Anticoagulants Anti Platelets & Hematinincs
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K.K. Akula (2010-11)
Coagulants and
AnticoagulantsKiran Kumar Akula Panjab University
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K.K. Akula (2010-11)
Haemostasis is the arrest of blood loss from damaged
vessels and is
essential to survival. The main phenomena are:
platelet adhesion and activation
blood coagulation (fibrin formation)
Thrombosis is a pathological condition resulting
from inappropriate
activation of haemostatic mechanisms:
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venous thrombosis is usually associated with stasis of
blood; a venous
thrombus has a small platelet component and a large
component of
fibrin
arterial thrombosis is usually associated with
atherosclerosis, and the
thrombus has a large platelet component.
A portion of a thrombus may break away, travel as
an embolus and
lodge downstream, causing ischaemia and infarction.
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K.K. Akula (2010-11)
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Factor I
Factor Il
Factor III
Factor IV
Factor V
Factor VII
Factor VIH
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Factor IX
Factor X
Factor XlFactor XII
Factor XIII
CLOTTING FACTORS
Fibrinogen
ProthrombinTissue Thromboplastin
Calcium Ions
Labile Factor
Stable Factor
Antihemophilic FactorChristmas Factor, or
Plasma Thromboplastin
Component (PTC)
Stuart-Prower Factor
Plasma Thromboplastin
Antecedent (PTA)
Hageman Factor
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Fibrin Stabilizing FactorATIII
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THE MAIN EVENTS IN THE FORMATION OF AN ARTERIAL THROMBUS. Exposure
of acidic phospholipids during platelet activation provides a surface on which
factors IXa and VIIa interact with factor X; factor Xa then interacts with factor
II. Activation of factor XII also initiates the fibrinolytic pathway (A similar series
of events occurs when there is vascular damage, leading to haemostasis) PAF,
platelet-activating factor; TXA2, thromboxane A2
K.K. Akula (2010-11)
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Flup-lure of atherosclerntic plaque in artery
T
Secrelion of preformed mediators (eg. HD PJ a nd synthe sis of mediators
Fu rth er aggregation _E
at platelets
_
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K.K. Akula(2010-11) BLOOD COAGULATION (FIBRIN FORMATION) The
clotting system consists of a cascade of proteolytic enzymes and
cofactors
Inactive precursors are activated in series, each giving rise to more
of the next
The last enzyme, thrombin, derived from prothrombin (II),
converts soluble fibrinogen (I) to an insoluble meshwork of fibrin inwhich blood cells are trapped, forming the clot
There are two pathways in the cascade:
the extrinsic pathway, which operates in vivo the intrinsic or contact
pathway, which operates in vitro
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Both pathways result in activation of factor X, which then converts
prothrombin to thrombin.
Calcium ions and a negatively charged phospholipid (PL) are
essential for three steps, namely the actions of:factor IXa on X factor VIIa on X factor Xa on II
PL is provided by activated platelets adhering to the damaged
vessel
Some factors promote coagulation by binding to PL and a serine
protease factor; for example, factor Va in the activation of II by Xa,
or VIIIa in the activation of X by IXa
Blood coagulation is controlled by:
-enzyme inhibitors (e.g. antithrombin III) -fibrinolysis (Plasmin)
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The coagulation cascade: sites of action of anticoagulantdrugs
/ in vivo pathway
K.K. Akula (2010-11)
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Extrinsic.: pathway
TTssue damage
Tissue factor
Intrinsic pathway
Contact
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White thrombi
Antiplatelet drugs
(Aspirin)
Fibrinolytic agentsK.K. Akula (2010-11)
Red thrombi
Injectable anticoagulants
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(heparin and newer
thrombin inhibitors)
Oral anticoagulants
(warfarin and related
compounds)7
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K.K. I. Drugs acting on coagulation cascadeAkula (2010-11)
Coagulation defects: Vit-K (for hemophilia, Christmas
disease) Thrombosis: (Myocaridal infarction, stroke, deep
vein thrombosis and pulmonary embolism)
Injectable anticoagulants: Heparin, LMWHs (enoxaparin,
dalteparin,fondaparinux), newer thrombin inhibitors (hirudin, hirugen,
argatroban)
Oral anticoagulants: Warfarin, phenindione, dephenadione,
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anisindione
II. Antiplatelet drugs
COX-inhibitors: Aspirin
Phophodiesterase inhibitors: Dipyridamole,
(sulphinpyrazone)
Thienopyridine derivatives: Ticlopidine, Colpidrogrel
Glycoprotein IIb/IIIa receptor inhibitors: Abciximab,
Tirofiban, Eptifibatide
Synthetic PGI2 analogues: Epiprostenol, AnagrelideTXA2-recetor antagonists: TXA2-synthesis inhibitors: 8
GR32191 Dazosiben
Ridogrel
III. Fibrinolytic or thrombolytics
Streptokinase, Urokinase, Anistreplase
Alteplase, Duteplase, Reteplase (rt-PA)
IV. Antifibinolytic/hemostatic drugs
Aminocaproic acid, Tranexamic acid, Aprotinin
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Drugs acting on coagulation cascadePhytomenadione Menadiol
K.K. Akula (2010-11)
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O2 + CO2 + Glutamic acid y-Carboxyglutamic acid
residues residues (in H, vu, lx, X) (in ||, vu, 1x, >
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(quinone) j
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Activation of prothrombin (factor K.K. Akula II) by(2010-11)
factor Xa
Negatively charged phospholipid surface (aggregating platelets)
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LLLLLLU 3 llllllil
Acidic phpsphplipid
1': Enzymic sites ' *f-Carbpxyglutamic
A acid residues
:I Activation + Site of cleavage of
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peptides ll by Xa