ANTICOAGULANTS

By: Dr. Punita Vasani

Assistant prof.
GAIMS, BHUJ.
 CLOTTING FACTORS
I. Fibrinogen VIII. Antihemophilic factor A
II. Prothrombin IX. Christmas factor
III. Tissue factor (Thromboplastin) X. Stuart-prower factor
IV. Calcium
XI. Plasma thromboplastin antecedent
V. Labile factor (Proaccelerin)
XII. Hageman factor
VI. Unassigned
XIII. Fibrin-stabilizing factor
VII. Stable factor (Proconvertin)
6
 Anticoagulant proteins :
Procoagulant factors: Antithrombin
Factors II,V, Protein C and S
VII,IX,XI, Antithromboplastin
Fibrinolysin system
 HAEMOSTASIS - cessation of blood loss
 Blood must remain fluid within the vasculature and yet clot quickly when
exposed to subendothelial surfaces at sites of vascular injury.
 The process of forming clots in the walls of damaged blood vessels:

Vascular phase

Platelet phase

Coagulation phase

Fibrinolytic phase
VASCULAR PHASE
PLATELET PHASE
COAGULATION PHASE
FIBRINOLYTIC PHASE
 Endothelial
injury

Transient VC

Primary haemostatic plug Expose to collagen & vWF (platelet plug)

Secondary haemostatic plug Tissue factor (coagulation cascade, definitive clot

Clot stabilization & resorption t- PA, Thrombomodulin

 THROMBOSIS

 The formation of an unwanted clot within a blood vessel

 most common abnormality of haemostasis

 Arterial thrombosis:  Venous thrombosis:

 Adherence of platelets to  Develops in areas of
arterial walls stagnated blood flow (DVT)
 “White” in color  “Red” in color
(fibrin + platelets) (fibrin + RBCs)
 Associated with ischemia, MI  Associated with Congestive
& stroke heart failure (CHF), cancer &
surgery
 Thrombus dislodge from arteries & veins  become an embolus

 Venous emboli can block arterioles in pulmonary circulation 

thromboembolism

 Thrombotic disorders:
 Acute myocardial infarction (MI)
 Deep-vein thrombosis (DVT)
 Pulmonary embolism
 Acute ischemic stroke

 These are treated with drugs such as:

 anticoagulants, fibrinolytics & antiplatelets
 COAGULATION PHASE
Two major pathways: Intrinsic & Extrinsic

13 soluble factors are involved in clotting → several of these steps

require Ca++ & platelet phospholipid
Biosynthesis of these factors occurs in liver → Vitamin K is
needed for the synthesis of factor II, VII, IX and X
Most of these factors are proteases

Normally inactive & sequentially activated

Hereditary lack of clotting factors lead to Hemophilia-A

 Intrinsic Pathway Extrinsic Pathway
(in vitro/vivo - slow) (in vivo - rapid)
Activated by contact Tissue injury

XII XIIa Tissue Factor

(Thromboplastin)
XI XIa
VIIa VII
IX IXa
PL, Ca2+
VIIIa PL, Ca2+

X Xa X XIII
Va PL,Ca2+

Factors affected Prothrombin Thrombin

XIIIa
by Heparin Stabilization

Vitamin K dependent factors: Fribrin Fibrin polymer

Fibrinogen
affected by Oral Anticoagulants monomer
 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 Common pathway
Prolonged PT
 COAGULANTS

Coagulants are the drugs that promote coagulation and

control bleeding.
• They are also called hemostatic agents.
• These drugs are of two types
– Systemic coagulants.
– Local coagulants (styptics).
 COAGULANTS

Systemic coagulants Local coagulants (styptics)

1. Vitamin-K 1. Adrenaline (0.1 % solution)

2. Ethamsylate 2. Fibrin
3. Desmopressin 3. Gelatin foam
4. Rutin 4. Thrombin
5. Fibrinogen 5. Oxidized cellulose
6. Adrenochrome
monosemicarbazone
7. Anti-hemophillic factor
 Systemic coagulants

Vitamin-K
• Vitamin K (Coagulation vitamin) is essential for the coagulation
process.

