KELAINAN PADA

HEMATOLOGI

dr. Kati Sriwiyati

 Formation of blood cells
 Occurs mostly in red bone marrow
 All cells arise from same blood stem cell (pluripotent
hematopoietic stem cells)
 Recently some have been found in adults which are mesenchymal
stem cells, which can also form fat cells, osteoblasts, chondrocytes,
fibroblasts and muscle cells

2
HEMATOPOIESIS
Blood stem cells divide into:
1.myeloid stem cells or
2.lymphoid stem cells

All except for

lymphocytes arise
from myeloid stem
cells

All originate in the

bone marrow

Not shown are

mast cells,
osteoclasts,
dendritic cells
5
 Also called RBCs or red blood
cells
 Biconcave discs and flexible
 Plasma membrane but no
nuclei or organelles
 Packed with hemoglobin
molecules
 Oxygen carrying protein
 4 chains of amino acids, each with
iron which is binding site for
oxygen; CO2 carried also heme

 Young ones still containing

ribosomes are called
iron atom

reticulocytes
 Live 100-120 days
6
THE RED BLOOD CELL
REVIEW RED BLOOD CELL DISORDERS
MARROW PRODUCTION
ANEMIA

 Abnormally low number of RBC or Hb levels

 Reduced oxygen carrying capacity
Causes
 Blood loss
 Increased rate of red cell destruction
 Hemolytic anemia

 Deficient or impaired red cell production

 Size of RBC’s
 Microcytic (Small)
 Macrocytic (Large)
 Normocytic (Normal Size)

 Concentration of Hgb
 Hypochromic (Less)
 Hyperchromic (More)
 Normochromic (Normal)

 Microcytic / Hypochromic
 Chronic Blood Loss, Iron Deficiency, Thalassemia

 Macrocytic (Megaloblastic) / Hyperchromic

 Vit B12 (Pernicious) or Folic Acid Deficiency

 Normocytic / Normochromic
 Hemolytic, Aplastic, Myelophthisic, Acute Blood Loss, Chronic Renal Failure
ANEMIA

Iron Deficiency Anemia

 Most common form of anemia
 Affects about one in five women
 Half of pregnant women and 3 percent of men in
the United States.
 The cause is a shortage of the element iron
 Nutritional imbalance
 Slow, chronic bleeding disorders
 Inability to recycle plasma iron
 ASH Teaching Slides: Blood Cells

Iron-deficiency anemia is indicated by red blood cells that

are paler and of a smaller size than normal.

Schrier, S. ASH Image Bank 202;2002:100345. Copyright ©2002 American Society of

Hematology.
ANEMIA

Vitamin Deficiency Anemias

 Folate and vitamin B-12 deficiency
 Intestinal disorder that affects the absorption
of nutrients
 Fall into a group of anemias called
megaloblastic anemias, in which the bone
marrow produces large, abnormal red blood
cells.
ANEMIA

Anemia of Chronic Disease

 Interfere with the production of red blood
cells, resulting in chronic anemia
 Kidney failure also can be a cause of anemia
 The kidneys produce a hormone called
erythropoietin, which stimulates your bone marrow
to produce red blood cells.
 A shortage of erythropoietin, which can result from kidney
failure or be a side effect of chemotherapy, can result in a
shortage of red blood cells.
ANEMIA

Aplastic Anemia
 Life-threatening anemia caused by a
decrease in the bone marrow's ability to
produce all three types of blood cells — red
blood cells, white blood cells and platelets
 Cause of aplastic anemia is unknown
 autoimmune disease
 Chemotherapy
 Radiation therapy
 Environmental toxins
ANEMIA

Anemias associated with bone marrow

disease
Leukemia and myelodysplasia, can cause
anemia by affecting blood production in the
bone marrow
Effects vary from a mild alteration in blood
production to a complete, life-threatening
shutdown of the blood-making process
 Myelodysplasia is a pre-leukemic
condition that can cause anemia.
 Other cancers of the blood or bone marrow, such as multiple myeloma,
myeloproliferative disorders or lymphoma, can cause anemia.
ANEMIA

Hemolytic Anemias
 Red blood cells are destroyed faster than
bone marrow can replace them.
 Autoimmune disorders can produce
antibodies to red blood cells, destroying
them prematurely
 Hemolytic anemias may cause yellowing of the
skin (jaundice) and an enlarged spleen.
ANEMIA

