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Antithrombics, Anticoagulants &
Antiplatelets
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Introduction
• Haemostasis is the arrest of blood loss from
damaged blood vessels and is essential to life.
• A wound causes vasoconstriction, accompanied
by:
 adhesion and activation of platelets
 formation of fibrin.
• Platelet activation leads to the formation of a
haemostatic plug, which stops the bleeding and is
subsequently reinforced by fibrin.
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The Coagulation and Fibrinolytic Pathways
Kohler H and Grant P. N Engl J Med 2000;342:1792-1801
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Antithrombics & Anticoagulants
• Drugs affect haemostasis and thrombosis in
three distinct ways, by influencing:
blood coagulation (fibrin formation)
platelet function
fibrin removal (fibrinolysis)
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Anticoagulants
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II: Parenteral anticoagulants
• Heparin
• Low molecular weight heparins
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Heparins
• Heparin is mucopolysaccharides.
• Commercial preparations are extracted from beef
lung or hog intestine.
• Heparin fragments (e.g. enoxaparin, dalteparin)
or a synthetic pentasaccharide (fondaparinux),
are referred to as low-molecular-weight heparins
(LMWHs),
• LMWHs are often used in place of unfractionated
heparin, which is reserved for special situations
such as patients with renal failure in whom
LMWHs are contraindicated
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HEPARIN
• Heparin inhibits coagulation by activating antithrombin III
which inturn inhibits thrombin and other serine proteases
• The LMWHs increase the action of antithrombin III on
factor Xa but not its action on thrombin, because the
molecules are too small to bind to both enzyme and
inhibitor,
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DRUG TARGETS
• Unfractionated
heparin(UFH)
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Unfractionated Heparin
• High Dose
– Treatment of venous/arterial thrombi
– Requires monitoring
– IV- 5,000 Units bolus, then 30,000-35,000
units/24 hrs
– 80 Units/kg bolus, then 18 Units/kg/hr to
maintain aPTT in therapeutic range
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Uses of low Dose Unfractionated Heparin
• Surgical Prophylaxis
– 5,000 Units SQ 2 hr preop
– 5,000 Units SQ every 12 hours
• Medical Prophylaxis
– 5,000 Units SQ every 12 hours
• No monitoring required
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DRUG TARGETS
• LOW MOLECULAR
WEIGHT
HEPARIN(LMWH)
• Enoxaparin
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Indications for and Contraindications to
some Parenteral Anticoagulant Agents
Anticoagulant Agent
Class
Approved & Appropriate
Indications
Contraindication
Unfractionated heparin
Antithrombin III
inhibitor
Treatment of venous
thromboembolism or unstable
angina; used when rapid reversal is
important
? Prophylactic treatment
Enoxaparin
(Lovenox)
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Dalteparin
(Fragmin)
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism or
unstable angina
Low-molecularweight heparin
Prophylaxis in moderate-risk or
high-risk patients, treatment of
venous thromboembolism
Tinzaparin
(Innohep)
Regional anesthesia
Pregnancy
Prosthetic Heart Valves
Regional anesthesia
Regional anesthesia
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Indications for and Contraindications to
some Parenteral Anticoagulant Agents (cont’d)
Ardeparin
Low-molecular-weight
heparin
Approved; not being
marketed
Regional anesthesia
Lepirudin
Hirudin derivative
Heparin-induced
thrombocytopenia with
thrombosis
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Argatroban
Direct thrombin inhibitor
Heparin-induced
thrombocytopenia with
thrombosis
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Danaparoid
Heparinoid
Prophylaxis against
thrombosis in heparininduced
thrombocytopenia
Thrombocytopenia other
than heparin-induced
thrombocytopenia
Bivalirudin
Hirudin derivative
Unstable angina or
angioplasty
Unknown
Fondaparinux
Synthetic factor Xa
inhibitor
Prophylaxis in highrisk patients?
Unknown
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Heparin-Antibiotic Interactions
•
The second-generation cephalosporins- cefamandole,
cefotetan, and cefoperazone, contain an Nmethylthiotetrazole (NMTT) side chain. This NMTT
group can:
•
- Dissociate from the parent antibiotic in solution or in vivo
and competitively inhibit vitamin K action, leading to
prolongation of the prothrombin time and bleeding.
•
- This side chain is also associated with a disulfiram-like
reaction to alcohol.
