When a small blood vessels is injured, hemorrhage is
• Vasospasm (reduces blood flow and
facilitates platelet aggregation and
• The formation of platelet plug (platelet
aggregation) to arrest bleeding.
• The formation of a fibrin clot (exposure of
the blood to tissue factors) to arrest
bleeding until the vessel is repaired.
• Fibrinolysis (the removal of the clot) after
the vessel is repaired.
Pathological Thrombus Formation
• A clot that adheres to a vessel wall = thrombus
• A clot that floats within the blood = embolus
• Both thrombi and emboli are dangerous because
they may occlude blood vessels and deprive
tissues of oxygen and nutrients
• Anticoagulants are drugs that retard coagulation
and thereby prevent the occurrence of a
• All clotting factors
are within the blood
• Clotting slower
• Activated partial
• Initiating factor is
outside the blood
vessels - tissue factor
• Clotting - faster - in
• Prothrombin test
Blood Vessel Injury
Vit. K dependent Factors
Affected by Oral Anticoagulants
Classes Of Drugs Used in the
Treatment of Clotting
Drugs used in clotting disorders
To reduce clotting
To facilitate clotting
(VII, IX, etc.
A. Oral anticoagulants
• Chemistry and mechanisms:
– They are structurally related to vitamin k
– These drug inhibit the synthesis of clotting
factors II (prothrombin), VII, IX, and X.
– Warfarin blocks the reduction of oxidized
vitamin K and thereby prevents the
posttranscriptional carboxylation of the above
Action of Coumarins
Oral anticoagulants – 4-hydroxycoumarins
• Extensively metabolized, highly bound to
• Cross the placenta, may cause fetal
hemorrhage and malformations. Pregnant
women with thrombosis should be treated
with standard or low molecular weight
• The onset of action is 3-5 days (time
required to deplete the pool of circulating
Adverse Effects of
– Minor bleeding: withdrawal of the drug and
administer vitamin K1.
– Severe bleeding: fresh frozen plasma or factor
• Cross the placenta:
Teratogenic （ damaging to the
developing fetus ）
• must not be given to pregnant women.
• Aspirin and Phenylbutazone (displace
warfarin from albumin, inhibit of platelet
• Antibiotics (decrease microbial vit. K
production in the intestine, inhibition of
metabolism of warfarin).
• Barbiturates and rifampin (decrease warfarin
effectiveness by inducing microsomal P450
• Oral contraceptives (decrease warfarin
effectiveness by increasing plasma clotting
factors and decreasing antithrombin III.
Therapeutic uses of
• Long-term management of patients
with deep vein thrombosis or atrial
fibrillation or artificial heart valve.
• In conjunction with heparin for the
treatment of MI.
2. Parenteral Anticoagulants
• Chemistry and Mechanisms: It is a
polymeric mixture of sulfated
• It is highly negatively charged at
physiological pH. Can be neutralized by
basic molecules such as protamine.
• Heparin is synthesized as a normal
product of many tissues including the
lung, intestine, and the liver. Commercial
preparations are derived from bovine lung
or porcine intestinal extracts (average
Heparin - Structure
Average molecular wt of 12,000 daltons (40 glucose
units) with the following structure:
Heparin binds to antithrombin III
(ATIII) and enhances its proteolytic
Active clotting factors
(IIa, IXa, Xa, XIa, XIIa, XIIIa
A. No Heparin
Active clotting factors
(IIa, IXa, Xa, XIa, XIIa, XIIIa
AT III +
B. With Heparin
Heparin mechanism of action
Mechanism of action of
• Heparin binds to antithrombin III and
enhances its proteolytic activity by 1000fold.
• Heparin has a direct anticoagulant activity
(can inhibit clotting in vitro).
• Heparin releases lipoprotein lipase from
vascular beds, which accelerate clearing
of lipoproteins from the plasma.
• Heparin must be given parenterally by
slow infusion or deep subcutaneous
injection. It is not injected IM due to the
potential of hematoma
• Heparin is metabolized in the liver by
heparinase to smaller molecular-weight
compounds, which are excreted in the
Adverse Effects of Heparin
– Minor bleeding: drug withdrawal
– Severe bleeding: Protamine sulfate (a
highly positively charged mixture of
• Thrombocytopenia (25% of patients). Oral
anticoagulant should be used.