Sickle cell anemia

 Defective form of hemoglobin that forces red
blood cells to assume an abnormal crescent
(sickle) shape.
 Mutation for the gene coding for the β-globulin chain
 Valine is substituted for glutamic acid HbS

 Red cells die prematurely, resulting in a chronic

shortage of red blood cells.
 Block blood flow through small blood vessels in the
body, producing other, often painful, symptoms.
SICKLE CELL ANEMIA
 Single base pair mutation results in a single amino acid
change.
 Under low oxygen, Hgb becomes insoluble forming long
polymers
 This leads to membrane changes (“sickling”) and
vasoocclusion
RED BLOOD CELLS FROM SICKLE CELL ANEMIA
 Deoxygenation of SS erythrocytes leads to
intracellular hemoglobin polymerization, loss of
deformability and changes in cell morphology.

OXY-STATE DEOXY-STATE
ANEMIA

α- Thalassemia
 Common in Asians
 Deletion of globulin chain loci
 4 possible degrees of α thalassemia:
 Silent carrier, loss of a single α globulin gene
 α thalassemia trait, loss of a pair of globulin gene
 HbH disease, only a single gene is present
 Hydrops fetalis, deletion of all α globulin
TALASSEMIA
POLYCYTHEMIA VERA

 An acquired disorder of the bone marrow

that causes the overproduction of all three
blood cell lines
 white blood cells, red blood cells, and platelets

 It is a rare disease that occurs more

frequently in men than women, and rarely in
patients under 40 years old.
 causes is unknown
POLYCYTHEMIA VERA

 Usually develops slowly, and most patients

are asymtomatic
 abnormal bone marrow cells proliferate
uncontrollably leading to acute myelogenous
leukemia
 Patients have an increased tendency to form
blood clots that can result in strokes or heart
attacks
 Some patients may experience abnormal bleeding
because their platelets are abnormal
WHITE BLOOD CELLS

 Collectively known as White Blood Cells

(WBC)

 Formed elements of the blood with

organelles and a nucleus but lack
hemoglobin

 Protect the body against microorganisms and

remove dead cells and debris from the body
 The total white blood cell count (WBC) and
differential are measured in an automated
counter
 WBC reflects the circulating pool of myeloid
and lymphoid cells
 WBC in each microliter (ml;mm3) is reported
 Relative proportion of each type of WBC is
indicated by a percentage
 Absolute number is the percentage of each
type of WBC multiplied by the total WBC

26
AKA WBCs: white blood
cells

27
WHITE BLOOD CELLS
WHITE BLOOD CELLS

Per µl blood Per µl of blood

Total WBC count 5,000 – 10,000

Neutrophils 50 - 70% 2,000 – 7,000
Lymphocytes 20 - 40% 1,000 – 4,000
Monocytes 1 – 6% 50 – 600
Eosinophils 1 – 5% 50 – 500
Basophils 0 – 2% 0 - 100
WBC DISORDERS

 Leukopenia
 Decreased peripheral white cell count due to
decrease numbers of any specific types of
leukocytes
 Leukocytosis
 Non–neoplastic elevation of WBC count
 WBC PMN Band Lymph Mono Eos Baso

Birth 6-30K 42-80% 2% 26-36% 3-8% 0-5% 0-2%

(0-1m)

Child 6-18K 18-44% 3% 46-76% 3-8% 0-5% 0-2%

(1m – 12m)

Child 5-14K 37-75% 3% 25-57% 3-8% 0-5% 0-2%

(1y – 16y)

Adult 4-10K 36-75% 2% 20-50% 3-8% 0-5% 0-2%

J. Levine
31
 WBC PMN Band Lymph Mono Eos Baso

Bacterial 16K↑ 79%↑ 8%↑ 8% 3% 1% 1%

Infection

Steroid 12K↑ 79%↑ 4% 14% 3% 0% 0%

Therapy
Splenectomy 13K↑ 50% 2% 40% 5% 2% 1%

Viral 3.5K↓ 50% 2% 40% 5% 2% 1%

Infection

Chemo <3K↓ 65% 0% 20% 12%↑ 2% 1%

J. Levine
32
 25% 65% 8% 2%

Proliferation Maturation Intravascular Tissues

6-7 days 6-7 days 12 h 12h

Bone Marrow
J. Levine
33
Proliferation 25 %

Source Undetermined (All Slides)

34
Myeloblast
J. Levine
Promyelocyte Myelocyte
Neutrophil - Maturation Phase

65 % of myeloid cells

Maturation 6-7 days

Source Undetermined (All Slides)

