coagulation cascade coagulants and anticoagulants fibrinolytics antiplatelets

1. COAGULANTS AND
Presenter:
Dr.Roohana Hasan
Moderator:
Dr.D.A.Rizvi

2. Overview
Introduction
Coagulation Cascade
Fibrinolysis
Natural Anticoagulants
Coagulants
Anticoagulants
Newer Anticoagulants
Fibrinolytics
Antiplatelets

3. • Hemostasis is the cessation of blood loss from a
damaged vessel.
Vascular Spasm
Platelet Plug
Formation
Blood
Coagulation
Wound causes vasoconstriction
which prevents blood loss
Starts with Platelet Adhesion (to the
exposed collagen of the damaged
endothelium)
Followed by Platelet Aggregation (by
loosing their individual membrane and
forming a gelatinous mass- Platelet Plug
loose initially but tightens when reinforced
by fibrin)

4. • Thrombosis is a pathological condition
resulting from inappropriate activation of
haemostatic mechanisms:
– - venous thrombosis is usually associated with
stasis of blood; a venous thrombus has a small
platelet component and a large component of
fibrin
– - arterial thrombosis is usually associated with
atherosclerosis, and the thrombus has a large
platelet component.
• A portion of a thrombus may break away,
travel as an embolus and lodge downstream,
causing ischaemia and/or infarction.

7. VIIa
Prothrombinase

8. • This system provides check and balances so
that clotting process does not go out of hands.
• It dissolves clots at the site of damage once
the damage is repaired.
• The process of dissolution of the clot is called
Fibrinolysis.
Fibrinolytic System

9. FIBRINOGEN
Fibrin degraded products
Thrombin

10. Natural Anticoagulant Mechanisms
Prostacyclin (PGI2)- a metabolite of arachidonic acid,
produced by endothelial cells.
Opposes the action of TXA2
Inhibits the platelet aggregation and release
Antithrombin III (AT3)- a plasma protein.
Blocks the action of factor XII, XI, IX, X and II

11. Protein C- plasma protein
Inactivates Factor VIII and V – not blocked by AT3
Enhances the activity of t-PA.
It is a Vitamin K endogenous anticoagulant which is activated by
thrombin through binding to its receptor Thrombomodulin.
• Heparan Sulfate- a proteoglycan related to
heparin, synthesized by endothelial cells.
Serves as a Cofactor
Enhances the activity of Antithrombin III

13. These are substances which promote
coagulation, and are indicated in
haemorrhagic states.
Fresh whole blood or plasma provide all the
factors needed for coagulation and are the
best therapy for deficiency of any clotting
factor; also they act immediately.

14. Classification
Vitamin K
K1 (from plants, fat-
soluble) : Phytonadione
(Phylloquinone)
K2 : Menaquinone
K3 (Synthetic) :
Fat Soluble- Menadione,
Acetomenaphthone
Water-soluble- Menadione
sod. bisulfite ,Menadione
sod. diphosphate
Miscellaneous
• Plasma Fractions- VIII, IX
and mixed factors
• Antifibrinolytics-
Aminocaproic Acid,
Trenexamic acid
• Aprotinin
• Fibrinogen (human)
• Antihaemophilic factor
• Desmopressin
• Adrenochrome
monosemicarbazone
• Rutin,
• Ethamsylate

15. • It is a fat-soluble dietary principle required for
the synthesis of clotting factors II
(prothrombin), VII, IX, and X.
• Vitamin K is a fat soluble vitamin found in
green leafy vegetables, such as cabbage,
spinach; and liver, cheese, etc.
Vitamin K

16. -Vitamin K and its Analogues
Natural Vitamin K or Phytonadione
•Obtained from leafy vegetables.
•Can be given orally or by IV injection.
•Rapid onset and prolonged effect.
•Requires bile salts for absorption.
•Deficiency can occur in obstructive jaundice and any
disease involving mal absorption of fats.

17. • Vitamin K2 or Menaquinone- synthesized by
intestinal flora.
• Hence, prolonged inhibition of growth of
iintestinal bacteria from antibiotic therapy can
lead to deficiency of Vitamin K.
• Vitamin K3 or Menadione- synthetic water
soluble analogue.
• Bile salts are not needed for absorption, can be
given orally in case of obstructive jaundice.