• It is not directly involved in the clotting process but required for the
synthesis of four clotting factors in the liver: Factor II,VII,IX and X.
• It occurs naturally in two forms:
– Phylloquinone (K1) from plant source and
– Menaquinone (K2) which is synthesized by colonic bacteria (E.coli)
in the colon.
• K3 is the synthetic form and is available as
– Fat-soluble forms (Menadione,
Acetomenaphthone) and
– water-soluble forms (Menadione sod. Bisulfate and Menadione
sod. Diphosphate).
• Dietary sources:
– Green leafy vegetables such as cabbage, spinach and liver, cheese,
cereals, nuts, and egg yolk etc.
– Wheat germ oil is the richest source.

• Physiological functions:
– Vit-K is essential for formation of clotting factor-II, VII, IX, X,
protein-C & S.
 Deficiency Symptoms

• Vit-K is only temporarily concentrated in liver and this store can be

exhausted within one week.
• The deficiency of vit-K occurs due to liver disease, obstructive
jaundice, malabsorption, long-term antimicrobial therapy, which alters
intestinal flora.
• The most important manifestation is bleeding tendency due to
lowering of the levels of prothrombin and other clotting factors in
blood.
• Haematuria is usually first to occur; other common sites of bleeding
are gastrointestinal tract, nose and under the skin where it presents in
the form of haemorrhagic spots.

• Recommended dietary allowance (RDA)

– Normal adult requirement is 50–100 μg/day.
– As it can be synthesized in the colon, even 3–10 μg/day may be
sufficient.
 Vit-K use:
• For prevention of haemorrhagic disease of the newborn: All newborns
especially premature infants have low levels of prothrombin and other
clotting factors.

– Vit- K: 1 mg IM soon after birth has been recommended

routinely.
– Alternatively, 5–10 mg IM to the mother 4–12 hours before delivery
can be given.
– Patients on prolonged antimicrobial therapy.
– As an antidote in overdose of oral anticoagulants.
– In patients suffering from liver disease (cirrhosis, viral hepatitis).
• Patients with obstructive jaundice or malabsorption syndromes
(sprue, regional ileitis, steatorrhoea, etc).
– The therapy given is Vit-K 10 mg IM/day, or orally along with
bile salts for better absorption.

• Menadione (K3) should not be used in patients with G-6-PD

deficiency.

• In the newborn menadione or its salts can precipitate

kernicterus.
 Intrinsic Pathway Extrinsic Pathway
(in vitro/vivo - slow) (in vivo - rapid)
Activated by contact Tissue injury

XII XIIa Tissue Factor

(Thromboplastin)
XI XIa
VIIa VII
IX IXa
PL, Ca2+
VIIIa PL, Ca2+

Xa
Recall X
Va PL,Ca2+
X XIII

Factors affected Prothrombin Thrombin

XIIIa
by Heparin Stabilization

Vitamin K dependent factors: Fribrin Fibrin polymer

Fibrinogen
affected by Oral Anticoagulants monomer
Classification

Edoxaban
 Parenteral anticoagulants
• A. Parenteral anticoagulants
– (i) Indirect thrombin inhibitors :
• Heparin,
• Low molecular weight heparins,
• Fondaparinux, Danaparoid
– (ii) Direct thrombin inhibitors :
• Lepirudin, Bivalirudin, Argatroban
 Unfractionated Heparin
and
Low-Molecular-Weight Heparin
 Heparin

• In 1916, McLean discovered an anticoagulant substance in liver.

• In 1918, Howell and Holt named it heparin (due to its extraction from
liver).

• In 1937, heparin was used in clinical practice after extracting the

purified form.

• It is a strong organic acid having molecular weight of 10,000-30,000 Da.

• As it is present in the mast cells, it is normally present in all
body tissues, which contain mast cells.

• Commercially, it is obtained from pig intestinal

mucosa & ox lung.

• It acts as anticoagulant both in vivo & vitro.

• It is also known as unfractionated heparin (UFH).

Unfractionated Heparin
 Mechanism of action
• Heparin binds to antithrombin III (natural endogenous anticoagulant)
and heparin-antithrombin- III complex is formed.(suicide inhibitor)

• This heparin-antithrombin-III complex inactivates the clotting factors of

both intrinsic & common pathway (XIIa, XIa, IX, Xa, XIIIa, II) by
binding to them.(low dose only intrinsic – aPTT)

• Thus, the anticoagulant effect is exerted mainly by inhibition of

factor Xa & thrombin mediated conversion of fibrinogen to fibrin
(refer coagulation cascade).
 Coagulation Cascade
Intrinsic Pathway Extrinsic Pathway
(surface contact) (tissue factor)

XIIa
VIIa
XIa
Heparin / LMWH
(AT-III dependent)
IXa
Hirudin
Xa (direct antithrombin)
aPTT Thrombin (IIa)
PT
Thrombin-Fibrin
Clot

Courtesy of VTI
• Heparin enhances the action of AT-III in two ways:
A. The long heparin molecule provides a scaffolding

B. Heparin induces conformational change in AT-III to expose its

interactive sites.

