College of Health Sciences

Integrated Sciences Division

BMS Department

CHS
 Objectives
At the end of the Chapter, the student must be able to:
1.define erythropoiesis, leukopoiesis and thrombopoiesis.

2.differentiate stem cells from progenitor cells

3.cite the functions of erythropoietin (EPO) and thrombopoietin

4.define hemostasis.

5.discuss blood coagulation in detail

6. discuss the extrinsic pathway of coagulation, with emphasis ONLY on

the roles of Tissue factor (TF), Factor X (10), Prothrombin, Thrombin,
Fibrinogen, Fibrin and Factor XIII (13)
 Objectives
 
7. discuss the intrinsic pathway of coagulation, with emphasis ONLY on the
roles of Factor VII (7) and Thrombin from the extrinsic pathway and Factor
XII (12)/Hageman Factor

* Knowledge of other clotting factors aside from those mentioned

above, is NOT required.

8. interpret data produced by common blood coagulation tests, such as the

following ONLY: Partial thromboplastin time (PTT), Prothrombin time
(PT), Thrombin time (TT) and Bleeding time (BT)
 Objectives
9. define the terms petechiae, purpura, ecchymoses and hematoma

10. discuss bleeding disorders in detail

11. cite the normal erythrocyte count and hemoglobin levels in males and
females

12. state the various physiologic compensations triggered by a

decline in O2 transport

13. define the following terms, state their normal values and discuss
their significance in assessing anemia: hematocrit (HCT), mean
corpuscular volume (MCV), and mean corpuscular hemoglobin
concentration (MCHC)

14. Discuss the major types of anemias

 Objectives

15. cite the normal leukocyte count and the normal

differential WBC count

16. define leukopenia and leukocytosis.

17. Discuss the different types of Leukemias and Lymphomas

 Ponder Points
1. Define
• Erythropoiesis
• Leukopoiesis
• Thrombopoiesis

2. Differentiate stem cells from progenitor cells

3. What are the functions of erythropoietin (EPO) and

thrombopoietin?

(Refer to pages 168 to 170)

Thrombocyte Disorders
 Blood Coagulation
• Hemostasis is the process of stopping blood
loss using blood coagulation

• Blood coagulation occurs as a result of a

cascade of several enzyme-linked reactions.

• The components of the coagulation cascade

are called clotting factors.
 Blood Coagulation Pathways
1. Extrinsic Pathway
- initiated by the activation of Tissue Factor (TF) /
Tissue thromboplastin by tissue damage

- called extrinsic because TF originates outside of

the blood.

- only produces a small amount of Fibrin which

causes minor initial coagulation
Extrinsic Pathway of Blood Coagulation

Cross-linking
XIII
XIII
2. Intrinsic Pathway
- called intrinsic because its main activator,
thrombin produced from the extrinsic pathway
is found in the blood.

- positive feedback causes more Thrombin

formation eventually leading to larger amounts
of Fibrin produced, enough to make coagulation
effective.

- also activated by Factor XII (Hageman Factor)

and Factor VII.
Intrinsic Pathway of Blood Coagulation
Interaction between the Extrinsic and Intrinsic Pathways
 Ponder Point
Define the following terms: (Page 179)
a. Petechiae
b. Purpura
c. Ecchymoses
d. Hematoma

Identify the significance and normal values of each of the

following Blood Coagulation Tests:

a. Partial Thromboplastin Time (PTT)

b. Prothrombin Time (PT)
c. Thrombin Time (TT)
d. Bleeding Time

(Refer to Table 7.2, page 179)

 Bleeding Disorders
Bleeding results from:

A. Platelets disorders

B. Clotting factor abnormalities

C. Abnormal fragility of thin and small blood

vessels
A. Platelet Disorders:
1. Thrombocytopenia:
Normal Thrombocyte Count:
130,000 – 360,000 platelets per
mm3
• Decrease in number of circulating
platelets

Purpura
• Bleeding as a result of minor
vascular pressure or trauma

• Results in petechiae and purpura

• Platelet counts < 100,000/mm3 

thrombocytopenia

• Bleeding only occurs when http://www.nlm.nih.gov/medlineplus/ency/images/

ency/fullsize/2578.jpg
platelet count < 50,000/mm3
A. Platelet Disorders:
1. Thrombocytopenia:

