Pharmacology of the blood
Done by: Abeer Khasawneh
بسم اهلل الرحمن الرحيم
اللهم صل على سيدنا محمد وعلى آله وصحبه وسلم, صالة تنحل بها العقد وتنفرج بها
الكرب وتقضى بها الحوائج, صالة تليق بمكانته عندك, عدد ما ذكره الذاكرون وغف ل
.عن ذكره الغاف لون
Today we will talk about the pharmacology of the blood, we will mainly
concern about the treatment of anemia as well as some problems seen in
blood like thromboembolic disorders, MI and DVT.
These thromboembolic disorders can be controlled by antiplatelet,
anticoagulant or hemolytic agents.
It's an important physiological process needed to arrest bleeding.
How does it occur? It's mainly seen or mediated by intrinsic and
So, blood coagulation is the process that generates thrombin and consists
of two interrelated pathways: the extrinsic and the intrinsic systems.
In general, activated factor X is important for the conversion of
prothrombin into thrombin (factor II), then once thrombin is formed, it
will convert fibrinogen into fibrin which is the mesh like matrix of the
blood clot, so the blood clot is mainly composed of fibrin. At the same
time, platelets are activated in which there will be an increase in the
platelets aggregation and adhesion.
Now, some definitions which are important to know:
It is what occurs physiologically in order to arrest bleeding. How does it
I. Vascular spasm (vasoconstriction) of the damaged blood vessels to
minimize blood loss.
II. Platelet plugs formation due to platelets aggregation & adhesion.
III. Blood coagulation or clotting which is seen by formation of fibrin.
So, you will see that any clot is rich in fibrin as well as platelets. But we
still have some differences; the thrombus that is formed in the arterial
side is mainly rich in platelets, while in the venous side it's mainly rich
in fibrin. And this may be considered as a part of the treatment of some
diseases, for example, antiplatelets are ineffective to treat thrombosis
that occurs in the venous side.
It's a pathological condition results from formation of haemostatic plug
within the vasculature in the absence of bleeding.
It's a clot that adheres to blood vessels, but in some cases, it may become
detached to form an embolus that may lodge downstream causing
ischemia and infarction at the site of occlusion.
Thrombus and embolus have a high chance to occlude the blood vessels
and limit blood flow. So in our treatment, by using of anticoagulants,
antiplatelets mainly in the arterial side and fibrinolytic agents, we are
looking to prevent or to decrease the extension or to make a lysis of
already formed thrombus.
The most important type of embolism is called pulmonary embolism. In
which the sites of occlusion are the pulmonary arteries and any branch
related to them. This condition may cause a fatal situation.
There are many reasons for thrombosis to occur:
1. Blood stasis.
- For example, patients who had a surgery like knee or hip
replacements, will stay immobile for a long period of time, maybe for 4
or 6 months, so this immobility will increase the risk of thrombosis.
- Because during pregnancy this female is presented in a
- Because it will increase the risk of arthrosclerosis of blood vessels.
5. using of contraceptives.
Drugs used in coagulation disorders are Anticoagulant, Antiplatelet, or
A drug that is used to prevent the propagation and extension of the
Drugs that inhibit platelets aggregation and adhesion. An example is
Thrombolytic or fibrinolytic agents.
Drugs that cause lysis of already formed thrombus. And they promote
removing the products of coagulation (fibrin removal).
What you have to know from the previous figure is that:
- Platelets play an important role in the coagulation process, so we
will use antiplatelets drugs.
- The most important clotting factors are II and X (that will lead to
the formation of fibrin). So, Anticoagulants will interfere with
these clotting factors, either by inactivating them or inhibiting the
activation or the synthesis of active clotting factors.
- If the thrombus (fibrin) is already formed, then we will use
fibrinolytic agents that will cause lysis of fibrin.
So here, you can see that the vascular injury is prevented by reducing
the risk factors. Platelets aggregation and adhesion are prevented by
antiplatelet. Thrombin generation and fibrin formation are prevented by
anticoagulant. And plasmin generation is prevented by fibrinolytic
In our body, we already have some endogenous compounds or proteins that will
prevent clot or fibrin formation, like protein S, protein C, antithrombin III and
prostacyclins or prostaglandins I2. These endogenous compounds will inhibit
platelets aggregation or thrombus formation. So some drugs as you will see may
increase the activity of already presented anticoagulant proteins or endogenous
Can be classified into 2 groups, either orally active anticoagulants or
parenterally used anticoagulants (most common example is heparin).
