion
  transport systems, and culminates in the
  degradation of nuclear DNA through the action of
  endonucleases

162

• (?) Cell Cycle Regulation

163

• Complex feedback pathways regulate the
  passage of cells through the G1, S, G2, and M
  phases of the growth cycle. Two key checkpoints
  control the commitment of cells to replicate DNA
  synthesis and to mitosis

164

• Many oncogenes and tumor-suppressor genes
  promote malignant change by stimulating cell
  cycle entry, or disrupting the checkpoint
  response to DNA damage

165

• Advances in the understanding of
  epigenetic gene expression regulation provide the
  basis for novel therapeutic approaches

166

• (?) Signal Transduction Pathways

167

• Essentially all external influences on
  cells of any organ are mediated by biochemical
  and molecular mechanisms that are triggered by
  interactions with membrane, cytoplasmic, or
  nuclear receptors

168

• Recently, our understanding of the
  receptors and the intermediate molecules that
  couple them with cellular pathways that influence
  the proliferation, activation, differentiation,
  or survival of hematopoietic cells has expanded
  significantly

169

• (?) The Inflammatory Response

170

• The inflammatory response is
  characterized by a rapid but relatively
  short-lived increase in local blood flow, an
  increase in microvascular permeability, and the
  sequential recruitment of different types of
  leukocytes

171

• Superimposed is a series of reparative
  processes (e.g., parenchymal regeneration,
  angiogenesis, production of extracellular matrix,
  and scar formation

172

• The early hemodynamic changes at a site
  of inflammation establish conditions that enable
  marginated leukocytes to engage in low-affinity
  selectin-mediated rolling interactions with
  endothelial cells

173

• In response to locally produced soluble
  and cell surface mediators, endothelial cells and
  rolling leukocytes become activated and
  sequentially express sets of complementary
  adhesion molecules that include 2 integrins,
  selectins, and members of the immunoglobulin
  superfamily

174

• Leukocyte and endothelial cell adhesion
  molecules mediate the high-affinity adhesive
  interactions necessary for leukocyte emigration
  from the vascular space and along chemotactic
  gradients

175

• ?? Therapeutic Principles

176

• (?) Antineoplastic therapy

177

• The safe and effective use of anticancer
  drugs in the treatment of hematologic
  malignancies requires an in-depth knowledge of
  the pharmacology of these agents

178

• In this field of medicine, the margin of
  safety is narrow and the potential for serious
  toxicity is real. The safe and effective use of
  anticancer drugs in the treatment of hematologic
  malignancies requires an in-depth knowledge of
  the pharmacology of these agents

179

• In this field of medicine, the margin of
  safety is narrow and the potential for serious
  toxicity is real At the same time, anticancer
  drugs cure many hematologic malignancies and
  provide palliation for others

180

• The discovery and development of
  treatments for leukemia and lymphoma have
  provided a paradigm for approaches to the
  improved treatment of the more common solid
  tumors

181

• (?) Treatment of Infections in the
  Immunocompromised Host

182

• Infection is a major cause of morbidity
  and mortality in patients receiving chemotherapy
  for treatment of hematologic neoplasms

183

• Severe neutropenia and monocytopenia
  often result from the combined effects of
  replacement of marrow with malignant cells and
  superimposed intense chemotherapy

184

• The severity and duration of the
  neutropenia determine the risk of infection.
  Bacterial infections may result in rapid clinical
  deterioration and, if not treated appropriately,
  death

185

• Fungal, viral, and parasitic infections also may
  result in potentially lethal complications during
  and after chemotherapy. Methods of diagnosis of
  bacterial, fungal, viral, and protozoal infection
  are considered and treatment regimens described

186

• The introduction of home antibiotic
  therapy is noted and may be appropriate for
  certain patients. Because prevention of infection
  during periods of neutropenia should reduce
  morbidity and improve outcome, attention is
  focused on various means of prophylaxis of
  bacterial, parasitic, viral, and fungal
  infections

187

• (?) Antithrombotic Therapy

188

• Antithrombotic drugs are among the most
  commonly used in medicine and are generally
  separated into anticoagulants, fibrinolytic
  agents, and platelet inhibitors based on their
  primary mechanism of action

189

• Warfarin is the only currently available
  oral anticoagulant. It acts by inhibiting vitamin
  K action, has a prolonged effect, requires
  monitoring, and is widely used for prevention and
  treatment

190

• Unfractionated heparin and the low
  molecular weight heparins are the most commonly
  used rapidly acting parenteral anticoagulants
  they inhibit activated serine proteases through
  antithrombin

191

• One synthetic agent in this class,
  fondaparinux, is specific for inhibition of
  factor Xa, and is effective for prevention and
  treatment of venous thromboembolism
• Several direct thrombin inhibitors have
  excellent anticoagulant action and offer an
  alternative to heparins