Metamyelocyte Band Neutrophil

35
J. Levine
 Definition

Neutropenia Neutrophila
Less than 1500/ml Greater than 7700/ml

Acquired
Or
Inherited
J. Levine

36
 Normal ANC is 1500-7700/ml
 Neutrophilia: abnormally high ANC
 Shift to the left: ↑’d release of
precursors from the bone marrow
 not necessarily associated with
neutrophilia

37
  Chronic Stimulation
 Acute shift from  Excess cytokine stimulates
marginating to circulating proliferative pool
pool
 ↑ measured WBC, not total
WBC  Causes:
 Causes:  Infection
 Steroid treatment  Down's Syndrome
 Exercise  Pregnancy/Eclampsia
 Epinephrine  Chemotherapy recovery
 Hypoxia  Myeloproliferative disorders
 Seizures  Marrow metastases
 Other stress

38
WBC DISORDERS

Neutropenia
 Reduction in the number of granulocytes
(<1500/µl)
 Increased risk of infection
 Reduced phagocytosis response
WBC DISORDERS

Neutropenia
 Decreased or defective granulopoiesis
 Aplastic anemia
 Anti-neoplastic agents
 Other drugs: chloramphenicol, sulfonamides,
chlorpromazine
 Accelerated removal or destruction
 Aggressive and chronic infections
Decreased Increased Shift to
Production Destruction Marginating Pool

Bone marrow Peripheral Move from the

circulation circulating pool to
attach along the
vessel wall
Medication: Autoimmune Severe infection
Chemotherapy diseases Endotoxin release
Antibiotics, etc (Rheumatoid Hemodialysis
arthritis, SLE, etc) Cardiopulmonary
bypass

41
WBC DISORDERS

Manifestation of Neutropenia
 Infections

Signs and Symptoms

 Malaise, chills, fever
 Ulcerative necrotizing lesions of the mouth,
skin vagina and GI tract
 Monocytes: circulating precursor of
the tissue macrophage.
 Also known as the reticuloendothelial
system
 Average count 300 cells /ml
 Range 0-800 cells/ml

43
 Monocyte Differentiation

into Macrophages
Differentiation
Intravascular
Maturation

Tissue:
Proliferation

30-48 hours 24 hours 72 h

Bone Marrow

Source Undetermined
44
Antigen presentation of phagocytized particles to T Cells

Cytokines/
chemokines
J. Levine
45
Follow neutrophils to sites of inflammation within 12-24h
Number 1/30th that of neutrophils
Pts w/ CGD, CHS and LAD also have defects in monocyte fxn

Chemoattractant

Phagocytosis
J. Levine
46
 Low counts  Elevated counts
 glucocorticoids  Malignancy
 stress  Granulomatous disease
 Marrow recovery
 Infections
 malaria
 TB
 Rocky Mountain Spotted
fever
 leishmaniasis
 brucellosis

47
Eosinophils

Intravascular
Maturation

Tissues
Proliferation

9 days 2.5 3-8

days hours
Bone Marrow

Myelocyte Eosinophil 48
Source Undetermined (Both Slides)
 Bright red granules
 IgE on cell surface (not on neutrophils)
 Play a key role in killing parasites
 Average absolute count 200/ml
 Non allergic individuals usually <400/ml

49
 Conditions:
 Neoplasm (Hodgkin’s disease, lymphoma other
tumors)
 Allergies-drugs, environmental (grass, trees, dust)
 Asthma
 Collagen vascular diseases-vasculitis
 Parasitic infection
 Idiopathic hypereosinophilia: elevated eosinophil
count associated with organ dysfunction (GI, skin,
CNS, cardiovascular).
 > 5000/µl requires treatment with
immunosuppressives and antihistamines
50
 Maturation of Basophils and Mast cells

Basophil

Intravascular

Tissues
Proliferation Maturation

2.5 7 days days

days
Maturation
Mast Cell
Proliferation in Tissues

J. Levine
51
 Basophils and mast cells

 Function remains obscure but may

play a role in host defense against
certain parasites

52
  High count
 Allergies
 Low count
 infection
 hypersensitivity
 endocrinopathies
 glucocorticoids
 myeloproliferative
disorders
 Systemic mastocytosis
 symptoms due to excess
histamine release

53
WBC DISORDERS

Reactive Leukocytosis
 Increase number of WBC
 Common reaction due to a variety of
inflammatory states caused by microbial or
non-microbial stimuli
 Usually non-specific
NONMALIGNANT LEUKOCYTE DISORDERS