• A specific pentasaccharide sequence binds to AT III with high

affinity to induce the conformational change needed for rapid
interaction with clotting factors. This has been synthesized and
named fondaparinux.
• Inhibition of IIa requires both the mechanisms, but Xa inhibition can
occur by mechanism ‘b’ alone.
Pharmacological effects of heparin

• As anticoagulant
• As antiplatelet agent: by inhibiting the platelet aggregation.
• By activating lipoprotein lipase from the vessels wall & tissues, it
acts as lipaemia clearing agent.
 Pharmacokinetics
• It is not absorbed by oral route due to its large size & highly ionized
nature.
• Therefore, it is given by IV route (acts immediately) and subcutaneous
route (acts within an hour).
• It does not cross BBB & placenta. Hence, can be given safely in
pregnancy.
• It is metabolized in liver by heparinase enzyme and excreted through
kidneys.
• The plasma t ½ is 1-2 hours and is dose dependent.
• It is prolonged in kidney & liver diseases and shortened in pulmonary
embolism.
• However UFH is safer than LMW heparins or fondaparinux in kidney
failure patients.
 Dose
 Adult: 5000–10,000 IU, IV bolus followed by 750–1000 IU/hr IV
infusion.
 Children: 50–100 IU/kg.
 A quick penetrating solution (QPS) formulation of heparin 1000 u/ml
has been recently developed for topical application to speed up healing
of post-infusion superficial thrombophebitis.
 Low dose (s.c.) regimen 5000 U of UFH is injected s.c. every 8–12
hours, started before surgery and for 7–10 days or till the patient starts
moving about. Prevent DVT, not prolong aPTT. Not to be used in
neurosurgery, spinal anaesthesia, ineffective in hip jt / pelvic surgery.
 Indications

• Prevent catheter thrombosis → cardiopulmonary bypass surgery

• Prophylaxis of postoperative venous thrombosis, Pulmonary
embolism.
• Rx of Deep venous thrombosis.

• Unstable angina and Post MI.

• To maintain patency of cannulae and shunts in dialysis pt.

 Adverse effects
• First clinical sign of adverse effect of heparin is: hematuria.
• The other side effects are
– bleeding
– Heparin induced thrombocytopenia (HIT) : Ab to heparin-platelet
complex formed. Discontinue & treat with direct thrombin inhibitor
– Transient reversible alopecia
– Osteoporosis
– rarely hypersensitivity reaction.
• Heparin induced thrombocytopenia
• PLATELET COUNT: <1.5 lac/cumm or 50% decrease in pretreatment
value
• 5-10 days after initiation of therapy.
• IgG antibodies to heparin+PF4
• Life threatening thrombotic complication (even after cessation) can occur
• Rx – discontinue heparin/LMWH
• Bivalirudin, Argatroban, Rivaroxaban
 Contraindications of UFH
• Bleeding disorders, h/o - HIT.
• Severe hypertension
• Subacute bacterial endocarditis (risk of embolism), large
malignancies (risk of bleeding in the central necrosed area of the
tumour), tuberculosis (risk of haemoptysis).
• Threatened abortion, piles, g.i.ulcers ( risk of aggravated bleeding).
• Ocular and neurosurgery, lumbar puncture.
• Chronic alcoholics, cirrhosis, renal failure.
• Aspirin and other antiplatelet drugs should be used very cautiously
during heparin therapy.
Low-molecular-weight heparin
Enoxaparin, Dalteparin, Ardeparin, Nadroparin, Reviparin,
Parnaparin

• Heparin has been fractionated into LMW forms (MW 3000–7000)

• They act only by inducing conformational change in AT III and not
by providing a scaffolding for interaction of AT III with thrombin.
So, selectively inhibit factor Xa with little effect on IIa.
• Lesser effect on aPTT and CT.
• Primarily excreted bykidney so not to be used in renal failure.
Unfractionated Heparin
Low-molecular-weight heparin
Advantages of LMWH over UH