- It is a large sulfated polysaccharide polymer that has a large
- Not absorbed orally. Used intravenously in which this will
produce an immediate effect, especially for acute cases like acute
MI, or can be used subcutaneously in which its onset of action
begins after 1 or 2 – 4 hours after administration (mostly after 60
- Shouldn't be used intramuscularly because it will increase the risk
of hematoma (bleeding in the muscles).
- It's active in vivo (inside the body) and vitro (outside the body).
What is the mechanism of action of heparin?
We have an endogenous anticlotting protein known as antithrombin III
that will irreversibly inhibit factor II (thrombin) as well as factor X.
Now, the activity of antithrombin III will be about 1000 fold by using of
heparin. So, we can say that the antiheparin mechanism of action is
done by the activation of antithrombin III which will mainly inactivate
thrombin factors II and X so that this enzymatic activity is accelerated
by using of heparin.
As you can notice from the picture. If I use heparin, the interaction will
be more, faster than in the absence of heparin. This antithrombin III will
arrest thrombin and factor X. Thrombin is important as we said to
convert fibrinogen into fibrin (the clot), so if I inhibit thrombin, I will
inhibit the activation of fibrin.
Therapeutic uses of heparin:
Anticoagulants are effective in the treatment of thrombosis in the
arteries as well as in the veins.
1. it's used in the treatment of deep venous thrombosis. From its name;
we will have a thrombus that occurs in the deep veins. Most commonly
in the lower legs, or sometimes in the pelvis.
2. Acute MI. In which I will use the intravenous root of administration.
So intravenous heparin is administered.
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3. Pulmonary embolism. Which is an embolic disorder that will cause
occlusion of the pulmonary artery.
4. Can be used prophylactically to prevent post operative thrombosis.
5. The drug of choice to control thrombosis in a pregnant female who is
presented in a hypercoagulable state (have a high recurrence toward
o Question: Why is heparin considered to be the drug of choice to
control thrombosis in a pregnant female?
- Because once you give a drug during pregnancy, you are
looking for its safety in which it can be determined by the drug
ability to cross the placenta. If this drug minimally crosses the
placenta, this means it's safe. So the large molecular weight
heparin mostly doesn't cross the placenta to produce any fetal
6. in patients who have prosthetic heart valves.
How to monitor heparin effect?
Overdose will lead to bleeding and subtherapeutic dose will lead to
thrombosis. So to monitor heparin effect we do a lab test known as aPTT
(activated partial thromboplastin time) and it's measured in seconds. It
should be 1.5 -2.5 above or fold the normal control which is 23-31
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Adverse effects of heparin.
1. the most important adverse effect of heparin or any other
anticoagulant is bleeding.
If bleeding is developed due to heparin use, what will you do?
- First of all, you should stop the drug.
- And then we will use the antidote. The antidote of heparin is
- We may use also blood transfusion or fresh frozen plasma.
The interaction between heparin and sulphate is a chemical interaction
(Chemical antagonism); the protamine is highly positively charged
compound (basic drug) that will interact with the negatively charged
The protamine is also given intravenously (infusion). It should be
given in an accurate calculated dose; because overdose of
protamine will cause bleeding (it has a weak anticoagulant effect).
So, 1mg of protamine sulphate is used for each 1oo unit of
2. Long term use of heparin will lead to osteoporosis.
3. It may lead to thrombocytopenia (decrease in platelets number). Once
it's developed, it's preferred to stop the drug,
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Now, what we talked about earlier was the large sulfated polysaccharide
polymer or what we call the unfractionated heparin. Better than the
unfractionated heparin is the low molecular one. So we did chemical /
enzymatic depolymerisation, to get a small polymer, known as low
molecular weight heparin.
