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ANTICOAGULANTS AND THROMBOLYTIC DRUGS
Haemostasis
Vascular injury results firstly in vasoconstriction and formation of platelet plug at
the site of injury (primary haemostasis).
The platelet plug is then stabilized by the formation of a fibrin meshwork,
resulting from activation of the coagulation cascade.
Fibrin is eventually cleared through digestion by fibrinolytic enzymes.
Primary Haemostasis
When endothelial integrity is breached, platelets adhere to exposed subendothelial
collagen. The adherent platelets become activated result in;
1) Exposure of fibrinogen receptors, allowing fibrinogen to bind and cross-
link adjacent platelets. The process is known as platelet aggregation. The
platelet fibrinogen receptor consists of a complex of glycoproteins IIb and
IIIa on the platelet membrane.
2) Release of contents of secretory granules including substances such as
adenosine diphosphate (ADP) which promote further platelet activation.
3) Synthesis of thromboxane A
2
which also acts to promote further platelet
activation and vasoconstriction.
Activation of the coagulation cascade;
The coagulation cascade can be divided into three parts;
1) The common pathway consists of those reactions subsequent to the generation of
factor Xa, culminating in the cleavage of fibrinogen by thrombin, with subsequent
polymerization of fibrin monomers into fibrin strands. Factor Xa may be
generated either by the extrinsic pathway or by the intrinsic pathway.
2) In the extrinsic pathway, tissue factor is expressed by cells or released following
tissue injury. Binding of tissue factor to factor VII greatly accelerates the
activation of factor VII and also the action of factor VIIa in the activation of
factor X..
3) The intrinsic pathway is initiated by the action of factor XII by contact of blood
with a ‘foreign’ surface. In vivo, this is usually the subendothelial tissues. A
sequence of reactions the results in activation of factor X. most coagulation
factors are synthesized in the liver, and the synthesis of the pro-coagulant forms
of factors II, VII, IX and X is dependent on the availability of vitamin K.
Fibrinolysis
The fibrinolytic system, just like the coagulation cascade, also consists of a series of
enzymatic steps, this time resulting in the breakdown of polymerized fibrin by plasmin
into degradation products (FDP). Plasmin is generated from the plasma protein
plasminogen by the action of tissue plasminogen activator (tPA), which is most efficient
in the activation of plasminogen, when it is bound to fibrin.
Pathophysiology
Thrombosis is haemostasis in the wrong place.

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When haemostasis proceeds in checked within a blood vessel, thrombosis occurs
and vascular occlusion may result. Thrombi may also break up into small pieces
and lodge at distant points within the circulation system (embolism).
The process of thrombosis in a blood vessel is promoted by one or more of three
underlying pathological events;
1) Abnormality of the vessel wall
2) Abnormalities of flow within a vessel wall
3) Abnormality of blood constituents
Thrombosis in arteries usually result from rupture of an atheromatous plaque, and
arterial thrombosis usually consists initially of platelets and subsequently of
fibrin. Venous thrombosis usually occur in the context of stasios of blood flow
e.g. during periods of immobility or during pregnancy when pressure from gravid
uterus may impede venous return.
ANTICOAGULANT DRUGS
HEPARIN
Anticoagulation can be achieved very rapidly with heparin, and it is therefore the
anticoagulant of choice in many acute thrombotic states such as treatment of deep
venous thrombosis (DVT) or pulmonary embolism and in severe unstable angina
in which it has an additive effect to aspirin.
Chemistry and pharmacology
Unfractionated heparin is a mixture of naturally occurring glycosaminoglycans
with polysaccharide chains of length and molecular weights ranging from 5000 to
30,000.
Low molecular weight heparins are manufactured from unfractionated heparin to
produce materials with an average molecular weight of 4000 – 6500.
All heparins exert their anticoagulant activity by binding to and greatly
accelerating the action of Antithrombin as an inhibitor of thrombin (factor IIa),
factor Xa and other serine protease coagulation factors.
All heparins must be given parenterally either by the intravenous route or by the
subcutaneous route.
The half-life of standard heparin following intravenous route is 45-60 minutes.
Heparins however have complex kinetics depending on the dose, molecular
weights and route of administration.
Low molecular weight heparins demonstrate less to cells and to heparin
neutralizing proteins than the unfractionated heparin. This leads to improved
bioavailability and to a longer half-life. These properties allow a more predictable
anticoagulant response and once daily dosing subcutaneous administration and
there is no need to monitor therapeutic doses with anticoagulation time assays.
Clinical us of unfractionated heparin
Heparin is used in;

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ANTICOAGULANTS AND THROMBOLYTIC DRUGS Haemostasis Vascular injury results firstly in vasoconstriction and formation of platelet plug at the site of injury (primary haemostasis). The platelet plug is then stabilized by the formation of a fibrin meshwork, resulting from activation of the coagulation cascade. Fibrin is eventually cleared through digestion by fibrinolytic enzymes. Primary Haemostasis When endothelial integrity is breached, platelets adhere to exposed subendothelial collagen. The adherent platelets become activated result in; 1) Exposure of fibrinogen receptors, allowing fibrinogen to bind and cross-link adjacent platelets. The process is known as platelet aggregation. The platelet fibrinogen receptor consists of a complex of glycoproteins IIb and IIIa on the platelet membrane. 2) Release of contents of secretory granules including substances such as adenosine diphosphate (ADP) which promote further platelet activation. 3) Synthesis of thromboxane A2 which also acts to promote further platelet activation and vasoconstriction. Activation of the coagulation cascade; The coagulation cascade can be divided into three parts; 1) The common pathway consists of those reactions subsequent to the generation of factor Xa, culminating in the cleavage of fibrinogen by thrombin, with subsequent polymerization of fibrin monomers into fibrin strands. Factor Xa may be generated either by the extrinsic pathway or by the intrinsic pathway. 2) In the extrinsic pathway, tissue fact ...
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