1. ANTICOAGULATION
LEARNING OBJECTIVES
• At the end of lecture students should be able to
know,
• How Blood Clots are formed.
• How the blood clots are broken down ?
• What drugs can be used to regulate clotting ?
• How to rectify clotting deficiencies
Coagulation Factors
• Factor Name
• I Fibrinogen
• II Prothrombin
• III Tissue Factor or thromboplastin
• IV Ca++
• V Proaccelerin
• VII Proconvertin
• VIII Antihemophilic A factor
• IX Antihemophilic B factor or Christmas
factor
Classes of Drugs
• Prevent coagulation
• Dissolve clots
• Prevent bleeding and hemorrhage - Hemostatic
• Overcome clotting deficiencies (replacement
therapies)
Blood Clotting
• Vascular Phase
• Platelet Phase

2. • Coagulation Phase
• Fibrinolytic Phase
Vascular Phase
• Vasoconstriction
• Exposure to tissues activate Tissue factor and
initiate coagulation
• Platelet phase
• blood vessel wall (endothelial cells) prevent platelet
adhesion and aggregation
• platelets contain receptors for fibrinogen and von
Willebrand factor
• after vessel injury Platelets adhere and aggregate.
• Release permeability increasing factors (e.g.
vascular permeability factor, VPF)
• Loose their membrane and form a viscous plug
• Coagulation Phase
• Two major pathways
• Intrinsic pathway
• Extrinsic pathway
• Both converge at a common point
• 13 soluble factors are involved in clotting
• Biosynthesis of these factors are dependent on
Vitamin K1 and K2
• Normally inactive and sequentially activated

3. • Hereditary lack of clotting factors lead to
hemophilia -A
• Intrinsic Pathway
• All clotting factors are within the blood vessels
• Clotting slower
• Activated partial thromboplastin test (aPTT)
• Extrinsic Pathway
• Initiating factor is outside the blood vessels -
tissue factor
• Clotting - faster - in Seconds
• Prothrombin test (PT)
• COAGULATION DISORDERS
• THROMBOSIS
• BLEEDING
• CLOTTING MECHANISM
• Physical trauma to vascular system causes:
• Vasoconstriction
• Platelet aggregation
• Formation of fibrin meshwork and clot
• Initially platelets adhere to the blood vessel at the site
of injury and adhered platelets release chemicals that
cause aggregation of platelets thus a plug is formed.
• Platelet activation and aggregation is promoted by
exposure to collagen, thromboxane A2 (powerful
stimulator), decreased prostacyclins and ADP.
• Platelet aggregation is essential for the clot formation.

4. • Factors released by injured tissues and platelets
stimulate the intrinsic and extrinsic pathways of
clotting cascade that lead to the formation of fibrin
that forms meshwork with aggregated platelets and
strengthen the plug.
• Intrinsic system takes several minutes for formation of
activated factor X, in extrinsic system activated factor
X is produced very rapidly within seconds.
• As wound heals fibrinolytic pathway is activated in
that plasminogen is converted to plasmin (fibrinolysin)
that interferes with clot propagation and dissolves
fibrin network.
• Clotting mechanism may be pathologically activated
resulting in thrombosis and embolism that produce
ischemia of various organs.
• PLATELET AGGREGATION
• Platelet activation and aggregation is promoted by:
• Exposure to collagen
• Thromboxane A2 (powerful stimulator)
• Decreased prostacyclins
• ADP

5. ANTICOAGULANTS
• Parenteral:
o HEPARIN
o HIRUDIN
• Oral:
• Coumarin Derivatives:
o WARFARIN
o DICOUMAROL
o ACENOCOUMAROL
ANTICOAGULANTS
• Indanedione Derivatives:
• PHENINDIONE
• DIPHENADIONE
• BROMINDONE
• Out of all these orally effective drugs
• warfarin is the most important and most
• widely used.