18. Mechanism of Action

19. • Dietary deficiency: of vit K is very rare in adults.
However, when it occurs 5–10 mg/day oral or
parenteral vit K rapidly corrects the defects.
• Prolonged antimicrobial therapy: treat in the
same way as dietary deficiency of vit K.
• Obstructive jaundice or malabsorption
syndromes (sprue, regional ileitis, steatorrhoea,
etc.): vit K 10 mg i.m./day, or orally along with
bile salts.
Indications

20. • Liver disease (cirrhosis, viral hepatitis):
• Newborns: All newborns have low levels of
prothrombin and other clotting factors.
 The cause is both lower capacity to synthesize
clotting factors as well as deficiency of vit K.
 The defect is exaggerated in the premature infant.
 Vit K 1 mg i.m. soon after birth has been
recommended routinely.
 Some prefer administering 5–10 mg i.m. to the
mother 4–12 hours before delivery.
 Haemorrhagic disease of the newborn can be
effectively prevented/treated.

21. • Overdose of oral anticoagulants:
 Phytonadione (K1) is the preparation of choice, because it
acts most rapidly; dose depends on the severity of
hypoprothrombinaemia (measured INR) and bleeding.
 Severe: 10 mg i.m. followed by 5 mg 4 hourly; bleeding
generally stops in 6–12 hours, but normal levels of
coagulation factors are restored only after 24 hr. This dose
of vit K will block anticoagulant action for 7–10 days.
 Moderate: 10 mg i.m. followed by 5 mg once or twice
according to response.
 Mild: Just omit a few doses of the anticoagulant.
• Prolonged high dose salicylate therapy causes
hypoprothrombinemia; vit K should be given
prophylactically. If bleeding occurs—treat as for oral
anticoagulants.

22. Adverse Effects
• Phytonadione injected i.m. or given orally hardly
produces any adverse effect; allergic reactions
are rare.
• Anaphylactic Reaction
• Hemolysis- in G6PD deficient patient.
• In the newborn menadione or its salts can
precipitate kernicterus:
by inducing haemolysis and increasing bilirubin
load.
by competitively inhibiting glucuronidation of
bilirubin. Glucuronide conjugation is, as such,
inadequate in neonates.

23. • Desmopressin- It releases factor VIII and von
Willebrand’s factor from vascular endothelium
and checks bleeding in haemophilia and von
Willebrand’s disease.
• Fibrinogen- The fibrinogen fraction of human
plasma is employed to control bleeding in
haemophilia, antihaemophilic globulin (AHG)
deficiency and acute afibrinogenemic states;

24. • Antihaemophilic factor- It is concentrated human
AHG prepared from pooled human plasma.
It is indicated (along with human fibrinogen) in
haemophilia and AHG deficiency.
It is highly effective in controlling bleeding
episodes, but action is short-lasting (1 to 2 days).
• Adrenochrome monosemicarbazone- It is
believed to reduce capillary fragility, control
oozing from raw surfaces and prevent
microvessel bleeding, e.g. epistaxis, haematuria,
secondary haemorrhage from wounds, etc.

25. • Ethamsylate- It reduces capillary bleeding when
platelets are adequate; probably exerts
antihyaluronidase action or corrects
abnormalities of platelet adhesion, but does not
stabilize fibrin (not an antifibrinolytic).
Ethamsylate has been used in the prevention and
treatment of capillary bleeding in menorrhagia,
after abortion, PPH, epistaxis, malena, hematuria
and after tooth extraction.
 Side effects are nausea, rash, headache, and fall
in BP (only after i.v. injection).

26. • Aprotinin- inhibits plasmin, kallikrein and
platelet activation .
Used for hyperplasminemia caused by
fibrinolytic drug overuse and to prevent blood
loss from cardiac bypass surgery.
Rutin -It is a plant glycoside claimed to reduce
capillary bleeding.

28. Drugs affecting Coagulation
Classes Drugs
Parenteral
• Indirect thrombin inhibitors
• Direct thrombin inhibitors
Heparin, LMWH and fondaparinux
Lepirudin, Bivalirudin and
Argotroban
Indandione
Phenindione
Anticoagulants

29. Heparin & its derivatives
• Heparin, a glycosaminoglycan found in the secretory
granules of mast cells is synthesized from UDP-sugar
precursors as a polymer of alternating D-glucuronic acid
and N-acetyl-D-glucosamine residues
• Heparin is artificially extracted from porcine intestinal
mucosa which is rich in mast cells.
Heparin derivatives are
fragments of heparin
ranging in molecular weight
from 1-10 kDa.
LMWH preparations differ
from heparin and, to a
lesser extent, from each
other in their
pharmacokinetic properties.