• Better subcutaneous bioavailability (70–90%) compared to UFH

(20–30%): Variability in response is minimized.
• Longer and more consistent monoexponential t½ (4–6 hours);
making possible once daily s.c. administration.
• Since aPTT/clotting times are not prolonged, laboratory
monitoring is not needed.
• dose is calculated on body weight basis.
• Risk of osteoporosis after long term use is much less with LMW
heparin compared with UFH.
 Protamine sulfate (heparin antagonist)
• It is a strong base and obtained from fish sperm.
• Protamine sulfate acts as an antidote for heparin overdose (UFH)
and is given in a dose of 1 mg IV for every 100 IU of heparin.
• It is used after cardiovascular surgeries when it has been
administered in higher doses and the action needs to be terminated
rapidly.
• Does not neutralize fondaparinux & partially to LMWH
Fondaparinux
 Fondaparinux
• Pentasaccharide ,bind to AT-III, confirmational change in factor Xa
without binding thrombin.
• It is a synthetic derivative of heparin.
• It has pharmacological similarity to LMWHs with longer plasma half-life
(17-21 hours).
• It has 100% bioavailability. 5-10mg SC, OD.
• The adverse effects like thrombocytopenia & osteoporosis are even
lesser than LMWHs.
• Lab monitoring of aPTT not required
• Indicated for DVT, PE, ACS
 Danaparoid
• It is a mixture of heparin like natural substances (heparan
sulfate)

• It is obtained from pig intestinal mucosa.

• It is used in patient with heparin induced thrombocytopenia

(HIT) as an alternative therapy.
DIRECT THROMBIN INHIBITORS
(DTIs)
( Bivalirudin, Argatroban)
 • Bivalirudin
• Synthetic analogue of hirudin (salivary gland of leech).
• binds firmly to the catalytic as well as the substrate recognition sites
of thrombin and inhibits it directly. Thus, it does not need AT-III
to exert its action.
• It has fast onset & offset of action due to proteolysis and renal
excretion.
• No risk of HIT, not antagonized by protamine.
• Indication: PCI (percutaneous coronary intervention) for STEMI
with an antiplatelet drug, UA - urgent PCI and for pt. at risk of HIT.
 Argatroban

• Binds to catalytic site of thrombin & not to substrate recognition site.

• It is a reversible direct thrombin inhibitor and given by IV infusion.
• It is used in-patients with heparin-induced thrombocytopenia as an
alternative therapy.
• Prolongs aPTT – dose regulation by INR
• Cleared by liver, can be given in renal diseases pt.
 ORAL ANTICOAGULANTS

 Vit K antagonists: coumarin

derivatives
 Act (only in vivo) by
inhibiting synthesis of
clotting factors.
 inhibit the enzyme vit K
epoxide reductase (VKOR)
PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS

COAGULATION FACTORS HALF-LIFE (h)

II 60
VII 4-6
IX 24
X 48-72
Protein –C 8
Protein- S 30

Peak anticoagulant effect may be delayed by 72 to 96 hours

 Why to add concomitant parenteral anticoagulation ?

 Delayed onset of action, concomitant parenteral anticoagulant should

be given in pts with established thrombosis or high risk for thrombosis.

 Warfarin monotherapy decreases the levels of two endogenous

anticoagulants, proteins C and S, thus increasing thrombogenic
potential. Overlapping warfarin for at least 5 days with an
immediately effective parenteral anticoagulant counteracts the
procoagulant effect of unopposed warfarin.
 Monitoring
• B/z of narrow therapeutic window of warfarin
• Standard procedure is to check the PT-INR as follows:
INR daily until it is in therapeutic range

3 times weekly for 2 weeks

Once stable & warfarin dose is known INR every 3-4

weeks or more frequently if introduction of any new
medication
Drug interactions
 Indications
• Atrial fibrillation
• Prosthetic heart valve
• Venous thromboembolism
• Primary pulmonary hypertension
• Rarely after Acute MI
(If associated with high risk of thromboembolism e.g. AF, mobile or
pedunculated mural thrombus or prior venous thromboembolism)
 Side effects of Warfarin

 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
 Osteoporosis
 Bleeding
• Most common complication
• In form of
• Mild: epistaxis, hematuria
• Severe: Retroperotoneal or gastrointestinal bleeding
• Life-threatening : Intracranial bleed
• Rate of major bleeding (defined as any visit to hospital for
hemorrhage) is 1- 3% per person-year
• Half of the complications occurs because INR exceeds
therapeutic range
• Can be minimized by keeping INR in therapeutic range
Symptomatic pts with raised INR
SYMPTOMS INTERVENTION
Mild bleeding Withhold warfarin