• Hypersensitivity reactions (chills, fever,
urticaria, anaphylaxis). Obtained from
animal sources (antigenic)
• Reversible alopecia
Therapeutic uses of Heparin
• Preoperative prophylaxis against
deep vein thrombosis.
• Heparin is administered following MI
or pulmonary embolism.
• Heparin prevents clotting in arterial
and heart surgery, during blood
transfusion, and in renal dialysis and
blood sample collection.
Contraindications and Drug
Interactions with Heparin
• Heparin is contraindicated in patients who
are bleeding, patients with hemophilia,
thrombocytopenia and hypertension.
• Heparin is contraindicated before and
after brain, spinal cord or eye surgery.
• Heparin should not be administered with
aspirin or other drugs that interfere with
• Positively charged drugs and
aminoglycosides can reduce the
effectiveness of heparin therapy.
B. Hirudin and Related
• Hirudin is a natural anticoagulant
obtained from Hirudo medicinalis,
the medicinal leech.
• It is a direct inhibitor of thrombin.
• These drugs are undergoing clinical
trials for the treatment of unstable
angina and acute MI.
3. Antiplatelet Drugs
• Platelet aggregation plays a central role in
the clotting process (esp.. clots that form
in the arterial circulation).
• Platelet aggregation is facilitated by
thromoboxane, ADP, fibrin and serotonin.
Platelet aggregation is inhibited by
prostacyclin and increased cAMP
• Antiplatelet drugs are agents that
decrease platelet adhesiveness induced
• They are useful in preventing arterial
thrombi since they are of platelet origin.
Platelet aggregation and
sites of drug action
.. .. …… TXA2
… ADP Ticlopidine
• Mechanisms and Pharmacological effects
– Aspirin and most other NSAIDs inhibit the
synthesis of prostaglandins:
• Decrease endothelial synthesis of PGI2
• Decrease thromoboxane A2 production
in platelets by inhibiting cyclooxygenase
type I and type 2.
• Irreversible inhibition of cyclooxygenase
and platelet aggregation for the life of
• It may cause bleeding, especially in the
GI, and hypoprothrombinemic effect
Therapeutic uses of Aspirin
• Prophylactic for transient
• Reduce the incidence of
• Decrease mortality in
• Mechanisms and Pharmacological effects:
– It inhibits adenosine diphosphate (ADP)-induced
expression of platelet glycoprotein receptors and
reduces fibrinogen binding and platelet
– It can be used in patients who are unresponsive to
aspirin to prevent thrombotic stroke.
– After oral ingestion, it is extensively bound to
plasma proteins and undergoes hepatic
– Can cause mild to severe neutropenia (frequent
complete blood count is advisable).
Dipyridamole (PERSANTINE) –
*inhibits platelets adhesion to damaged
*may increase the antiaggregating effect of
*↑ dosage ⇒ increase in platelets c-AMP
formation and ↓ platelet Ca which inhibits
pt. with intolerant to aspirin
• It is Fab fragment of a chimeric
human-murine monoclonal antibody.
• It is used solely for the prevention of
thrombosis in patients undergoing
• It binds to platelet glycoprotein
IIb/IIIa receptors and prevents
binding by fibrinogen.
C. Fibrinolytic Drugs
• Recently formed thrombus is easily lysed by
• Aged thrombi (72 hrs) are usually resistant.
• They are primarily used to dissolve clots in
patients undergoing MI, thromotic stroke or
Fibrinolysis and sites of
Fibrin split products
• Chemistry and Mechanisms:
– Altephase: recombinant forms of human
tissue plasminogen activator (t-PA).
– Urokinase: a protein obtained from
– Streptokinase: a protein obtained from
– Anistreplase: a performed complex of
streptokinase and plasminogen.
Mechanisms of action
• Urokinase and the recombinant forms of tPA (altepase) directly convert
plasminogen to plasmin.
• Streptokinase must combine with
plasminogen first to form an activator
complex that convert the inactive
plasminogen to plasmin.
