Anemia

Definition: anemia represent as decrease in the number of

circulation red blood cell (RBC), represented by RBC count, Hb
concentration, hematocrit

Criteria anemia in adults

Normal RBC. Cenral palor RBC’s are microcytic Macrocytic anemia
about 1/3 the size of RBC (smaller) & hypocromic
Women Men (↓Hb)

RBC(x1012/L) <4.0 <4.5

Clinical manifestation
Hemoglobin (g/L) <110 <120
 Pathophysiology
<100 (pregnant)

Hematocrit (%) <37 <40

 General presentation
Mechanism
Fatigue Anorexia Dyspnea on excertion
 Deficiency RBC production
Dizziness Headache Pallor of skin or mucous
Nutrient deficiency Stem cell defect
membrane
Hb DNA disorder Renal disease
 Other presentation
 Increased RBC destruction over production Involve in many other body systems

Diagnosis (Diagnosis of anemia & etiological of anemia)

History + Manifestation + Laboratory evaluation

Lab evaluation: blood count, reticulocyte count, blood smear, bone

marrow examination
 RBC loss without RBC destruction
Treatment
 Acute blood loss  Etiological treatment

 Chronic blood loss  Blood transfusion (packed RBC)

Classification (according to pahtophysiology & morphology) Indication: significant hypoxic symptoms, Hb<60g/L

Pathopyhysiology
Anemia of depressed
erythropoiesis Aplastic anemia
Hemolytic anemia
Haemorrhagic anemia Hematopoesis of bone marrow

Morphology MCV (fl) Common disease

Macrocytic >100 Megaloblastic anemia

anemia

Normo cytic 80-100 Aplastic anemia, acute Definition (pancytopenia with hypocellular bone marrow)
anemia haemorrhage, the erlies stage of
most anemia Aplastic anemia is bone marrow failure syndromes, characterized
by hypocellular bone marrow & pancytopenia (reduction in
Microcytic anemia <80 Iron deficiency anemia, Chronic number of RBC, WBC, PLT) in peripheral blood, the major
haemorrhage, Thalassemia
symptoms are anemia, infection & bleeding
Classification (according to etiological & severity)

Acording to etiologic factor According to severity of anemia  Manifestation according to severity

Inherited AA (Fanconi anemia) Severe AA SAA CAA
Acquired AA Chronic AA Onset Acute, quickly Chronic, slowly

Anemia Mild at first, Severe

Etiological aggravated gradually

 Drugs  Chemical (Benzene) Bleeding Severe, GI bleeding, Mild, petechiae, purpura

Encephalorrhagia
 Antibiotics (chloromycetin  Radiation
→ adverse effect: bone Infection Severe, septicemia Mild, flu
marrow toxicity)  Viruses
Prognosis Bad, highly mortality Not to bad
 Analgesic  Viral hepatitis

 Antithyroid agents  Parvovirus B16 with Lab evaluation

sickle cell anemia
 Antidiabetic agents  Peripheral blood routine:
 Other causes:
 Sedative
 Pancytopenia (↓RBC, WBC, PLT)
 Immunologic disease
 Cytotoxic agent
 Reticulocytes ↓

Pathogenesis SAA CAA

 Stem cell injury (Seed theory) Neutrophil < 0.5×109/L >0.5×109/L

PLT 20×109/L >20×109/L

 Defective hematopoietic microinvonment (Soil theory)
Reticulocyte < 15×109/L >15×109/L
 Abnormal immune mediation (Incest theory)
SAA: Fatty marrow CAA: scant hematopoietic cells in fat
tissue  Bone marrow smear

Clinical features SAA: severe hypocellularity in CAA: depressed , or active

many sites, no megakaryocyte, non- proliferation, decreased
hematopoietic cells are active megakaryocytes
 General

Progressive anemia: Fatigue, anorexia, dyspnea on excertion,

dizziness, headache, pallor of skin or mucous membrane,  Bone marrow biopsy
pounding sensation in ears

Bleeding (early symptoms): easy brushing, nose bleeding,

heavy menstrual flow, oozing from gums, petechiae
(sometimes), retinal hemorrhage, intracranial hemorrhage
(high mortality)

Infection: Septicemia (high mortality)

No obvious swelling of the liver, spleen, & lymphoid nodes

* High mortality rate of Septicemia & Intracranial

hemorrhage (several month to 1 year after onset)

Diagnosis
 History + Clinical features + PE + Laboratory data

Differential diagnosis Body iron distribution

 MDS (Myelodysplastic syndrome)  Total body iron

 Refractory anemia
Adult males: 50mg/kg Adult females: 40mg/kg
 Deformed hematopoiesis in two or three cell lines

