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Pharmacology 3.2

1 Sem/A.Y. 2015-2016

Hematinics, Hemostatics and Coagulants

Glenn V. Guevara, MD
B. Erythropoiesis

OUTLINE
A.
B.
C.
D.
E.
F.
G.
H.
I.

September 11, 2015

Introduction
Anemia
Iron Deficiency Anemia
Hypoproliferative Anemia
Megaloblastic Anemia
Myelopoiesis
Megakaryopoiesis
Hemostasis
Summary

HEMATINICS, HEMOSTATICS AND COAGULANTS

A. INTRODUCTION
A. Hematopoiesis

Figure 2: Erythropoiesis

Erythropoietin: main regulator of erythropoiesis

o Stimulate hematopoietic stem cells from the bone
marrow to form RBCs
o Released by kidneys in response to low O2 tension
o Factors that decrease tissue oxygenation: low blood
pressure, anemia, low hemoglobin, poor blood flow,
pulmonary disease
o Increased number of RBCs results to an increased O2
carrying capacity, inducing a negative feedback on
EPO

Figure 3: Erythropoietin stimulation and inhibition

Figure 1: Hematopoiesis

Formation of blood components

o Erythropoiesis: formation of RBCs
o Myelopoiesis: formation of granulocytes and
monocytes
o Megakaryopoiesis: formation of platelets
Derived from hematopoietic stem cells

Iron: needed for maturation of red blood cells

o Each RBC contains several hundred hemoglobin
molecules which transport oxygen
o Iron is needed for the production of heme
Cobalamin
Folic Acid
B. ANEMIA
Decrease in the amount of RBCs or hemoglobin in the
blood
Leads to lowered ability of blood to carry oxygen

Causes:
o
Blood loss (most common cause): trauma, GI
bleeding, abnormal menstrual bleeding
o
Decreased RBC production
Nutrient deficiency (iron, cobalamin, folic acid);
most common cause among decreased RBC
production

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Thalessemia
Bone marrow cancers
Kidney disease
Chronic infections
Fluid overload- decrease in RBC production due to
volume expansion
Increased RBC breakdown- Sickle Cell Disease

Hematocrit (Hct)
Male
Female

Male
Female

Hgb Count
13.8 to 18.0 g/dl (8.56-11.17
mmol/L)
12.1 to 15.1 g/dl (7.51-9.37 mmol/L)
11-16 g/dL (6.83-9.93 mmol/L)
11-14 g/dL (6.83-9.93 mmol/L)
RBC Count
4.7-6.1 millions/uL
4.2-5.4 millions/uL

MCV

80-100 fl (femtoliters)

Male

Types of Anemia
o
By size: normocytic, macrocytic, microcytic
o
By color: normochromic, hypochromic, hyperchromic

Female
Children
Pregnant

Signs and Symptoms

45 %
40 %

MCH
27-31 pg/cell (picograms)
MCHC
32-36 g/dL or 19.9-22.3 mmol/L
Table 1: Normal values for CBC
C. IRON DEFICIENCY ANEMIA
Most common cause of anemia
Due to increased iron demand, iron loss or decreased
iron intake
More common in females (so take care and love your mom, sisters,
daughters and girlfriends, boys. There are a lot of illnesses associated
with women.)

Microcytic and hypochromic

Figure 4: Shows a somewhat good looking man with a

creepy gaze. Also shown are the General Signs and
Symptoms of Anemia.
Diagnostic Tests
o Hemoglobin Count hemoglobin concentration
o Hematocrit - proportion of blood volume occupied by
RBC; also called "packed cell volume" or "erythrocyte
volume fraction" (about 3x the Hgb concentration)
o RBC Count number of RBC
o Mean Corpuscular Volume (MCV)

Average volume or size of RBC

MCV = (Hct x 10) / RBC number in million

Normal MCV and decreased Hgb/Hct =

normocytic anemia; low MCV = microcytic and
vice versa
o Mean Corpuscular Hemoglobin (MCH)

Average mass of hemoglobin per RBC in a

sample of blood

Assess COLOR of the ANEMIA

MCH = (Hgb x 10) / RBC number in million

o Mean Corpuscular Hemoglobin Concentration
(MCHC)
Concentration of hemoglobin in a volume of packed
RBC the HUE OF RBC
MCHC = MCH/MCV x 100
This is more sensitive for measuring the actual
color because it considers both MCV and MCH
o Blood Smear morphology of RBCs

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Causes:
Increased demand
o Growth and development children, adolescents
o Pregnancy
Blood loss
o Parasitic infections
o Menorrhagia
o Peptic ulcers
o Patients on anticoagulants (aspirin, clopidogrel, etc)
Decreased intake
o Low iron diet: vegetarians, vegans
o Malabsorption: intestinal resection, celiac disease,
inflammatory bowel disease, decreased acidity of
stomach (due to prolonged proton pump inhibitor use,
e.g. omeprazole)
A.

