AN OVERVIEW ON ANTITHROMBOTIC THERAPHY

1. Under the guidance of: Submitted by:
Mrs.Santhi krupa, M.Pharm V.Vani Aparna,
Assistant profesor B.Pharmacy-IV/1sem
Department of Pharmacology. 137N1R0040
RECENT ADVANCES IN ANTI THROMBOTIC
THERAPHY
A Seminar submitted to
Vijaya Institute of Pharmaceutical Sciences for Women
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2. CONTENTS
Introduction
Components of thrombus
Natural history
Causes
Types of thrombosis
Pathalogical conditions of thrombosis.
Signs & Symptoms
Clinical spectrum of VTE.
Recent advances in antithromboitic therapy.
Conclusion
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3. INTRODUCTION
 Thrombosis is the formation of a blood clot inside a blood vessel,
obstructing the flow of blood through the circulatory system.
 When a blood vessel is injured, the body uses platelets and fibrin to
form a blood clot to prevent blood loss.
 Even when a blood vessel is not injured, blood clots may form in the
body under certain conditions.
 A clot that breaks free and begins to travel around the body is known
as an embolus.
 Thromboembolism is the combination of thrombosis and its main
complication, embolism.
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4.  When a thrombus is significantly large enough to reduce the
blood flow to a tissue, hypoxia can occur and metabolic
products such as lactic acid can accumulate.
 A larger thrombus causing a much greater obstruction to the
blood flow may result in anoxia, the complete deprivation of
oxygen and infarction, tissue death.
 An antithromboitic agent is a drug that reduces the
formation of thrombus.
 Normally, blood flows through arteries and veins smoothly
and efficiently, but if a clot or thrombus, blocks the smooth
flow of blood, it results in severe thrombosis or even cause
death.
 Diseases arising from clots in blood vessels include heart
attack and stroke, among others.
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5. COMPONENTS OF THROMBUS:
The most important components of a thrombus are :
1.Fibrin
2.Platelets
Fibrin is a protein that forms a mesh that traps red blood cells,
while platelets are a type of blood cell, form clumps that add to the
mass of the thrombus.
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6.  Fibrin is the more important component of clots that form
in veins.
 Platelets are the more important component of clots that
form in arteries where they can cause heart attacks and
strokes by blocking the flow of blood .
 There are various drugs used to treat thrombosis,like,
a) Thrombolytics-used to dissolve fibrin.
b) Anticoagulants-reduces fibrin formation &prevents
clots.
c) Antiplatelets-prevent platelets from clumping
&prevents clots.
 Thrombolytic agents can be differentiated from
fibrinolytic agents as they dissolve the fibrin only while
thrombolysis refers to the dissolution of the entire
thrombus 6

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8. CAUSES:
There are three main causes of thrombosis:
1.Hypercoagulability
2.Injury to the endothelial cells of
blood vessel wall
3.Abnormal flow of blood
Increased Levels of Natural Procoagulant.
Low levels of natural anticoagulants such as antithrombin, protein C, and protein S.
Factor V
 Prothrombin 20210 Mutation.
Hyperhomocysteinemia.
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9. TYPES OF THROMBUS:
A thrombus can block the flow of blood through a vein or artery.
Two different types of thrombus can form:
-Arterial thrombus
-Venous thrombus

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10. Arterial thrombosis:
 Arterial thrombi are typically composed mainly of platelet
aggregates, giving the appearance of ‘white thrombi’.
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11. Venous Thrombosis:
Venous thrombosis occurs in the veins and is categorized further
according to where it occurs including:
- Deep vein thrombosis
- Portal vein thrombosis
-Renal vein thrombosis
-Jugular vein thrombosis
-Budd-Chiari Syndrome
-Paget-Schoetter disease
-Cerebral venous sinus thrombosis
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12. TYPES OF VENOUS THROMBOSIS
cerebral venous
sinus thrombosis
paget
schroetter
disease
Budd-chiari
syndrome
jugular vein
thrombosis.
. renal vein thrombosis. portal vein thrombosisdeep vein thrombosis.
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13. PATHALOGICAL CONDITIONS OF THROMBOSIS
1.STROKE:
A stroke is the rapid decline of brain function due to a
disturbance in the supply of blood to the brain.
In thrombotic stroke, a thrombus (blood clot) usually forms
around atherosclerotic plaques.
Thrombotic stroke can be divided into two categories—large
vessel disease and small vessel disease.
Acute thrombus in the right MCA M1 branch
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14. 2.MYOCARDIAL INFRACTION:
It is caused by ischemia, often due to the obstruction of a
coronary artery by a thrombus.
This restriction gives an insufficient supply of oxygen to the
heart muscle which then results in tissue death.
Myocardial infraction
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15. Signs and Symptoms of Thrombosis
-Pain
-Swelling of the affected area with erythema and warmth
-Discoloration including a bluish or
suffused color
Signs and symptoms on physical examination
-Positive Homan’s sign
-Pain on palpation
-Presence of a palpable cord
-Evidence of collateral circulation, usually manifested by
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16. Clinical Spectrum of VTE:
The clinical spectrum of venous thromboembolism
(VTE) ranges from deep vein thrombosis (DVT) to pulmonary
embolism (PE).
Deep vein thrombosis (DVT)
Blood clots may form in the deep blood vessels, most commonly in the
legs and groin, and can block normal blood flow returning from the legs
to the heart.
Venous clots that form in regions of slow to moderate flow are
composed of a mixture of red cells, platelets, and fibrin and are known as
mixed platelet fibrin thrombi.
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17.  Pulmonary Embolism (PE)
 PE results from a piece or all of a blood clot that breaks off and
is carried by the blood stream to the lung where it obstructs the
blood vessel.
 Superficial Thrombophlebitis
 Superficial thrombophlebitis is due to blood clots that form in
veins that are closer to the surface of the skin and are
associated with inflammation
 Superficial thrombophlebitis is often observed in individuals who
are heterozygous or homozygous for the factor V Leiden mutation.
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18. RECENT ADVANCES IN ANTTHROMBOITICS
THERAPY:
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19. Intravascular blood coagulation is intrinsically prevented in 3 steps.
Firstly, thrombin is converted after binding to TM, the anticoagulant
factor which leads to the rapid cleavage and activation of the
anticoagulant protein C. This further down regulates formation of
thrombin by inactivating the coagulation factor V and VIII .
Secondly, circulating proteinase inhibitors such as tissue factor
pathway inhibitor, C1 inhibitor and antithrombin III retain the
coagulation factors in the inactivated state.
Finally, activation of the plasma protein thrombin-activated
fibrinolysis hinders fibrin inside the clot by removing carboxy-terminal
lysine residues. 19