 Hypoplastic Leukimia
 Distribution:
 ↑ blast cell in the marrow
 Storage iron: ferritin,hemosiderin
 PNH (Paroxysmal Nocturnal Hemoglobinuria)  Transport iron: transferrin
 (+) Ham’s test (Acidified serum lysis test)  Functional iron: Hb, myoglobin, enzymes
 (+) Rous test (to examine hemosiderin (Iron storage Stages of iron deficiency
complex))
 Decrease of stores (ferritin)
Treatment
 Iron deficiency hematopoiesis
1) Supportive management
 Iron stores depleted with insufficient absorption to
 Prevention of infection
counteract normal losses
 Maintain dental hygiene
 Leads to decreased hemotopoesis but no clinical anemia
rd
 Antibiotic: initial empiric choice, 3 generation
 Iron deficiency anemia
(cephalosporin, vancomycin, amphotericin)
 Hemoglobin falls
 Marrow growth factor: G-CSF (Granulocytes-Colony
Stimulating Factor), GM-CSF (Granulocytes
Epidemiology
Macrophages-Colony Stimulating Factor)
 Most common nutritional deficiency
 Correct blood transfusion
 Common in young children & pregnant women
 Control bleeding: platelet transfusion
Pathogenesis
2) Therapy for SAA

 SCT (Stem cell (bone marrow) transplantation)

Decrease iron intake Chronic blood loss
 Allogenic SCT (BMT) – not identical

Indication for SCT  Increased physiologic  gastrointesti

requirements for iron nal bleeding for males
o Younger patient (<40) with SAA
 inadequate diet  excessive
o Not or small blood transfusion, without any infection menstrual flow for females
 GI tract diseases
o There is donor’s HLA matching to the patient

 Immunosuppressive therapy (ATG, ALG, CsA, IVIG)

3) Therapy of CAA

 Androgen, TCM Clinical manifestation

1) Anemia symptoms
Iron deficiency anemia

Definiton: a microcytic & hypochromic anemia resulting from low

storage of iron
 Fatigue Dizziness Total iron-binding capacity
Headache
Saturation of transferrin ¯ (<15%)
Palpitation Dyspnea Lethargy

Disturbances in menstruation Serum transferrin receptors

2) Symptoms or iron deficiency

Irrittability Poor attention span

Differential diagnosis (Other microcytic anemia)
Poor work performance Increase frequently of infection
 Thalasemia
Defective structure & function of epithelial
 Normal/increase serum iron values & Transferrin
Pica: habitual ingestion of unusual substance (geophagia saturation
(clay, soil), amylophagia (laundr starch), pagophagia (ice)
 Siderobalastic anemia
Especially manifestation of iron deficicncy especially after
hookworm infestation  Normal iron values despite microcytic & hypocromic
RBC
In infant: development delay, behavior disturbance
 Anemia of chronic infectious disease
In pregnant women: increase preterm delivery, low-birth-
weight newborn  Normocytic & normochromic RBC

3) Underlying disease  Normal/increase ferritin level

Advance tissue iron deficiency:  TIBC is below normal

 Cheilosis/glossitis: fissure at the corner of the mouth Treatment

 Koilonychia; spooning of finger nail  Treatment of underlying disease

 Iron therapy (Oral & IM)

 Oral iron therapy

o Ferrous sulfate tablets, ferrous gluconate

o Improve iron absorption:

Enhanced: Vitamin C, Inhibited: spinach,
Lab findings meat, orange juice, fish tea, milk, coffee

o Duration of treatment: 3 - 6 months

1) Blood test
o Expected response: brisk reticulocytosis within 5 to 10
days
↓Hb ↓MCV Aniocytosis: unequal RBC Hypochromia
size
 Intramuscular therapy

o Indication: intolerance to oral iron or disorder of GI

2) Bone marrow test tract
 Mild to moderate erythroid hyperplasia (25-35%; N16- o Dosage: iron to be injected (mg) = (15 - Hb/g%/) x
18%) body weight (kg) x 3
 Bone marrow showing absence of stainable iron o Adverse effects: pain at the injection site, anaphylactic
reaction (5%)
3) Iron metabolism test

Serum iron concentration ¯

Serum ferritin levels ¯ (<12ug/l)

 Hemolytic anemia

Definition: is a disorder in which the red blood cells are destroyed

(hemolysis) due to shortened red cell life span followed by
inability of bone marrow to produce destroyed RBC.
 Pathophysiologic characters: ↑plasma free hemoglobin,
General features ↓hepatogloblin, hemoglobinuria, hemosiderinuria