Diagnostic Tests
(Why do we need to know this? Kinda boring but just see yourself as House,
Shepherd, Yang or Grey diagnosing your anemia patient. Wee!)

CBC (see diagnostic tests of anemia)

Serum iron

It is the amount of circulating iron bound to transferrin

It can increase immediately on initiation of Fe

supplementation
Serum ferritin

Most SENSITIVE indicator but is not reliable if within

normal limits

Remember that ferritin is the storage form of iron

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Total Iron Binding Capacity (TIBC)

Most SPECIFIC indicator (when levels are high)

It measures the blood capacity to bind iron with

transferrin. It is an indirect measure of transferrin

Transferrin is the transporter of iron in the blood. An

increase would point to an increased need for iron
(2017B)

It is usually elevated in IDA

Transferrin Saturation Index (Percent Saturation/ Iron
Saturation)

It is the percent saturation or iron saturation of

transferrin

How much iron is currently bound to transferrin

(2017B)

SI/TIBC x100
Table 2: Normal values
Serum Iron
Male
65-176 g/dL
Female
50-170 g/dL
Children
50-120 g/dL
Newborn
100-250 g/dL
Serum Ferritin
Male
18-270 ng/mL
Female
18-160 ng/mL
Children
7-140 ng/mL
Newborn
25-200 ng/mL
Total Iron Binding Capacity
240-450 g/dL
Transferrin Saturation Index
Male
>15-50%
Female
>12-50%
Still Possible
5-10%
Definitely Abnormal
<5%

Figure 5: Increasing severity of iron imbalance up to Iron

Deficiency Anemia. Note the boxes in green, which indicate
which stage would the first time the lab findings will appear
(2017B). As the disease progresses, the other parameters that
were normal become lower.

With a Negative Iron Balance, bone marrow iron stores,

serum ferritin decrease while TIBC increases.

With Iron Deficient Erythropoiesis, also SI, % saturation,

marrow sideroblasts decrease while RBC
protoporphyrin increases.

With IDA (which is severe), there is also morphological

change in the RBC

Table 3: Differentiating microcytic anemia causes via lab

tests. These are the different diseases that can present with
microcytic anemia but focus your attention on IDA. Theres a
lower serum iron, % saturation, and serum ferritin but a higher
TIBC. If you order for a smear in IDA patients, youd see a
microcytic & hypochromic morphology.
Tests

Inflammation

Thalassemia

Smear

Iron
Deficiency
Micro/hypo

N/micro/hypo

Serum Iron
TIBC
%saturation
Ferritin
Hemoglobin

<30
>360
<10
<15
(N)

<50
<300
10-20 (N)
30-200 (N)
(N)

Micro/hypo w/
targeting
(N) to high
(N)
30-80
50-300
Abnormal

Sideroblastic
Variable
(N) to high
(N)
30-80
50-300
(N)

Figure 6: Hemoglobin Synthesis. Protoporphyrin IX is the

step before heme. When it binds to iron, then there is the
formation of heme. If there is an increase in protoporphyrin if
there is no iron available in circulation. Thus no heme is formed.
In severe forms of iron deficiency anemia, you see a lot of
immature RBC in the blood. Thus, youll need iron
supplementation to normal it out.

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B.

Iron
In 1 mL of RBC, you will get 1 mg iron
Daily need: 15-20 mg/day (of elemental iron) due to 1015% absorption of dietary iron
o M: 1 mg/day
o F: 1.5 mg/day
o Higher requirement for:
Pregnant: 2-3x (5-6 mg)
Children/adolescents: 1.5x
Vegetarian diet has 50% less iron absorption
High in Fe:
o red meat
o egg yolk
o dark leafy greens (spinach)
o dried fruit (raisins, prunes)
o iron enriched foods (cereals, grains)
o mollusks (clams, oysters)
o beans (soybeans)
Different forms of Iron:

Heme iron
o Red meat (Eww. Eat white meat to be healthy.)
o absorbed directly through the heme transporter

FerrIc: IV supplement (e.g. Ferric Dextran)

o
Why is it given parenterally?
This is because it must be first converted to
ferrous by duodenal cytochrome B (a
ferrireductase) to be absorbed in GIT.

