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Hematologic Diseases
General Introduction
of Hematology
2015/7/21
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Components and functions of blood
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Two major components:
blood cells(cellular fraction)
plasma (non-cellular fraction)
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Primary functions :
red blood cell: to transport O2 and CO2
neutrophils: to destruct microorganisms
lymphocyte: to mediate immune reaction
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T cell: (thymus dependent ): cell- mediated
immune
B cell: (BM dependent ): humoral-mediated
immune
Monocytes: to phagocytize and modulate immune
reaction
Eosinophils: to be involved in IgE immune
reaction
Basophils: to be involved in type I
hypersensitivity
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Plasma: relevant to coagulation factors,
immunoglobulins and complements
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Compositions of hematopoietic organs
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Hematopoietic organs: blood, bone marrow, liver,spleen,
lymph nodes
Structure of bone marrow:
outside cortex:
inside medulla : 50% hematopoietic and 50% fat tissues
hematopoietic cells are arranged in cords around sinusoid
mature cell are released into sinusoid through endothelia
cell of sinus
abundant blood vessles are linked to sinusoid
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Hematopoiesis in adult:
To be confined to bone marrow and
lymphocyte
Hematopoiesis in fetal:
Yolk sac, liver and spleen
Extramedullary hematopoisis:
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Process of hematopoiesis
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Hematopoietic cell:
Pluripotential stem cell
CD34+/ CD38A small compartment of stem cells
A large compartment of proliferating cells of
committed lineage
A large compartment of maturing cells of both
myeloid and lymphoid
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Hematopoietic growth factor:
Erythropoietin(EPO):
G-CSF,GM-CSF :
Thrombopoietin (TPO), IL-11:
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Classification and characteristics
of hemayologic diseases
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Diseases of red blood cells:
Aplastic anemia, IDA, hemolytic anemia,
megaloblastic anemia, thalassemia,
sideroblastic anemia
Diseases of white blood cells:
Leukepeania, leukecytosis, leukemia,
lymphoma, myeloma, myelodisplastic
syndrome(MDS)
Diseases of bleeding and thrombosis: ITP, DIC,
hemophila
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Characteristics of blood diseases
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Numerous types
Low incidence
High mortality
Poor prognosis
Multi-system involved
Lab-test dependent diagnosis
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Diagnosis of hematopoietic diseases
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History: symptoms, period of diseas, inductive
factors, personal history, occupation history,
family history, diet habit, drug take-in history, age,
sex
Physical examination: pallor, purpura, fever,
sternum tenderness, lympho node,
hepatomegaly, splenomegaly
Laboratory tests: BRT, morphology, bone marrow
biopsy, DIC examination, hemolytic examination,
biochemical and immunologic examination,
chromosome banding technique, FCM detection
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The progresses in hematologic diseases
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Immunotherapy: leukemic vaccine, dendritic
vaccine, cytokine gene-transduced vaccine,
recombinant hematopoietic growth factor : rIL2,rIL-11,rTPO, rEPO,rGM-CSF,
Hematopoietic stem cell transplantation:
BMT,peripheral stem cell transplantation, cord
blood transplantation
Gene therapy: hemophilia, thalassemia, leukemia,
gene chip
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Introduction of anemia
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Concept of anemia
Anemia is a syndrome, not a name of a
disease
Anemia is a common symptoms in many
diseases
In anemia status, Hb and RBC are lower
than normal
Decreases of Hb is more important in judge
degree of anemia
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Causes and mechanisms of anemia
The injury of progenitor of erythrocyte:
physical,chemical, viruses factors
The lack of hematopoietic factors: ferritin,vitB12,
folic acid,vitB6,vitC
The lack of bone marrow tissues: leukemia,
lymphoma,MM, solid tumor infiltrate to bone
marrow
Increase of red blood cell destruction: hereditary
and acquied hemolytic anemia: abnormal of
RBCmembrane, Hb, RBC enzymes
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Classification of anemia
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According to the causes and mechanisms of
anemia to type:
Decrease of red blood cell production(AA,
IDA,leukemia)
Increase of red blood cell destruction
(hemolytic anemia)
Acute or chronic blood loss, GI tumor
hypermenorrhea, hemorrhiod, hook-worm
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Accoding to morphology:
Microcytic hypochromic anemia:IDA
Megalocytic anemia: deficiency folic acid and
vitB12
Normal erythrocytic anemia: AA, hemolytic
anemia
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Clinic features of anemia
Shortness of breath on exertion
Palpitation
Tiredness, weakness or fatigue
Faintness tinnitus
Headache
Spots before the eyes
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Factors influencing symptoms of anemia:
The rapidity of onset and severity of anemia
The ability of patients to make cardiovascular
compensations
Age: old person with severe symptoms
Sex: female with severe symptoms
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Diagnosis of anemia
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Whether anemia exist
How severe anemia is
Original causes diseases of anemia
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Treatment of anemia
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Primary diseases and causes
Supportive treatment: blood transfusion
Hematopoietic factors: EPO, iron, folic acid
vitb12
Immune suppressor: CsA, Prednision,
Splenectomy: HS AIHA
BMT: AA, PNH, MDS
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Iron Deficiency Anemia(IDA)
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Concept and characters of IDA
IDA is usually caused by chronic blood loss or
lack of hematopoietic nutrient ferritin by
malabsorption.