 Leukemoid reaction – this is an extreme neutrophilia with a

WBC count > 30 x 109/L
 Many bands, metamyelocytes, and myelocytes are seen
 Occasional promyelocytes and myeloblasts may be seen.
 This condition resembles a chronic myelocytic leukemia
(CML), but can be differentiated from CML based on the fact
that in leukemoid reactions:
 There is no Philadelphia chromosome
 The condition is transient
 There is an increased leukocyte alkaline phosphatase score
(more on this later)
 Leukemoid reactions may be seen in tuberculosis, chronic
infections, malignant tumors, etc.
LEUKEMOID REACTION
LEUKEMOID REACTION
NEOPLASTIC PROLIFERATION OF WHITE CELLS

1. Leukemia – neoplasms of the

hematopoietic stem cells
2. Malignant lymphomas – cohesive tumor
lesions; neoplastic lymphocytes
3. Plasma cell dyscrasias – arising from the
bones; localized disseminated
proliferation of antibody forming cells
4. Histocytoses – proliferative lesions of
histiocytes
NEOPLASTIC PROLIFERATION OF WHITE CELLS

Leukemia
 Malignant neoplasm of the hematopietic
stem cells
 BM replaced by unregulated, proliferating,
immature neoplastic cells  blood 
leukemia  enter spleen, lymph nodes
 Most common cancer in the paediatric age
 Leading cause of death in children between 3
and 14 years old
NEOPLASTIC PROLIFERATION OF WHITE CELLS

Classification of Leukemia
A. According to cell type and state of cell
maturity
 Lymphocytic – immature lymphocytes and their
progenators
 Myelocytic – pluripotent myeloid stem cells and
interferes with maturation of all granulocytes, RBC
and platelets
B. Acute or Chronic
 Acute – immature cells (blast)
 Chronic – well differentiated leukocytes
NEOPLASTIC PROLIFERATION OF WHITE CELLS
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (MORPHOLOGY)

 Congenital
 Pelger-Huet anomaly
 Bilobed and occasional unsegmented neutrophils
 Autosomal recessive disorder
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (MORPHOLOGY) CONTD.

 Neutrophil hyper-segmentation
 Rare autosomal dominant condition
 Neutrophil function is essentially normal
 May-Hegglin anomaly
 Neutrophils contain basophilic inclusions of RNA
 Occasionally there is associated leucopenia
 Thrombocytopenia and giant platelet are frequent
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (MORPHOLOGY) CONTD.

 Alder’s anomaly
 Granulocytes, monocytes and lymphocytes contain granules which stain
purple with Romanowsky stain
 Granules contain mucopolysaccharides
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (MORPHOLOGY) CONTD.

 Chediak-Higashi syndrome
 Autosomal recessive disorder
 Giant granules in granulocytes, monocytes and lymphocytes
 Partial occulocutaneous albinism
 Depressed migration and degranulation
 Recurrent pyogenic infections
 Lymphoproliferative syndrome may develop
 Treatment is BMT
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (MORPHOLOGY) CONTD.

 Acquired
 Toxic granulation
 Dohle bodies
 Pelger cells
 Hypersegmented neutrophils
LEUCOCYTES BENIGN DISORDERS
QUALITATIVE CHANGES (FUNCTIONAL)

 Leucocyte adhesion deficiency

 Chronic granulomatous disease
 Chediak-Higashi syndrome
 Primary immunodeficiency
 Severe combined immunodeficiency
 Common variable immunodeficiency
 Isolated IgA deficiency
 T-cell immunodeficiency
 Thymic aplasia (Di George syndrome)
ACUTE LEUKEMIA (CELL KINETIC STUDIES)

 Block in the differentiation of leukemic cells

with prolonged genration time  clonal
expansion of the transformed stem cells +
failure of maturation  accumulation of
leukemic blast  suppress normal
hematopoietic stem cells
ACUTE LYMPHOCYTIC LEUKEMIA (ALL)

 Most common leukemia in children (80%)

 Treatable and potentially curable
 Classified according to lymphocytes and
state of maturation
1. Early B cell
2. Pre-B cell
3. Mature B cell
4. Early T cell
5. Mature T cell
 Predominan limfoblas 50-90%
 Gambaran :
 sel besar, inti besar
 Sitoplasma relative sedikit
 Kromatin inti agak gelap
 Nukleoli 1-2
 Bentuk limfosit tua sedikit
Hapusan sumsum tulang dengan pewarnaan giemsa perbesaran
1000x
ACUTE MYLEOCYTIC LEUKEMIA (AML)