Causes:
• Decreased platelet production
• Increased platelet clearance from the
blood
Causes of Thrombocytopenia:

1. Decreased platelet production:

Caused by:
a. Marrow suppression:
•  RBC, WBC & platelets
•  Megakaryocytes
b. Therapeutic agents:
Eg: Thiazide diuretics, gold, phenylbutazone &
some antibiotics that selectively inhibit platelet
formation
c. Chronic alcohol consumption: ethanol marrow
suppression
d. Congenital defects & folic acid / vitamin B12
deficiencies
e. Marrow tumor metastasis
2. Increased clearance:
a. Non-immune:
a.1. Disseminated Intravascular Coagulation
(DIC): Systemic coagulation 
consumption of platelets 
thrombocytopenia
a.2. Certain hemangiomas  endothelial
damage  thrombocytopenia
a.3. Some protozoan infections  platelet
damage
a.4. Splenomegaly  more platelets
sequestered  thrombocytopenia
2. Increased clearance:
b. Immune:
b.1. Idiopathic thrombocytopenic purpura (ITP)
• Increased removal of platelets from blood or phagocytic
destruction due to binding of Ab or immune complexes
on the platelet surface
• Cause is idiopathic
• Characterized by petechial and purpuric bleeding in skin
& mucous membranes
Types:
a. Acute ITP: affects children < 6 yrs
– Most cases resolve in few weeks to 6 months; often
arises following a viral infection

b. Chronic ITP: affects mostly adults and women

b. Immune:
b.2. Drug-induced thrombocytopenia via an
immune mechanism
• Disrupt the immune response causing Ab to the drug
to complex with it and then bind to the platelets
• Presentation is similar to ITP
Eg. Thiazide diuretics, quinidine, quinine, heparin
b. Immune
b.3. Thrombotic thrombocytopenic purpura
(TTP)
Antibodies damage endothelium

Widespread platelet adherence to damaged blood vessels

Thrombocytopenia
Widespread coagulation in small blood vessels
B. Acquired Clotting Factor Disorders:
1. Impaired hepatic synthesis

Most clotting factors are produced in the liver

• Occurs if liver damage is severe
• Lack of vitamin K
– Antibiotic therapy (Moxalactam)   vitamin
K – producing bacteria   clotting factor
synthesis

– Malabsorption
• Bile synthesis or Bile duct obstruction  
absorption of vitamin K  clotting factor
synthesis
2. Disseminated Intravascular Coagulation (DIC)
• Generalized coagulation leads to consumption of
clotting factors

3. Anticoagulant therapy may cause a hypocoagulation

disorder
e.g. Heparin and Warfarin
May lead to:
• GI bleedings
• Skin ecchymoses formation
• Hematoma
 Ponder Point
Enumerate factors that could
predispose a patient to
thrombocytopenia

(Refer to Figure 7.15, page 181)

C. Small vessel fragility / Vascular purpura
• Produces petechiae or purpura in the skin or
GI mucosa due to bleeding from small blood
vessels
• Vascular weakness comes from:

1. Vascular damage
2. Defective vascular support
Henoch-Schonlein
purpura

Vit. C def
Marfan’s
syndrome

Senile purpura
Erythrocyte Disorders
 Erythrocyte Disorders
• Anemia:  RBC or Hemoglobin

• Normal:

Males: 4,600,000 - 6,200,000 cells per mm3

Females: 4,500,000 - 5,100,000 cells per mm3
  Hemoglobin levels
(normal range: ♂= 14–18 g/dL, ♀= 12–16 g/dL )

 O2-carrying capacity

Compensation: Tissue hypoxia

a. Arteriolar
Compensatory
dilation
mechanisms
b. Cardiac output
c. Shift to Adequate Inadequate
anaerobic
compensation compensation
glycolysis
d. EPO secretion
O2-levels Anemia
restored
 Assessment of Anemia
TEST DEFINITION NORMAL VALUE

Hematocrit Volume of RBC's Males: 40 – 54%

expressed as a percentage Females: 38 – 47%
of the total blood volume

Mean Corpuscular Measure of the average femtoliter 96 – 80

Volume (MCV) RBC volume/size (fL)