1) Features of increased RBCs breakdown Clinical features

 Increased indirect bilirubin  Acute (Intravascular hemolysis)

Acute onset, fever, chills & lower back pain, noticeable

 Increased Stercobilinogen, urobilinogen hemoglobinuria, heart failure, renal failure

 Low or absent haptoglobin  Chronic (extravacular hemolysis)

May cause jaundice Anemia,, jaundice, enlargement of the liver, spleen, gall stone,
liver failure, ect
2) Features of increased RBCs production
Lab test
 Reticulocytosis (n=0.5 – 2 %)
 RBC destruction

 BM erythroid expansion  Documenting marrow compensation

3) Features of increased RBCs damage  Define of etiology

 Morphology - Shortened survival by 51Cr labelled Diagnosis

Causes History + clinical features + laboratory finding

Differential diagnosis

 Reticulocytosis

 Jandice

Treatment
Pathogensis
 Etiological treatment
 Extravascular hemolysis (occur in reticuloendothelial cells)
 Corticosteroids
 RBCs are removed from circulation by phagocytes in
spleen, liver, or bone marrow  Blood transfusion (washed RBC)

 Splenectomy

Classification of hemolytic anemia

 Pathophysiologic characters: ↑Indirect billirubin,

(+)Stercobilinogen, (+)Urobilinogen

 Intravascular hemolysis (destruction of RBC inside vessel)

Membrane defects

Hereditary Acquired
(morphological abnormalities of RBC) • PNH
(Paroxysmal
• Hereditary Spherocytosis nocturnal
(spherical RBC) hemoglobinuria)

• Hereditary Elliptocytosis  Thalassemia

(Elongated or spherical RBC)
 Hb Electrophoresis
• Hereditary Stomatocytosis
(Cup-shape RBC)  Alpha thalassemia: HbA, HbA2, HbF ↓

 Beta thalassemia: HbA2, HbF ↑

 Hereditary (spherical RBC)

Autoimmune hemolytic anemia (Extrisic factor)

Cause:

 Characteristics: defect of RBC membrane leading to • Causes

spherecytosis; decreased deforrmability of cell; abnormal
osmotic fragility • Transfusion, pregnancy, drugs

 Major manifestation: Anemia, splenomegaly, jaundice, gall • Warm auto antibodies (IgG), cold auto antibodies
stone (due to ↑ bile pigment production)
(IgM)
 Paroxysmal nocturnal hemoglobinuria Warm AIHA Cold AIHA

 Clonal cell disorder • Antibodies or • IgM directed to

complements combine with antigen I on red cells
 Acquired deficit of GPI-associated protein (CD55,CD59…) RBC
• Seen in elderly,
 Intravascular hemolysis classically at night • Macrophage lymphomas, EBV-infection,
recognize Fc receptor of Ig or
 Major manifestation: Hemolytic anemia, deficient C3b, causing destruction of • Coombs test + for C3,
hematopoesis (cytopenia), and tendency to thrombosis RBC (-) for IgG
(venous thrombosis due ↑ platelets aggregation)
• DAT: Coombs test (+) • Treatment: stay warm
for IgG and C3
 Testing: Ham test(+), CD55/CD59 lacked
Complement-IgG mediated
Enzyme defect (RBC interior)
hemolytic anemia
G6PD deficiency (Glucose-6-phosphate-dehydrogenase)

Thalassemia

Pyruvate kinase deficiency

Bleeding disorders
 G6PD deficiency (X linked condition)
Typical signs of platelet disorders (Petechia & Purpura)
 Characteristic: Depressed functions of G6PD, Decreased
 Characteristic: small red or purpule spot on the body, do not
generation of glutathione, Hemolysis during oxidative stress
blanch with pressure
(infection, drugs, fava beans-favism), Deformed Hb leading to
Heinz body formation
 Petechia: 1-2mm
 Major manifestation: Anemia, hemoglobinuria, jaundice,
mesenteric & renal ischemia  Purpura: 3-5mm

Typical sign of coagulation factor disorders (Ecchymosis)