The morphologic characteristic of IDA is
microcytic hypochromic anemia.
IDA is one of the most common nutritious anemia
in the world.
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Iron metabolisms
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In general, iron metabolism depends on a precise
balance between iron absorption and excretion.
Iron is supplied by food,10 to 20 mg of iron is presented
in the average daily food, which is enough to healthy
adult male and nonmenstrating female.
Iron absorption occurs mainly in the duodenum and
proximal jejunum. Gut mucosal cells regulate
absorption by storage iron.
Normally, 5-10% dietary iron is absorbed.
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Iron enters the mucosal cells is either bound to
transferrin or transported into the portal
circulation or remains in the mucoscal cell .
Transferrin delivers either to bone marrow
tissues for Hb synthesis or to liver to store.
The reticuloendothelial system phagocytoses
senescent red blood cells. About 2/3 iron
obtained by metabolism of Hb within the
reticuloendothelial system binds rapidly to
plasma transferrin for transport to marrow
reuseness. The others is stored within the
macrophage as ferritin or hemosiderin.
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Approximately 1mg of iron is lost daily by the
adult male and nonmenstruating female via
sweet, urine, stool. Menstruating females lose
an additional 10-30mg of iron with each
menstrual period.
Daily needed iron:
adult male: 1mg/d
children: 2mg/d
menstruating female: 3mg/d
pregnant and breast feeding woman: 4mg/d
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Causes and primary disease of IDA
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Inadequate dietary iron related to inappropriate
food , Iron deficiency occurs more commonly in
populations whose diets often lacking of meats.
Increased iron requirement: woman with
menstruation and pregnancy. Infancy and
adolescence when growth is rapid.
Decreased iron absorption: partial and total
gastrectomy and achlorhydria.
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Blood loss: predominant cause of iron deficiency
young woman -menstrual blood loss: during a
normal menstrual period, approximately 32mg
iron may be lost(2:1)
old man and non-menstrual woman-gastrointenstinal blood loss : GI tumor,
young man blood loss – peptic ulcer, hemorrhoid,
children blood loss – hookworm disease,
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Clinical features of IDA
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General symptoms of anemia: palpitation, shortness
of breath, tiredness, headache
Specific symptoms of IDA: spoon-shaped
nails(koilonychia) with dry , brittle, ridged changes
A hunger for unusual substances : ice, clay, hair,
Digestive symptoms: sore tongue, atrophy of the
gastric mucosa, plummer-vinson syndrome
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Laboratory tests of IDA
BRT: Hb decrease, WBC and platelet are normal
Bone marrow: microcytic hypochromatic
changes in morphology, intracellular iron is
<15%, extracellular iron is negative
Iron metabolism index: serum iron decrease,
serum ferritin protein decrease, total iron binding
capacity increase
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Diagnosis and differential diagnosis
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History
Morphologic characteristics of RBC
BM examination and iron staning
Serum iron and serum ferritin level
Diagnostic treatment with iron
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Treatment of IDA
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Treatment of primary diseases
Treatment with iron –ferrintherapy
Oral iron: ferrous sulfate: 300mg tablet daily
and gradually increase to three time daily post
meal
Injection iron: iron dextran: im, 50-100mg
daily,total iron needed:
( Hb15g/dl -patient’s Hbg/dl ) x300mg+500mg
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Hemolytic anemia
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Introduction
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Hemolytic anemia results from an increased
rate and speed in RBC destruction.
