1. BLOOD COAGULATION,
ANTICOAGULANT,
THROMBOLYTICS &
ANTIPLATELET DRUGS.

2. WHAT IS COAGULATION?
Coagulation is a complex process by which blood forms
clots. Blood must be remain fluid with in the vasculature
and yet clot quickly when expose to non endothelial
surface at a site of vascular injury.
It is an important part of haemostasis (the cessation of
blood loss from a damaged vessel), where in a damaged
blood vessel wall is covered by a platelet and fibrin-
containing clot to stop bleeding and begin repair of the
damaged vessel.
Disorders of coagulation can lead to an increased risk of
bleeding (hemorrhage) or clotting (thrombosis).
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3. Factor Common Name
I Fibrinogen
II Prothrombin
III Tissue Factor(Thromboplastin)
IV Ca2+
V Proaccelerin
VII Proconvertin
VIII Antihemophilic Globulin
IX Plasma thromboplastin component
X Stuart Factor
XI Plasma thromboplastin
antecedent
XII Hageman factor
XIII Fibrin Stabilizing Factor

4. THE COAGULATION CASCADE
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6. COAGULANTS
These are substances which promote coagulation, and
are indicated in haemorrhagic states.
Fresh whole blood or plasma provide all the factors
needed for coagulation and are best therapy for deficiency
of any clotting factor.
They also act immediately.
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7. VITAMIN K
It is a fat soluble dietary principle required for the
synthesis of clotting factors.
Dietary sources are-green leafy vegetables, such as
cabbage, spinach and liver, cheese, etc.
Vit K acts as a cofactor in the synthesis of coagulation
proteins-prothrombin, factors VII, IX and X.
The vit K dependent change confers on them the capacity
to bind Calcium and to get bound to phospholipid
surfaces.
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8. DEFICIENCY
Deficiency of vit K occurs due to :-
 Liver disease
 Obstructive jaundice
 Malabsorption
 Long-term antimicrobial therapy
 Deficient diet
Dose: Phytonadione 10mg/ml i.m. inj.
Menadione sod.bisulfite: 20 mg.
Toxicity: Flushing
Breathlessness
Fall in B.P.
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9. ANTICOAGULANTS
An anticoagulant is a drug that helps prevent the
clotting (coagulation) of blood.
These drugs tend to prevent new clots from forming
or an existing clot from enlarging.
They don't dissolve a blood clot.
Anticoagulants are also given to certain people at risk
for forming blood clots,
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10. CLASSIFICATION
1. Used in vivo:-
A. Parenteral anticoagulants:
Heparin,
Heparinoids-Heparan sulfate,
Danaparoid,Lepirudin,Ancrod.
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11. B. Oral Anticoagulants:
i. Coumarin derivatives:-
*Bishydroxycoumarin(dicumarol),
*Warfarin sodium
ii. Indandione derivatives:-
*Phenindione
2. Used in vitro:-
A. Heparin(150 U to prevent clotting of 100 ml blood.)
B. Calcium complexing agents:-
*Sodium citrate(1.65 g for 350 ml of blood)
*Sodium oxalate(10 mg for 1 ml blood)
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12. HEPARIN
Heparin is a non-uniform mixture of straight chain
mucopolysaccharides with MW 10,000 to 20,000.
It contains polymers of two sulfated disaccharide
units:
D-glucosamine-L-iduronic acid
D-glucosamine-D-glucuronic acid
It carries strong electronegative charges and is the
strongest organic acid present in the body. 12

13. OCCURRENCE OF HEPARIN
Heparin is found in the secretory granules of mast
cells.Thus ,heparin is present in all tissues containing
mast cells;richest sources are lung, liver and intestinal
mucosa.
Commercially it is produced from ox lung and pig
intestinal mucosa.
PHARMACOLOGICAL ACTIONS
• Heparin is a powerful and instantaneously acting
anticoagulant, effective both in vivo and in vitro.
• Heparin produces its anticoagulant effect by
activating plasma antithrombin iii(AT III a serine
proteinase inhibitor) and may be other similar
cofactors. 13