FerrOus: Oral preparations (e.g. Ferrous gluconate)

o Why oral? Because it can be directly absorbed by
the intestinal cell via DMT 1
Remember: Fair (Fer) ROD and RICky B
ROD: FerRous, Oral, Direct, DMT 1
RICky B: FerRiC, IV, duodenal cytochrome B
Storage and Transport (Mentioned last year. From 2017 B)

Inside the intestinal cell, iron is stored as ferritin.

If iron is needed, it moves out as ferrous, becomes

converted to ferric, and ferric binds to transferrin ->
circulates in blood
Katzung: Ferritin is a B-globulin that can bind 2 molecules of
ferric iron.
C. Management
Packed RBC Transfusion for SEVERE ACUTE ANEMIA
o Usually secondary to blood loss
o Supplementation can be started as adjunct but onset of
effects will be delayed
Oral iron
Parenteral iron
D. Oral Iron Preparations (Refer to Table 4)

What you need to memorize in the table is the

elemental iron.

Remember that the supplement is often iron + a base

salt (sulfate, fumarate). Sometimes they dont show the
elemental Fe in parenthesis and you have to compute
from the dosage. (2017B)

Elixirs are available for children and for patients who

cannot swallow.

Ferrous gluconate- given to children with iron

deficiency anemia. It is usually prepared as an elixir
and combined with multivitamins.

Extended release has excipients to prolong release

(2017B)

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Ferrous fumarate- usually combined with

multivitamins like folic acid and Vit-B complex
To reverse the anemia
o You need to give iron supplementation for 312 months.
o In Harrisons, they suggested giving
300mg/day elemental iron but according to
WHO, you can start with 60 mg/day elemental
iron for patients with mild-moderate anemia.
o Eg. If a patient needs 60mg/day of elemental
iron, you can give ferrous sulphate hydrated
which has 65 mg. If you have a patient who
needs 300mg/day of elemental iron, then you
need to give 5 tablets of ferrous sulphate
hydrated.

Benefits of Effective Iron Supplementation Programs

(Mentioned last year. From 2017 B)

Children/adolescents
o improved behavioral and cognitive development
o improve child survival

Pregnant women and their infants:

o decreased incidence of low birth weight babies
and perinatal mortality
o decreased maternal mortality/obstetrical
complications

All individuals
o improved fitness and work capacity
o improved cognition
Table 4: Common Oral Iron Preparations
Generic Name

Percent
Elemen
tal Iron

Tablet

Elixir
(5 ml)

Properties

Ferrous
sulphate
hydrated
(dehydrate
tetrahydrate)

20 %

325
(65)

300
(60)

Commonly
given due to
tolerability,
effectiveness
and low cost
More of the GI
irritation effect

195
(39)

90
(18)

Ferrous
sulphate
dessicated
(monohydrate)

30-32%

Extended
Release
ferrous sulfate

20%

525
(105)

Ferrous
fumarate

33 %

325
(107)

195
(64)
Ferrous
bisglycinate

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20%

75 (15)

With incipients
to prolong
release

H% elemental
iron; same
effectiveness as
sulfate
100
(33)
Iron amino acid
chelate; good
absorption &
high

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bioavailability
Ferrous
gluconate

12%

325
(39)

300
(35)

Polysaccharide
iron
(eg.
Maltose iron)

100%

150
(150)

100
(100)

Similar efficacy
and tolerability
as
that
of
sulfate
Ferric complex
with hydrolysed
starch; less GI
irritability;

E. WHO Guidelines of Iron Supplementation (from lecturers

lecture slides)

The goal is to reverse anemia and provide 1g iron

stores for up to 3-12 months.

Patients under iron supplementation have to be

evaluated every month (2017)

Dosage: 60mg-300mg/day (300 is what Harrisons

recommends but for mild to moderate anemia, start at
60 mg)

Adults: 60 mg
Pregnant: 60 mg iron/400 g folic acid for 6 months of
pregnancy but may extend 3-6 months postpartum
o Start supplementation at the SECOND
trimester (2017)
st
o Higher toxicity in 1 trimester (2017)
o Metallic taste exacerbates vomiting in the
st
mother in 1 trimester (2017)
Child 6-24 months: 12.5 mg iron/50 g folic acid
(N 6-12 months; LBW <2500g 2-24 months)
Child 2-5 yrs: 20-30mg iron
Child 6-11 yrs: 30-60 mg
Adolescents and adults: 60 mg
Severe anemia
o Child <2 yrs: 25 mg iron + 100-400 g folic
acid x 3 months
o Child 2-12: 60 mg iron+ 400 g folic acid x 3
months
o Adolescents, adults, pregnant women: 120
mg iron+ 400 g folic acid x 3 months