30. Mechanism of Action:
Heparin binding to antithrombin 3 induces a
conformational change in antithrombin that
renders its reactive site more accessible to
the target protease
Antithrombin inhibits activated coagulation
factors (Xa, IIa, IXa, XIa, XIIa and XIIIa)in the
intrinsic and common pathways
This induces a conformational change in the
reactive center loop of antithrombin that
accelerates its interaction with factor Xa and
IIa . To potentiate thrombin inhibition
At low concentrations of heparin, factor Xa
mediated conversion of prothrombin to
thrombin is selectively affected. The
anticoagulant action is exerted mainly by
inhibition of factor Xa as well as thrombin (IIa)
mediated conversion of fibrinogen to fibrin.
Inhibition
of
Thrombin

31. Other Pharmacological Properties:
• High doses of heparin can interfere with
platelet aggregation and thereby prolong
the bleeding time.
• Lipoprotein lipase hydrolyzes triglycerides
to glycerol and free fatty acids.
• Heparin "clears" lipemic plasma in vivo by
causing the release of lipoprotein lipase
into the circulation

32. LMWH
• Predominat effect on factor
Xa
• LMWHs have greater anti-
factor Xa activity than anti-
IIa activity, and the ratio
ranges from 3:1 to 2:1
depending on the
preparation.
• Given by subcutaneous
route and have a greater half
life

33. Fondoxiparinux
• It is a synthetic
derivative of heparin
• It causes selective
inhibition of factor Xa
without binding
thrombin
• Does not show any
effect on thrombin itself
due to its shorter
polymer length
• It has lesser antiplatelet
effect hence chances of
bleeding in minimal.

34. LMWH preparations
• Enoxaparin
• Dalteparin
• Tinzaparin
• Ardeparin
• Nadroparin
• Reviparin
Not absorbed through the GI mucosa and
therefore must be given parenterally.
LMWH and fondaparinux are absorbed more
uniformly after subcutaneous injection.
Heparin appears to be cleared and degraded
primarily by the reticuloendothelial system; a
small amount of undegraded heparin also
appears in the urine.

35. Toxicity and Adverse Events
• Bleeding
– Major bleeding occurs in 1-5% of patients treated with intravenous
heparin for venous thromboembolism
– Incidence of bleeding is proportionate to the degree of prolongation of
the aPTT
If life-threatening hemorrhage occurs, the effect of heparin can be
reversed quickly by the intravenous infusion of protamine sulfate, a
mixture of basic polypeptides isolated from salmon sperm. Protamine
binds tightly to heparin and thereby neutralizes its anticoagulant effect.
• Heparin-Induced Thrombocytopenia:
– Heparin-induced thrombocytopenia (platelet count <150,000/mL or a
50% decrease from the pretreatment value) occurs in 0.5% of medical
patients 5-10 days after initiation of therapy with heparin
• Abnormalities of hepatic function test
• Risk of osteoporosis is lower with LMWHs or fondaparinux than it is
with heparin

36. Contraindications
• Bleeding disorders, history of heparin induced
thrombocytopenia.
• Severe hypertension (risk of cerebral haemorrhage),
threatened abortion, piles, g.i. ulcers (risk of
aggravated bleeding).
• Subacute bacterial endocarditis (risk of embolism),
large malignancies (risk of bleeding in the central
necrosed area of the tumour), tuberculosis (risk of
hemoptysis).
• Ocular and neurosurgery, lumbar puncture.
• Chronic alcoholics, cirrhosis, renal failure.
• Aspirin and other antiplatelet drugs should be used
very cautiously during heparin therapy.

37. Protamine Sulfate
• The effect of heparin can be reversed quickly by the
intravenous infusion of protamine sulfate, a mixture of basic
polypeptides isolated from salmon sperm. Protamine binds
tightly to heparin and thereby neutralizes its anticoagulant
effect
• Dose: 1 mg of Protamine Sulfate for 100 U of Heparin
• Protamine only binds long heparin molecules.
• Therefore, protamine only partially reverses the anticoagulant
activity of LMWHs and has no effect on that of fondaparinux.
Heparin Antagonist

38. Parenteral Anticoagulants
• Hirudin is a specific irreversible inhibitor of
thrombin obtained from salivary gland of Leech.
• Lepirudin is the recombinant form of Hirudin.
• Used as an anticoagulant in hepain induced
thrombocytopenia and associated
thromboembolic disease.
• It has an off-labelled use in prevention of
ischemic complications associated with unstable
angina.
• Side effects- heamorrhage, heamaturia and
increased transaminase.