Mean Corpuscular Measure of the g / dL 36 – 32

Hemoglobin concentration of
Concentration (MCHC) Hemoglobin in a given
volume of packed RBC's
Erythrocyte Assessment
 Ponder Point

Discuss the significance of the reticulocytes and

the reticulocyte count in assessing anemia

(Refer to page 186)

 Causes of Anemia
A. Impaired Erythrocyte Production
1. Marrow defects
2. Deficiencies
a. Iron deficiency
b. Vitamin B12 deficiency
c. Folic acid deficiency

B.Hemolytic Anemia
1. Intrinsic hemolytic anemia
a. Sickle cell anemia
b. Thalassemia
 Causes of Anemia
A. Impaired Erythrocyte
Production
1. Marrow defects
• In most cases, it is idiopathic
a. Due to abnormalities in the
stem or progenitor cells in the
various blood cell lines
• The defect can be detected by
analyzing the circulating cells
Pure red cell aplasia
• A rare condition of defective
red cell progenitors only
Aplastic anemia
• There is pancytopenia
• Reduction of all blood cells
• Leads to anemia, bleeding &
infections
• Therapy: bone marrow
transplant
A. Impaired Erythrocyte Production
1. Marrow defects
b. Specific marrow suppression due to:
a. infections
b. chemotherapy
c. radiation
d. drug reactions
2. Deficiencies
a. Iron deficiency
o Blood iron level is not enough to satisfy the marrow
demand.
o An average 1-2 mg of iron are lost via the urine,
feces, skin and must be replaced daily from diet
o An additional 1 mg in women is lost (loss via
menstruation)
o Most women do not compensate for this additional
loss and are therefore at marginal iron deficiency
state.
Physiologic Recycling of Iron
2. Deficiencies
a. Iron deficiency
Sources of iron:
• Meat, liver, eggs, nuts, legumes & beans

Absorption of iron:
• Animal products (contained in heme)  easily
absorbed

• The absorption of iron in plants depends on the

processing by gastric acids

• Hence, gastrectomy (removal of stomach)  

iron absorption
2.Deficiencies
b. Iron deficiency

Storage of iron:
Depletion + non-replacement of iron stores 
anemia
Iron is stored in
• Intestinal epithelium
• Liver
• Macrophages
Causes of iron deficiency anemia:
• Dietary iron deficiency
• Absorption disorders
• Chronic blood loss
• GI bleeding
• Heavy menstrual flow

Blood picture:
Microcytic ( MCV), hypochromic ( MCHC)
b. Vitamin B12 (cobalamin) Deficiency
Vit. B12 is required for normal DNA synthesis
Lack of Vit. B12

Mitosis in progenitor lines  Pancytopenia

RNA nor protein synthesis is affected so cell growth
proceeds with no cell division

Marrow precursors remain enlarged (megaloblastic
anemia)

Enlarged erythrocytes released in circulation
(quickly destroyed & removed from circulation)
b. Vitamin B12 (cobalamin) Causes of Vit.B12
Deficiency
deficiency:
• Rarely diet
Sources of Vit. B12: • Malabsorption (most
common)
• Meat, liver, seafood, • Lack of Intrinsic
dairy products
Factor (IF)
• Not synthesized by
• Resection of
human tissue
• Daily requirement: 1 μg stomach or ileum
(microgram)
• Body stores can supply
about 2-5 mg
 Cobalamin Absorption
Gastric pepsin breaks down food and Vit B 12 is released

Vit B12 complexes with R binder and is transported to the small intestines

Pancreatic enzymes release Vit B12

Vit B12 binds to Intrinsic Factor from gastric epithelium

IF of the IF-Vit B12 complex binds to receptors in the distal ileum

Vit B12 is absorbed through distal ileal cells, IF remains outside to be reused

Vit B12 binds to Transcobalamin II to be transported to the tissues that require it. ( i.e
bone marrow )
Pernicious anemia:

Autoimmune chronic gastritis


Autoimmune attack on IF & parietal cells

Lack of Vit. B12 absorption

Megaloblastic anemia

Blood Picture:
Macrocytic ( MCV), Normochromic (Normal MCHC)
 Ponder Points
Identify other causes of a decrease in Vitamin
B12 absorption

Why do some patients who suffer from Vit. B12

deficiency anemia experience some degree of
neuropathy?