BM has the capacity to compensate production
of RBC from 6-8 folds. Compensated hemolytic
disease has a persistently elevated reticulocyte
count with a normal Hb.
In situ hemolysis: RBC are destructed in BM
before they are released into blood (<10%)
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Extravascular hemolysis: RBC are
phagocytosed by reticuloendothelial
system and removed from the circulation
because of inflexible prematurely. AIHA,
HS,
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Intravascular hemolysis : RBC are actually
lysed in the circulation and blood vessels.
PNH, DIC
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physiopathology of hemolytic anemia
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Increased hemolysis:
Increased serum bilirubin
Increased urine urobilinogen
Decreased serum haptoglobin
Increased production of RBC:
Reticulocytosis and polychromasia
Erythroid hyperplasia in BM
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RBC damage:
Morphology: fragment, microspherocytes, spherocytes
Increased osmotic fragility
Short RBC survival time
Hemoglobinemia and hemoglobinuria
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Classification of hemolytic anemia
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RBC intrinsic abnormal
Memberane (hereditary spherocytosis)
Enzyme (G-6PD deficiency)
Hemoglobinopathy( sick cell diseases)
Globin synthesis (thalassemia)
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RBC extrinsic abnormal(usually acquired)
Abtibody induced (coomb’s positive hemolytic
anemia):
worm antibody and cold antibody
Drug induced (penicillin)
Toxin mediated (burns, sepsis)
Mechanical hemolysis(heart valve surgery)
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Clinic features of hemolysis
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General symptoms of anemia
Jaundice
Hemoglobinuria
Acute hemolysis: high fever, cold, pain of
back, nausea and vomit, occurs rapidly with
intravascular hemolysis
Chronic hemolysis: splenomegaly, uncler on
ankle skin and bile pigment stone, occurs
slowly with extravascular hemolysis.
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Laboratory tests
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BRT: Hb decrease with specific morphology
changes in mature RBC, reticulocytosis( at least
>5%)
BM: erythroid hyperplasia
Short RBC survival time
Specific test for hemolytic anemia: coombs test,
Ham test, Rou’s test,
High free Hb concentration in serum
Increased serum indirect bilirubin and urobilirubin
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Diagnosis of hemolytic anemia
Three steps:
 Be sure whether anemia Is hemolytic
anemia?
 Exact kind of hemolysis
 What is primary diseases led to hemolytic
anemia?
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Treatment of hemolytic anemia
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Corticosteroid: prednisone, DXM,
methylprednisolone to be used in autoimmune
hemolytic anemia(AIHA)
Dosage : 30-60mg/d to Hb elevated to normal,
gradually drop down once a week and then
maintain with low dose (5-10mg/d) for 3-6
months
Side-effect: higher blood suger, gestrouncler,hypertention, sodium-water retention
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Immunsuppressor: CsA, danazol, azathioprin
Splenectomy:patients have no therapuetic
effect to corticosteroid after 3-6 months, or
patients with HS
Blood transfusion: washed RBC, RBC ,
transfusion should be matched well in ABO
and Rh type.
Hematopietic stem cell transplantation
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Myelodysplastic syndromes
(MDS)
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Concept of MDS
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MDS are characterized by slow development
of a refractory anemia to standard anti-anemia
therapy.
MDS is divided into primary (de novo)and
secondary MDS.
Patients with secondary MDS usually have
prior treatment with radiation therapy or
chemotherapy or both for primary neoplasma,
such as lymphoma, solid tumor.
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The incidence of MDS is higher in 50-60 year
old person.
The patients present with the insidious onset
of anemia.
Most of cases of MDS finally transfer to
leukemia. Therefore, MDS is also called as
“preleukemia stage”.