20. THROMBIN INHIBITORS:
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21. FACTOR Xa INHIBITORS
Inhibition of factor Xa seems to be the most logical step to
effectively reduce thrombin production by extrinsic or
intrinsic path-ways without interfering with basal thrombin
activity.
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22. TISSUE FACTOR INHIBITORS
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23. INHIBITORS OF PLASMINOGEN ACTIVATOR
INHIBITORS-1:
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24. PLATELET gpIIb/IIIa RECEPTOR ANTAGONISTS:
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25. THROMBOXANE A2 SYNTHETASE INHIBITORS&RECEPTOR
ANTAGONISTS
Thromboxane receptor antagonists like vapiprost or ifetroban
have been found to be more helpful than antithrombins and
aspirin in preventing cyclic flow variations.
TxA2 is important and stimulates platelet secretion and
aggregation.
These compounds also antagonize TxA2/PG endoperoxide-
induced vasoconstriction as well as release of serotonin from
activated platelets.
TxA2/PG endoperoxide- dependent reocclusion induced by
clot-bound thrombin after successful lysis
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26. ADP RECEPTOR ANTAGONISTS
 ADP present in high concentrations of the platelet & released
during platelet aggregation.
 It undergoes shape changes & increases intecellular calcium.
 ADP released flevels,leading to opening of receptor modulated
ca+cations.
 Due to this the conformational change and activation of surface
gpIIb/IIIa receptors ,leading to final common pathway in
platelet aggregation . Activated platelets present on endothelial
CD39 cells, represent a novel antithrombotic agent to treat high-
risk of thrombosis.
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27. GUANYLATE CYCLASE ACTIVATOR.
NO-releasing compounds activate guanylate cyclase to elevate the
intracellular levels of cGMP, PDE inhibitors prevent degradation of
cGMP.
An increase in the intracellular level of cGMP reduces the free
cytosolic Ca2+ in platelets.
A novel activator of guanylate cyclase was found to inhibit platelet
activation and platelet aggregation in vitro through NO-independent,
cGMP-dependent mechanism.
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29. P-SELECTIN INHIBITORS:
•The initiating event in this cascade is the adhesion of leukocytes
to the vascular endothelium through selectins and other adhesion
molecules.
•P-selectins are upregulated on endothelial cell and platelet
phospholipid surfaces by thrombin, tumor necrosis factor and
cytokines.
•Effective protection from thrombus formation and clot
propagation may be achieved by blocking the inflammatory
component of the thrombotic process which may prove to be an
efficient alternative mechanism of anticoagulation.
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30. PLATELET COLLAGEN RECEPTOR
ANTAGONISTS:
Collagen interactions with platelets are important targets for
pharmacological control.
 Platelets have 2 major receptors for pharmacological control,
The integrin a2b1 receptor – adhesion and platelet anchoring.
Ig superfamilyGPVI –signalling & platelet activation.
In addition, gpIb-V-IX is an indirect collagen receptor acting via vWF
as a bridging molecule and is essential for platelet interactions with
collagen at high shear rates.
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31. CONCLUSION
The recent advanced antithrombotic compounds, namely
direct FXa inhibitors, direct FVIIa inhibitors, tissue factor pathway
inhibitors, have shown promising potential as antithrombotics.
However, no specific antithrombotic agent has currently displaced
heparin, coumarins and aspirin as the agent of choice for different
thrombotic complications, may be because of their side effects or
their high cost. So it is necessary in the future to search new
chemical entities required to prevent and treat thrombotic
disorders for millions of the people worldwide.
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