 Ecchymosis: >5mm
Hemostasis
 Definition: capacity to minimize loss of blood following
injury to blood vessel by repairing of injury wall under
responsible of coagulation & fibrinolysis
 System involved:
 Vascular system:
Injured vessel initiate
vasoconstriction
 Platelet system:
injured vessel expose
collagen that initiates
platelet aggregation
and help form plug
 Coagulation
system: protein
factor of intrinsic &
extrinsic pathway
produce a permanent
fibrin plug
 Secondary hemostasis:
Intrinsic pathway
 All
components required for
initiating this pathway are
circulating in the blood
 triggered
by contacting with collagen
or glass
Hemolytic balance:
Clot inhibition/lysis: Protein C system, Antithrombin III,
TFPI, Heparin, Fibrinolytic system
Anticoagulant
Protein C system
Antithrombin III
TFPI
Heparin
Target to Inhibit different
coagulant factors except FI
Extrinsic pathway
 Initiated
by the release of tissue
factor and calcium from
damaged tissue
Fibrinolytic system
Plasminogen (inactive form)
Plasminogen activators (t-PA, u-PA)
Plasmin
Fibrin
Fibrin Degradation Products (FDP)
Inhibitors of plasminogen activators
and plasmin (PAI, a2-AP, etc.)
Target to dissolve FI
Lab evaluation (Screen test)
Platelet count, Bleeding time (BT), Prothrombin time (PT),
Activated Patial Thromboplastin Time (APTT), Thrombin time (TT)
 Bleeding time: provide assessment of platelet count &
function, normal range: 2-8minutes
 Prothrombin time: measure effectiveness of extrinsic pathway,
normal range: 10-15seconds
 Thrombin time: Time for Fibrinoge → fibrin, measure of
ribrinolytic pathway, normal value: 9-13 seconds
*Cause of prolong TT: Heparin, hypofibrinogemia,
dysfibrinogemia, Elevated FDPs or para protein, Thrombin
inhibitor thrombin-Ab
Lab evaluation Test for factor deficiency
Normal PT & Abnormal APTT Isolated deficiency in intrinsic
pathway (Factor VII, IX, XI)
Abnormal PT & Normal APTT Isolated deficiency factor VII (rare)
Multiple factor deficiencies (II, VII,
X – common),
Classification of bleeding disorders
 Vessel defects: anaphylactoid purpura
 Platelet disorders: Idiopathic thrombocytopenic purpura
 Factor deficiencies: Hemophilia A, B
 Other disorders: Oral anticoagulants, liver disease
Hemophilia
Definiton: inherited bleeding disorder that is caused by
the lack or defect of the proteins that is needed for
blood to clot.
Homophilia A Hemophilia B
• 80- • 10-15% of all
85% of all Hemophiliacs Hemophiliacs
• Deficie
ncy of Factor VIII (Coded by HEMA
gene)
• X-
linked disorder
•  Sing & test: same as Hemophilia A (Normal bleeding time,
Deficiency of Factor IX Normal fibrinogen level, Prolonged aPTT), except serum factor
IX test
•
Lab Test - Prolonged APTT
Prevention: Genetic counseling, termination of pregnancy

• Joint Cassation of bleeding:

and muscle hemorrhage, easy bruising
and prolonged bleeding from wounds RICE: Rest, Ice, Compression, Elevation
• Lab Treatment:
Results - Prolonged APTT

• Treatm
1) Clotting factor therapy
ent of hemophilia A is accomplished
by infusion of factor VIII concentrate 2) Transfusions

3) Exercise so the muscle can strengthen and protect joints.

Hemophilia A Hemophilia B

 Cryoprecipitate  Fresh Frozen Plasma (FFP)

 Recombinant factor VIII  Recombinant factor IV

 DDAVP (Desmopressin)
for mild Hemophilia A
Hemophilia A (Classic hemophilia)

 Cause: Lack of activity of the activity of plasma protein factor

VII ITP (Idiopathic Thrombocytopenic Purpura)

 Symptoms: Definition: is automimmune disorder characterized by

autoantibody-induced platelet destruction
Brushing Spontaneous bleeding
Syndrome manifestation: Acute-children, chronic-adult
Prolonged Blood in urine &
bleeding stool Etiology & Pathogenesis
Bleeding into joint with pain & swelling
 Infection (virus or bacterium)
GI tract & Urinary tract hemorrhage
Acute ITP (virus associated):

 Sign & Test: Normal bleeding time, Normal fibrinogen level,  Cross reactivity of anti-viral antibodies with normal
Prolonged aPTT platelet glycoprotein to destroy platelet.

Hemophilia B (Christmas Hemophilia)  Direct effect on magakaryocytes to decrease the production

of platelet.
 Cause: Lack of activity of the activity of plasma protein factor
IX

 Lack factor IX → blood gets into joint → cause disability  Immune factors

Chronic ITP (auto immune destruction)

 Hemophilia A seven tines more common than Hemophilia B
 Platelet-associated antibody, PAIgG, PAIgM, PAIgA,
 Symptoms: PAC3 → which bind to platelets’ IIb/IIIa glycoprotein
receptor → Antibody-coated platelets → cleared from
Nose bleeds, brushing Spontaneous bleeding circulation by spleen.