 Acute Non-lymphocytic Leukemia (ANLL)

 Most common in adults; >50% 60years old
 70% of adults will enter remission with
induction chemo
 25-35% of those in remission will have a 5 year
survival rate
 BM transplant
 Leukositosis
 Hitung jenis :
 mieloblas meningkat (>20%)
 Promieloblas meningkat
 Mielosit sedikit
 Metamielosit sedikit
 Neutrofil batang meningkat
 Neutrofil segmen meningkat

 Ada hiatus leukemikus

CHRONIC LEUKEMIA

 Insidious onset
 Incidental findings during routine exam
CHRONIC LYMPHOCYTIC LEUKEMIA

 Proliferation and accumulation of mature

lymphocytes which are immunologically
incompetent
 B cell line (US)
 T cell line (Asia)

 Hairy cell leukemia

 Leukositosis
 Predominan limfosit kecil 65-75%
 Stadium lanjut  limfosit kecil 95-98%
 Limfoblas sedikit
 Limfosit besar sedikit
 Smudge cell meningkat
This is a microscopic view of bone marrow from a person with chronic
lymphocytic leukemia; it shows predominantly small, mature lymphocytes.
 ASH Teaching Slides: Blood Cells

Hairy-cell leukemia. The characteristic cell of this

type of leukemia has projections uniformly
distributed around its border that give it a hairy
appearance.
Maslak, P. ASH Image Bank 2007;2007:7-00011. Copyright ©2007 American Society of Hematology.
CHRONIC MYELOCYTIC LEUKEMIA

 15% of all leukemias

 Chromosomal abnormality (Ph1)
 Mostly B cell disease
 Leukocytosis
 Splenomegaly
 Hepatomegaly
 Lympadenopathy
 Bone marrow transplant  5 year survival for
50-75% of patients
 Leukositosis
 Hitung jenis :
 mieloblas dan promielosit ada 5%
 Mielosit, metamielosit, batang, segmen banyak
 tidak ada hiatus leukemikus
 Eritrosit kurang
 Retikulosit normal atau meningkat
 Kadang-kadang basophil dan eosinophil meningkat
 ASH Teaching Slides: Blood Cells

Chronic myelogenous leukemia. The blood smear shows

an increased number of neutrophils, a type of white
blood cell.
Maslak, P. ASH Image Bank 2001;2001:100202. Copyright ©2001 American Society of
Hapusan sumsum tulang dengan pewarnaan
giemsa a. perbesaran 200x, b.
perbesaran 1000x
A
B

C D

A : Picture of bone marrow smear (control); Normal granulocytes and erythroblasts

are evident.
B : Acute lymphoid leukemia (ALL); There is a marked proliferation of small
lymphoblasts.
C : Acute myeloid leukemia (AML); There is a marked proliferation of large
myeloblasts.
MALIGNANT LYMPHOMAS

 Primary solid tumors of the lymphoid system

 Cancers involving lymphocytes during
maturation or storage in the bone marrow
 Third most common malignacy in children
MALIGNANT LYMPHOMAS

Hodgkin’s Lymphoma
 Disorders primarily involving the lymphoid
tissues
 Anatomical spread
 Morphological presence of Reed-Sternberg
cells
 60-90% cure rate
 ASH Teaching Slides: Blood Cells

Hodgkin lymphoma. The large cells with an owl-like

appearance are called Reed-Sternberg cells and are a sign
of Hodgkin lymphoma.

Kadin, M. ASH Image Bank 2002;2002:100484. Copyright ©2002 American Society of

MALIGNANT LYMPHOMAS

Manifestations of Hodgkin’s
 A symptoms
 Painless progressive enlargement of a single or
group of nodes (neck)
 May spread continuously through out the
lymphatic system
 B symptoms
 Fever, night sweat, weight loss
 Fatigue, anemia
MALIGNANT LYMPHOMAS

Non-Hodgkin’s Lymphoma
 Involves lymphoid tissue and may spread to
various tissues
 Mostly B cell (80%)
 Cause may be viral or genetic
 EBV
 Immunosuppresed patients
 AIDS
 After organ transplant
SCHISTOCYTES
BURR CELLS
SPUR CELLS
TARGET CELLS
HYPOCHROMIC MICROCYTIC ANEMIA
SPHEROCYTES
TEAR DROP CELLS