• Anistreplase (anisoylated plasminogen
streptokinase activator complex, APSAC).
• Bleeding: Fibrinolytic drugs may lyse
both normal and pathologic thrombi. Less
effect is seen with t-PA (selectively
activates plasminogen that is bound to
fibrin) than streptokinase. Bleeding can
be controlled by Aminocaproic acid
(inhibits plasminogen activation)
• Hypersensitivity reaction: streptokinase
• Arrhythmias (bradycardia,tachycardia):
Free radicals generated after fibrinolysis.
– Mature blood cells is formed in the
bone marrow, removed from
circulation by RE cells in the liver and
spleen. This process is called
– This process requires minerals,
vitamins and regulated by
hematopoietic growth factors.
– It is a subnormal concentration of RBC’s or
hemoglobin in the blood.
– Can be caused by chronic blood loss, bone
marrow abnormalities, increased hemolysis,
– Drugs can cause toxic effects on blood cells.
– Nutritional anemias are caused by dietary
deficiencies of iron, folic acid and vitamin B12
Myoglobin and enzymes
• They are used to prevent and treat iron deficiency
– Ferrous sulfate and related compounds:
• They administered orally
• A typical daily dose is 100-200 mg iron/day (only
25% of orally administered iron is absorbed)
• May require 3-6 months to replenish body stores.
– Iron dextran:
– In patients who are intolerant of or
unresponsive to oral therapy.
– May cause anaphylactic reactions.
• Folic acid or vitamin B12 deficiency may
cause megaloblastic anemia.
• Both are cofactors in many enzymatic
reactions involving the addition of singlecarbon units.
1. Folic acid
• Folic acid deficiency may be caused by:
– Dietary deficiency during pregnancy and
– Poor absorption caused by pathology of the
• Folic acid deficiency may lead to megaloblastic
anemia. It is important to evaluate the basis of
megaloblastic anemia prior to instituting
therapy because vitamin B12 deficiency can
cause symptoms of the same disorder. In this
case, folic acid therapy will not correct the
neurologic damage associated with B12
Used to treat pernicious anemia.
Common B12 preparations include:
• Administered orally or parenterally.
• When a person has a deficiency of intrinsic
factor, which is secreted by the gastric
mucosa and is needed for vitamin B12
absorption, vitamin B12 deficiency
pernicious anemia develops.
• These people require vitamin B12
• Stored in the liver; excreted in the urine.
• Essential for cell growth and replication and
for the maintenance of myelin throughout
the nervous system.
• Used to treat pernicious anemia, which is a
megaloblastic anemia characterized by
decreased gastric production of
hydrochloric acid and the deficiency of the
intrinsic factor (normally secreted by the
parietal cells of the gastric mucosa and is
essential for vitamin B12 absorption).
• Drug interactions:
• Alcohol may decrease the absorption of oral
• Adverse reactions:
• No dose-related adverse reactions.
IV. Hematopoietic Growth Factors
• Endogenous growth factors:
– Colony-stimulating factors (CSF) and
erythropoietin are glycoproteins that
stimulate the differentiation and maturation
of bone marrow progenitor cells.
• Growth factor preparations:
– Epoetin alfa
– Filgrastim and sargramostin
Growth factor preparations
• Epoetin alfa:
– It is a form of erythropoietin produced by
recombinant DNA technology. Natural
erythropoietin is secreted by the kidneys to
stimulate erythroid cell differentiation and
– It is used in the treatment of anemia that is
due to inadequate erythropoiesis (patients
with chronic renal failure, chemotherapyinduce anemia in cancer patients, AZTinduced anemia in HIV infected patients).
Growth factor preparations
• Filgrastim and sargramostin:
– Filgrastim is recombinant human granulocyte
colony stimulating factor (G-CSF), Sargramostin is
recombinant human granulocyte-macrophage
colony-stimulating factor (GM-CSF).
– Both are primarily used to treat neutropenia
associated with cancer chemotherapy and bone
marrow transplantation (to accelerate granulocyte
and myeloid cell recovery following chemotherapy
or bone marrow transplantation).
– Both can be administered IV or subQ until the
neutrophil count has reached 10,000/µL.