F. Adverse Reactions & Precautions of Oral Iron

Oral iron may cause GIT distress in 15-20% of patients
o Most common complaint which can decrease compliance
since treatment lasts for months
o Abdominal pain, nausea, vomiting, constipation
o You may switch to delayed release iron supplements
because they have less GIT adverse reactions
o This is often dose-related, another rationale to start low
(Katzung)
Black stools are a side effect of oral iron. It has no
significant clinical effect except possible masking of
gastrointestinal bleeding in fecalysis. (Katzung)
Taking the following with oral iron can DECREASE
absorption:
o milk, caffeine, antacids, calcium supplements
Vitamin C can INCREASE absorption. If you really need to
reverse anemia immediately, then you can give your iron
supplements with Vit C.

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G. Response to Treatment
Reticulocyte count increases in 4-7 days after initiation of
therapy and peaks at 1 weeks
After 4 weeks of treatment, you need to see a Hemoglobin
levels > 20g/dL. Thus first follow up is after 1 month.
Absence of response may be due to poor absorption,
noncompliance to medication, or confounding diagnosis
Iron tolerance test this is for adverse reactions and the
response of a patient
o Give 2 iron tablets on an empty stomach
o Serum iron in 2 hours: If increase is at least 100 g/dL,
your treatment is adequate.
H. Parenteral Iron Therapy
Indicated for:
Poor tolerance to oral iron
Acute condition (blood loss) AS ADJUNCT to packed RBC
transfusion
Most common use: Large demand for iron from patients
being treated with erythropoietin (which cannot be
satisfied by oral iron) especially hemodialysis patients or
patients with kidney problems
Calculate the daily dose as follows:
Body Weight (kg) x 2.3 x (15 px Hgb in g/dL) + 500 or
1000 mg (depending on target iron stores)
Two ways to administer
Administer total dose of iron required to correct deficit and
provide at least 500 mg iron stores (can lead to more ADRs)
Give repeated small doses for certain period of time (most
commonly used by doctors)
Forms of parenteral iron
Iron dextran
o Contains 50 mg/mL elemental iron
o Not being used anymore high risk of anaphylaxis
o Given <500mg IV/IM (half-life 6 hrs)
Sodium Ferric Gluconate, Iron Sucrose, Ferumoxytol
newer drugs
o Given in chronic renal failure (CRF)
o IV ONLY (Katzung)
o Ferritin levels between 500 and 1200 mg/mL and
transferrin saturations of <25%
o Lower risk of anaphylaxis
Precautions (Katzung) (2017B)
Monitor iron storage levels via SI or TIBC.
Be careful in giving parenteral iron because overdose and
toxicity can occur more easily as compared to the oral form.
o So, it is important to properly calculate the daily dose
needed by the patient.
I. Iron Toxicity
Acute
Exclusively in young children who swallow 10 tablets or
more
Effects include necrotizing gastroenteritis, vomiting,
abdominal pain, bloody diarrhea, shock, lethargy, dyspnea,
coma and death
Treatment includes:
o Whole bowel irrigation
o Deferoxamine (iron chelating compound)
o Supportive therapy
o According to Katzung, it is useless to give activated
charcoal because it does not bind iron.

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Chronic
Seen in patients given iron for a prolonged period of time at
maximum dose
Usually there is hemochromatosis aka iron overload results
when there is excess iron deposition in heart, liver, pancreas
etc
May be inherited or acquired (mostly acquired)
o Inherited hemochromatosis
o B-thalassemia leading to repeated RBC transfusions
(Katzung)
Treatment includes the ff:
o Intermittent phlebotomy (removes blood and therefore
excess iron; 1 unit/week)
o Deferasirox: an oral iron chelator
According to Katzung, phlebotomy is what is usually done
because iron chelators are more complicated, expensive,
and hazardous.
o It is only used as a last resort if a phlebotomy is not
enough.
D.

