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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
No change in PT
Defective Intrinsic Pathway
No change in APTT
Prolonged PT
Defective Extrinsic Pathway
Prolonged APTT
Prolonged PT
Defective in Common pathway
Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Tissue Factor
XIIa
XII
Thromboplastin
XIa
XI
IXa
IX
Xa
X
Factors affected
By Heparin
VIIa
Prothrombin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Fibrinogen
XIII
VII
X
Thrombin
Fribrin monomer
Fibrin polymer
Activation
XIIa
Inactive XI
Active XIa
+
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
Anticoagulant
Parenteral
Prototype
Heparin
Action
Inactivation of clotting
Factors
Effect
Prevent venous
Thrombosis
Anticoagulant Warfarin Decrease synthesis of
Oral
Clotting factors
Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase Fibinolysis
Decrease platelet
aggregation
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
NAD
NADH
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 interactionprototype Warfarin
Category
Drugs that Increase
Warfarin Activity
Mechanism
Representative Drugs
Decrease binding to
Albumin
Aspirin, Sulfonamides
Inhibit Degradation
Cimetidine, Disulfiram
Decrease synthesis of
Clotting Factors
Antibiotics (oral)
Drug interactionprototype Warfarin
Drugs that promote
bleeding
Drugs that decrease
Warfarin activity
Inhibition of platelets
Aspirin
Inhibition of clotting
Factors
heparin
antimetabolites
Induction of metabolizing
Enzymes
Barbiturates
Phenytoin
Promote clotting factor
Synthesis
Reduced absorption
Vitamin K
OC
cholestyramine
colestipol
Fibrinolysis
Enhance degradation of clots
 Activation of endogenous protease
 Plasminogen (inactive form) is
converted to Plasmin (active form)
 Plasmin breaks down fibrin clots

Fibrinolysis

Exogenously administered drugs




Streptokinase - bacterial product - continuous use
- immune reaction
Urokinase - human tissue derived - no immune
response
Tissue plasminogen activator (tPA) - genetically
cloned - no immune reaction - EXPENSIVE
Inhibitors of fibrinolysis - aminocaproic acid

Lysine analog- inhibits proteases
Drug preparations : To
reduce clotting
 Heparin


Parenteral - 1000 - 40,000 U/ml
Warfarin (generic , Coumadin)


(generic, Liquaemin sodium)
Oral : 2 - 20 mg tablets
Dipyridamole (Persantine)

Oral : 25,50,75 mg tablets
Drug preparations :
to lyse clots

Alteplase recombinant (tPA, Activase)


streptokinase (Kabikinase, streptase)


20, 50 mg Lyophilized powder - reconstitute for iv
Parenteral : 250000 - 1.5 million units per vial .
Lyophilized powder. Reconstitute for iv
Urokinase ( Abbokinase)

Parenteral : 250000 units per vial. Powder to
reconstitute to 5000 u/ml for injection
Drug preparations
: clotting deficiencies

Vitamin K ( Phytonadione (K1), Mephyton


Plasma fractions - for hemophilia



Antihemophilic factor ( VIII, AHF)
Parenteral
Factor IX complex (konyne HT, proplex T)


Oral : 5 mg tablets
Parenteral : in vials
Due to HIV risks in blood products
recombinant proteins of the factors are made.

E.g. transgenic goats secreting factors into milk
Drug
preparations : to
stop bleeding
Systemic use : aminocaproic acid (Amicar);
Tranexamic acid (cyclokapron),Vitamin K
 Local adsorbable drugs






Gelatin sponge (Gelfoam)
Gelatin film
Oxidized cellulose ( Oxycel)
Microfibrillar collagen (Avitene)
Thrombin