ANTICOAGULANTS &

ANTIPLATELETS

1
 Background

• Physical trauma to the vascular system

initiates interactions betwn platelets,
endothelial cells & the coagulation cascade
• Results in formn of a platelet-fibrin plug

2
 Role of platelets
Activation of platelets involve 3 steps:
• Adhesion to the site of injury
• Release of intracellular granules
• Aggregation of platelets

3
 Coagulation factors
1. Fibrinogen 8. Antihaemophilic
2. Prothrombin factor/globulin
3. Tissue thromboplastin, 9. Christmas factor
TF 10. Stuart Prower factor
4. Calcium 11. Plasma thromboplastin
5. Proaccelerin, Ac antecedent (PTA)
globulin 12. Hageman factor, glass
7. Proconvertin contact factor
13. Fibrin stabilizing factor

4
 Coagulation factors (contd)
Factors 2, 7, 9 and 10 are vit K dependent
procoagulants

5
 Anti-platelet agents
1. Aspirin
2. Ticlopidine
3. Clopidogrel
4. Dipyridamole
5. Sulfinpyrazone
6. Glycoprotein 2b/3a receptor antagonists:
a) abciximab
b) tirofiban
c) eptifibatide

6
 Aspirin
• Irreversibly acetylates & inactivates enzyme
cyclooxygenase
• Thereby inhibiting thromboxane A2
production

7
 Aspirin (contd)
• Inactivates COX in other tissues, incl
endothelial cells
• Such cells recover rapidly by synthesizing
new enzyme

8
 Aspirin (contd)
• Platelets are anucleate
• Can’t synthesize new enzyme
• Remain inactive for rest of their life-span

9
 Aspirin (contd)
• Prompt aspirin ↓es incidence of
progression to MI in unstable angina
• ↓es secondary MI by 25% in MI
• ↓es incidence of 1st infarct

10
 Aspirin (contd)
• Aspirin+Dipyridamole ↑es patency
of coronary bypass grafts, when begun
before surgery

11
 Aspirin (contd)
• Same combn ↓es incidence of cerebral
emboli in pts on warfarin who’ve prosthetic
intracardiac valves

12
 Aspirin (contd)
• ↓es frequency of TIAs in occlusive
cerebrovascular ds
• ↓es incidence of 2nd stroke by 25%

13
 Aspirin (contd)
• Maintains patency of AV cannulas in renal
failure pts requiring HD
• Aspirin+Dipyridamole slow the progression
of some forms of GN

14
 Aspirin (contd)
• Not effective in maintaining patency of
vessels following percutaneous angioplasty
or stent placement

15
 Aspirin (contd)
• Loading dose 200-300 mg
• 75-100 mg/d
• BT is prolonged causing an ↑ed incidence
of haemorrhagic stroke+GI bleed

16
 Ticlopidine
• Also acts as an inhibitor of platelet
aggregation
• Inhibits ADP pathway involved in binding
of plts to fibrinogen & to each other

17
 Ticlopidine (contd)
• Bound extensively to plasma proteins &
undergoes hepatic metabolism

18
 Ticlopidine (contd)
• Superior to aspirin or warfarin in
maintaining coronary stent patency
• Decreases the incidence of thrombotic
stroke
• SE: neutropaenia, TTP

19
 Dipyridamole
• Usually given in combn with aspirin
• ↑es intracellular level of cAMP by
inhibiting cyclic nucleotide
phosphodiesterase

20
 Dipyridamole (contd)
• Inhibits thromboxane A2 synthesis
• May potentiate the effect of prostacyclin
(PGI2) to antagonize plt stickiness &
therefore decrease plt adhesion to
thrombogenic surfaces

21
 Dipyridamole (contd)
• It is a coronary vasodilator & is employed
to prophylactically treat angina pectoris
• With warfarin, it is effective in inhibiting
embolization from prosthetic heart valves

22
 Clopidogrel
• Analogue of ticlopidine
• Selectively & irreversibly blocks ADP
binding to platelets
• Prevents ADP-mediated activation of the
glycoprotein complex gp2b/3a, thereby
inhibiting platelet aggregation

23
 Clopidogrel (contd)
• Extensively metabolized by liver
• Action is due to one of its metabolites
• Elimination by both renal & faecal routes

24
 Clopidogrel (contd)
• Primary adv effect is bleeding
• Clopidogrel can inhibit cytochrome P-450,
so may interfere with metabolism of
phenytoin, tolbutamide, warfarin,
fluvastatin, tamoxifen