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Causes and mechanisms
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Following factors injury stem cell and lead
to develop of MDS
Drugs and chemicals
Radiation
infection
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Clinical features of MDS
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Fatigue and tiredness
Infection, fever, bleeding
Leukocytopeania, thrombocytopeania,
anemia—pancytopeania
Plapitation, short of breath
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Classification of characteristics
FAB classification of subtypes
Type
blood
bone marrow
RA(56%)
blast < 1%
blast < 5%
RAS(21%)
blast <1%
blast <5%
sideroblast >15%
RAEB(10%)
blast < 5%
blast 5-20%
RAEB-T(1%) blast >5%
blast 20-30%
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Diagnosis of MDS
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Pancytopeania
Refractory anemia, infection, bleeding
malhematopoiesis at least two cell lines: myeloid
or erythroid or megakaryocyte line in bone marrow
Bone marrow biopsy demonstrated ALPC
(abnormal location of premarture cell) and
increased lattic fibers.
Hematopoietic sites with island of pre-erythrocytes
or increased erythroblast.
Exclude the diagnosis of other anemia, leukemia
and myelofibrosis.
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图1
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正常骨髓象
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图2
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MDS-RA（红系变化为主）
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图3
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MDS-RA（粒系变化为主）
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图4 MDS-RA（巨核细胞变化为主）
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图5
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MDS-RAS
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图6 MDS-RAEB
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图7
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MDS-RAEB-T
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图8 CMML
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Treatment of MDS
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Supportive treatment: blood transfusion, antobiotics,
GM-CSF
Inductive differentiation treatment: all trans-retinoic acid
(RA) 40-60mg/d , 2-3 months
Low –dosage chemotherapy: cytarabine (Ara-C) 1025mg/d i.v 2-3 weeks
Stamulate erythropoiesis: EPO 2000-3000U/d. I.H 2-3
months, stanozolol 6mg/d, po 2-3 months
Allo-BMT or allo- PBSCT
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Leukemia
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What is leukemia
Stem cell disease
malignant cloning
leukemic stem/progenitor cells
production
differentiation/maturation stop
infiltration of
tissues/oranges
lymphoid (B/T)
myeloid (MM/E/Meg)
immature
acute
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mature
immature
chronic
acute
mature
chronic
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Classification of leukemia
According to maturation and natural disease stage:
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Acute leukemia (AL)：
low grade differentiation with the most of blast /
immature cells, disease develops very fast and
prognosis is very bad, mean natural disease stage is
about 3 months or so.
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Chronic leukemia (CL):
high grade differentiation with the most near mature
/mature cells, disease develops relatively slowly and
prognosis is comparatively good, mean natural
disease stage is several years .
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According to involved cell line:
Acute leukemia:
Acute lymphoblast leukemia(ALL):L1-L3
Acute myelocytic leukemia (AML): M1-M7
Or acute non-lymphocytic leukemia (ANLL)
Chronic leukemia:
Chronic myelocytic leukemia (CML)
Chronic lymphocytic leukemia (CLL)
Hairy leukemia (HL)
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Current status of leukemia in China
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Incidence of leukemia is 2-3/100,000 with the
tendency of increasing yearly!
Low than Europe and America, same as Asian
countries
Acute > chronic（5.5:1）
ANLL > ALL（adult / children）
CML > CLL
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Causes and mechanisms
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Virus etiology: RNA virus (RT-virus)，
HTLV-1,
Radiation：x-ray, r-ray, isotope，
Chemicals and drugs: anti-tumor drugs, antibiotics:
chloramphenicol, chemicals: benzene,
Hereditory factors：family leukemia, chromosome
changes, tumor gene expression
Develop from other blood diseases：MDS, PNH, ML,
MM,MF,
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Acute leukemia
Classification of acute leukemia (FAB)