6. o HEPARIN
• WARFARIN
• DICOUMAROL
• PHENINDIONE
o SODIUM CITRATE
o SODIUM OXALATE
o EDTA
HEPARIN:
• Heparin is highly acidic drug and is mixture of
mucopolysaccharides.
• It occurs in mast cells, richest source being lungs,
liver and intestine.
• It is obtained from bovine lung and porcine intestine
for commercial use.
• Commercial preparations of heparin available in un-
fractionated form (UFH) are composed of high
molecular weight heparin and low molecular weight
heparin fractions.
MECHANISM OF ACTION:
• Antithrombin III a naturally occurring
anticoagulant, normally prevents the coagulation
by blocking the activated factors II, IX, & X.
• Normally the activity of antithrombin III is very
slow, heparin accelerates the activity of
antithrombin III 1000 fold.

7. • Antithrombin III acts as heparin cofactor and
inhibits activated factors of clotting; factor IIa and
factor Xa are most sensitive to inhibition.
MECHANISM OF ACTION:
o Heparin blocks antithrombin III without being
consumed itself. Once antithrombin binds
with activated clotting factors, heparin
detaches from antithrombin III intact and
binds with other molecules of antithrombin III.
o HMW heparin has high affinity for
antithrombin III and markedly blocks blood
coagulation.
o LMW fraction inhibits activated factor X but
has less effect on antithrombin III and on
coagulation.
ACTIONS OF HEPARIN
• Heparin prevents blood coagulation within body and
outside the body, it decreases thrombus formation.
• It does not act as thrombolytic agent i.e. it does not
dissolve already formed thrombus.
• Heparin also decreases the platelets by increasing the
platelet aggregation that may lead to paradoxical
thromboembolism and by the formation of antibodies
against platelets.
Unfractionated heparin (UFH)
• Advantage:
• A short half-life(60 minutes)
• easily reversed (by protamine sulfate)
• Disadvantage:

8. • Intravenous administration necessitates
hospitalization before surgery,
• Inconvenient and expensive.
Low-molecular-weight-heparin (LMWH)
• Allowed bridging therapy to be administered to
outpatients.
• Doses of LMWH that are recommended for treatment
of venous thromboembolism are administered once or
twice daily, generally for 3 days before surgery.
• Required to determine whether the benefit of bridging
therapy outweighs the associated risks of bleeding.
Low-molecular weight heparin
• Low-molecular weight heparin is gradually replacing
heparin for treatment of most patients with venous
thromboembolism and acute coronary syndromes
because it has more convenient and cost-effective
• It has similar results to heparin
• Administered by subcutaneous
• injection
• LOVENOX® is an example
• PHARMACOKINETICS:
• Heparin does not cross cell membrane and is not
absorbed from gut. It is given subcutaneously or
intravenously.

9. • Heparin should not be given intramuscularly as it
produces hematoma.
• Heparinase present in liver degrades heparin.
• Some of the parent drug and inactive metabolites are
excreted in urine; half-life of heparin is 80 minutes.
• Heparin does not cross placenta but should be used
carefully during pregnancy as it can produce maternal
bleeding.
SIDE EFFECTS:
• Main problem with heparin therapy is hemorrhage,
careful monitoring of APTT (Activated Partial
Thromboplastin Time) is essential to prevent
bleeding.
• Dose of heparin is so adjusted that APTT is raised to
2–2½ times to that of control value. (Normal 30
seconds).
• Patients with hepatic and renal impairment are more
prone to develop hemorrhage.
• Risk of hemorrhage is less with LMW heparin than
with HMW heparin.

10. • SIDE EFFECTS:
• As heparin for commercial use is of animal origin it
may produce hypersensitivity reactions. Chills fever,
urticaria, itching and anaphylactic shock may occur.
• On prolonged use heparin may produce osteoporosis,
spontaneous fractures of bones and alopecia.
• Heparin also produces thrombocytopenia that is either
mild or transient due to platelet aggregation or severe
due to platelet antibodies.
SIDE EFFECTS
• Bleeding
• Hypersensitivity reactions
• Osteoporosis
• Spontaneous fractures of bones
• Alopecia
• Thrombocytopenia
TREATMENT OF HEPARIN OVERDOSE
• Protamine sulfate is antidote of heparin
• It binds with heparin
• 1 mg of protamine sulfate neutralizes 100 units of
heparin
CONTRA-INDICATIONS
• Hypersensitivity
INDICATIONS
• Prevention of thromboembolism in:
• Deep vein thrombosis
• Prolonged immobilization