•
- Clinical bleeding has been less frequently reported with
Cefotetan than with cefoperazone or cefamandole.
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Monitoring of Heparin therapy
s.q. – no monitoring required
i.v. - partial thromboplastin time (P.T.T.) or
ACTIVATED PARTIALTHROMBOPLASTIN
TIME aPTT
*daily or more frequent if PTT varies
mechanism – measures intrinsic pathway
Toxicity = UFH – Protamine
LMWH – Protamine not fully effective
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Side Effects Of Heparin
Heparin induced thrombocytopenia
Bleeding
Hypersensitivity
Osteoporosis
Monitor aPTT & platelet count
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Stead L and Judson K. N Engl J Med 2006;355:e7
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HEPARIN
Adverse Reaction
Hemorrhage
Treatment
Reduce The Dose
Discontinue The Drug
Protamine Sulfate
Transfusion
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Therapy of HIT
• There are two recommended approaches:
– Use of the heparinoid danaparoid
– The direct thrombin inhibitor lepirudin (recombinant
hirudin)
– Based upon the data published to date, either
danaparoid or lepirudin should be used to treat HIT that
is complicated by thrombosis; these agents should also
be considered for prophylactic therapy in patients with
HIT without thrombosis until the platelet count has
recovered
– HIT=HEPARIN INDUCED THROMBOCYTOPENIA
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Oral Anticoagulant
Heparin
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Role of Vitamin K
• The Vitamin K dependent clotting factors are
carboxylated in a reaction that is linked to the
oxidation of the reduced form of the vitamin .
• The non carboxylated forms of these clotting factors
are inactive because they cannot bind calcium.
• When Vitamin K is deficient, non-carboxylated
prothrombin is secreted and this protein is non
functional.
• Carboxylation of terminal glutamic acid side chains
(known as the Glu to Gla conversion) allows the
clotting factors to bind calcium which in turn bridges
the clotting factors to phospholipid surfaces, a
necessary requirement for their activity to coagulation
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The four Vitamin K dependent clotting factors are synthesized in
the liver.
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In short……
• Warfarin inhibits vitamin K epoxide reductase
component 1 (VKORC1), thus inhibiting the reduction
of vitamin K epoxide to its active hydroquinone form
• The effect of warfarin takes several days to develop
because of the time taken for degradation of
preformed carboxylated clotting factors.
• Onset of action thus depends on the elimination halflives of the relevant factors. Factor VII, with a half-life
of 6 h, is affected first, then IX, X and II, with half-lives
of 24, 40 and 60 h, respectively.
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Monitoring of Warfarin therapy
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Thrombolytic agents
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Thrombolytic agents
• When the coagulation system is activated, the fibrinolytic
system is also set in motion via several endogenous
plasminogen activators, including tissue plasminogen
activator (tPA), urokinase-type plasminogen activator,
kallikrein and neutrophil elastase.
• Plasminogen is deposited on the fibrin strands within a
thrombus.
• Plasminogen activators cleave plasminogen, a zymogen
present in plasma, to release plasmin
• Plasmin is trypsin-like, acting on Arg-Lys bonds, and thus
digests not only fibrin but fibrinogen; factors II, V and VIII; and
many other proteins.
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Thrombolytic agents (2)
• Its action is localised to the clot, because
plasminogen activators are effective mainly on
plasminogen adsorbed to fibrin; any plasmin
that escapes into the circulation is inactivated
by plasmin inhibitors, including PAI-1 which
protect us from digesting ourselves from
within.
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Streptokinase
• Streptokinase is a protein extracted from cultures
of streptococci.
• It activates plasminogen.
• Infused intravenously, it reduces mortality in
acute myocardial infarction, and this beneficial
effect is additive with aspirin.
• Its action is blocked by antibodies, which appear
4 days or more after the initial dose: its use
should not be repeated after this time has
elapsed.
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• Alteplase and duteplase are, respectively, singleand double-chain recombinant tPA.
• They are more active on fibrin-bound
plasminogen than on plasma plasminogen, and
are therefore said to be 'clot selective'.
• Recombinant tPA is not antigenic, and can be
used in patients likely to have antibodies to
streptokinase.
• Because of their short half-lives, they must be
given as intravenous infusions.
• Reteplase is similar but has a longer elimination
half-life, allowing for bolus administration and
making for simplicity of administration. It is
available for clinical use in myocardial infarction.
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Unwanted Effects And
Contraindications
• bleeding, including gastrointestinal
haemorrhage and haemorrhagic stroke.