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ALL subtypes: L1-L3
L1: small lymphoblast and immature lymphocytes
with comparative good prognosis
L2: small and large lymphoblast and immature
lymphocytes with comparative bad prognosis
L3: large lymphoblast and immature lymphocytes
with very bad prognosis
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ANLL subtype : M1-M7:
M1: acute myelocytic leukemia without
differentiation, myeloblast >90%
M2: acute myelocytic leukemia with partial
differentiation, myeloblast between 3189%
M3: acute premyelocytic leukemia(APL)
M4: acute myelomonocytic leukemia(AMML)
M5: acute monocytic leukemia
M6: acute erythroleukemia
M7: acute megakaryocytic leukemia
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MIC typing
MICMB typing
Morphology: FAB typing
Immunology: monoclonal antibodies typing
Cytogenetics: chromosome analysis and typing
Molecular Biology: gene detect and analysis
APL: M3b+ CD33+/ CD13+t(15,17)+ PML-RARa
M3b
CD33+/ CD13+
t(15,17)
PML-RARa
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Clinical manifestations of
acute leukemia
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Four clinical features:
Anemia: aggressive
Bleeding: multi-site
Fever: infectious
Infiltration: extensive and multi-system:
liver, spleen, lympho node, gum, eye, glands,
breast, bone, CNS, testicle, lungs,
heart,chloroma
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急性白血病的实验室检查
•血象: WBC 增高, 可见白血病细胞
正常, 少数白血病细胞
减低, 不见白血病细胞
HB, RBC 不同程度降低
Plt 明显降低,
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Laboratory examination
of acute leukemia
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BRT:
WBC increase with many leukemic cellsin PB
WBC normal with little leukemic cells in PB
WBC decrease without leukemic cells in PB
Hb and RBC decrease in different degrees
platelet sharply decrease, <60x109/L
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•Hyperleukocyte leukemia:
acute leukemia with WBC > 100x109/L
•Hyperblast crisis:
acute leukemia with blast cells
>100x109/L
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•myelogram
Extreme cellularity
Leukemic blast cell >30%
Depression of erythrocyte
Depression of megakaryocyte
Abnormal morphology and structure: Auer
body, nuclear changes
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Characters of cytohistochemistry in AL
ALL
AML
AMoL
POX
-
+-+++
- or +
PAS
+-+++
- or +
- or +
NSE
-
- or +
+
NaF can’t inhibit
ALP
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+-+++
+or -
NaF can inhibit
+ or ++
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•Immunologic examination
B cell: CD10+, CD19+, CD20+,CD22+, TdT+,
HLA-DR+
T cell: CD3+, CD7+, TdT+,
granulocyte：CD13+, CD33+,HLA-DR+, MPO+
monocyte: CD14+
megakaryocyte: CD41+, CD42+,PPO+
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•Chromosome and gene detect:
M2: t(8;21)(q22;q22)
AML/ETO
M3: t(15;17)(q22;q21)
PML/RARa
M4Eo: inv/del(16)(q22)
CBFB/MYH11
M5: t/del(11)(q23)
MLL/ENL
L3(B): t(8;14)(q24;q32)
MYC and IgH
ALL(5-20%): t(9;22)(q34;q11)
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bcr/abl
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• Biochemistry test
serum uric acid increase: uricemia
coagulation factors deficiency
CSF: high pressure of CSF
WBC increase )>0.01x109/L with leukemic
cells in CSF
protein increase >450mg/L
glucose decrease
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Diagnosis and differential diagnosis
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MDS: pancytopenia with excess blast and
immature cells , but <30%
AA: pancytopenia without blast and
immature cells
ITP: thrombocytopenia along,
megakaryocyte increase obviously, PAIg+
Megaloblast anemia: erythroleukemia(M6)
Acute agranulocytosis: premyelocyte
increases without Auer body
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Treatment of acute leukemia
non-curable
curable
give-up treatment
combined chemotherapy
clinical complete curable
complete eliminated curable
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immunotherapy
HPST
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Chemotherapy
The principles of chemotherapy
early：as early as possible
combination：CCSA+CCNSA
high dosage: dosage – effect relationship
interval： 2-3W
repeat：to eliminate minimal residual
leukemic cells
individuation：experience and drug
sensitivity test in vitro
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Steps of chemotherapy:
Inductive remission treatment (IR): from
diagnosis to get complete remission by 1-2
protocols. A critical therapeutic step.
Consolidation and intensification treatment (CI):
6-9protocols after IR to eliminate minimal
residual leukemic cells. An inevitable step.
Maintenance treatment(MT):2-3year’s treatment
after CI. An important step to prevent relapse
and prolong disease free survival time (DFS).