Bleeding in joints (weight bearing joint) Blood urine & stool

 Liver & spleen
Prolonged bleeding from cuts, tooth, extraction, & surgery
 PAIgG produced in spleen
Excessive bleeding following circumcision
 Platelet were destroyed in spleen and liver
  Hereditary Treatment (return the platelet level into safe level)

 HLA—DRW9, HLA—DQW3(+)  General therapy

 Esterogen (common in female <40y & pregnancy) Rest Trauma avoided

Infection control Avoided drugs: aspirin, heparin

 estrogen→ platelet destroyed in spleen

Clinical manifestation  Chemical

therapy
Manifestation Acute ITP Chronic ITP
 Glucocorticoids
Incindence Children (2-4y) Adults (15-40y)
o Impaired clearance of antibody-coated platelets by
Sex No difference M/F: ¼ reticulo-endothelial system

Infection Common Rare o Inhibition of antibody production

Onset Abrupt, <1w Insidious, >6m o Stabilization of vessel wall

Bleeding Severe, pupura, Mild or moderate,  Immunosuppressive agents

Ecchymosis, Petechia, purpura,
Internal bleeding mucosal bleeding o Dose: high; Response rate – 85%

Splenomegaly No No o Mechanism: impairs clearance of antibody-coated

platelets by competitive binding to the Fc receptor of
Platelet count <20x109/L (30-80)x109/L macrophages in the spleen

Spontaneous Common Rare o Indication for IVIg: Emergencies, Preparation for

remission splenectomy, Refractory ITP

 Platelet transfusion
Laboratory evaluation:
Used in life threatening bleeding (Platelet <10x109/L)
 Blood test: (Platelet↓) acute <20x10 /L, chronic (30-
9

80)x109/L  Surgical therapy

 Bone marrow test: Normal or megakaryocyte ↑ Splenectomy (choice for adult steroid-dependent & steroid-
resistent patient
 Platelet associated antibody: PAIgG↑

Diagnosis
Leukemia
 Mucocutaneous Spontaneous bleeding，purpura
Definition: Leukimia is a group of clonal malignant diseases
 No splenomegaly developed from hematopoietic stem cell or progenitor cell that lead
to Suppression of normal hematopoiesis, Infiltration in outside of
 Platelets less than normal bonemarrow.

 Premature megakaryocyte increased or normal Classification

 Anyone of： Acute Leukemia Chronic Leukemia

 Sensitive to prednisone  Acute lymphocytic Leukemia  Chronic Granulocytic

(ALL) Leukemia (CGL, CML)
 Effective to surgical therapy
 Acute myelogenous  Chronic lymphocytic
 Increased PAlgG Leukemia or Acute non- Leukemia (CLL)
lymphocytic Leukemia
 Shortened life-span of platelets (AML，ANLL)

Differential diagnosis
Etioogy
AA, MDS, SLE, TTP, Drug-induced thrompocytopenia
  Virus (ATLV, HTLV-I, HTLV-II, HTLV-III)
L3: identical morphologically
 Chemical substance (Benzene poisoning) to Burkitt’s lymphoma.have
manifest deeply blue
 Ionizing radiation (basophilia) cytoplasm and
prominent vacuolation
Pathogenesis (mutation of hematopoetic stem cell)

1) Those that confer a proliferative or and survival

KIT FLT3 ↑， NF-1 ↓

2) those that impair hematopoietic differentiation and confer  AML (Acute myelogenous Leukimia)
properties of self-renewal
(M0, MI, M2, M3, M3v, M4, M4e0, M5a, M5b, M6, M7)
RUNX1-ETO, CBFB-SMMHC, TEL-RONX1 fusions mutation
M0: Acute myeloblastic leukemia, minimal differentiated
Properties of LSC (Leukemic stem cell)

 Self-renewal, quiescent, proliferation, multi-potentiality,

differentiation damaged Minimal differentiated:
CD33,CD13+
 Immunophenotype of LSC:

AML: CD34+CD38-CD71-CD90-CD117+ CD123+, HLA-DR-

CML: CD34+CD38- M1: Acute myeloblastic leukemia, without maturation

Acute Leukemia

Characterize by accumulation of blastcell. Accumulations of Myeloblast ≥90%

blastcells result in:

 Suppression of normal hematopoesis lead to anemia,

infection, bleeding

 Clinical manifestation related to involvement of organs

M2: Acute myeloblastic leukemia, with maturation
outside BM
Myeloblast 30~89%
FAB Classification

 ALL (Acute lymphocytic leukemia)

L1: lymphoblast cells are

small, usually <12 um in
diameter. With scanty
cytoplasm and inconspicuous M3: Acute promyelocytic leukemia, hypergranular
(indistinctive) nucleoli. More
common in children
(approximately 85% of
children cases of
AL).Prognosis is better.
Hyperangular

L2: lymphoblasts are larger in

size (>12um), have more
prominent nucleoli and
M3V: Acute promyelocytic leukemia,variant, microgranular
abundant cytoplasm. more
common in adult ,worse in
prognosis
  Acute promyelocytic leukaemia ( A M L with t(15;17)
(q22;q12), ( P M L / R A R ) and variants) 9866/3

 AML with 11q23 (MLL) abnormalitie

Micrograndular
Clinical manifestation (related to pancytopenia)

1) Infection (associated with granulocytopenia and defect in

immune system)
M4: Acute myelomonocytic leukemia
 General feature: 1.fever T>38.5○C; 2.the local
inflammation is mild; 3.progress rapidly, and easy to
spread; 4.increased opportunistic organisms infection.
Blast ≥30%
 Infection site: Respiratory tract (nasal cavity, oral cavity,
Monocyte>20% throat, lung), digestive tract (esophagus, GI, anal areas),
skin etc. - Oral candidiasis, pneumonia; dysphagia;
CD14+ esophageal candidiasis, perirectal abscesses

 Infective pathogens: Gram-negative and positive bacteria

are major pathogens of infection including - E.coli,
Pseduomonas-aeruginosa, klebsiella pneumonia,
M4e0: Acute myelomonocytic leukemia with eosinophilia Staphylococcus
M5a: Acute monoblastic leukemia, poorly differentiated
2) Anemia
M5b: Acute monoblastic leukemia, differentiated
 Early of onset

 Developed progressively
Monoblast+
3) Bleeding (petechia, ecchymosis)
Promonocyte ≥30%
 Mainly caused by thrombocytopenia, but also related to
CD14+ dysfunction of blood vessel that associated with
infections and anemia

M6: Acute erythroleukemia 4) Manifestation cause by involvement of organs outside BM

 Peripheral WBC：

Immature erythrocyte  WBC may be ↑/normal/↓.

>50%
 Pancytopenia: common in ALL than that in ANLL
Blast ≥30% leukemic immature cells can be found in 85% patients.

 Hyperleukeocytosis: refered to WBC>100×109, more

frequently occurred in M4, M5 subgroup. It is a factor
M7: Acute megakaryoblastic leukemia reflect worse prognosis.

 Enlargement of liver, spleen, & lymphnode:

Megablast ≥30%  Hepatomegaly and splenomegaly are more common in

ALL (75~85%) than in ANLL (40%).
CD41+,CD61+,
 Lymphadenopathy is prominent in ALL & rare in
CD42+ AML.

 Hepatomegaly are usually mild to modest .A “huge

spleen” is an indication to be CML.
AML with recurrent cytogenetic abnormalities
 Infiltration of oral mucous and gum:
 A M L with t(8;21)(q22;q22), ( A M L 1 / E TO ) 9 8 9 6 / 3
 Gum hypertrophy occurred in 50% M4, M5 patients. It
 A M L with inv(16)(p13q22) or t(16;16)(p13;q22), (CBF is rare in other subtype of AL (5~8%).
/MYH11) 9871/3
  Infiltration of skin: 2) Bone marrow aspiration: (posterios iliac cres, sternum)

 Frequently occur in M4, M5 patients. Presents as  Cellularity:

leukemia cutis.
 Hypercellular (typically is found in 90% patients).
 Massive myeloblast cells can be found in infiltration
node on the skin.
 Some elderly patients/AL related to treatment/secondary
 Sweet Syndrome: is a imflammation change caused by leukemia has a normal or hypocellular.
infiltration of granulocyte, Frequently occurred on skin
of limbs, present as larger erythema nodosa, allergic  Leukemic cells: can be found and take ≥30%
purpura nonerythroid cells.

 Auer rods (spindle-shaped)can only be found in AML

(especially: M1,M2,M3,M4)

3) Cytochemical Stain
5) CNS-L

 Common in ALL (50%), only 5~7% in AML

 Many are asymptomatic, sometime present with

intracranial hypertension, stiff-neck, papilledema,
nervous lesion (V cranial nerve lesion).

 CNS-L can be diagnosed by determine of cerebrospinal

fluid cytology.

