ANTI-COAGULANTS
DR.UZMA RIAZ
Thrombosis
• Venous thrombosis is associated with stasis of blood
• Has small platelet component and large component of fibrin
• Arterial thrombosis is associated with atherosclerosis
-initiated due to endothelial injury leads to atheromatous plaque
formation
• Plaque rupture, platelet adhesion, activation, aggregation initiates
thrombus growth
• Thrombus has large platelet component
• Arterial thrombus may break away, emboli form leads to ischemia
and infarction
Hemostasis
• Spontaneous Arrest of Bleeding from a Damaged Blood Vessel;
This occurs by the following steps
1. Vasospasm
2. Platelet Adhesion
3. Platelet Aggregation
4. Platelet Plug
5. Fibrin Reinforcement of platelet plug
Coagulation
This is the conversion of blood in the liquid form to a solid gel or clot.
Normally there is a balance between Procoagulants (thromboxane,
thrombin, activated platelets etc.) and Anti-coagulants
(heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin)
Whenever this balance is disturbed coagulation occurs:
• Procoagulants > Anticoagulants
• Injury to blood vessel
• Blood stasis
Clotting Factors
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I - Fibrinogen
II - Prothrombin
III - Tissue Thromboplastin
IV - Calcium
V - Proaccelerin
VII - Proconvertin
VIII- Antihemophilic globulin
IX - Christmas Factor
X - Stuart Power Factor
XI - Plasma Thromboplastin anticedent (PTA)
XII - Hageman Factor
XIII -Fibrin-stabilizing factor
INITIATION OF BLOOD COAGULATION
Intrinsic Pathway
Extrinsic Pathway
Blood trauma/ contact with collagen
Tissue trauma
Activation of factor
XII, IX, VIII
Leakage of Tissue Factor
Ca+2, factor VII
X
X
Xa
Ca+2
Ca+2
Prothrombin activator
Prothrombin
activator
Ca+2
Prothrombin
(factor II)
Xa
Thrombin
Prothrombin
(factor II)
Thrombin
Activation of certain factors (VII, II, X and protein C and S) is essential for
coagulation. This activation requires vit K (reduced form)
Classification
A. Parenteral Anti-Coagulants
1. Indirect Thrombin Inhibitors
a) Heparins
i) High Molecular Weight Heparin
Unfractionated Heparin (UFH)
ii) Low Molecular Weight Heparins
Enoxaparin
Dalteparin
Tinzaparin
Reviparin
Danaparoid
2. Direct Thrombin Inhibitors
Hirudin
Lepirudin
Bivalirudin
Argatroban
B. Oral Anti-Coagulants
1. Coumarins
Warfarin
Dicumarol
2. Indanediones
Phenindione
Heparin,History
• McLean, a 2nd year medical student attempting to extract coagulant
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substances from various tissues during a vacation project. But found
instead a powerful anticoagulant. He discovered in 1916 that liver
contains a powerful anticoagulant.
Howell and Holt in 1918 named it heparin because it was
obtained from liver
Occurs in mast cells (richest source of mast cells are lungs, liver and
intestinal mucosa)
Commercial heparin is extracted from porcine intestinal mucosa and
bobine lung
It is a mixture of straight chain anionic (negative charge)
glycosaminoglycan with a wide range of molecular weights
It is strongly acidic because of presence of sulfate and carboxylic
acid groups
Heparin-Kinetics
• Heparin is highly charged, thus crosses cell membranes very poorly,
hence given Parenterally
• Low dose: Subcutaneous
• High Dose: Subcutaneous or IV Injection
• Metabolized by liver, half life depends on dose
Heparin-Mechanism of Action
• Once the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and IIa
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(especially IIa,IXa,Xa), need to be neutralized by Anti-thrombin III (AT III).
Heparin accelerates the interaction of the active clotting factors with AT III.