39. Other Parenteral Anticoagulants
Drug Mechanism Uses
Drotrecogin
Alfa- human
recombinant
protein C
inhibitor of Va and VIIIa Used as an anticoagulant and decrease
mortality risk from severe sepsis.
Desirudin A direct thrombin inhibitor Desirudin is indicated for the prophylaxis of
DVT in patients undergoing elective hip
replacement surgery
Bivalirudin A direct thrombin inhibitor Used as an alternative to heparin in patients
undergoing percutaneous coronary
angioplasty or cardiopulmonary bypass
surgery.
Argatroban A direct thrombin inhibitor used in heparin induced thrombocytopenia.
Higher risk of bleeding, monitoring of aPTT
and PT
Danaparoid Inhibits activation of factor
Xa
Used for the treatment of heparin induced
thrombocytopenia and postoperative DVT

40. DIRECT FACTOR Xa INHIBITORS
Rivaroxaban and Apixaban
• It is an orally active direct inhibitor of activated factor Xa which has
become available for prophylaxis and treatment of DVT.
• Its anticoagulant action develops rapidly within 3–4 hours of
ingestion and lasts for ~24 hours.
• It requires no laboratory monitoring of PT or aPTT, and is
recommended in a fixed dose of 10 mg once daily starting 6–10
hours after surgery for prophylaxis of venous thromboembolism
following total knee/hip replacement.
• In comparative trials, its efficacy has been found similar to a
regimen of LMW heparin followed by warfarin.
• Rivaroxaban has also been found equally effective as warfarin for
preventing stroke in patients with atrial fibrillation.
• Side effects reported are bleeding, nausea, hypotension,
tachycardia and edema.

41. ORAL DIRECT THROMBIN INHIBITOR
Dabigatran etexilate
• It is a prodrug which after oral administration is rapidly hydrolysed
to dabigatran,a direct thrombin inhibitor which reversibly blocks the
catalytic site of thrombin and produces a rapid (within 2 hours)
anticoagulant action.
• In the UK, Canada and Europe it is approved for prevention of
venous thromboembolism following hip/knee joint replacement
surgery.
• Administered in a dose of 110 mg (75 mg for elderly > 75 years)
once daily, it has been found comparable to warfarin.
• In another large trial dabigatran etexilate 150 mg twice daily has
yielded superior results to warfarin for prevention of embolism and
stroke in patients of atrial fibrillation.
• In the USA it is approved for this indication. Adverse effects are
bleeding and less commonly hepatobiliary disorders.

42. Oral Anticoagulants
Warfarin and
related compounds:
Chemically various
derivatives of 4-
hydroxycoumarin are
available and have
activity as vitamin K
antagonists

43. Mechanism of Action
They inhibit the enzyme vit
K epoxide reductase
(VKOR) and interfere with
regeneration of the active
hydroquinone form of vit
K which acts as a cofactor
for the enzyme γ-glutamyl
carboxylase that carries
out the final step of γ
carboxylating glutamate
residues of prothrombin
and factors VII, IX and X

44. Pharmacological Properties
• The usual adult dosage of warfarin is 2-5 mg/day for 2-4
days, followed by 1-10 mg/day as indicated by
measurements of the international normalized ratio (INR)
• Because of the long t1/2 of some of the coagulation
factors, in particular factor II, the full anti-thrombotic
effect of warfarin is not achieved for several days.
• Warfarin also can be given intravenously without
modification of the dose. Intramuscular injection
is not recommended because of the risk of
hematoma formation.

45. Drug Polymorphism:
• Polymorphisms in two genes, CYP2C9 and
VKORC1(vitamin K epoxide reductase
complex, subunit 1) account for most of
the genetic contribution to the variability
in warfarin response
CYP2C9 Pharmacokinetics Common variations in the
CYP2C9 gene are associated
with higher drug
concentrations and reduced
warfarin dose requirements
VKORC1 Pharmacodynamics Polymorphism in VKORC1
explains 30% of the
variability in warfarin dose
requirements.

