Dr Rahul Kunkulol's Power Point Presentations

3. HAEMOSTASIS-
Cessation of blood loss from damaged blood

4. Vasoconstriction
Exposure to
tissues activate
Tissue factor
and initiate
coagulation
Tissue Factor

6. WHAT ARE PLATELETS ?
White, discoid
Smallest element of flowing blood
• 1 - 2 microns diameter
Lipid bilayer membrane
Normal range 150000 – 450000 microlitre blood
Formed from cytoplasm of megakaryocytes
No nucleus

8. Normal Function of Platelets
Haemostasis
Preventing
bleeding
from
wounds
Integrity
and repair
of the
vessel wall

11. Collagen VWF
INJURY
Platelet Adhesion
& Secretion
Platelet aggregation
Tissue Factor
Coagulation Cascade
Thrombin
Fibrin
Haemostatic plug
Vaso-
constriction
Blood Vessel
Endothelium
Subendothelium

12. Thrombogenesis
 Platelet aggregates bound
together by fibrin strands
(white clots)
 Consist mainly of fibrin
and RBCs (red clots)
Arterial thrombus

13. Platelets and Thromboemolism
 Occludes artery /
disintegrates into
emboli occluding
distal vessels resulting
in ischemic necrosis
of tissue supplied by
the artery.(AMI)
 Veins low pressure :
Reduced blood flow
(stasis)
 Especially in valve
pockets
 Causes tissue drained by
the vein to be
edematous and inflamed
(DVT)

14. Vascular Injury
 Trauma
 Surgical manipulation
 Prior thrombosis
 Atherosclerosis
Vascular
Injury

15. PLATELET AGGREGATORS
Collagen
Von willebrand factor
ADP
Thromboxane A2
Stress
Thrombin

16. Damaged blood vessel
Release of collagen Activation of platelets
Arachidonic acid Release of thrombinRelease of
ADP
Cyclic endperoxidase
COX
Release of TXA2
Activation of glycoprotein IIB/IIIA receptors
Fibrinogen fibrin
Activates P2Y1
Gq Gi
Changes in platelet shape
Increases phospoinositol
inhibits adenylcyclase,
decrease CAMP ?

17. Targets for anti-platelet therapy
Aspirin
NSAIDs
ADP
receptor
COX-1
TXA2
GPIIb - IIIa
Signalling
pathways
ADP receptor
antagonists
Clopidogrel THROMBIN
receptor
Thrombin
inhibitors
II
Phosphodiesterase
inhibitors
dipyridamole
Fibrinogen Receptor
Antagonists
AA

18. PGI 2- (Prostacyclins)
Naturally occurring potent vasodilator and inhibitor of platelet
aggregation.
Produced by vessel walls, also present in brain ,gut and kidney.
Formed from PG endperoxidase by the action of COX
Inhibit platelet aggregation by stimulating adenylcyclase increasing cyclic
AMP levels in platelets.
Prostacyclins causes hypotension , tachycardia ,headache. intense facial
flushing
Very unstable ,1/2 life of 3 mins.
Prostacyclins (Epoprostananol)-used during haemodialysis.

19. CLASSIFICATION OF
ANTIPLATELET AGENT-
1. PGI 2
2. TXA2 inhibitors-
• Ticlopidine, Clopidogrel
3. ADP antagonists-
• Dipyridamole, Pentoxifylline
4. Phospodiesterase inhibitor-
5. Glycoprotein IIB/IIIA receptors antagonists-
Abciximab, Eptifibatide, Tirofiban

20. Damaged blood vessel
Release of collagen Activation of platelets
Arachidonic acid Release of thrombinRelease of
ADP
Cyclic endperoxidase
COX
Release of TXA2
Activation of glycoprotein IIB/IIIA receptors
Fibrinogen fibrin
Activates P2Y1
Gq Gi
Changes in platelet shape
Increases phospoinositol
inhibits adenylcyclase,
decrease CAMP ?

21. • MOA-
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).

22. For complete inactivation of platelet COX
dose of aspirin req. is 160 mg daily.
Reason—
Higher doses decrease efficacy of aspirin as
they inhibit production of prostacyclins which
is spared at low doses. (75-150mg)
Higher doses also increase toxicity
esp.. Bleeding.

23. USES OF ASPIRIN
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

24. 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.
Dose-loading 500mg for rapid onset of action. Usual dose 250mgBD
AE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic Thrombocytopenia
Uses- Prevention cerebrovascular events, in 2ndary prevention of stroke
Unstable angina
Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting

25. Clopidogrel
Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia.
Less used than Ticlopidine
MOA, PK profile same as Ticlopidine
Dose 75mg/day
Rest same as Ticlopidine.