This low molecular weight heparin has many advantages compared
with the large or unfractionated one:
1. First of all, the mechanism of action is mostly the same. Both of them
will activate antithrombin III that will inactivate factor X as well as
factor II (thrombin). But the low molecular weight heparin will activate
antithrombin III that mainly inactivates factor X more than factor II
(thrombin). So it selectively accelerates the interaction between
antithrombin III and factor X (Reduced activity against thrombin
relative to factor Xa), so that, it can be used in lower doses compared
with unfractionated heparin.
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2. The low molecular weight heparin has more predictable
3. Can be used in lower doses as we said earlier.
4. given only subcutaneously, so it can be used for in and outpatients.
5. Have a good bioavailability compared with the unfractionated
6. As well as there is no need to be monitored by using the aPTT test. So
this will save money and effort.
7. It can be used in pregnancy because it can't cross the placenta. It's
preferred to be used in pregnancy, given subcutaneously so that it can
be used by the female herself.
8. Less thrombocytopenia.
9. Less bone loss.
10. No antidote.
An example is Enoxaparin. It has a long duration of action, by that it can
be used once or twice daily.
o Question: Do you prefer to use the low molecular weight heparin
or the unfractionated one?
- We prefer to use the low molecular weight heparin. But in
emergency cases like in the case of acute MI, I will use the
unfractionated heparin intravenously.
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o Question: How can I treat bleeding caused by the low molecular
- I'll stop using the drug itself and I will not use any antidote. This
criterion (having no antidote) is not considered as a disadvantage,
because the tendency to bleeding or what we call bleeding risk is
Oral anticoagulants (Warfarin)
Beginning with the differences between heparin and warfarin. Warfarin
is given orally, while heparin is given parenterally. In structure,
warfarin is related to vitamin k, in which its mechanism of action is
done by inhibiting the activation or synthesis of vitamin k dependent
clotting factors (II, VII, IX, X). Or what is known as 1972.
This drug is contraindicated during pregnancy. Because it can cross the
placenta and leads to fetal malformations and may induce abortion
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(teratogenicity). While heparin is safe in pregnancy. Heparin has a rapid
onset of action while warfarin has a delayed onset of action; it needs 812 hours to produce its effect.
o Question: Can you explain why does warfarin has a delayed onset
- Warfarin will not inhibit the already presented clotting factors.
It inhibits the synthesis of new ones. So by that it has a delayed
onset of action. It will go to the liver to inhibit the synthesis of
new clotting factors. This is seen after the depletion of the older
ones. So after the depletion of the old clotting factors, it will
inhibit the synthesis of new ones. By that, it can't be used for
It's only active in vivo, why? Because the synthesis is mainly done in the
liver. They inhibit the synthesis of vitamin k dependent clotting factors
in the liver so it's only active in vivo.
This drug has a narrow therapeutic index, as well as having many drugs
Therapeutic uses of warfarin
1. It inhibits vitamin k epoxide reductase enzyme in the liver which is
important for the synthesis of vitamin k dependant clotting factors
2. it's used prophylactically, when? I. in prevention of thromboembolic
disorders during orthopedic organological surgery or gynecologic
surgery. II. In patients with history of MI. III. Patients with prosthetic
heart valves. IV. as well as patients with chronic atrial fibrillation which
is a type of supraventricular arrhythmia.
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3. it's used also in the treatment or prevention of progression or
recurrence of deep venous thrombosis. Usually, we will begin with
heparin because of its rapid onset of action, and then we switch to
How to monitor warfarin?
In order to prevent the risk of bleeding, warfarin is controlled by a lab
test called PT (prothrombin time). Each case has a specific prothrombin
time measured daily and the dose is adjusted until INR is stabilized
We have some variations between hospital and lab. To overcome the
variations in the prothrombin time we make what we call INR
(international normalized ratio and should be between 2-3.5).
Adverse effects of warfarin
The most important side effect is bleeding. To overcome bleeding, what
we will use?
- First of all, stop the drug.
- Then use Antidote which is vitamin k (phytomenadione). But this
vitamin K has a delayed onset of action; it needs about 24 hours to
produce its effect.
- In some cases we will use fresh frozen plasma which contains the
o Question: If someone taking warfarin got injured, in this case, will
he/she have bleeding or not?
- There will be prolonging of the bleeding time.