192

• Several fibrinolytic agents are
  available, all of which convert plasminogen to
  plasmin to accelerate clot lysis. Differences
  among them include their degree of fibrin
  specificity, half-life, and antigenicity.
  Antiplatelet agents play an important role in
  prevention and treatment of arterial thrombosis

193

• (?) Hematopoietic Cell Transplantation

194

• Hematopoietic cell transplantation has
  evolved from a treatment of last resort for
  patients with refractory leukemias to an
  effective, and in some instances front-line,
  therapy for a broad array of hematologic
  malignancies and genetic disorders of the marrow
  and selected solid tumors

195

• (?) Immune Cell Therapy

196

• Antigen-specific T cells, which recognize
  processed fragments of proteins presented in
  association with major histocompatibility complex
  (MHC) molecules, represent an important component
  of the host response to intracellular pathogens
  and tumors

197

• Adoptive T cell immunotherapy, in which
  T cells are administered to augment or establish
  an immune response, is an emerging modality for
  the treatment of both infectious and malignant
  diseases

198

• Studies in murine models have elucidated
  many of the principles for effective T cell
  therapy and provided valuable insights for
  applying this approach to the treatment of human
  disease

199

• Over the past few years, advances in
  cellular and molecular immunology have resulted
  in the identification of candidate target
  antigens for immunotherapy and the development of
  efficient techniques for isolating and
  propagating T cells

200

• Dendritic cells (DCs) have been
  identified as specialized antigen-presenting
  cells (APCs) that elicit and regulate
  antigen-specific CD4 and CD8 T cell immunity in
  vivo. Culture techniques that use DCs have been
  used to facilitate the in vitro isolation of
  antigen-reactive T cells for cell therapy

201

• (?) Vaccine Therapy

202

• Vaccines are biologic substances that are
  designed to stimulate the host immune system to
  elicit a neutralizing response against clinically
  relevant targets

203

• Active immunotherapy with vaccines has
  been extremely effective as prevention against
  self-limiting infectious pathogens. However,
  effective vaccine therapy of chronic infectious
  diseases or cancer, in the therapeutic setting,
  remains a promising but largely unrealized goal

204

• Hematologic malignancies are an excellent
  model system for vaccine therapies, in part
  because of accessibility and susceptibility to
  immune effector mechanisms and availability of
  tumor cells for studies of mechanism

205

• (?) Therapeutic Apheresis

206

• Therapeutic apheresis provides a means to
  rapidly alter the composition of blood
  components. It can be a valuable and safe initial
  treatment of a number of illnesses associated
  with quantitative and/or qualitative
  abnormalities of blood cells or plasma

207

• Cell depletions are useful in symptomatic
  thrombocythemia and hyperleukocytosis. They
  provide autologous or allogeneic stem and
  progenitor cells for hematopoietic reconstitution
  or immunocytes for immunomodulation

208

• Plasma exchange is useful in certain
  paraproteinemias, antibody-mediated disorders,
  and toxin-mediated diseases. It also can be used
  to replace a deficient plasma constituent. Red
  cell exchange is used primarily for severe
  manifestations of sickle cell disease

209

• Selective extraction techniques are
  available for immunoglobulin G and low-density
  lipoprotein, and modulation of certain immune
  responses is possible with photopheresis. Adverse
  effects with current techniques are infrequent
  and usually mild

210

• (?) Gene Transfer for Therapy

211

• The term "gene therapy" describes
  treatment resulting from insertion of a gene(s)
  into somatic cells. High-level expression of a
  transferred gene (or transgene) can be achieved
  in almost any type of mammalian cell

212

• Once inside the cell, the transgene can
  direct synthesis of an intracellular cell surface
  or secreted protein that can complement a genetic
  deficiency or confer upon the cell a desired
  phenotype or function

213

• Alternatively, the transferred genetic
  material can repress expression of genes encoding
  unwanted or mutated proteins through "gene
  interference" or gene complementation

214

• Conceivably, transfer and expression of
  appropriate genes could correct genetic
  deficiencies or generate somatic cells with a
  desired characteristic(s) that can result in
  therapeutic benefit

215

• Many clinical trials have involved gene
  therapy for patients with various hematologic
  diseases, such as leukemia, lymphoma, Gaucher
  disease, aplastic anemia, hemoglobinopathies, or
  coagulation factor deficiencies

216

• The full application of this technology
  in clinical practice has not yet been realized

217

• (?) Pain Management

218

• The ancient Greeks said it well "Call no
  mortal happy til he has passed the final limit of
  his life secure from pain" (Sophocles, Oedipus
  the King, trans. David Grene University of
  Chicago Press, 1954)

219

• Hematologists are singularly trained to
  appreciate the wisdom of this quote. Pain is a
  frequent visitor to the hematologist's waiting
  room

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Thank you