6) Involvement of other organ

 Bone pain is common, Eyes, lung, pleura, heart,

pericardium, kidney can also be involvement
4) Immunophenotypic marker in AL
7) Leukocytosis

 High number of circulating bastcells (>50000/mm3

specially M5) → ↑ blood velocity & is associated with
small vessel leukoblastic emboli → leukocytosis

8) Related to metabolic abnormality

Hyperuricemia Hypercalcinemia

Tumor lysis syndrome: characterized by rapid development of

hyperuricemia, hyperkalemia, hyperphosphatemia, &
hypocalcemia etc.

Lab findings

1) Blood routine exam:

 WBC count:

 Although WBC count may be ↑/normal/↓, but ↓/normal

hemacytes (blood cells) may appears.

 Especially thrombocytopenia can reflect the normal

hematopoietic status. Some patients present with
pancytopenia. 5) Cytogenetic

 Leukemic cells can be found (90% of cases)

 cannot decreased in 3d and
blood bacterial culture is
negative, amphotericin B
would be used empirically

 Bleeding-Platelet transfusion

o If no sign of bleeding but PLT<10000/mm3 → platelet

Risk group in AML according to cytogenetic: transfusion should be executed routinely

o If sign of bleeding + DIC although PLT<50000/mm3

→ platelet transfusion should also be executed

Diagnosis

Symptom & sign → abnormal blood routine test → bone marrow  Chemotherapy
aspiration
o Chemotherapy protocol in ALL
Fever, anemia, bone If symptom happens, If abnormality in
pain, fatigue, bleeding, blood routine test & blood test found, bone a) VP and VDP,VDLP
hepatomegaly, blood smear muts be aspiration must be
splenomegaly, done done b) High dose Ara-C(HDAC), High dose methotrexate
lymphadenopathy, etc (HDMTX)

Establishment: blastcell ≥30 % (FAB) ,or ≥20% (WHO,2003) o Chemotherapy protocol

in AML
Differential diagnosis

 Blastcells≥30% never can be seen in any other disease except

Acute Leukemia.

 Aplastic Anemia, Infectious monocytosis, Infectious

lymphocytosis etc.
o M3 (APL) induction remission therapy
Therapy
a) ALL-Trans- retinoic acid (ATRA) 45mg/m2/day P.O
 Principle: till CR or addition of Idarubicin .no Ara-c needed.

b) As2O3 20mg/day 30days

o Non-APL induction remission therapy

 Supportive care a) DA (3+7) daunorubicin and cytarabine: D 45 mg/m2

 High WBC (Infection)
o
When WBC>10,000/mm3 → Oral allopurinol
o
When WBC>50,000/mm3
No fever T<101OF,
prophylactic oral use of
CO-SMZ, fluconazol,
Itraconazole
o Consolidation therapy
With fever T>101OF,
broad spectrum
antibiotics (eg Imipenen)
must be used.
If pneumonia has been
confirmed or temperature
days (1, 2, 3); Ara-C 100mg/m2 day 1~7; CR Rate
60%
b) AML with multilineage dysplasia: FAT fludarabine
and cytarabine and topotecan; CR Rate 80%
a) Patients with t(8:21), or inv(16)etc: high-dose
cytarabine, at least three cycles, cure rate of 60–70%
b) M3(APL) ATRA+D or ID As2O3
c) Chemotherapy or stem cell transplantation
  Bone marrow transplant  Immunodeficiency of the host

 Indications: ALL; Relapse/refractory; CR2; CR1, high risk o AIDS, BMT, ABSCT, Heriditary Immunodeficiency &
t(9;22),(4,11),+8,WBC>30~100; AML other disease with Immunodeficiency

 Mechanism: Classification:

o Collection of stem cell  Hodgkin Disease

o Pretreatment (Conditioning regiment)  RS cells can be found

o Tranfusion of stem cell  Nodular sclerosis

o Reconstitution of hematopoiesis & immune system  Lymphocyte predominance

 Post-transplant therapy  Lymphocyte depletion

o Topoisomerase I Inhibitors: 9-aminocamphothean  Mixed cellularity

o MDR Reversing Agents: cyclosporine,quinine, PSC-833  Non-Hodgkin Disease

o Toxins Bound to Antibodies and RIT (CD33)

o Fludarabine Clinical manifestation

o Minitransplant  Hodgkin Disease

o Immunologic approachs: infusion of allogeneic  Enlarged Lymph node: usually firm & rubbery & often
bulky. Involvement: supraclavicular, cervical, axillary.
lymphocytes
 Regional complication results in compression