46. Uses
• 1.Treatment & Prevention of Deep Venous
Thrombosis in- • Bedridden (Immobilized
patients) • Old people • Post-operative • Post-
stroke patients • Leg fractures • Elective Surgery
• Ischemic Heart Disease Unstable angina -After MI
After angioplasty CABG, stent replacement;
Prevent recurrence
• Rheumatic Heart Disease/ Atrial Fibrillation
Warfarin, heparin, low dose aspirin, Decrease
stroke due to emboli

47. • Cerebrovascular Diseases- Cerebral Emboli
(Prevention of recurrence)
• Vascular Surgery, Prosthetic heart valves,
Retinal vessel thrombosis, Extracorporeal
circulation, Hemodialysis To prevent
Thromboembolism
• Defibrination syndrome or DIC- Abruptio
placenta, malignancies, infections; increased
consumption of clotting factors

48. Adverse Effect and Toxicities:
• Haemorrhage:
– INR should be maintained between 2-3 and risk of bleeding is
potentiated beyond INR 3.
– Risk of Intracranial haemorrhage, GI bleeding, intraperitoneal,
retroperitoneal increases
– Vitamin K supplementation(iV/oral) is required when INR >5 with
temporary discontinuation of drug
• Birth defects:
– Administration of warfarin during pregnancy causes birth defects
and abortion.
– A syndrome characterized by nasal hypoplasia and stippled
epiphyseal calcifications that resemble chondrodysplasia punctata
may result from maternal ingestion of warfarin during the first
trimester
• Skin necrosis: Rare
• Purple Toe Syndrome: painful, blue-tinged discoloration of the
plantar surfaces and sides of the toes that blanches with
pressure and fades with elevation of the legs.

49. Contraindications
• Hypersensitivity
• Bleeding Disorders like Hemophilia
• Thrombocytopenia
• Intracranial Hemorrhage
• GIT Ulcerations
• Threatened abortion
• Advanced renal or hepatic disease

50. Other Vitamin K Antagonists
Phenprocoumon It has a longer plasma t1/2 (5 days) than
warfarin, as well as a somewhat slower
onset of action and a longer duration of
action (7-14 days).
Acenocoumarol It has a shorter t1/2 (10-24 hours), a more
rapid effect on the PT, and a shorter
duration of action (2 days). The
maintenance dose is 1-8 mg daily.
Indandione It is similar to warfarin in its kinetics of
action, has higher chances of
Hypersensitivity

51. Indandione Derivatives
• Anisindione (MIRADON) is available for clinical
use in some countries.
• It is similar to warfarin in its kinetics of action but
offers no clear advantages and may have a higher
frequency of untoward effects.
• Phenindione (DINDEVAN) still is available in some
countries.
• Serious hypersensitivity reactions, occasionally
fatal, can occur within a few weeks of starting
therapy with this drug, and its use can no longer
be recommended

52. FIBRINOLYTICS (Thrombolytics)
• These are drugs used to lyse thrombi/clot to
recanalize occluded blood vessels (mainly
coronary artery).
• They are therapeutic rather than prophylactic
and work by activating the natural fibrinolytic
system .

53. Streptokinase
• Streptokinase was the first thrombolytic agent approved
for clinical use, and it has been used extensively.
• Streptokinase is a purified bacterial protein isolated from
Lancefield group C strains of b-hemolytic streptococci.
• This produces a conformational change that exposes the
active site on plasminogen that cleaves Arg560 on free
plasminogen to form plasmin.
• Due to its bacterial origin, streptokinase stimulates an
immune response and the production of antibodies in
humans. Because circulating (neutralizing) antibodies can
inactivate the drug, streptokinase cannot be re-
administered for at least 6 months

54. Tissue Plasminogen Activator and
R-tpa
• It is a poor plasminogen activator in the absence of fibrin
• t-PA activates fibrin-bound plasminogen several
hundredfold more rapidly than it activates plasminogen in
the circulation
• Alteplase(ACTIVASE) is produced by recombinant DNA
technology.
• The currently recommended regimen for coronary
thrombolysis
– 15-mg intravenous bolus, followed by
– 0.75 mg/kg of body weight over 30 minutes
– 0.5 mg/kg (up to 35 mg accumulated dose) over the
following hour
• Reteplase: is a recombinant form of TPA having a longer
half life.