The negatively charged heparin molecule binds to the positively charged lysine sites
on AT III
This causes a conformational change in AT III and exposing its active arginine site
The serine active sites of the active clotting factors bind to the reactive arginine site
of AT III
The resulting complex is removed by the reticuloendothelial system
This process is accelerated 1000-3000 times by heparin
• The active heparin molecules bind tightly to antihormbin and cause a
conformational change in this inhibitor. The conformational change of
antithrombin exposes its active site for more rapid interaction with the
proteases (the activated clotting factors) Heparin functions as a cofactor for
the antithrombin protease reactio without being consumed. Once the
antithrombin protease complex is formed, heparin is released intact for
renewed binding to more antithrombin.
• Heparin catalyzes the reaction without being consumed
• Once antithrombin-clotting factor complex is formed, heparin is
released for renewed binding to more antithrombin
• High molecular weight Heparins accelerates the inactivation of
clotting factors IIa and Xa.
• Low molecular weight heparins accelerate the inactivation of only
Factor Xa
Mechanism
Heparin
No heparin
Active clotting factors
Active clotting factors
Slow
Antithrombin III
Inactive clotting factors
Fast
Antithrombin
III
+
Heparin
Inactive clotting factors
Character
HMW Heparins
LMW Heparins
Molecular Weight
High
(30000 Daltons)
Low
(5000 Daltons)
Biotransformation
Low
High (90%)
Half Life
Shorter-depends on dose Longer-independent of
dose
Mechanism of Action
Inactivate both factor
IIa and factor Xa
Inactivate only factor Xa
Anti-coagulant effect
More effective
less effective
Monitoring
By aPTT
Adverse
Effects
Can be given once or twice daily
without monitoring, but requires
special assay if necessary
Less chance of
thrombocytopenia and long term
osteoporosis
Excretion
Cleared by the
Reticuloendothelial system
Cleared unchanged by kidneys
Reversal
By protamine
Not fully reversed by protamine
Expense
Not expensive
Expensive
Dose
Response
Use
Less predictable dose response
because of binding to plasma
proteins, macrophages and
endothelial cells
Has a more predictable
dose-response because it
does not bind to plasma
proteins, macrophages, or
endothelial cells.
More effective for
a) Orthopaedic procedures
on lower limb
b) Pulmonary Embolism
c) Unstable Angina
Advantages of LMWH over UFH
• Better subcutaneous bioavailability(70-90%) compared to UFH(20•
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30%)
Longer and more consistent half life: once daily subcutaneous
administration
Since aPTT/clotting times are not prolonged, lab. monitoring is not
needed
Lower incidence of haemorrhagic complications
Appear to have lesser antiplatelet action so less interference with
haemostasiss
Uses of Heparin (Anti-coagulants in General)
1.Treatment & Prevention of Deep Venous Thrombosis in
• Bedridden (Immobilized patients)
• Old people
• Post-operative
• Post-stroke patients
• Leg fractures
• Elective Surgery
2. Ischemic Heart Disease
Unstable angina
After MI
After angioplasty CABG, stent replacement; Prevent recurrence
3. Rheumatic Heart Disease/ Atrial Fibrillation
Warfarin, heparin, low dose aspirin,
Decrease stroke due to emboli
4. Cerebrovascular Diseases
Cerebral Emboli (Prevention of recurrence)
5. Vascular Surgery, Prosthetic heart valves, Hemodialysis
To prevent thromboembolism
6. DIC
Abruptio placenta, malignancies, infections; increased consumption of
clotting factors
Adverse Effects
1.Bleeding(most common)
2. Allergy and Anaphylaxis
3. Increased hair loss, alopecia
4. Long term-Osteoporosis, spontaneous fractures
5. Thrombocytopenia
Heparin-induced Thrombocytopenia HIT)
• 2nd most common side effect after bleeding
• Occurs in 3-5% of patients 5 to 10 days after initiation of therapy
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of standard heparin
Lower incidence in low molecular wt heparin.
In 1/3 of pts is preceded by thrombosis
Can be life-threatening.
Due to production of IgG against complexes of heparin with
platelet (platelet factor 4)
The complexes activate more platelets with the release of more
platelet factor 4 or other cytokines.