• If serious, this can be treated with tranexamic
acid , fresh plasma or coagulation factors.
• Streptokinase can cause allergic reactions and
low-grade fever.
• Streptokinase causes a burst of plasmin
formation, generating kinins and can cause
hypotension by this mechanism.
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Contraindications
•
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active internal bleeding,
haemorrhagic cerebrovascular disease,
bleeding diatheses,
pregnancy,
uncontrolled hypertension,
invasive procedures in which haemostasis is
important
• recent trauma-including vigorous
cardiopulmonary resuscitation.
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Clinical use
• The main use is in acute myocardial infarction,
with ST segment elevation on the ECG within 12 h
of onset (the earlier the better!).
• Other uses include:
– - acute thrombotic stroke within 3 h of onset (tPA), in
selected patients
– - clearing thrombosed shunts and cannulae
– - acute arterial thromboembolism
– - life-threatening deep vein thrombosis and pulmonary
embolism (streptokinase, given promptly).
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Antiplatelets
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Platelet Adhesion And Activation
• When platelets are activated, they undergo a sequence of
reactions that are essential for haemostasis, important for
the healing of damaged blood vessels, and play a part in
inflammation
• These reactions include:
 adhesion following vascular damage (via von Willebrand
factor bridging between subendothelial macromolecules
and glycoprotein [GP] Ib receptors on the platelet surface)
 shape change (from smooth discs to spiny spheres with
protruding pseudopodia)
 secretion of the granule contents (including platelet
agonists, such as ADP and 5-hydroxytryptamine, and
coagulation factors and growth factors, such as plateletderived growth factor)
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Platelet Adhesion And Activation(2)
 biosynthesis of labile mediators such as plateletactivating factor and thromboxane (TX)A2
 aggregation, which is promoted by various agonists,
including collagen, thrombin, ADP, 5hydroxytryptamine and TXA2, acting on specific
receptors on the platelet surface; activation by agonists
leads to expression of GPIIb/IIIa receptors that bind
fibrinogen, which links adjacent platelets to form
aggregates
 exposure of acidic phospholipid on the platelet surface,
promoting thrombin formation (and hence further
platelet activation via thrombin receptors and fibrin
formation via cleavage of fibrinogen;.
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Antiplatelet Drugs
• They decrease platelet aggregation and inhibit
thrombus formation in the arterial circulation
where the thrombi is mainly of platelets and
little fibrin
• Includes:
Aspirin,Abciximab,Clopidogrel,Dipyridamole,
Eptifibatide,Pasugrel,Ticagrelor,Tirofiban
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Aspirin
• Aspirin: This is a salicylate
• Salicylates inhibit biosynthesis of
prostaglandins by binding covalently and
irreversibly to the enzyme cyclo-oxygenase.
• Very low doses of aspirin may selectively block
thromboxane synthesis without affecting
prostacyclin
• Inhibition of synthesis of thromboxanes will
prevent platelet aggregation and thrombus
formation
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Aspirin
• Low-dose aspirin profoundly (> 95%) inhibits platelet TXA2
synthesis, by irreversible acetylation of a serine residue in
the active site of cyclo-oxygenase I (COX-I).
• Clinical trials have demonstrated the efficacy of aspirin in
several clinical settings
• Adverse effects of aspirin, mainly on the gastrointestinal
tract, are, however, clearly dose related, so a low dose
(often 75 mg once daily) is usually recommended for
thromboprophylaxis.
• Thromboprophylaxis is reserved for people at high
cardiovascular risk (e.g. survivors of myocardial infarction),
in whom the cardiovascular benefit of aspirin usually
outweighs the risk of gastrointestinal bleeding.
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Dipyridamole
• Dipyridamole inhibits platelet aggregation by several
mechanisms, including inhibition of
phosphodiesterase, block of adenosine uptake into red
cells and inhibition of TXA2 synthesis.
• studies shows that a modified-release form of
dipyridamole reduced the risk of stroke and death in
patients with transient ischaemic attacks by around
15%-similar to aspirin (25 mg twice daily).