55. • Tenecteplase -This genetically engineered
substitution mutant of native t-PA has higher
fibrin selectivity, slower plasma clearance (longer
duration of action) and resistance to inhibition by
PAI-1.
• It is the only fibrinolytic agent that can be
injected i.v. as a single bolus dose over 10 sec,
while alteplase requires 90 min infusion.
• This feature makes it possible to institute
fibrinolytic therapy immediately on diagnosis of
ST segment elevation myocardial infarction
(STEMI),

56. Urokinase:
• It is a protease enzyme obtained from human
urine and is now produced by cultured human
kidney cells.
• It is a direct plasminogen activator and
degrades both fibrinogen and fibrin.
• Half life is 20 min
• It has more fibrin specificity than
Streptokinase.

57. Hemorrhagic Toxicity of Thrombolytic
Therapy
• The major toxicity of all thrombolytic agents is hemorrhage,
which results from two factors:
1) The lysis of fibrin in hemostatic plugs at sites of vascular injury,
and
2) The systemic lytic state that results from systemic plasmin
generation, which produces fibrinogenolysis and degradation
of other coagulation factors (especially factors V and VIII).
• Intracranial hemorrhage is by far the most serious problem.
Hemorrhagic stroke occurs with all regimens and is more
common when heparin is used

58. Uses of fibrinolytics
• Acute myocardial infarction
• Deep vein thrombosis
• Pulmonary embolism
• Peripheral arterial occlusion
• Stroke

59. Contraindicatons

60. Inhibitors of Fibrinolysis
• Aminocaproic Acid
– Aminocaproic acid is a lysine analog that competes for lysine
binding sites on plasminogen and plasmin, blocking the interaction
of plasmin with fibrin.
– Aminocaproic acid is thereby a potent inhibitor of
fibrinolysis and can reverse states that are associated
with excessive fibrinolysis.
– For intravenous use, a loading dose of 4-5 g is given
over 1 hour, followed by an infusion of 1-1.25 g/hour
until bleeding is controlled.
– No more than 30 g should be given in a 24-hour period.
– Rarely, the drug causes myopathy and muscle necrosis.

61. Tranexamic Acid
• Tranexamic acid is a lysine analog
that, like aminocaproic acid, competes
for lysine binding sites on plasminogen
and plasmin, thus blocking their
interaction with fibrin.
• The FDA approved oral tranexamic
acid tablets for treatment of heavy
menstrual bleeding in 2009.
• When used for this indication,
tranexamic acid usually is given at a
dose of 1 g four times a day for 4 days.

63. AVE5026
• Ultralow-molecular-weight heparin with a
mean molecular weight of 2400
• Primarily targets fXa
• Given subcutaneously, the half-life is 16 to 20
hours, enabling once-daily administration.
• Excreted renally
• Anticoagulant effects are not neutralized by
protamine sulfate

64. Idrabiotaparinux
• Hypermethylated derivative of fondaparinux
• Binds antithrombin with high affinity
• Has a half-life of 130 hours; idrabiotaparinux is
given subcutaneously on a once-weekly basis.
• Excreted unchanged by the kidneys.
• Differs from idraparinux in that it contains a
biotin moiety that enables reversal with
intravenous avidin

65. Ximelagatran
• First target-specific oral anticoagulant in trials
• Ximelagatran is the oral prodrug of Melagatran
• Hepatotoxicity
– Did not receive FDA approval in 2004
– On the market in Europe but pulled in 2006
• ‘proof of principle’
– “efficacious” as warfarin
– Wider therapeutic index
– Little dosage adjustment/ no monitoring

67. Otamixaban
A parenteral direct fXa inhibitor
Has a rapid onset of action
produces a predictable anticoagulant effect
Has a short half-life
25% of the drug is cleared by the kidneys.
These features render otamixaban an attractive
candidate to replace heparin in patients with
ACS

68. • RB006
• An RNA aptamer that targets factor IXa with high affinity and
specificity,
• When given intravenously, produces a rapid and dose-proportional
anticoagulant effect
• Immediately reversed by intravenous administration of RB007, the
complementary oligonucleotide antidote.
• RB006 is not cleared renally
• does not appear to be immunogenic
• has the potential to inhibit the activation of coagulation induced by
exposure of blood to artificial surfaces, such as stents or cardiac
bypass circuits
• potential to replace heparin and protamine sulfate in patients
undergoing cardiopulmonary bypass surgery.
• May also be useful for patients at high risk of bleeding and for those
with renal impairment
• Phase II REVERSAL-PCI study, the efficacy and safety of
RB006/RB007 are being compared with those of heparin in 26
patients undergoing elective PCI

69. Edoxaban
• Oral thrombin Inhibitor
• rapidly absorbed
• half-life of 9 to 11 hours
• ENGAGE-AF-TIMI 48 trial is comparing 2 doses
of edoxaban (30 or 60 mg once daily) with
warfarin in 16 500 patients with AF.