This stimulates the formation of more IgG.
This snow-ball effect uses up platelets and also leads to
thrombosis. Systemic bleeding and localized infarction (due to
thrombosis) occur.
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• Once thrombocytopenia is determined, heparin must be stopped.
Direct thrombin inhibitor should be given
• Platelets must NOT be given because they will react with antibody
already being produced against them, causing greater chance of
thrombosis.
Heparin and Pregnancy
• Heparin does not cross the placenta, therefore it must be used
instead of warfarin in cases of requiring anticoagulant therapy in
pregnancy.
• Warfarin crosses the placenta and induces changed in the fetus to
produce the fetal warfarin syndrome – not good.
Contraindications
1. Hypersensitivity
2. Bleeding Disorders like Hemophilia
3. Thrombocytopenia
4-. Intracranial Hemorrhage
5. GIT Ulcerations
6. Threatened abortion
7. Advanced renal or hepatic disease
Antidote –Protamine Sulfate
• Protamine is a highly basic peptide that combines with heparin as
an ion pair to form a stable complex devoid of anticoagulant activity
• Hemorrhage – can be reversed by protamine sulfate titrated so that
1 mg of protamine sulfate is administered for every 100 U of
heparin remaining in the patient.
• Protamine sulfate is also an anticoagulant because it interacts with
platelets, fibrinogen, and other clotting factors – so it can make
hemorrhage worse if more is given than necessary.
Direct Thrombin Inhibitors (DTIs)
• The DTIs bind thrombin without additional binding proteins, such as
anti-thrombin, and they do not bind to other plasma proteins such
as platelet factor 4.
• Hirudin and Bivalirudin bind at both the catalytic or active site of
thrombin as well as at a substrate recognition site
• Argatroban bind only at the thrombin active site
Lepirudin
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Monitored by aPTT
Action independent of antithrombin
Use in thrombosis related to heparin induced thrombocytopenia
No antidote
Adverse effect: Antibody formation against thrombin-lepirudin
complex
Bivalirudin: Inhibits platelet activation also
Use in percutaneous coronary angiography
Argatroban: Used in heparin induced thrombocytopenia with or without
thrombosis
Monitored by aPTT
Dose reduction in liver disease
Oral Anti-Coagulants,History
• Following the report of a hemorrhagic disorder in cattle that resulted
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from the ingestion of spoiled sweet clover silage, Campbell and Link,
in 1939, identified the hemorrhagic agent as bishydroxycoumarin
(dicoumarol).
In 1948, a more potent synthetic congener was introduced as an
extremely effective rodenticide; the compound was named warfarin
as an acronym derived from the name of the patent holder,
Wisconsin Alumni Research Foundation.
Warfarin's potential as a therapeutic anticoagulant was recognized
but not widely accepted, partly due to fear of unacceptable toxicity.
However, in 1951, an Army inductee uneventfully survived an
attempted suicide with massive doses of a preparation of warfarin
intended for rodent control.
Since then, these anticoagulants have become a mainstay for
prevention of thromboembolic disease
Wisconsin Alumni Research Foundation
Coumarin--Warfarin
Warfarin-Pharmacokinetics
1. Rapidly and completely absorbed after oral administration
2. 100% Bioavailability
3. Highly plasma protein bound (99%)
4. Crosses the placenta (teratogenic)
5. Appears in milk; infants given Vitamin K
6. Variable but slow clearance;depends on hepatic P450s
7. Biotransformation by the liver: Oxidation, Glucuronidation
8. Takes 12-16 hours before effect is observed
Vitamin K-Dependent Clotting
Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
No Synthesis
of Functional
Coagulation
Factors
Mechanism of Action
• Coumarins block the Gamma Carboxylation of glutamic acid residues
of Clotting factors II,VII, IX, X as well as the endogenous anticoagulants C & S.
• This is coupled with oxidative deactivation of Vitamin K
• Coumarins and Indanediones inhibit the enzyme Vitamin K
epoxide reductase that converts Vitamin K epoxide back into the
active hydroquinone (reduced form)
• Thus they prevent the activation of Vitamin K and hence along with
it carboxylations of clotting factor residues
Why Carboxylation is necessary?