• The main side effects of dipyridamole are dizziness,
headache and gastrointestinal disturbances; unlike
aspirin, it does not increase the risk of bleeding
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Ticlopidine
• It belongs to ADENOSINE (P2Y) RECEPTOR
ANTAGONISTS (THIENOPYRIDINES)
• It inhibits ADP-induced platelet aggregation by
irreversible inhibition of P2Y12 receptors
• It causes neutropenia and thrombocytopenia
and is now little used
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Clopidogrel
• It also belongs to ADENOSINE (P2Y) RECEPTOR ANTAGONISTS
(THIENOPYRIDINES)
• Clopidogrel is well absorbed when administered by mouth,
and in urgent situations is given orally as a loading dose of 300
mg followed by maintenance dosing of 75 mg once daily.
• It is a prodrug and is converted into its active sulfhydryl
metabolite by CYP enzymes in the liver including CYP2C19.
• Poor metabolisers are at increased risk of therapeutic failure.
• Potential for interaction with other drugs, such as omeprazole
, that are metabolised by CYP2C19
• Clopidogrel can cause dyspepsia, rash or diarrhoea.
• The serious blood dyscrasias caused by ticlopidine are very
rare with clopidogrel
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Clopidrogel induced TTP
• It can cause TTP (thrombotic
thrombocytopenic purpura) manifested as:
Thrombocytopenia
Microangiopathic hemolytic anemia
Fever
Neurologic changes
Renal abnormalities
Case rate 3.7/year/million
Mortality 10-20%
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Glycoprotein Iib/Iiia Receptor Antagonists
• They prevent platelet aggregation by blocking the binding of
fibrinogen to receptors of platelets.
• Abciximab is a monoclonal antibody which binds to glycoprotein
Iib/IIIa receptors and other related sites.
• It is licensed for use in high-risk patients undergoing coronary
angioplasty, as an adjunct to heparin and aspirin.
• It reduces the risk of restenosis at the expense of an increased risk
of bleeding.
• Immunogenicity (thrombocytopenia)limits its use to a single
administration.
• Tirofiban is a synthetic non-peptide and eptifibatide is a cyclic
peptide based on the Arg-Gly-Asp ('RGD') sequence that is common
to ligands for GPIIb/IIIa receptors.
• Given intravenously as an adjunct to aspirin and a heparin
preparation, they reduce early events in acute coronary syndrome,
• long-term oral therapy with GPIIb/IIIa receptor antagonists is not
effective and may be harmful.
• Unsurprisingly, they increase the risk of bleeding.
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Epoprostenol (PGI2),
• Epoprostenol (PGI2), an agonist at prostanoid IP
receptors , causes vasodilatation as well as inhibiting
platelet aggregation.
• It is added to blood entering the dialysis circuit in order
to prevent thrombosis during haemodialysis, especially
in patients in whom heparin is contraindicated.
• It is unstable under physiological conditions and has a
half-life of around 3 min, so it is administered by an
intravenous infusion pump.
• Adverse effects related to its vasodilator action include
flushing, headache and hypotension.
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ANTIPLATELET THERAPY
• Aspirin: Primary prevention of MI in high risk
persons
Secondary prevention of MI,TIA & stroke
• Clopidogrel: for persons who can’t take aspirin
• Aspirin+clopidogrel: Acute coronary
syndromes
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Summary of uses of fibrinolytic &
antiplatelet drugs
Fibrinolytic agents and aspirin are used in
therapy of acute myocardial infarction the
sooner these agents are given after onset the
better.
 The preferred fibrinolytic agent is
streptokinase except where there has been
severe streptococcal infection or previous
treatment with streptokinase
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• Aspirin reduces the risk of occlussive
cardiovascular disease in patients who have
recovered from myocardial infarction or have
unstable angina.
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Aspirin
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Clinical use of antiplatelet drugs
• The main drug is aspirin. Other drugs with distinct actions (e.g.
dipyridamole, clopidogrel) can have additive effects, or be used in
patients who are intolerant of aspirin.
• Uses of antiplatelet drugs relate mainly to arterial thrombosis and
include:
 AMI
 high risk of myocardial infarction, including a history of MI, angina
or intermittent claudication
 following coronary artery bypass grafting
 unstable coronary syndromes (clopidogrel is added to aspirin)
 following coronary artery angioplasty and/or stenting (intravenous
glycoprotein IIb/IIIa antagonists, e.g. abciximab, are used in some
patients in addition to aspirin)
 transient cerebral ischaemic attack ('ministrokes') or thrombotic
stroke, to prevent recurrence (dipyridamole can be added to
aspirin)
 atrial fibrillation, if oral anticoagulation is contraindicated.
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END
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