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Chemotherapy protocols for ALL
IR
CI
MT
 VP:
EA:
chose CI
V2mg/d1,8,15,22
E100mg/d1-3 protocols,
P:60mg/d1-28
A150mg/D1-7 last for 3-5
 VDP:VP
VLDP:
years
D40mg/d1-3
HD-MTX:
 VLDP:VDP
1.5-3.0g/d1
L10000U/d19-28
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Chemotherapy protocols for ANLL
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IR
DA: D40mg/d1-3,
A150mg/d1-7
HA: H4mg/d1-7
A150mg/d1-7
HOAP: HA
V2mg/d1
P60mg/d1-7
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CI
DA
MD-Ara-c
MA:A
M8mg/d1-3
A150mg/d1-7
ME:M
E100mg/d1-7
MT
depends,
follow-up,
retreat when
relapse
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Treatment for special type of AL
APL(M3): All-trans retinoic acid (ATRA) or Arsenic
low dosage HA
anti-DIC
Elderly leukemia: low dosage +longer treatment stage
CNS leukemia: subarachnoid cave injection + skull
radiation
Testicle leukemia: radiation
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Supportive treatment
•Anti-infection: anti-bacterial, anti-virus, anti-fungi
•Improve anemia: blood transfusion
•Control bleeding: platelet transfusion, coagulation
factors transfusion, fresh plasma
•Supply nutrition: amino-acid, albumin, vitmines ,
trance elements, immunoglobulin
•Prevent uricemia and renal lesion:
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Hematopoeitic stem cell transplantation
Auto-HST
auto-BMT
auto-BM bank
auto-PBHST
auto-PBHS bank
auto-CBHST
auto- cord blood bank
Allo-HST
allo-BMT
(sibling)
allo-PBHST
1/4 HLA match
allo-CBHST
Unrelated-HST unrelated- BMT
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unrelated-PBSCT
HPS bank, 1/10000
unrelated-CBSHT
Cord bank
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Chronic myelocytic leukemia
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clinic features
onset is slowly
no specific manifestations
giant spleen
sternal tenderness
WBC increase obviously, > 50x109/L
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Development of disease
•Chronic phase(CP): 1-3years， disease is stable,
blast cells<10%
•Accelerate phase(AP)：several months to years，
disease develop fast and blast cell >10%
•Blast crisis phase(BC)：several months only,
prognosis is very bad, blast cells> 20%
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Laboratory test
•BRT：
WBC >20, >50, >100x109/L
DC: myelocyte,metamyelocyte, Nst increase
Eo, Ba increase
Hb and Plt decrease in terminal phase
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•myelogram
extreme hypercellularity, M:E increase
myelocyte, metamyelocyte and Nst increase
Eo, Ba increase
erythrocyte and megakaryocyte normal
ALP activity decrease or negative
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•Cytogenetics and moleculor biology:
t(9;22)(q34;q11)
bcr-abl fusion gene
P210 protein
• Biochemistry：uric acid increase in
serum and urine
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Diagnosis and differential diagnosis
• leukomoid reaction(LR):
primary diseases: severe infection, tumor, TB
Eo,Ba normal
ALP +++，Ph chromosome• Myelofibrosis（MF）：
immature erythrocyte and granulocyte appears
in PB with tear –drop like RBC
Ph – and ALP +
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Treatment:
• chemotherapy:
single drug: hydroxyurea, 3g/d
myleran:6mg/d
combined chemotherapy：
HA:H2-4mg/d,A100-150mg/d
MA: M4-6mg/d
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A: 50-100mg/d
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•Blast crisis：same as acute leukemia
•Interferon ： a-IFN 3,000,000-9,000,000U/d
for 1-2years to get Ph chromosome negative
•Glivec: a strong inhibitor of tyrosinase to P210
•leukapheresis：to eliminate extra leukemic cells
• radiation in spleen area
•aplenectomy
• allo-BMT or allo-PBSCT
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介绍
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陈述讨论目的
介绍自己
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讨论主题
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陈述内容要点
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第一个主题
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有关该主题的详细内容
支持信息和示例
该主题与听众的联系
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第二个主题
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有关该主题的详细内容
支持信息和示例
该主题与听众的联系
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第三个主题
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有关该主题的详细内容
支持信息和示例
该主题与听众的联系
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现实生活
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讲述现实生活中的一则示例或轶事
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如有必要，对听众的处境表示有同
感
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意义
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用有力的陈述来概括您对该主题的
感想或看法
总结希望听众记住的要点
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下一步
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总结对听众的要求
总结您要进行的工作
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