• Carboxylation is necessary for ability of clotting factors to bind Ca
and to get bound to phospholipid surfaces which is necessary
for coagulation
• Factor VII affected first, then IX, X, and finally Factor II (depends
upon half lives of circulating factors)
H
N
Glu residues
in prothrombin
O
H
N
O
H
COOH
COOH
COOH
O
OH
CH3
CH3
vitamin K
hydroquinone
Gla residues
in prothrombin
O
vitamin K
2,3-epoxide
R
R
O
OH
vitamin K
reductase
vitamin K
epoxide
reductase
O
CH3
R
O
vitamin K
Anticoagulant coumarins
and 1,3-indandiones
Uses
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Same as Heparin and other Anticoagulants
Monitoring necessary because of its low therapeutic index
PT (Prothrombin time is noted; time taken for blood to clot)
Patients on Heparin are shifted to oral warfarin after 3-5 days
Adverse Effects
1. Bleeding
Most common and most serious adverse effect;
Epistaxis, hematuria, GIT Bleeding, internal hemorrhages
2. Cutaneous Necrosis
This is due to decreased activity of Protein C
Protein C and Protein S found in bone & other tissues also require
Gamma carboxylations
3. Infarction of breast, fatty tissues, intestine and extremities due to
venous thrombosis caused by again decreased activity of Protein C
Antidote of Warfarin
• Stop Warfarin
• Give Vitamin K (Antidote)
• Also Fresh frozen plasma, Prothrombin complex concentrates and
Recombinant factor VIIa can be administered
Contraindications
1. Pregnancy
Fetal protein in bone and blood affected
-Causes birth defects including abnormal bone formation, bone
hyperplasia
-CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal
death may occur
2. Other contraindications same as heparin
Drug Interactions of Warfarin
A.Pharmacokinetic Interactions
1. Agents that inhibit metabolism of warfarin
• Cimetidine
• Imipramine
• Cotrimoxazole
• Chloramphenicol
• Ciprofloxacin
• Metronidazole
• Amiodarone
2. Drugs that increase metabolism of Warfarin
• Barbiturates
• Rifampin
3. Drugs that displace warfarin from binding sites on
plasma albumin
• Chloral hydrate
• NSAIDs
4. Drugs that decrease GIT absorption of warfarin
• Cholestyramine
B. Pharmacodynamic Interactions
1. Synergistic effect
• Heparin
• Aspirin
• Antibiotics: Decrease bacterial flora—decrease Vitamin K synthesis—
increased warfarin effect
Physiological/Pathological Factors affecting
Warfarin Action
1. Increased warfarin action
• Malnutrition, debility (Decreased Vit. K)
• Liver disease, chronic alcoholism (Decreased clotting
factors)
• Hyperthyroidism (Increased degradation of Clotting
factors)
• Newborns (Decreased vitamin K)
2. Decreased Warfarin Action
• Pregnancy (Increased clotting factors)
• Nephrotic syndrome
• Warfarin resistance (Genetic)
Character
HEPARIN
WARFARIN
Route of
Administration
Parenteral
Oral
Polarity
Polar charged molecule
Uncharged
Onset of Action
Rapid
12-16 Hours
Mechanism of Action Accelerates inactivation
of clotting factors by
Antithrombin III
Inhibits gamma
Carboxylation of glutamic
acid residues of clotting
factors
Therapeutic Index
Not low; safe
Low; not safe
Monitoring
aPTT
PT
Adverse Effect
Differences
Thrombocytopenia,,Oste
oporosis, alopecia,
anaphylaxis
Cutaneous Necrosis,
Infarction of breast, fatty
and other tissues
Management of Patient
Start with Heparin
Switch over to warfarin
in 3-5 days
Antidote
Protamine Sulfate
Vitamin K
Contraindication
Not
Pregnancy
Interactions
Not significant
Significant