26. • MOA
Inhibition of PDE (phospodiesterase enzyme) and/ or by
blockade of adenosine which act at A2 receptor to stimulate
adenylcyclase thus increase CAMP causing platelet inhibition.
Current recommended use-
Along with Warffarin in primary prophylaxis of thromboemboli in pts
with prosthetic heart valves

27. Xanthine analogue
Increases deformability of RBCs thus increases
microcirculation, reduce fibrinogen levels, inhibit pl.
aggregation.
Uses- CVAs esp.TIA(transient ischemic attacks) ,
Ischemic ulcers of legs
Dose 400mg tds

28. Glycoprotein IIB/IIIA receptors antagonists
Platelet surface receptor, receptor for fibrinogen and von
willebrand factor,which anchors platelets to foreign
surface and each other thereby mediating aggregation.
Receptor is activated by TXA2, Collagen, and thrombin
to developbinding sites for its ligands.
Inhibition of binding to this receptor blocks platelet
aggregation induced by the agonist.

29. Abciximab
Monoclonal antibody cause platelet receptor blockade.
Given IV max. effect seen with in 2hrs, DOA 10-12 hrs.
Use- percutaneous angioplasty for coronary thrombosis
Prevents restenosis, recurrent and death when used in conjugation with aspirin and
heparin.
Dose-0.25mg bolus---0.125microgm/kg/min for 12hrs IV
AE-bleeding
Contraindication same as fibrinolytics

30. Questions
 Discuss in detail antiplatelet drugs. Add note on
use of low dose Aspirin as an antiplatelet agent.
 Short note:
 Low dose Aspirin
 Ticlopidine
 Glycoprotein IIb/IIIa antagonists

32. Coagulation Phase
Two major pathways
• Intrinsic pathway
• Extrinsic pathway
13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent on Vitamin K1 and K2
Most of these factors are proteases
Normally inactive and sequentially activated
Hereditary lack of clotting factors lead to hemophilia -A

33. Clotting factors
35

34. Intrinsic Pathway
 All clotting factors are
within the blood vessels
 Clotting slower
 Activated partial
thromboplastin test (aPTT)
 Blood sample + calcium
 Mix with negatively charged
phospholipid
 Kaoline (aluminum silicate)
 Determine clotting time
 Generally clotting occurs in
26 to 33 seconds
 Used to detect defects in
the intrinsic pathway
Extrinsic Pathway
 Initiating factor outside the
blood vessels - tissue factor
 Clotting - faster - in Seconds
 Prothrombin test (PT)
 Tissue Thromboplastin factor III
 Mix with phospholipid extract
 Add calcium and blood sample
 Determine clotting time
 Generally 12 - 14 seconds
 Used to detect defects in
extrinsic pathway

35. Diagnosis of coagulation defects
• Defective Intrinsic
Pathway
Prolonged APTT
No change in PT
• Defective Extrinsic
Pathway
No change in APTT
Prolonged PT
• Defective in
Common pathway
Prolonged APTT
Prolonged PT

36. Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin II Thrombin IIa
Fibrinogen Fribrin monomer
Fibrin polymer
XIII
Intrinsic Pathway Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants

37. Activation
Inactive XI Active XIa
XIIa
+

39. ANTICOAGULANTS
 These are the drugs used to reduce coagulability of blood.
 Classification
In vitro anticoagulants In vivo anticoagulants
Heparin A) -Heparin
Sodium citrate -Low molecular weight Heparin
Sodium oxalate -Danaparoid
Sodium edetate -Lepirudin
-Heparan sulfate
B) Oral anticoagulants

40. B) Oral anticoagulants
 Warfarin sodium
 Bishydroxycoumarin (dicumarol)
 Acenocoumarol
 Phenindione

41. Heparin
Chemistry & Occurence
Straight chain mucopolysaccharide,
glycosaminoglycans
MW 10000-20000. Average=15,000 d (~45monosaccharide
chains) Strongest organic acid in the body.
Heparin is present in all tissues containing
mast cells, richest source are liver, lung
(bovine) and intestinal mucosa (porcine)
LMWH isolated from standard heparin by
gel filtration chromatography or partial
depolymerization. (1000-10000 daltons).

