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

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Anticoagulants Anti Platelets & Hematinincs