14. Heparin
Antithrombin III
Thrombin

15. 15

16. ACTIONS
2. ANTIPLATELET:-
Heparin in higher doses inhibits platelet aggregation
and prolongs bleeding time.
3. LIPAEMIA CLEARING:-
Injection of heparin clears turbid post-prandial
lipaemic by releasing a lipoprotein lipase from the
vessel wall and tissues, which hydrolyses triglycerides
of chylomicrones and VLDL to free fatty acids; these
then pass into tissues and the plasma looks clear.
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17. PHARMACOKINETICS
Heparin is a large, highly ionized molecule; therefore
not absorbed orally.
Injected i.v. it acts instantaneously,but after s.c.
injection anticoagulant effect develops after 60 min.
Heparin does not cross blood-brain barrier or
placenta.
It is metabolized in liver by heparinase and fragments
are excreted in urine.Heparin released from mast cells
is degraded by tissue macrophages.
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18. ADVERSE EFFECTS
1. Bleeding due to overdose is the most serious
complication of heparin therapy.Haematuria is
generally the first sign.
2. Thrombocytopenia is another common problem.
3. Reversible alopecia is infrequent.
4. Osteoporosis may develop on long-term use of
relatively high doses.
5. Hypersensitivity reactions are rare.
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19. CONTRAINDICATIONS
1. Bleeding disorders,heparin induced
thrombocytopenia.
2. Severe hypertension,threatened abortion,
piles,g.i.ulcers.
3. Subacute bacterial endocarditis, large ,tuberculosis.
4. Chronic alcoholics, renal failure.
5. Aspirin and other antiplatelet drugs should be used
very cautiously during heparin therapy.
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20. HEPARIN ANTAGONIST
Protamine sulfate:-
 It is a strongly basic, low molecular weight protein
obtained from the sperm of certain fish.
 Given i.v. it neutralises heparin weight for weight,i.e. 1
mg is needed for every 100 U of heparin.
 In the absence of heparin, protamine itself acts as a
weak anticoagulant by interacting with platelets and
fibrinogen.
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21. ORAL ANTICOAGULANTS
Oral anticoagulants are medicines used for people
who are at risk of developing abnormal blood clotting.
The oral anticoagulants are a class of pharmaceuticals
that act by antagonizing the effects of vitamin K.
Clotting in the limb vessels can cause gangrene.
Clots can dislodge and go to the lungs, known as
pulmonary embolism.
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22. EXAMPLES OF ORAL
ANTICOAGULANTS
Recemic Warfarin sodium
Bishydroxycoumarin(Dicumarol)
Acenocoumarol(Nicomalone)
Ethylbiscoumacetate
Phenindione
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23. WARFARIN
Warfarin is a synthetic derivative of coumarin, a
chemical found naturally in many plants, like,
woodruff (Galium odoratum, Rubiaceae), and at lower
levels in licorice, lavender, species.
Warfarin is prescribed to people with an increased
tendency for thrombosis or in those individuals that
have already formed a blood clot (thrombus).
Warfarin is contraindicated in pregnancy, as it passes
through the placental barrier and may cause bleeding
in the fetus.
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24. MECHANISM OF ACTION
Warfarin is an analogue of Vitamin K. Warfarin
inhibits the vitamin K-dependent synthesis of
biologically active forms of the calcium-dependent
clotting factors II, VII, IX and X, as well as the
regulatory factors protein C.
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25. MECHANISM OF ACTION
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26. ADVERSE EFFECTS
Bleeding
Alopecia
Dermatitis
Urticaria
Hematuria
TREATMENT: give fresh blood transfusion, supplies
clotting factors & replenishes lost blood.
Give vit K-specific antidote but it takes 6-24 hours for
clotting factors to be resynthesised & released in blood
after vit K administration.
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28. USES OF ANTICOAGULANTS
The aim of using anticoagulants is to prevent thrombus
extension and embolic complications by reducing the rate of
fibrin formation.
USES:-
1.Deep vein thrombosis and pulmonary embolism.
2.Myocardial infarction
3.Unstable angina
4.Rheumatic heart disease;Atrial fibrillation
5.Cerebrovascular disease
6.Vascular surgery, prostatic heart valves, retinal vessel
thrombosis
7. haemodialysis.
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29. THROMBOLYTICS
(Fibtinolytics)
These drug use to lyse thrombi(clot)
Streptokinase
Urokinase
Anistreplase
tissue Plasminogen Activators (t-PA)
Alteplase
Reteplase
Tenecteplase
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30. FIBRINOLYSIS
Endothelial cells secrete tissue plasminogen activator (t-
PA) at sites of injury.
 t-PA binds to fibrin and cleaves plasminogen to plasmin,
resulting in fibrin digestion. Plasminogen activator
inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA; a2-
antiplasmin (a2-AP) inactivates plasmin.
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32. Plasmin is an endogenous fibrinolytic enzyme that
degrades clots by splitting fibrin into fragments.
Plasmin itself can not be used because naturally
occurring inhibitors in plasma prevent its effects.
Fibrinolytic drugs catalyze the conversion of precursor
plasminogen into active plasmin.
Rapidly lyse or break down thrombi.
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33. 33