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o Question: Why do injuries of people with diabetes mellitus take a
long time to heal?
- Answer: you have to know that DM is not related to hemostasis.
Those patients have what we call neuropathy as well as ischemia
(decreased blood supply to the site of injury). So in this case, we
will be afraid that the patient might get infected in the area of
o Question: What is the effect of increasing the dose of vitamin K on
its onset of action?
- Answer: Even if we increase the dose of vitamin K, it will still have
a delayed onset of action. Because it needs time to inhibit the
action of warfarin and the inhibition of the synthesis of vitamin k
dependent anticlotting factors.
Contraindications of Anticoagulants
Chronic use of anticoagulants may increase the risk of bleeding. Because
of that, anticoagulants are contraindicated in:
1. Patients with bleeding tendency.
2. Recent surgery.
3. Uncontrolled hypertension.
4. Patients with peptic ulcer.
5. Patients with renal or hepatic disease.
6. Patients with intracranial hemorrhage.
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So, before you make any dental procedure for any patient, you should
ask him/her if he/she uses an anticoagulant or antiplatelet. And looking
for the dose, because they may have a chance of bleeding.
We have a high drug-drug interaction with warfarin and other drugs. Some
drugs may increase the level and action of warfarin, thus increasing the risk
of bleeding. Some drugs may inhibit warfarin metabolism, like erythromycin
antibiotic. Other drugs may accelerate warfarin metabolism, thus inhibiting
its therapeutic response. An example is the hepatic enzyme inducers, like
rifampicin and Barbiturates.
Warfarin is highly protein bound. Some drugs may displace warfarin
from its binding sites. So this will increase the free warfarin
concentration, by that increasing its therapeutic response or
We said that the most common and cheapest example is Aspirin. This
drug is effective to prevent thrombosis in the arterial side (vessels). It
inhibits platelets aggregation and adhesion.
Mechanism of action
As we said before, it inhibits the synthesis of thromboxane A2 which is
important for platelets activation and aggregation.
The most important adverse effect is bleeding and the most common
antiplatelet to cause bleeding is Aspirin.
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Fibrinolytic agents or thrombolytic agents.
Drugs that will cause lysis of already formed thrombus, in which their
activity will decrease if the thrombus becomes aged. So their activity will
be less if we have an old or aged thrombus.
How do they work? (mechanism of action)
As we said before, prothrombin is converted into thrombin. Then
thrombin will convert fibrinogen into fibrin (clot).
An example is the tissue plasminogen activator (tPA). It's expensive and
has less antigenic reactions or immune response. It will accelerate the
conversion of plasminogen into plasmin. Plasmin will cause degradation
of the fibrin clot giving more fibrin degradation products. So we can say
that fibrinolytic agents are plasminogen activator.
متعارف بين الناس انه هاي االبرة تسمى إبرة الحياة. النها ممكن تنقذ حياة اإلنسان في بعض
.)MI(الحاالت متل الجلطة الدماغية واحتشاء عضلة الق لب
These drugs are expensive. Their injection may cost 1000 JD. They can
save the patient's life. Epinephrine can be used as a saver only in the
anaphylactic shock but not in the thromboembolic disorders.
The cheapest plasminogen activator is Streptokinase. It's obtained from
bacteria (Hemolytic petus streptococcus). Because of that, continuous
use of these drugs will lead to allergic or antigenic reactions.
1. To treat acute MI, in which they will be given within 12 hours from
the onset of symptoms. The earlier the better.
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2. In ischemic stroke within 3 hours from the onset of symptoms and as
earlier, as it will give better response. Now, stroke could be either
hemorrhagic or ischemic one. So, before you give fibrinolytic agents,
you should exclude the hemorrhagic stroke. If it's ischemic, then you
should use those fibrinolytic agents. But if it's hemorrhagic, they are
If serious bleeding developed, we will use Tranexamic acid, which is
plasminogen inhibitor that inhibits the action of plasmin (inhibits the
activation of plasminogen into plasmin). Or we use fresh frozen plasma.