Severe bleeding Vit K 10 mg slow i/v infusion ± FFP (15

ml/kg)
Life threatening bleeding or pt can’t tolerate Prothrombin complex concentrate (II,IX & X)
volume overload
Prosthetic valves pts Vit K should be strictly avoided, unless there is life
threatening intracranial bleed (Valve thrombosis)

Subcutaneous Vit K gives variable results and should be avoided

 Teratogenicity

• Occurs in 3.5 – 6 %
• Depends on time of gestation and dose of warfarin given
• Usually in first trimester of pregnancy
• It causes characteristic embryopathy consist of :
• Nasal hypoplasia and
• Chondrodysplasia punctata (epiphyseal and vertebral bone stippling)
• Cleft lip and (or) palate
• Choanal stenosis/atresia
• Central nervous system abnormalities
• Coarctation of aorta (Rare malformations described following first
trimester exposure to warfarin)
• Occurs especially if warfarin dose is > 5 mg/day
Lateral view X-ray showing calcifications and irregular ossification of lumbar
and sacral vertebrae, consistent with warfarin embryopathy
 ACENOCOUMAROL (acitrom)
• Same as warfarin with following differences:
– Shorter half life 10-16 hrs
– More rapid onset of action
– Shorter duration of action (2 days)
– Causes GI disturbances, oral ulcerations and dermatitis
• 4 mg on day one, 4-8 mg on the day 2nd then maintenance
dose 1-8 mg according to response by PT test
Newer Oral Anticoagulants

Oral XaIs
Rivaroxaban
Apixaban
Edoxaban
Warfarin

oDTIs
Dabigatran
Warfarin Vs newer oral anticoagulants (direct Xa / IIa inhibitors)

Warfarin Oral XaIs / oDTIs

• Slow onset & offset of effect • Rapid onset & offset of therapeutic effect
• Long half life • Short half life
• PT INR monitoring req. • Lab. monitoring not req.
• More drug interactions. • Fewer drug interactions
• Risk of bleeding • Lower risk of bleeding
• Narrow therapeutic range • Antithrombotic efficacy equal to / better
than warfarin.
• Fixed dosage guidelines depending on
indication.
 Rivaroxaban (Xarelto)

• Direct factor Xa inhibitor

• Half life: 7 - 9 hours
• 2/3rd of rivaroxaban is metabolized by CYP3A4 system in liver
• A/E : beeding, nausea,hypotension, tachycardia & oedema
• ( Xarelto – 2.5, 10, 15, 20 mg )
 Rivaroxaban (Xarelto)

• For Px of DVT and PE 6-10 hrs after surgery – 10mg OD

• TKR – 12 days
• THR – 35 days
• For Rx of DVT and PE (3 months) → 15mg BD → 20mg OD
• For preventing stroke in pts with AF.
• For Px of ACS – 2.5 mg with aspirin & clopidogrel.
 Apixaban (Eliquis)

• Direct factor Xa inhibitor

• Half life – 12 hours
• BA -85%
• Should not be used in hepatic and renal impairement
• Uses: Px of VTE, stroke in AF patients
• Rx of DVT and PE
Newer Oral Anticoagulants

Oral XaIs
Rivaroxaban
Apixaban
Edoxaban
Warfarin

oDTIs
Dabigatran
 Dabigatran etexilate (Pradaxa)
• Oral Direct thrombin (factor IIa) inhibitor
• Prodrug
• Dabigatran etexilate → dabigatran
• Rapid anticoagulant effect within 2 hrs
• It is a substrate for P-gp.
• For prevention of VTE following hip/knee jt. replacement surgery –
110mg OD Uses
• Prevention of embolism & stroke in pts of AF
• A/E – bleeding less, dyspepsia
• Reversal agent - idarucizumab
 Anticoagulant drugs to treat thromboembolism

Drug Class Prototype Action Effect

Anticoagulant Heparin Inactivation of clotting Prevent venous
Parenteral Factors Thrombosis

Anticoagulant Warfarin Decrease synthesis of Prevent venous

Oral Clotting factors Thrombosis

Prevent arterial
Antiplatelet Aspirin Decrease platelet
Thrombosis
drugs aggregation

Thrombolytic Streptokinase Fibinolysis Breakdown of

Drugs thrombi
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