HYPOPROLIFERATIVE ANEMIA

At least 75% of all cases of anemia are hypoproliferative in

nature

A. Types and Diagnoses

Table 5: Diagnosis of Hypoproliferative Anemia

Involved in erythropoiesis; stimulates progenitor

proliferation and maturation
Involved in wound healing; it stimulates angiogenesis
and smooth muscle fiber proliferation
Involved in the brains response to neuronal injury
Involved in vasocontriction-dependent hypertension
Increases iron absorption by suppressing hepicidin

C. Recombinant Human Erythropoietin

Epoietin alfa or Darbopoietin alfa

Increase Hct by 4 points and Hgb by 1g/dL in 2 weeks

Darbopoietin alfa has a half-life 3-4x longer than that of

epoietin alfa; it is a second generation erythropoiesisstimulating agent

Adverse effects known include, but are not limited to,

allergic reactions, hypertension, migratory
thrombophlebitis, microvascular thrombosis, pulmonary
embolism, thrombosis of retinal artery, temporal veins,
renal veins, headache, tachycardia, edema, shortness of
breath, GI upset (nausea, vomiting, diarrhea), stinging
sensation at injection site, flu-like symptoms

In light of this, iron supplementation and anticoagulants

may be needed
Dosage for epoietin alfa (Guevarra, 2014):
o CRF: 50-150U/kg 3x/week IV or 80-120U/kg 1-3x/week
IV /SQ (Hgb 10-12g/dL 4-6weeks; Hct 33-36% 2-4
months) ; maintained at 300U/kg
o AIDS: 100-300U/kg 3x/week IV/SQ
o Cancer: 150U/kg 3x/week; can reached 450-600U/kg
1x/week
o Surgery: 150-300U/kg OD for 10 days, day of surgery
and 4 days after surgery
Dosage for darbopoietin alfa (Guevarra, 2014):
o CRF: 45g/kg 1x/wk IV/SQ
o Carries an increased risk of cancer recurrence.

Iron Deficiency anemia

Most common type

Anemia of chronic disease

Caused by chronic inflammation (rheumatoid arthritis), TB,

tissue injury, and cancer
Anemia of renal disease

Anemia results due to inadequacy of erythropoietin

production secondary to impaired renal function

Examples are chronic renal failure (CRF), uremia, PCKD

Anemia of metabolic disease

Hypothyroidism and starvation

*Usual observation is that red cells are normocytic and
normochromic
B. Endogenous erythropoietin

Produced in the kidney by intestinal fibroblasts; hypoxia

stimulates its synthesis

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E. MEGALOBLASTIC ANEMIA
Disorders characterized by presence of macrocytic red
cells in bone marrow
Causes:
O Cobalamin/folate deficiency
O Abnormality (genetic/acquired) in cobalamin/folate
metabolism
O DNA synthesis defects

Cobalamin

A water soluble vitamin containing a cobalt molecule

Plays a role in regulating normal function of CNS, blood

formation, DNA synthesis, DNA regulation

Synthesized by microorganisms mainly

Coenzymes are methylcobalamin, a coenzyme involved

in methionine, S-adenosylmethionine, and tetrahyrofolate
production, and adenosylcobalamin

Obtained via intake of fish, meat, dairy products

We obtain 5-30 g via diet, we lose 1-3 g per day, a store

of 2-3 mg is good for 4 years

Passively absorbed in the buccal area, duodenum, and

ileum; actively absorbed in the ileum in the presence of
gastric intrinsic factor

Normal range is 150-600 pmol or 200-900 pg/ml

Cobalamin deficiency can be caused by (Guevarra, 2014):
O Pernicious anemia due to IF loss secondary to
atrophic gastritis

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O
O
O
O
O
O

Inadequate amount of intake

Gastric and/or ileal resection
Decrease in gastric acid amount via proton pump
inhibitors and/or H2 blockers
Alcoholism
Metformin intake
Malnutrition

Cobalamin deficiency results to (Guevarra, 2014):

O Topic in question, megaloblastic anemia
O Progressive swelling of myelinated neurons
O Demyelination
O Neuronal cell death; these are seen in the spinal
column and cerebral cortex
O Hand and foot paresthesia
O Decrease in vibration and position sense, with
associated unsteadiness
O Decrease in deep tendon reflexes
O Confusion, moodiness, loss of memory
O Loss of central vision
Vitamin B12 therapy (Guevarra, 2014)
O Given in cyanocobalamin and/or hydroxocobalamin,
as these are the active medicinal forms
O If there is inadequate intake, give orally; if there is IF
deficiency and/or gastric and ileal problems, give
parenterally
O Cyanocobalamin is the first choice: give drug IM /
SQ (not IV as there is a risk of anaphylaxis; skin test
needed), 1-1000g 1-3x / week; supplementation is
80g mixed w/ IF (not reliable; e.g. vegetarians)
O An alternative is hydroxocobalamin, given 100 g
IM; this has a more sustained effect, lasting 3 months
O Treatment usually lasts for 6-12 months, as a long
term treatment; cyanocobalamin is given monthly in
the form of 100 g injections
O Also given for cases of neuropathies such as
trigeminal neuralgia and multiple sclerosis, psychiatric
disorders, poor growth and/or nutrition, as a tonic for
patients suffering from tiredness and/or easy fatigue
Folic acid