Now, you should be able to compare between heparin and warfarin:
Root of comparison
1. route of
Parenterally (IV or SC) orally
2. onset of action
3. mechanism of
Activates antithrombin Inhibits the synthesis
Slower (delayed onset
of vitamin K
4. use during
6. The use of antidote
in the case of
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It has different causes. Now, when we can say it's anemia? When the Hb
level is below than the normal, referring to the age and sex.
In males, the Hb level should be (13.5 or14-17.5). In females, it should
be (11.5 or 12.5 -15.5). The Hb is the site in the RBC that is important
for oxygen carrying.
The clinical features of Anemia (general symptoms)
- Pallor, fatigue, shortness of breath (Dyspnea) and palpitations.
These are called unspecific symptoms.
It's classified depending on the RBCs size into different classes:
1. Microcytic anemia.
When the RBCs size becomes smaller. It's seen due to Iron deficiency.
2. Macrocytic anemia.
When we have large RBCs size. It's seen in Megaloblastic anemia which
is due to B12 or folic acid deficiencies.
3. Normocytic anemia.
We have normal RBCs size. And it occurs due to chronic disease.
The most common cause is Iron deficiency anemia. And it's highly seen
in developing countries.))الدول النامية
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IRON DEFICIENCY ANEMIA
The iron is important for Hb production. Low hemoglobin synthesis will
decrease the capacity of RBC to carry oxygen.
We get Iron from diet. It's mainly absorbed in the GIT in the duodenum.
It's absorbed from the intestinal surface to be transported in the blood by
a protein carrier known as transferrin.
Excess iron is stored in the bone marrow, the liver, the spleen as well as
in the muscles.
The dietary iron is represented in the form of heme (Fe+2) (Ferrous
form). Non heme iron (ferric form), should be used by gastric HCl to
form the heme one in order to be absorbed. So, some doctors advise that
once you have an iron deficiency anemia, it's preferred to increase
vitamin C intake by using for example, citrus juice or citrus fruits
(lemon and orange).
Vitamin C will increase the reduction of ferric form to ferrous one in
order to be absorbed. And it's important to know, that if we have an
iron poisoning, you should avoid using vitamin C, like juice or any
other thing that contains vitamin C. So vitamin C is important to
accelerate the absorption of Iron. For example, assume that we have
a patient with cancer and Gastrectomy (he/she had removed his/her
stomach) and there is no HCl secretion. Then those individuals are
suspected to develop iron deficiency anemia.
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Once the iron stores are decreased, the Hb synthesis will decrease, this
will cause gradual fall in RBC production in the bone marrow.
Newly formed RBC will look small. So that they are microcytic as well as
the Hb concentration inside this RBC is very low. We can say that iron
deficiency anemia is microcytic hypochromic anemia. Microcytic (small
RBC). Hypochromic (low Hb concentration inside the RBC).
So, how do we diagnose iron deficiency anemia? By using the
generalized signs and symptoms. For example, in blood film the RBC is
microcytic. And we also measure the Hb level. Sometimes we measure
the ferritin level (stored form of Iron).
This figure represents koilonychia, which is a cup shaped nails. They are
convex and most common in children. There will be Spooning of the
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Iron deficiency anemia is common in females more than males because
of blood loss during menstruation or high demand during pregnancy.
The common causes of Iron deficiency anemia are:
1. Dietary deficiency – poverty for example or they are vegetarians, or
2. Chronic blood loss – for example Menorrhagia
3. Increased demand – Pregnancy.
4. Inadequate absorption- Gastrectomy.
Treatment of Iron deficiency anemia
1. You should remove the cause if it's possible. For example, in
pregnancy there is a high blood demand, so we should administer
iron. If there is bleeding or hemorrhage, then we should control it.
2. Then, we need iron supplement that will extend also for 3 months
to increase the concentration of the stored iron.
Iron is given either orally or parenterally.
Oral Iron Preparations.
Examples are: ferrous sulphate and ferrous gluconate in the form of
tablets and ferrous fumarate in the form of syrup. The tablet looks
like candy. So it will cause common toxicity in children.