25
 Abciximab
• Chimeric monoclonal antibody
• Composed of Fab fragments of a murine
monoclonal antibody directed against
gp2b/3a complex joined to the constant
regions of human immunoglobulin

26
 Abciximab (contd)
By binding to gp2b/3a, the antibody
blocks the binding of fibrinogen & von
Willebrand factor, thus aggregation
doesn’t occur

27
 Abciximab (contd)
Given iv as an adjunct to PCI
Heparin or aspirin is given with abciximab

28
 Abciximab (contd)
After cessation of infusion, platelet
function gradually returns towards normal
Antiplatelet effect persists for 24-48 hrs
AE: potential bleed

29
 Eptifibatide & Tirofiban
Similar to abciximab
Blocks gp2b/3a receptor
Mimic the arginine-glycine-aspartic acid
sequence of fibrinogen accounting for
their specific antagonism at this receptor

30
 Eptifibatide & Tirofiban (contd)
↓es the thrombotic complicns
associated with ACS
When iv infusion is stopped, rapidly
cleared, but effect can persist for 4 h

31
 Eptifibatide & Tirofiban (contd)
Eptifibatide & its metabolites are cleared
by the kidney
Tirofiban is excreted unchanged by the
kidney
Major s/e is bleeding

32
 Anticoagulants
• Acute venous thrombosis, pulm embolism
• Chronic oral anticoagulation to prevent
cerebral arterial embolism from cardiac
sources viz, ventricular mural thrombi or
arterial thrombi or from an atherosclerotic
partially stenosed carotid/vertebral artery

33
 Anticoagulants (contd)
• Less successful in peripheral/mesenteric
arterial thrombosis

34
 Anticoagulants (contd)
These agents retard fibrin deposition on
established thrombi & prevent formn of
new thrombi
Two types: heparin & vit K antagonists

35
 Heparin
• Naturally occurring mucopolysaccharide
polymer with tetrasachharide sequences that
bind to & activate antithromin 3
• Reduces thrombin generation & fibrin
formn in acute venous & arterial
thrombosis or embolism

36
 Heparin
• UFH catalyses inactivation of thrombin &
factors 10a by antithrombin

37
 Heparin
• Injectable, rapidly acting anticoagulant
• Used acutely to interfere with formn of
thrombi
• Normally occurs as a macromolecule
complexed with histamine in mast cells
• Extracted for commercial use from
porcine intestine or bovine lung
38
 Heparin
Initial loading dose of 5000-10000 units
followed by ivi to keep APTT 1.5-2 times
the pt’s pre-heparin APTT
Usually 800-1000 units heparin/h
(Usual duration of combined heparin &
warfarin therapy is 5-7 days)
or, 5000 units qid s/c or iv
39
 Heparin APTT algorithm
Measure APTT every 10h (every 4h if
APTT>7, & stop the ivi)
a) 5-7: -500iu/h e) 1.5-2.5: 0
b) 4-5: -300iu/h f) 1.2-1.4: +200
c) 3-4: -100iu/h g)<1.2: +400
d) 2.5-3: -50iu/h

40
 Heparin (contd)
1mg ivi Protamine neutralizes 90u
Max dose: 50mg (if exceeded may itself
have anticoagulant effect)

41
 Heparin (contd)

UFH is heterogenous
Only 20% biologically active

42
 LMWH (contd)
• Produced by chemical or enzymatic
cleavage of UFH
• Inactivates factor 10a more than thrombin
(2a), thus minimally prolonging aPTT

43
 LMWH (contd)
Advantages:
1. Administration sc od/bd
2. Predictable pharmacokinetics APTT
monitoring not needed
3. Less immunogenic & less likely to cause
thrombocytopaenia

44
 LMWH (contd)
• Contraindicated in CCR < 10 ml/min
• Dose adjusted in < 30 ml/min, cachexia,
obesity, pregnancy
• Only partially reversible with protamine

45
 Heparin
• Thrombocytopenia in 10% (usu mild)
(50,000-110,000/µl)
• More common in heparin derived from
beef lung as opposed to porcine intestinal
mucosa

46
 Heparin (contd)
• Antibodies arising from exposure to UFH
often cross-react with LMWH
• LMWH cannot be used to treat pts with
established thrombocytopenia