Vitamin that is obtained from fresh green vegetables, fruits,

liver, and yeast; 90% of vitamin is destroyed in the heat of
cooking

Normally we obtain 50-500 g of it per day; vegetarians

only obtain roughly 2 mg/day

We usually require 400 g per day; pregnant women

require 500-600 g per day; they must have an intake of at
least 400 g per day to prevent defects in the neural tube

Absorbed in duodenum and proximal jejunum (proximal

small intestine), transported while bound to a plasmabinding protein

Normal range is 9-45 nmol or 4-20 ng/mL

Deficiency (Guevarra, 2014)
O Causes are alcoholism, diseases of the proximal small
intestine, inhibitors of dihydrofolate reductase such as
methotrexate and trimethoprim, drugs that interfere
in folate storage in tissues such as oral
contraceptives
O Deficiency of folic acid can result to higher incidences
of defects in the neural tube (anencephaly,
encephaloceles, spina bifida), the topic in question
(megaloblastic anemia), coronary artery and
peripheral vascular diseases, venous thrombosis or
hyperhomocysteinemia

2018-A

Therapy (Guevarra, 2014):

O Given as folic acid, orally or parenterally or part of
MV prep
O Given as a prophylaxis in pregnant women, (dose
of 400-500 g per day); for hemolytic anemia it is
given at a dose of 1 mg per day
O Can be given as folinic acid (leucovorin calcium), a
derivative of tetrahydrofolate
O Folinic acid circumvents DHF reductase inhibition (ex.
Resulting from methotrexate intake); it is an antidote
for folate antagonist toxicity (ex. Resulting from
trimethoprim and pyrimethamine intake)
O Has no advantage over folic acid; it is actually more
expensive
O Avoid multivitamin preparations; do multivitamin
preparations only if there is evidence of vitamin
deficiency
O Folic acid is well tolerated by the body, even at doses
as high as 15 mg per day
O Folic acid can decrease, even counteract effects of
drugs like phenobarbital, phenytoin, primidone
F. MYELOPOIESIS

Myeloid growth factors are glycoproteins that stimulate the

proliferation and differentiation of one or more myeloid cell
lines
Enhance the function of mature granulocytes and
monocytes
Produced naturally by a number of different cells, including
fibroblasts, endothelial cells, macrophages, and T cells
GM-CSF is capable of stimulating the proliferation,
differentiation, and function of a number of the myeloid cell
lineages
G-CSF is restricted to neutrophils and their progenitors,
stimulating their proliferation, differentiation, and function

A. Conditions that affect Myelopoiesis

Autologous bone marrow transplantation

Intensive myelosuppressive cancer chemotheraphy
Zidovudine induced neutropenia in AIDS patients
Severe congenital neutropenia

B. Recombinant GM-CSF (Sargramostim)

Produced by yeast
2

125-500g/m /d SQ (Half-life: 2-3hrs) [Katzung says: Serum

T1/2 of 2-7 hours after IV or SQ administration
Slow infusion: 3-6 hours
Lower doses mainly affects neutrophils; larger doses
affect monocytes/eosinophils
Adverse Effects: bone pain, malaise, flu-like symptoms,
fever, diarrhea, dyspnea and rash, transient
supraventricular arrhythmia, elevation of serum creatinine,
bilirubin and hepatic enzymes

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C. Recombinant G-CSF (Filgrastim/Pegfilgrastim)
Filgrastim
o produced by Escherichia coli
o Stimulates CFU-G to increase neutrophil
production; stimulation of CFU-G to increase
neutrophil production
o 1-20g/kg/d IV infusion for 30 mins
o Patient on cancer chemotherapy: 5g/kg/d; daily
administration for 14-21 days
Pelfigrastim
o gene through conjugation of a 20,000-Da
polyethylene glycol moiety to the G-CSF
glycoprotein produced by E. coli
o Longer half-life
o 6mg SQ
G. MEGAKARYOPOIESIS