11. • Myocardial infarction
• In vitro:
• To prevent blood coagulation during blood sampling
• Hemodialysis
DEEP VEIN THROMBOSIS
• BOLUS 5000–10000 IU I/V
M.DOSE 5000 IU 2–3 TIMES DAILY S/C

12. HIRUDIN:
• Hirudin is powerful and specific thrombin inhibitor
• Its action is independent of antithrombin III.
• It can inactivate the fibrin bound thrombin in thrombi.
• ORAL ANTICOGULATS
• Oral anticoagulants are chemically related to
vitamin K;
• They prevent coagulation within body and are not
effective outside the body (In vitro)
• Warfarin
• Warfarin is an oral medication
• It is a synthetic derivative of coumarin, a chemical
found naturally in many plants -- it decreases blood
coagulation by interfering with vitamin K metabolism
• It stops the blood from clotting within the blood
vessels and is used to stop existing clots from getting
bigger (as in DVT) and to stop parts of clots breaking
off and forming emboli (as in PE)
• Dicumarol

13. • It is a potent oral anticoagulant that acts by inhibiting
the synthesis of vitamin K-dependent clotting factors
(prothrombin and factors VII, IX and X) in the liver; it
is starting to largely replace warfarin
• Dicumarol is produced naturally by conversion of
nontoxic coumarin in moldy sweet clover hay,
lespepeza hay or sweet vernal hay
• It is used especially in preventing and treating
thromboembolic disease
• Formerly called bishydroxycoumarin
MECHANISM OF ACTION:
• Warfarin and other anticoagulants resemble
vitamin K and vitamin K is essential for the
formation of activated clotting factors II, VII, IX
and X by the liver. Only reduced form of vitamin K
is effective for this purpose.
• Reduced form of vitamin K is oxidized to vitamin
K epoxide during the activation of clotting factors.
MECHANISM OF ACTION:
• Vitamin K epoxide is reduced back by vitamin K
epoxide reductase and is used for the formation of
clotting factors.
• Oral anticoagulants inhibit the enzyme vitamin K
epoxide reductase competitively thus they prevent the
formation of active form of vitamin K and its action.
• Unlike the heparin, their peak effect appears after 36–
48 hours, and they have long duration of action (4–7
days).
• PHARMACOKINETICS

14. • They are well absorbed from gut; food delays their
absorption, are highly bound to plasma proteins
(99%) and are mainly concentrated in liver, which is
the main site of their action.
• They do not cross blood brain barrier but cross
placenta and predispose fetal and neonatal bleeding.
• Drugs have high affinity for protein binding like
sulfonamides can displace oral anticoagulants and
increase their effects.
• Oral anticoagulants are metabolized in liver and their
metabolites are excreted in urine.
DRUGS INCREASING WARFARIN ACTION
DRUGS DECREASING WARFARIN
ACTION

15. SIDE EFFECTS OF ORAL ANTICOAGULANTS
• Bleeding
• Phenindione can produce skin rashes, blood
dyscrasias, jaundice, fever, nausea, vomiting and
red discoloration of urine.
Warfarin-induced Skin Necrosis
• CONTRAINDICATIONS

16. • Pregnancy & lactation
• Bleeding disorders
• Thrombocytopenia
• Uncontrolled hypertension
• Gastrointestinal ulcers
• CONTRAINDICATIONS
• Tuberculosis
• With aspirin
• With tetracyclines and other broad spectrum
antibiotics
• Vitamin K deficiency
• INDICATIONS
• To prevent thrombus formation in:
• Acute myocardial infarction
• Deep vein thrombosis
• Pulmonary embolism
• Cerebrovascular accident (Stroke)
• Atrial fibrillation
• Prosthetic heart valves
• Thromboembolic Risk When Discontinuing
Warfarin
• Venous thromboembolism (VTE):
• The absence of OAC during the first month of an
acute VTE event－Recurrence 40%/month
• During the second and third month－ Recurrence
10%/2month
• After the 3 month treatment－15%/year

17. • Surgery should be deferred following an acute
episode of venous thromboembolism until patients
have received at least 1 month, and preferably 3
months, of anticoagulation.
• REFERENCES

18. • BASIC AND CLINICAL
PHARMACOLOGY,KATZUNG,11th EDITION.
• THANKYOU