47
 Heparin (contd)
• HIT results fm generation of an
autoantibody to a complex of UFH with
anti-heparin protein platelet factor 4 (PF-4)
• Heparin-PF-4 antibody complexes can bind
to the platelet Fc receptor & cause platelet
activation, agglutination & arterial
thrombosis

48
 Heparin (contd)
• So, recognition of thrombocytopaenia &
paradoxical thrombosis is critical,
discontinuation can be life saving
• Heparin use for >5 months may cause
osteoporosis (activation of osteoclasts)

49
 Coumarin anticoagulants
• Warfarin & dicoumarol
• Prevent reduction of Vit K epoxides in liver
microsomes & induce a state of Vit K defcy
• ie, inhibits reduction of Vit K to its active
form

50
 Warfarin
• Slows thrombin generation & clot formn by
impairing biologic activity of prothrombin
protein complex proteins
• Used to prevent recurrence of venous
thrombosis & pulm embolism

51
 Warfarin (contd)
• Leads to depletion of Vit K-dependent
clotting factors 2, 7, 9, 10, proteins C & S
• Good oral absorption
• 4-5 days to achieve full anticoagulant effect

52
 Warfarin (contd)
• Initial INR : ↓ factor 7, (factor 2 takes
several days)

53
 Warfarin (contd)
• Rapid depletion of anticoagulant protein C
& slower onset of anticoagulant effect, pt
might develop ↑ed hypercoagulability
during 1st few days if not combined with a
parenteral anticoagulant

54
 Warfarin (contd)
• Because commercial thromboplastins have
different potencies, PT can vary widely

55
 Warfarin (contd)
• 1mg/d to prevent clot formn at tip of
chronic indwelling venous catheters. No
effect on PT
• Various drugs that alter liver microsomal
metabolism of coumarin or compete for
albumin-binding sites can ↑ or ↓ potency of
these drugs

56
 Warfarin (contd)
• Single uncomplicated thromboembolic
event achieve maximal benefit after 3-6
months of anticoagulation

57
 Warfarin (contd)
• 10% pts on oral anticoagulation for 1 yr
have a bleeding complication requiring
medical supervision
• 0.5-1% have a fatal haemorrhage

58
 Warfarin (contd)
• Coumarin effect can be reversed by FFP or
Vit K
• FFP works immediately, but effect lasts
only for a few hrs
• Vit K takes 8-12 h to be effective

59
 Warfarin (contd)
• Haemorrhagic skin necrosis (deficient in
protein C, an anticoagulant protein whose
activity is reduced by Vit K antagonists)
• Inherited coumarin resistance

60
 Target INR 2.5
1. Pulm embolism
2. Proximal & calf DVT
3. Recurrence of venous thromboembolism when
no longer on warfarin therapy
4. Symptomatic inherited thrombophilia
5. AF
6. Cardioversion
7. Mural thrombus
8. Cardiomyopathy

61
 Target INR 3.5
1. Recurrence of venous thromboembolism
while on warfarin therapy
2. Antiphospholipid therapy syndrome
3. Mechanical prosthetic valve
4. Coronary artery graft thrombosis

62
 Excessive oral anticoagulation

INR >3.0 <6.0 (target INR 2.5)

INR >4.0 <6.0 (target INR 3.5)
a) Reduce warfarin dose or stop
b) Restart warfarin when INR <5.0

63
INR >6.0 <8.0 no bleeding or minor
bleeding
a) Stop warfarin
b) Restart when INR <5.0

64
INR >8.0, no bleeding or minor bleeding
a) Stop warfarin
b) Restart when INR <5.0
c) If other risk factors for bleeding give 0.5-
2.5 mg of vit K (oral)

65
Major bleeding
a) Stop warfarin
b) Give prothrombin complex concentrate 50
units/kg or FFP 15ml/kg
c) Give 5 mg of vit K (oral or iv)

66
 Anticoagulation in chronic AF
RISK FACTORS:
1. Prior TIA
2. Systemic embolus or stroke
3. HTN
4. Poor LVF
5. Rheumatic mitral valve disease
6. Prosthetic heart valve
7. CCF
67
Age (years) Risk factors Recommendatio
ns

<65 absent Aspirin

present Warfarin INR
2.5 (2-3)
65-75 absent Aspirin or
warfarin
present Warfarin INR
2.5 (2-3)
>75 All patients Warfarin 2.5 (2-
3) 68