(Refer to page 188)

c. Folic Acid (or Folate) Causes of folic acid
Deficiency deficiency
o Also produces megaloblastic •
anemia (similar to Vit. B12 Fad diets
deficiency) • Overcooking
• Intestinal resection
o  Serum folate • High demand states:
– Pregnancy
o No neuropathy – Infant growth spurts
– Prolonged marrow
overactivity
Sources of folate: – Rapidly growing
o Meat, eggs, leafy vegetables
malignancies
Stores of folate:
o Body stores provide about 5
months of folate supplies
B. Hemolytic Anemia
1. Intrinsic hemolytic anemia
- Hemolysis caused by hereditary defects ,
involving:
a. Defective RBC enzyme systems
b. Defective RBC membranes
c. Abnormal hemoglobins

(hemoglobinopathies)
c.1. Sickle cell anemia
c.2. Thalassemia
B. Hemolytic Anemia

2. Extrinsic hemolytic anemia

- Hemolysis caused by damaging external

factors that affect normal RBC’s
- These factors cause surface changes on the
RBC that eventually cause increased
clearance by the spleen and macrophages
OR direct rupturing while in the blood.
The types of extrinsic hemolytic anemias are
a. Immune hemolysis
b. Mechanical hemolysis
 Sickle Cell Anemia
o RBCs contain HbS hemoglobin instead of HbA

Under certain conditions, HbS polymerises


Long, insoluble filaments

Distortion of RBC shape (sickle)
Less flexibility

Sickled RBCs removed by spleen and marrow
(in ~ 20 days)

Anemia

o Blood picture: Normocytic (Normal MCV),

Normochromic ( Normal MCHC)
 Sickle Cell Anemia

Biochemistry, 4th ed by Champe, Harvey &

Ferrier
Clinical course:
• Variable
• Chronic anemia
• Weakness
• Sickle crisis :
Hypoxemia, acidosis, pregnancy, cold weather

acute sickling

blockage of small blood vessels

widespread ischemic organ damage
• Deep pain is due to bone necrosis due to occlusion of small blood
vessels within the bone
Sickle cell trait Affected Populations
• One defective • African blacks
gene instead of (most affected)
two
• Middle Eastern
• Few populations
complications
• Indian populations
• Carriers so can
pass the • Eastern
defective gene
to their children Mediterranean
origins
 Thalassemia
• Hb is made of 2 alpha-globin chains and 2 beta-
globin chains

• In thalassemia, there is defective production of

either the alpha or beta-globin chains (most
common).

• Affects populations with origins in countries

around the Mediterranean

• Blood picture: Microcytic ( MCV),

Hypochromic ( MCHC) anemia
Pathogenesis of Beta-Thalassemia
 Forms of Beta-Thalassemia
1. β-Thalassemia major (Cooley’s anemia)
• Two defective genes (homozygous)
• Life-threatening disease
• Requires continuous blood transfusions

2. β-Thalassemia minor (β-Thalassemia trait/carrier)

• Only one defective gene (heterozygous)
• A milder form of the disease
• Essentially asymptomatic
Leukocyte Disorders
 Normal Values
Leukocyte Count:
5,000 – 10,000 cells per mm3

WHITE BLOOD CELL DIFFERENTIAL COUNT

1. Granulocytes:
a. Neutrophils : 54-62% of circulating leukocytes.
b. Eosinophils : 1-3% of circulating leukocytes
c. Basophils: less than 1% of circulating leukocytes
2. Agranulocytes:
a. Monocytes : 3-9% of circulating leukocytes.
b. Lymphocytes: 25-33% of circulating leukocytes
 Ponder Point

Differentiate the following terms:

a. Leukopenia
b. Leukocytosis

Refer to page 194

 Leukocyte Disorders
Leukemias
• Primary malignant tumors of leukocyte precursors in the
marrow

• No distinct masses are formed but instead the leukocyte

precursors proliferate within the marrow

• The term “Leukemia” is used when there is the

appearance of leukocytes of varying degrees of
differentiation in the circulation causing an overall
increase of circulating blood cells.