 Associated systemic symptoms: fever >38.5OC ; night

Lymphoma sweats; weight loss>10% body weight
Definition: lymphomas are immune malignant diseases generated  Non-Hodgkin Disease
from lymp node or lymphatic tissues. They constitute extremely
heterogenous disease. It can be classified into Hodgkin’s disease  Indolent lymphoma ：
(HD)-according R-S cell and Non-Hodgkin Lymphomas (NHL)
o present with widespread central and peripheral
Mechanism: adenopathy ,but progress slowly
 Accumulation of gene alteration in the tumor genome o lymphonode can be moving ,hardness like rubber.
o Activation of proto-oncogenes by chromosmal tranlocation
o blood, BM, liver usually be involved
(e.g t(14;18),t(18;22) → Bcl-2 → apoptosis)
o the function of BM ,liver usually are normal
o Other mechanism of proto-oncogenes alteration (e.g proto-
oncogenes amplification (myc))
 Aggressive ：
 Infection of the tumor clone by an oncogenic virus o Symptomatic at diagnosis
o EBV: EB involvement in NHL (13.95%), HD (40%),
o Short disease history
Burkitt (90%)
o Enlarging lymph node
o HHV-8 (Human herpes virus-8)
o Obstructive symptoms
o HTLV-1 (Human T Lymphocytes Virus)
o Extranodal involvement
 Stimulation and selection of tumor cell by an antigen
o Deep mass >10 cm
o Mutation of Ig gene usually are driven by Ag
 Very aggressive (Burkitt and lymphoblastic lymphoma)
o Biased (berat sebelah) usage of Ig gene
o They are common in young adult and children
o Ag receptor expressed by
NHL cell
 o Rapidly enlarging mass in abdominal, blood and BM  Before starting treatment: efficacy should predict,
involvement are common Integral with the tumor (tumor score), International
Prognostic Index (IPI) can predict efficacy.
o LDH level is extremely high (Burkitt)
 CHOP (21-28 days a course)
o Rapidly enlarging mass in mediastinal area
(lymphoblastic lymphoma).  CY 750mg/m2 iv day 1

Diagnosis (depend on biopsy of lymphnode or lesion are involve)  Adr 50mg/m2 iv day 1

 Routine examination may help:  VCR 1.4mg/m2 iv day 1

 Patient history, PE  P 100mg po day 1-5

 Hemogram, Ig, Liver/Kidney function test

 X-ray, Abdominal & pelvic CT  Tumor score:

 Bone marrow or CSF cytology (if necessary) 1) Systemic symptoms

 Staging 2) Stage III or IV

 (I) Involvement of a single lymph node region or structure 3) Any mass >7cm

 (II) Involvement of two or more lymph node region on 4) LDH >1.10 (normal level)
same side of the diaphragm
5) β2-microglobulin >1.5 (normal level)
 (III) Involvement of two or more lymph node region on
both side of the diaphragm If Tumor score >3 If Tumor score<3

 (IV) Involvement of one or more extranodal site Poor prognosis CHOP successful rate (80%)

A：asymptomaitic B：fever、sweating 3) Chronic NHL

X：huge tumor mass ，>10cm  10-20% Limited lesion (Stage I,II): can be used
radiotherapy alone
E： extranodal site near only one lymph node region  Advance disease (III, IV): Treatment is still controversial

CS：clinic staging PS：pathologic staging  50% of the patient 8 year after diagnosis may develop into
invasive tumor

Treatment 4) HSCT

1) Very aggressive NHL  Auto HSCT

 Alkalinize urine (sodium bicarbonate )  A110-HSCT

 Chemotherapy：hyper-CVAD 5) Rituximab

 CY (Cyclophosphamide): 300mg/m2 IV 3hr g12h×3day

 Mesna 600mg/m2 IV 24hr×3day (1h before starting CY)

 After last dose of CY:

o Adr 25mg/m2 IV 24hr×2day (adriamycin)

o VCR 1mg IV 24hr×2day

o Decadron 40mg/day po day1-4,11-14

o G-CSF 5ug/kg adr until day 21 or WBC>30,000

2) Subacute NHL (CHOP)

 Rituximab as Initial therapy for Indolent NHL
 Investigator Pts CR/Cru RR

Solal-Celigny(’99) 50 41% 69%

Hainsworth (’00) 41 5% 54%

 Rituximab+CHOP in aggressive NHL

CR/CRu PR ORR

Intent to treat 20 (61%) 12 (36%) 32 (97%)

(n=33)

Evaluable 19 (61%) 11 (35%) 30 (97%)