Anticoagulants and Thrombolytics
S. Ramakrishnan
Objectives
To learn how Blood Clots are formed.
How the blood clots are broken down ?
What drugs can be used to regulate clotting ?
How to rectify clotting deficiencies
Blood clots - Thrombus
Thrombus dislodge from arteries and veins and become an embolus.
Venous emboli can block arterioles in the lung and pulmonary circulation
Thromboembolism
Classes of Drugs
Prevent coagulation
Dissolve clots
Prevent bleeding and hemorrhage - Hemostatic
Overcome clotting deficiencies ( replacement therapies)
Blood Clotting
Vascular Phase
Platelet Phase
Coagulation Phase
Fibrinolytic Phase
Vascular Phase
Vasoconstriction
Exposure to tissues activate Tissue factor and initiate coagulation
Tissue Factor
Platelet phase
Non-nucleated - arise from magakaryocytes
blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation
platelets contain receptors for fibrinogen and von Willebrand factor
after vessel injury Platelets adhere and aggregate.
Release permeability increasing factors (e.g. vascular permeability factor, VPF)
Loose their membrane and form a viscous plug
Platelets and Thromboemolism
Arteries : White Thrombus
Platelets adhere
Release ADP
More adhesion/ aggregation
Reduced blood flow (stasis)
Fibrin clot
Veins low pressure : Red thrombus is formed
Especially in valve pockets
Contains a long tail of fibrin
Can detach and form emboli
Coagulation Phase
Two major pathways
Intrinsic pathway
Extrinsic pathway
Both converge at a common point
13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent on Vitamin K1 and K2
Most of these factors are proteases
Normally inactive and sequentially activated
Hereditary lack of clotting factors lead to hemophilia -A
Intrinsic Pathway
All clotting factors are within the blood vessels
Clotting slower
Activated partial thromboplastin test (aPTT)
Extrinsic Pathway
Initiating factor is outside the blood vessels - tissue factor
Clotting - faster - in Seconds
Prothrombin test (PT)
Prothrombin time (PT)
Tissue Thromboplastin factor III
Mix with phospholipid extract
Add calcium and blood sample
Determine clotting time
Generally 12 - 14 seconds
Used to detect defects in extrinsic pathway
Activated partial thromboplastin time (APTT)
Blood sample + EDTA or Citrate
No clot ( recalcification will result in clot in about 2 - 4 min)
Add calcium
Mix with negatively charged phospholipid
Kaoline (aluminum silicate)
Determine clotting time
Generally clotting occurs in 26 to 33 seconds
Used to detect defects in the intrinsic pathway
Diagnosis of coagulation defects
Prolonged APTT Defective Intrinsic Pathway
No change in PT
No change in APTT Defective Extrinsic Pathway
Prolonged PT
Prolonged APTT Defective in Common pathway
Prolonged PT
Blood Vessel Injury
IX
IXa
XI
XIa
X
Xa
XII
XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa
VII
X
Prothrombin
Thrombin
Fibrinogen
Fribrin monomer
Fibrin polymer
XIII
Intrinsic Pathway
Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Activation
Inactive XI
Active XIa
XIIa
+
Thrombosis
Arterial Thrombosis :
Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia
Venous Thrombosis :
Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated with Congestive Heart Failure, Cancer, Surgery.
Anticoagulant drugs to treat thromboembolism
Drug Class Prototype Action Effect
Anticoagulant
Parenteral
Heparin
Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin
Decrease synthesis of
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin
Decrease platelet
aggregation
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase
Fibinolysis
Breakdown of
thrombi
Heparin
Sulphated carbohydrate
Purified from bovine lungs
Different size
Active in vitro and in vivo
Administration - parenteral- Do not inject IM - only IV or deep s.c.
Half-life 1 - 5 hrs - monitor aPTT
Adverse effect - hemorrhage - antidote - protamine sulphate
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Oral anticoagulants : warfarin, dicumarol
Coumarins - warfarin, dicumarol
Isolated from clover leaves
Structurally related to vitamin K
Inhibits production of active clotting factors
Absorption rapid - binds to albumin
Clearance is slow - 36 hrs
Delayed onset 8 - 12 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late pregnancies
Mechanism of action
Descarboxy Prothrombin
Prothrombin
Reduced Vitamin K
Oxidized Vitamin K
NADH
NAD
Warfarin
Antiplatelet drugs
Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve replacement and shunts
Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine
Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)
Inhibits platelet aggregation
Prophylactic use of Aspirin
Low dose daily ( 180 mg/day)
Prevents ischemic attack (ministroke) and MI
335 mg/day reduced the risk of heart attack in patients over 50
More than 1000 mg/day NO EFFECT
High dose inhibits prostacyclin synthesis in cells surrounding vessels. PS normally prevents platelet aggregation. Therefore, inhibition of PS leads to abrogation of the prophylactic benefit of Aspirin
Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency
Drug interaction- prototype Warfarin
Drugs that Increase
Warfarin Activity
Decrease binding to
Albumin
Inhibit Degradation
Decrease synthesis of
Clotting Factors
Aspirin, Sulfonamides
Cimetidine, Disulfiram
Antibiotics (oral)
Category Mechanism Representative Drugs
Drug interaction- prototype Warfarin
Drugs that promote
bleeding
Inhibition of platelets Aspirin
Inhibition of clotting heparin
Factors antimetabolites
Drugs that decrease
Warfarin activity
Induction of metabolizing Barbiturates
Enzymes Phenytoin
Promote clotting factor Vitamin K
Synthesis OC
Reduced absorption cholestyramine
colestipol
Fibrinolysis
Enhance degradation of clots
Activation of endogenous protease
Plas