42. MOA
 Heparin binds to antithrombin III -----complex
 Increases thrombin –AT reaction 1000folds.
 Heparin induces conformational change in ATIII to
expose its interactive sites.
 Long heparin molecule provides scaffolding for
clotting factors ( Xa & IIa) aswellas ATIII.
 At low conc. interferes with intrinsic pathway while
at high common pathway.
 ATIII inhibits activated clotting factors of intrinsic
and common pathway including thrombin, Xa, IXa
and thus acts as Succide substrate

43. ATIII-SUCCIDE SUBSTRATE

44. Thrombin inhibition catalysed by
heparin
AT
R
H
AT H
AT H
AT H
R
P
P
P
P
R
R

45. FXa inhibition catalysed by
heparin
AT
R
H
AT H
AT H
AT H
R
P
P
P
P
R
R

46. Anticoagulant Properties of Heparin
1. Inhibits the thrombin-mediated conversion of
fibrinogen to fibrin
2. Inhibits the aggregation of platelets by
thrombin
3. Inhibits activation of fibrin stabilizing enzyme
4. Inhibits activated factors XII, XI, IX, X and II

47. Pharmacokinetics
 Not effective orally
 Sc/ iv administration
 Onset immediate, peak in 5-10mins
 Metabolized in liver
 Excretion through kidney.

48. 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
 therapeutic goal – 2-2.5 times normal control value
(-30 sec)

49. Low Dose Unfractionated Heparin
 Surgical Prophylaxis
 5,000 Units SC 2 hr preop
 5,000 Units SC every 12 hours
 Medical Prophylaxis
 5,000 Units SC every 12 hours
 No monitoring required

51. ADVANTAGES OF LMWH
1. Less anti IIa activity
than anti Xa activity
2. Good pk profile
3. More predictable dose
response
4. Can be given by
subcutaneous route
5. No monitoring required,
can be given OPD basis
6. Less anti-platelet effects
7. Longer t1/2’s
8. Decreased hospital stay
9. More favorable benefit –
risk ratio

52. LMWH
 1mg/ kg S.C BD for DVT
 30mg/ Kg S.C. for DVT
prophylaxis of Knee and hip
surgery
 1mg/ kg S.C BD for DVT
 30mg/ Kg S.C. for DVT
prophylaxis of Knee and hip
surgery

53. Adverse effects
 Allergic and anaphylactic manifestations
 Bleeding (1-33%)-antidote- Protamine sulphate
 Heparin induced thromocytopenia. (more than
25%)
 Alopecia
 Osteoporosis
 Hyperkalemia

55. Mechanisms of HIT
 Type 1 (Non immune):
 Fall in platelet count occurs within the first two days after
heparin initiation, and returns to normal with continued
heparin administration, and is of no clinical consequence.
 Direct effect of heparin on platelet activation.
 Type 2 (Immune):
 Approx 0.3 to 3 percent of patients receiving heparin
 Mediated by antibodies to a heparin-platelet factor 4
complex.
 Seen with unfractionated heparin but in not with LMWH

57. Warfarin
Warfarin, a coumarin derivative, is the most
commonly used oral anticoagulant (OAC) .
Warfarin is a vitamin K antagonist - Impairs the
generation of active vitamin K, decreasing the
amounts of vitamin K dependent coagulation factors
• (FII, FVII, FIX, FX)
Depending on factors such as age, risk factors,
recurrence, etc., warfarin may be continued for
anywhere from 1 month to lifelong

58. Oral anticoagulants : warfarin, dicumarol
 Coumarins - warfarin, dicumarol
 Isolated from clover leaves
 Structurally related to vitamin K
 Inhibits production of active clotting factors
 Absorption rapid –high plasma protein binding binds
to albumin
 Clearance is slow - 36 hrs
 Delayed onset 8 - 12 hrs
 Overdose - reversed by vitamin K infusion
 Can cross placenta - do not use during late pregnancies

59. Mechanism of action
Descarboxy Prothrombin Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NADHNAD
Warfarin

62. Warfarin Monitoring
• Why monitor? Need to balance proper
anticoagulation without bleeding risk.
• Monitored with PT, expressed as INR:
Warfarin
Monitoring
• Where ISI = International Sensitivity Index,
assigned by each thromboplastin manufacturer
• Warfarin is given orally and titrated to achieve
an INR of typically 2.0 – 3.0
INR =
[Patient PT /
Mean Normal
PT]ISI

63. INR : International Normalized
Ratio.
 Different thromboplastins vary in sensitivity
 To give PT values a consistent basis of comparison
from lab to lab, WHO instituted the INR:
 A uniform value in which the PT is expressed as a
ratio.
 Many manufacturers aim for an ISI of 1.0.
 INR is affected by diet (because of the vitamin K
dependent mechanism of action), other medications,
 Monitored routinely, every 2 to 4 weeks