70. • Other oral fXa inhibitors under development
include
• Betrixaban (15-hour half-life and extrarenal
clearance)
• YM150
• TAK442

72. PRIMARY HEMOSTATIC PLUG
Platelet activation and
aggregation:
• Change in shape of the
platelets
• Release of Ca and ADP from
the platelet granules.
• Receptor activation
Platelets have 2 receptors:
– GpIb: binds to vWF leading to
adhesion
– GpIIb-IIIa complex: leading to
aggregation by collagen

73. Role of
Cyclooxygenase
PAR1 and PAR4 are
protease-activated
receptors that
respond to
thrombin (IIa) to
promote platelet
aggregation and
secretion.
P2Y1 and P2Y12 are receptors for ADP; when
stimulated by agonists, these receptors
activate the fibrinogen-binding protein
GPIIb/IIIa and cyclooxygenase-1 (COX-1) to
promote platelet aggregation and secretion

74. Classification
• TXA2 inhibitors- Aspirin
• ADP antagonists- Ticlopidine, Clopidogrel,
Ticaglelor, Canglelor
• Phospodiesterase inhibitor- Dipyramidole,
Cilostazol
• Glycoprotein IIB/IIIA receptors antagonists-
Abciximab, Eptifibatide, Tirofiban

76. Aspirin
• In platelets major COX product is TXA2 , a labile
inducer of platelet aggregation and potent
vasoconstrictor.
• Aspirin blocks production of TXA2 by covalently
acetylating serine residue near the active site of
COX, this enzyme produces cyclic endperoxidase
precursor of TXA2.
• Since platelets do not synthesize new proteins
hence the action of aspirin on platelets is
permanent (7-10 days)

77. Uses
• Prevention of AMI in pts. Of unstable angina
• Prevention of reinfarction in pts. Of AMI and IHD
• Prevention of stroke in pts. Of cerbrovascular
accidents and h/o TIA
• For improving prognosis in patients with
atherosclerotic peripheral vascular diseases
• Percutaneous angioplasty for coronary
thrombosis ,
• Primary prophylaxis of thromboembolism in pts
with prosthetic heart valves

78. ADP antagonists- Ticlopidine
• Ticlopidine blocks Gi coupled ADP receptors
• It is a prodrug requires conversion to active form by
Cyp450.
• Rapid absorp. ,high bioavailability Maximal inhibition
of platelet inhibition it takes 8-11 days after starting
therapy.
• AE- Nausea ,Vomiting, Diarrhea, Neutropenia,
Thrombotic Thrombocytopenia
• Uses- Prevention cerebrovascular events, in secondary
prevention of stroke Unstable angina Combination –
Aspirin + ticlopidine---angioplasty, coronary artery
stenti

79. Clopidogrel
• This newer and more potent congener of
ticlopidine has similar mechanism of action,
ability to irreversibly inhibit platelet function
and range of therapeutic efficacy, but is safer
and better tolerated

80. Dipyramidole
• It inhibits phosphodiesterase as well as blocks
uptake of adenosine to increase platelet cAMP
which in turn potentiates PGI2 and interferes
with aggregation.
• Levels of TXA2 or PGI2, are not altered, but
platelet survival time reduced by disease is
normalized.

81. Glycoprotein (GP) IIb/IIIa receptor
antagonists
• GP IIb/IIIa antagonists are a newer class of potent
platelet aggregation inhibitors which act by
blocking the key receptor involved in platelet
aggregation.
• The GPIIb/IIIa is an adhesive receptor (integrin)
on platelet surface for fibrinogen and vWF
through which agonists like collagen, thrombin,
TXA2, ADP, etc. finally induce platelet
aggregation.
• Thus, GP IIb/IIIa antagonists block aggregation
induced by all platelet agonists.

82. Uses
• Coronary artery disease
• Acute coronary syndromes (ACSs)
• Cerebrovascular disease
• Prosthetic heart valves and arteriovenous
shunts
• Venous thromboembolism
• Peripheral vascular disease

84. Drug Interactions
Amiodarone Cimetidine Clopidogrel
Azole
antifungals
Cotrimoxazole Fluoxetine