34. Streptokinase
Source:
 It is a protein produced by beta-hemolytic
streptococci. It has no intrinsic enzymatic activity.
MOA:
It combines with proactivator plasminogen to form a
complex.
This complex catalyzes the conversion of
plasminogen to active plasmin.
So rapid lysis of the clot by plasmin.
This complex also catalyzes the clotting factor V and
VII.
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35. Plasma half life: (t ½) 40-80 minutes
The streptokinase-plasminogen complex is not inhibited by
natural alpha 2-antiplasmin
Adverse effects: Not clot specific.
So can create a generalized lytic state when administered I/V.
Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
Hemorrhage --- most serious cerebral hemorrhage
Allergic reactions, rarely anaphylaxis and fever.
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36. A two chain serine protease containing 411
amino acid residues isolated from cultured human
kidney cells.
MOA:
It converts plasminogen to active plasmin.
It is not clot specific:
So can create a generalized lytic state when administered
I/V.
Thus, both protective haemostatic thrombi and target
thromboemboli are broken down.
Ph. K Given I/V.
t½ : 15-20 minutes
Metabolized by liver.
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37. Anistreplase
A complex of purified human plasminogen & bacterial streptokinase
that has been acylated to protect the enzymes active site.
On I/V administration, the acyl group spontaneously hydrolyzes.
Free activated streptokinase - proactivator complex produces lysis of
clots also degrades fibrinogen.
Advantages:
Rapid I/V injection may be given.
Greater clot selectivity .
More thrombolytic activity.
Dose: A single I/V injection of 30 units over 3-5 minutes
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38. t-PA is a natural serine protease.
It preferentially activates fibrin bound plasminogen.
Human t-PA has been manufactured by recombinant
DNA technology for therapeutic use.
Alteplase: Recombinant form of t-PA.
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39. USES OF THROMBOLYTICS
1. Acute myocardial infarction: due to coronary artery
thrombosis. Best given within 6 hrs.
2. Pulmonary embolism: with hemodynamic
instability.
3. Severe deep vein thrombosis:
4. Acute ischemic stroke: (only t-PA)
Antifibrinolytics: used for treatment of fibrinolytic toxicy.
eg: Epsilon Amino Caproic Acid (EACA)
Tranexamic acid
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40. PLATELET ADHESION AND
AGGREGATION
GPIa/IIa and GPIb are platelet membrane proteins that bind to
collagen.
Von Willebrand factor (vWF), it causing platelets to adhere to
the subendothelium of a damaged blood vessel.
PAR1 and PAR4 are protease-activated receptors that respond
to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP
when stimulated by agonists, these receptors activate the
fibrinogen-binding protein GPIIb/IIIa.
COX-1 to promote platelet aggregation and secretion.
Thromboxane A2 (TxA2) is the major product of COX-1
involved in platelet activation. Prostacyclin (PGI2) synthesized
by endothelial cells inhibits platelet activation.
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42. Antiplatelet Drugs
Aspirin:
Aspirin irreversibly inhibit COX (up to the life-
time of the platelets 8-10 days).
Both PGI2 and TXA2 synthesis are inhibited.
To separate this action aspirin in small dose 75-
100 mg/day inhibits TXA2 synthesis without
significant effect on the endothelial PGI2.
This low dose of aspirin may also causes peptic
ulcer bleeding in patients > 60 years.

43. Ticlopidine:
Ticlopidine inhibits ADP- dependent platelet aggregation.
It is more effective than aspirin, but aspirin is safer and
less expensive.
It is used to prevent stroke in patient who are intolerant to
aspirin.
A/E: neutropenia (do WBC count / 2 weeks), GIT upset
especially diarrhea.
Clopidogrel:
It acts like ticlopidine, but not associated with
neutropenia.
It is more effective and more expensive than aspirin, but
safer than ticlopidine.

44. Dipyridamole:
It inhibits phosphodiesterase enzyme, so increasing
intraplatelet cAMP.
It may also increase PGI2 in vascular endothelium.
It has coronary VD activity.
Epoprostenol:
It is a prostacyclin.
Used during renal dialysis to prevent platelet loss.
It is used with or without heparin.
It is a potent VD.

45. Other Antiplatelet drugs
Dazoxiben: It inhibits TXA2, but not PGI2. it is being
evaluated in cardiac diseases.
Sulphinpyrazone: It is a uricosuric agent and has an
antiplatelet effect. It inhibits prostaglandin
synthetase.
Fish oil: (omega 3-marine triglyceride): It may form
abnormal thromboxane.

46. Drug Class Prototype Action Effect
Anticoagulant Heparin Inactivation of clotting Prevent venous
Parenteral Factors Thrombosis
Anticoagulant Warfarin Decrease synthesis of Prevent venous
Oral Clotting factors Thrombosis
Prevent arterial
Antiplatelet Aspirin Decrease platelet
Thrombosis
drugs aggregation
Thrombolytic Streptokinase Fibinolysis Breakdown of
Drugs thrombi

47. Thank you !
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