64. Drug interaction- Prototype Warfarin
Category Mechanisms Examples of
drugs
Drugs that
Increase
Warfarin Activity
Decrease binding to Albumin Aspirin,
Sulfonamides
Inhibit Degradation Cimetidine,
Decrease synthesis of Clotting Factors Antibiotics (oral)
Drugs that
promote
bleeding
Inhibition of platelets Aspirin
Inhibition of clotting Factors Heparin
Antimetabolites
Drugs decrease
Warfarin activity
Induction of metabolizing Enzymes Barbiturates
Increases synthesis of Clotting Factors Vitamin K

65. New Anticoagulants
Limitations of
traditional
anticoagulants, both with
Heparin and Warfarin,
have prompted the
development of new
agents

66. New Anticoagulants
Parenteral
FXa
Inhibitors

67. FXa Inhibitors
Parenteral synthetic pentasaccharide
analogs
• Synthetic and highly selective
inhibitor of FXa
• Acts as cofactor to AT
• Administered by subcutaneous
injection ONCE A DAY
• Absolute bioavailability of
100%
Fondaparinux
(Arixtra®)

68. FXa Inhibitors
Parenteral synthetic pentasaccharide
analogs
• LMW mixture of heparinoids
(glycosaminoglycans, GAGs); acts as
cofactor to AT
• Anticoagulation effect is predominantly
mediated by inhibition of FXa
• Also has some anti-IIa effects
• Fast acting, generally predictable dose
response
Danaparoid

69. Direct Thrombin Inhibitors
• Recombinant hirudin, a
derivative of the saliva of the
medicinal leech Hirudo medicinalis
• First direct thrombin inhibitor
(DTI) to be approved by the
FDA for anticoagulation in
patients with (HIT)
• Can be monitored with APTT,
TT, chromogenic anti-IIa.

70. Direct Thrombin Inhibitors
• A synthetic anticoagulant for
prophylaxis or treatment of
thrombosis in patients with
heparin-induced
thrombocytopenia (HIT)
• Active against both free and clot-
bound thrombin
• Argatroban is typically monitored
by APTT, but other methods like
the chromogenic anti-IIa assay
may be more accurate.
Argatroban

71. Direct Thrombin Inhibitors
• Synthetic polypeptide hirudin analog
that interacts with the thrombin
active site to reversibly inhibit
thrombin
• Alternative to heparin
• Administered parenterally
• Short half life
• Monitored by Activated Clotting
Time (ACT)
Bivalirudin

72. Direct Thrombin Inhibitors
• Studies have shown similar
efficacy and bleeding risk to
warfarin
• Does not need monitoring
• Was not FDA approved:
more studies needed to
assess liver failure risk
Ximelagatran
oral anticoagulant

75. The Extent of Thrombotic
Disease Annually in the U.S.
1.5 million MIs-Mortality of 30% (450,000)
500,000 CVAs -Mortality of 30% (150,000)
2 million DVTs
200,000 deaths from PE

76. Venous Thromboembolism
Third most common
cardiovascular disease
Significant morbidity and
mortality
VTE includes:
• Deep Venous
Thrombosis (DVT)
• Pulmonary Embolism
(PE)

77. Economy Class Syndrome
Medical condition called Venous
Thromboembolism
Fibrin thrombi.
3months anticoagulants theraphy is required
in DVT and PE
For prophylaxis of pts.undergoing surgery---
LMWH—Decreases risk of leg vein
thrombosis & PE.
Anticoagulants are indicated for prophylaxis
in bedridden, old, postoperative, post stroke,
postpartum, leg fracture patients

78. Deep Vein Thrombosis
 Blood clot of lower leg or
thigh
 Approximately 1 per 1,000
people affected by DVT
 Hospitalization for 5
to 7 days
 50% of patients with DVT
are asymptomatic

79. Pulmonary Embolism
Dislodged blood clot
entering the pulmonary
circulation
Accounts for 5-10% of all
hospital deaths
80% of patients die within
the first 2 hours CT Scan of Pulmonary Embolism

80. Deep Vein ThrombosisEmbolusPulmonary Embolism

81. AMI AND UNSTABLE
ANGINA
Arterial thrombi-platelet thrombi
Use of anticoagulants???
Beneficial in preventing mural thrombi at infarction site
and venous thrombi in leg veins.
Can be given for short periods till the Pt. is ambulatory.
Heparin iv for 2-8 days followed by oral anticoagulant for
3 months.
Short term use in unstable angina.