• Aleukemic leukemia: Proliferation of precursors is

confined to the marrow only .
• The excessive production of leukocytes is due
to a retained ability to divide as they mature
and differentiate

• This results in a large number of dividing cells

which increase at the expense of the bone
marrow
Consequences of Leukemia
Classification:
• Classification according to progression:
– Acute
– Chronic
• Classification according to cell line affected:
– Granulocytic (myeloblastic) leukemias
– Lymphoblastic (lymphocytic) leukemias
Classification of Leukemia
 Classification of Leukemia
A. Acute Lymphocytic Treatment & Prognosis:
Leukemia (ALL) • Aggressive combination
• Mostly seen in children and
chemotherapy
adolescents
• Is the most common • Bone marrow
malignancy affecting transplantation
children

Signs and Symptoms: Prognosis: good in children,

• Erythropoiesis  anemia  less optimistic in adults
weakness
• Thrombocytopenia  
bleeding tendency
• Susceptibility to infections
• Bone pain
• Cervical lymphadenopathy
B. Acute Myeloblastic Leukemia (AML)
• Typically occur in persons > 55 years of age

• Presentation is similar to ALL & diagnosis is

confirmed by bone marrow biopsy

• Prognosis: more optimistic than ALL

• 70% of cases are cured following intensive

therapy although many patients relapse within
18 months
C. Chronic Lymphocytic Leukemia (CLL)
• Most common forms of leukemias typically seen
in persons > 50 years of age
• Onset: Gradual
• Symptoms of fatigue, weight loss and anorexia
are more age-related
• Cells involved: mostly B lymphocytes
• Non-functional lymphocytes  defective
antibody production
• Infiltration of lymph nodes  lymphadenopathy
• Survival can be prolonged by chemotherapy
D. Chronic Myeloblastic leukemia (CML)
• Age group: peak incidence at 25 – 60 y/o
• Cell line affected: Granulocyte
• Liver & spleen infiltration  hepatomegaly &
splenomegaly
• 90% of cases have damaged chromosome #22
(Philadelphia chromosome)
• Therapy has no impact on survival
• Blast crisis:
 Occurs in the disease’s later stage
 Resembles acute leukemia, where large numbers
of immature leukocytes rapidly enter the blood
causing rapid deterioration of the patient’s
condition
 Lymphoma
• Solid malignant tumor of lymphoid tissue
(lymphocytes and their precursors)

• 2nd most common tumors after carcinomas

• Marrow and lymphoid tissue replacement

• Tumor expansion produces local effects

• Immune deficiencies due to loss of normal lymphoid

tissue

• Anemia

• Lymphadenopathy
 Hodgkin’s Lymphoma / Disease (HD)
• Relatively rare

• Possible etiology: Genetic & Epstein-

Barr Virus (EBV) infection

• Occur mostly in young males and

blacks

• Manifestations;
a. Usually arises in a single, painless
cervical LN, then spread to adjacent
LNs and lymphoid organs
b. Splenomegaly & lymphadenopathy
c. Fatigue, wasting, fever
d. Depression of T-cell function
 Hodgkin’s Lymphoma

• Diagnosis: Presence of Reed-Sternberg (RS)

cell
 Staging of Hodgkin’s Lymphoma

• Therapy and prognosis would depend on the stage of the lymphoma, as well as
the age of the patient. Younger patients have a better prognosis.
 Non-Hodgkin’s Lymphoma (NHL’s)
• Arises in lymphoid tissue affecting the T- & B-cells
in particular

• Primary site: LNs and may spread to other LNs

and lymphoid organs but in a less systematic
pattern as compared to HD.

• Abnormal cells may escape into the blood after

metastasis and may give a blood picture similar
to leukemia.

• Staging of NHL’s is based on cytologic features

and prognosis:
a. Low Grade NHL
b. Intermediate Grade NHL
c. High Grade NHL
 Reference
• Unless otherwise specified, all information and multimedia
in this presentation were obtained from:

Pathophysiology : Concepts and Applications for Health

Care Professionals , Third edition

By Thomas J. Nowak & A. Gordon Handford

Chapter 7 BLOOD DISORDERS

Pages 168 – 174
178 – 181
183 – 192
194 – 198