Thrombopoietin, a cytokine that predominantly stimulates

megakaryopoiesis. It is produced by the liver, marrow
stromal cells, and many other organs. It is the primary
regulator of platelet production.
Interleukin-11 (IL-11) was cloned based on its activity to
promote proliferation of an IL-6-dependent myeloma cell line
Stimulates hematopoiesis, intestinal epithelial cell growth,
and osteoclasto-genesis and inhibits adipogenesis
Enhances megakaryocyte maturation in-vitro; in-vivo
increases peripheral blood platelet counts
Recombinant Interleukin-11 (Oprelvekin)
o

Bacterially derived 19,000-Da polypeptide

25-50 g/kg/d SQ; Half-life: 7 hours

Administered daily; response in 5-9 days

Used for chemotherapy induced thrombocytopenia

in non-myeloid malignancies (20,000/L). Aim:
platelet count reaches 100,000/L

Adverse Effects: Fluid retention and associated

cardiac symptoms, such as tachycardia palpitation,
edema, shortness of breath, blurred vision, injection
site rash or erythema, and paresthesias.

Recombinant Thrombopoietin
o

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Recombinant Human Megakaryocyte Growth and

Development Factor (rHuMGDF) and Recombinant
Human Thrombopoietin (rHuTPO) mixed results on
efficacy
Mimics of recombinant thrombopoietin used
exclusively for ITP

Romiplostim small peptide that binds with high

affiity to the thrombopoietin receptor
Safe and efficacious in patients with ITP
Platelet ct >50,000/L in 8 weeks of study
1-10 g/kg/d SQ

Eltrombopag 6 week course of 50-75mg/d

orally
Well-tolerated

H.

HEMOSTASIS

A. Elements of Hemostasis

Primary Hemostasis
o Affected by: aspirin and NSAIDs
o Adequate vascular response, platelets, levels of Von
Willebrand factor

Secondary Hemostasis
o Affected by: warfarin and heparin
o Involve the extrinsic factors
o Adequate level of clotting factors, vitamin K

B. Bleeding Disorders

Causes
o Inherited coagulation disorders
clotting factor deficiency
hemophilia
o Hemorrhagic diathesis of liver disease
o surgical procedures / multi-organ injuries
o vitamin K deficiency
C. Diagnostic Tests

platelet count: 150,000-400,000/m2

bleeding time (measure platelet function): 1-9 mins

prothrombin time (measure extrinsic pathway; used for

warfarin): 11-13.5 sec

partial thromboplastin time (measure intrinsic pathway;

used for heparin): 25-35sec
D. Vitamin K

cause of bleeding disorder

fat soluble

needed for complete synthesis of certain proteins that are

required for blood coagulation (II, VII, IX, X) - 1972

also used to manipulate binding of calcium in bone and

other tissues
RDI

Infants: 1020g/day

Children & adolescents: 15100g/day

Males: 120 g/day

Females: 90 g/day (lower than males)

Vitamin K Deficiency
o Uncommon
o Causes:
Resection of SI
Malabsorption syndrome
Prolonged use of broad spectrum antibiotics
Diet low in vit. K
CKD
Alcoholics
Liver disease
Anticoagulants
Salicylates
Barbiturates
Cefamandole
o Usually occurs in newborns right after birth
clotting factors are 30 to 60% of adult values
due to reduced synthesis of precursor proteins and
the sterility of their guts

st

Vit. K deficiency bleeding in 1 week of the infant's

life is 0.25 to 1.7%
given especially in premature babies

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F. Tissue Plasminogen Activator (TPA) Inhibitors

Used to control bleeding in patients

Seen in the final stage of thrombin formation

Inhibitors of fibrinolysis

Plasmin has a role in the lysis of clot made by secondary

hemostasis
Aminocaproic acid

Competes for lysine binding sites on plasminogen and

plasmin, blocking the interaction of plasmin with fibrin
A very potent inhibitor of fibrinolysis (thrombi that formed
during treatment with the drug are not lysed)
Used to reduce bleeding after prostatic surgery or after
tooth extractions in haemophiliacs
also used to prevent bleeding after surgical procedures
(ability to treat a variety of bleeding disorders has been
unsuccessful)
st
Loading dose: 4-5g IV/PO during the 1 hour then 1-1.25g
PO q1Hour ; continuous IV infusion at 1g/Hr (continue for 8
hours or until bleeding is controlled, not to exceed 30g/day)

Tranexamic acid

Like aminocaproic acid, competes for lysine binding sites

on plasminogen and plasmin, thus blocking their interaction
with fibrin
Safer than aminocaproic acid
Can be used for the same indications as aminocaproic
acid and can be given IV or orally Usually given 1g 4x/day
for 4 days (500mg 3x/day for 4-7days)