82. RHD, AF
Warfarin / low dose aspirin /
LMWH are effective in
preventing stroke due to
embolism from fibrillating atria.
Warfarin the most effective.
(3-4week theraphy)

83. Blood Hypercoagulability
Increased procoagulants
Decrease in inhibitors
Impaired fibrinolysis
Occurs in obstretic conditions,
mallignancies, infections.

85. • Enhance degradation of clots
• Activation of endogenous
protease
• Plasminogen (inactive form) is
converted to Plasmin (active
form)
• Plasmin breaks down fibrin
clots
Fibrinolysis

86. FIBRINOLYTICS

87. • Streptokinase - bacterial product -
continuous use - immune reaction
• Urokinase - human tissue derived - no
immune response
• Tissue plasminogen activator (tPA) -
genetically cloned - no immune reaction -
EXPENSIVE
FIBRINOLYTICS
Inhibitors of
fibrinolysis

88.  Streptokinase is a protein (but not an
enzyme in itself) synthesized by streptococci
that combines with the pro-activator
plasminogen.
 This enzymatic complex catalyzes the
conversion of inactive plasminogen to
active plasmin

89.  Urokinase is a human enzyme synthesized by
the kidney that directly converts plasminogen to
active plasmin.
 Plasmin formed inside a thrombus by these
activators is protected from plasma antiplasmins,
which allows it to lyse the thrombus from within

90.  Plasminogen can also be activated endogenously
by tissue plasminogen activators (t-PAs).
 Activate plasminogen that is bound to fibrin,
which (in theory) confines fibrinolysis to the
formed thrombus and avoids systemic
activation.
 Human t-PA is manufactured as ALTEPLASE
by means of recombinant DNA technology.

91.  RETEPLASE is less expensive than Alteplase.
It lacks the major fibrin-binding domain thus is
less fibrin-specific than Alteplase
 TENECTEPLASE is a mutant form of t-PA
that has a longer half-life, and it can be given as
an intravenous bolus. Tenecteplase is slightly
more fibrin-specific than Alteplase

94. DOSES
• Dose:250000 U loading dose
followed by 100000 U every hr for
24 -72 hrs
Streptokinase
• Loading dose of 300000 U
followed by 300000 U/hr for 12
hrs
Urokinase
• 60mg iv over 1 hr followed by
40mg iv at a rate of 20mg/ hr
Alteplase
(t-PA)

95. Contraindications to Antithrombotic
Therapy
• Pre-existing coagulation or platelet
defect, thrombocytopenia, or other
bleeding abnormality
• Inaccessible ulcerative lesion(e.g.,
gastrointestinal tract lesion)
• Central nervous system lesion (e.g.,
caused by stroke, surgery, trauma)
• Malignant hypertension
• Advanced retinopathy
• Old age (relative)
• Aspirin or other antiplatelet drugs
• Neoplastic disease
General
risk
factors

96. Contraindications to Antithrombotic
Therapy
• Recent thoracic, abdominal, or
central nervous system surgery
• Recent cerebrovascular accident,
trauma, or neoplasm
• Bleeding ulcer
• Anticipated invasive procedures
(arterial punctures, biopsies, central
lines)
• Concurrent hemostatic dysfunction
Specific to
thrombolytic
agents

97. • AMI
• Multiple pulmonary emboli.
• Pulmonary embolism with
hemodynamic instability
• Central DVT
• Pheripheral vascular disease
Indications

98. Drug preparations : to stop
bleeding

99. Fibrinolytic Inhibitors:
Aminocaproic Acid
 Similar to the amino acid lysine, is a synthetic
inhibitor of fibrinolysis
 Competitively inhibits plasminogen activation
 Oral dosage of EACA is 6 g four times a day
 Tranexamic acid is an analog of aminocaproic
acid and has the same properties. It is
administered orally with a 15 mg/kg loading
dose followed by 30 mg/kg every 6 hours

100. USES
 Adjunctive therapy in hemophilia
 Bleeding from fibrinolytic therapy
 Prophylaxis for re-bleeding from intracranial
aneurysms.
 Postsurgical gastrointestinal bleeding ,post
prostatectomy bleeding ,bladder hemorrhage
secondary to radiation and drug-induced cystitis.
 Adverse effects
 Intravascular thrombosis from inhibition of
plasminogen activator
 Hypotension, myopathy, abdominal discomfort,
diarrhea, and nasal stuffiness

101. Drug preparations: clotting deficiencies
Vitamin K
• Oral : 5 mg tablets
Plasma fractions - for hemophilia
• Antihemophilic factor ( VIII, AHF)
• Parenteral
Factor IX complex
• Parenteral : in vials