Any iron supplement will cause GIT adverse effects: nausea, vomiting
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It's the best to take the iron supplement before meal, about half an hour
before meal. But some patients, because they can't tolerate these adverse
effects, they take them after or during meal. And you know that some
types of food may affect the iron absorption, like Calcium containing
food (milk) and oxalic acid containing food (tea).
o Question: which one do you prefer to use? The ferrous sulphate
tablet which is 200 mg or the ferrous gluconate tablet which is
- Both of them are effective and are used orally to control iron
deficiency anemia. But here, you shouldn't look to the total
concentration of the tablet; you should look to the concentration
of iron element itself. Now, the ferrous sulphate although it's 200
mg, but it contains Iron in a higher level than the ferrous
So, we will use the tablet and we will continue at least for 3 months to
Failure to respond to oral iron preparation causes:
1. Patients noncompliance (due to development of Iron adverse effects:
Nausea, Vomiting, and GI irritation)
2. Continued blood loss
By that, I will switch to the parentral Iron supplement.
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• Iron parentral preparation can be used when:
1. Intolerance to oral preparation
2. Rapid response is required
3. Iron cannot be absorbed from GIT
Parentral rout of administration has some adverse effects; an example is
the Iron Sorbitol Citrate given IM, it will cause staining of the skin. And
this is actually painful.
It's developed because of either Vitamin B12 deficiency (more common)
or Folate deficiency. Both of them are important for the synthesis of
DNA and RNA nucleotides.
The less common cause is seen in vegetarians. Because the main source
of B12 is an animal one. So there will be higher chance of developing
B12 deficiency anemia.
The most common cause is pernicious anemia that occurs due to
deficiency of Intrinsic factors secreted by the parietal cells which are
important for B12 absorption.
This B12 is mainly stored in the liver. The source may be sufficient for 3
years. This disease used to be rare, but nowadays it's very common. Any
one that looks fatigue, pale, having impairment in memory and
dementia, should go and measure the B12 level.
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You as a dentist may face such cases, so you have to know the general
symptoms or criteria for iron deficiency anemia like mucosal change or
glossitis (beefy red tongue).
B12 is not only important for RBC or hemoglobin production. It's also
important for neurons. So B12 deficiency may lead to neurological
symptoms. The early one is paresthesia, and the late one is difficulty in
How is it treated?
1. By B12 supplement if we have no malabsorption and it's not a
2. If no then I can give IV or IM B12. Examples are
Hydroxycobalamin and Cyanocobalamin.
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So 1 mg is given twice weekly for 3 weeks. Then 1mg is given monthly
as a maintenance dose therapy.
Sometimes we don't have only B12; but we might have a B complex like
B1 and B6.
Megaloblastic anemia is a macrocytic one as we said before and occurs
due to B12 or folic acid deficiencies which are hematologically
o Question: Treatment of B12 deficiency anemia can be corrected or
improved by administration of folic acid. But, can we use folic
acid alone to treat Megaloblastic anemia?
- If we have macrocytic anemia, it's either due to B12 or folic acid
deficiency, so if we use folic acid alone, it can correct or improve
the anemia, but it will not improve the neurological
manifestations due to B12 deficiency and they may become
irreversible. So the best choice of treatment is either B12 or
The main source of Folic acid is green vegetables. It's Important for RBC
production. Now, Folic acid to be active it should be activated to
tetrahydrofolate which is important for DNA and RNA synthesis.
Causes of folate deficiency:
1. Poor intake-old age, alcohol excess.
3. Excess utilization-pregnancy.
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Treatment of FA deficiency
Folic acid deficiency anemia is corrected by folic acid, 5mg is taken
daily. It's very important to correct or treat this anemia especially in
pregnant females. Deficiency in folic acid during pregnancy will lead to
a disease known as spina bifida (neural tube defects) and Malformations
in the baby. This baby will have openings in his/her back. So any
married female that is planning to have a baby, should take folic acid
one month before and 2 months after pregnancy (the 1st 2 months of the
1st trimester). She needs a high supplement of folic acid, 5mg is
sufficient for her taken daily to prevent the development of neural tube
defects in the baby.
It's a hormone secreted by the kidney to stimulate RBC production in the
bone marrow. Patients with renal failure, can't produce or secret
Erythropoietin by that they need a replacement therapy. We can use
Erythropoietin exogenously, given intravenously or subcutaneously to
treat anemia due to renal failure.
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