*Adverse effects of both drugs: hypersensitivity reactions,

nausea, vomiting, diarrhea, clotting problems (loss of vision,
infarct, embolism)

I. SUMMARY
Erythropoietin stimulates erythropoiesis. (without it there
will be no erythropoiesis that will happen)
Iron is needed for maturation of RBC.
Defective RBCs are formed in patients with Vit. B12 and B9
are deficient.
GM-CSF, G-CSF, IL-11 and thrombopoietin are helpful in
certain conditions that produce neutropenia or
thrombocytopenia
Vit. K supplementation can be given to patients with certain
bleeding disirders.
TPA inh. can be given to patients suffering bleeding from
trauma, surgery, etc.

GUIDE QUESTIONS
1. All of the following substances delay absorption of
ingested iron EXCEPT:
A. caffeine
B. milk
C. sodium ascorbate
D. calcium ascorbate
2. Which of the following parenteral iron preparations has a
higher incidence of anaphylactic reactions?
A. ferric gluconate
B. ferric sucrose
C. ferric dextran
D. ferric oxide
3.Lexi, a 32-year-old female, diagnosed with iron deficiency
anemia, needs 60mg a day of elemental iron. To minimize
the incidence of adverse reactions, you decided on a once

2018-A

a day dosing regimen for the patient. Which of the

following drugs will be best suited for the patient?
A. ferric-maltose complex 150 mg
B. ferrous sulfate dessicated 325 mg
C. ferrous fumarate 200mg
D. ferrous gluconate200 mg
4. Which of the following iron preparations is usually found
in multivitamin medicated syrups because of its low
elemental iron content?
A. ferrous gluconate
B. ferrous sulfate dessicated
C. ferrous fumarate
D. ferric-maltose complex
5. Which of the following conditions associated with
cobalamin deficiency will benefit most from oral
cyanocobalamin?
A. atrophic gastritis
B. inflammatory bowel disease
C. chronic alcoholism
D. ileal resection
6. The conditions that will least likely benefit from epoeitin
alfa treatment
A. massive traumatic blood loss
B. chronic renal failure
C. cancer
D. AIDS
57. Which of the following will most likely happen when
correcting cobalamin deficiency with folic acid
supplementation?
A. lower incidence of homocysteinemia and venous thrombosis
B. lower incidence of megaloblastic anemia
C. decreased risk for nerve degeneration
D. increased risk for neural tube defects
8. In a patient with neutropenia, which of the following
agents will be least beneficial?
A. sargamostim
B. Romiplostim
C. filgrastim
D. perfilgrastim
9. Thrombocytopenia from immunosuppressive
chemotherapy can be treated with the following
medications EXCEPT:
A. elthrombopag
B. romiplostim
C. sargramostim
D. Oprelvekin
10. Which of the following available vitamin K preparations is
toxic for humans?
A. phylloquinone
B. menaquinone
C. menatetrenone
D. menadione
Answers:
1)C 2)C 3)C 4)A 5)C 6)A 7)B 8)B 9)C 10)D

OBJECTIVES
None.

REFERENCES
1.
2.
3.

Dr. Guevarras Lecture

Katzung
2017B trans

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APPENDIX
Table 6: Vitamin K1 vs. Vitamin K2
Vitamin K1

Vitamin K2

Form

Phylloquinone,
Phytomenadione,
Phytonadione,

Menaquinones, Bacteria in SI can convert

vit .K1 to K2

Source

Leafy green vegetables:

dandelion greens, spinach, lettuce
, cabbage, cauliflower, broccoli,
and brussels sprouts
Fruits:
avocado, kiwifruit and grapes
Small intestine
Anemia, bruising, bleeding gum or
nose, heavy menstrual bleeding
At birth:

IV: 0.5 to 1.0 mg

Newborns:

Human milk (14 g/L)

Vit. K formula-derived milk

(100 g/L)

Animal Meat:
chicken, beef, their fat, livers, and organs
Fermented or aged cheese, eggs

Absorption
Signs and Symptoms of
Deficiency
Therapy

Bacteria in SI can convert K1 to K2

Small intestine
Deficiency Osteoporosis, Coronary heart
disease, Severe aortic calcification
Menopausal women:

Orally (45 mg daily)

To prevent osteoporosis
Rapid reversal from warfarin for pre-op:

Orally (1-2.5 mg)

Figure 1: Events in Hemostasis

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Figure 2: Factors that favor and inhibit thrombosis

Figure 3: Myelopoiesis

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Figure 4: Megakaryopoiesis

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