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Anticoagulants
Dr Shoaib
PGR MD Cardiollogy
CPEIC Multan

Outline
 General Overview of Anticoag
ulants
 Overview of Blood Coagulation
 Anticoagulant Drugs
 History of Anticoagulant Drugs
 Use of Anticoagulants Today,
Prevention
 Future Outlook

Anticoagulants – General Overview
 Drugs that help prevent the clotting (coagulat
ion) of blood
 Coagulation will occur instantaneously once
a blood vessel has been severed
 Blood begins to solidify to prevent
excessive blood loss and to prevent
invasive substances from entering
the bloodstream

A Blood Clot
 Consists of platelets
meshed into fibrin
 A web-like accumulati
on of strands with RB
Cs
 There are two major f
acets of the clotting m
echanism – the platel
ets, and the thrombin
system

Platelets
 Tiny cellular elements, made in the bone mar
row, that travel in the bloodstream waiting for
a bleeding problem to develop
 When bleeding occurs, chemical reactions ch
ange the surface of the platelet to make it act
ivated and become “sticky”
 These activated platelets begin adhering to t
he wall of the blood vessel at the site of blee
ding

Thrombin System
 Calcium ions must be present for
the thrombin system to begin
 The thrombin system consists of s
everal blood proteins that activate
when bleeding occurs
 The activated clotting proteins en
gage in a cascade of chemical re
actions that finally produce a subs
tance called fibrin
 Fibrin strands stick to the expose
d vessel wall, clumping together a
nd forming a web-like complex of
strands
 Red blood cells become caught u
p in the web, causing a clot

Coagulation Factors
Factor Name
I Fibrinogen
II Prothrombin
III Tissue Factor or
thromboplastin
IV Ca++
V Proaccelerin
VII Proconvertin
VIII Antihemophilic A
factor
IX Antihemophilic B
factor or Christmas
factor
Factor Name
X Stuart or Stuart-
Prower factor
XI Plasma thomboplastin
antecedent
XII Hageman factor,
contact factor
XIII Fibrin stabilizing factor
Prekallikrein factor
High-molecular-weight
kininogen

Heparin
 Heparin is a naturally-occurring anticoag
ulant produced by basophils and mast ce
lls to prevent formation and extension of
blood clots
 Heparin does not disintegrate clots that h
ave already formed. It permits the body's
natural clot lysis mechanisms, i.e. fibrinol
ysis, to work normally to break down pre
viously formed clots
 As the thrombokinase is released, it neut
ralizes the action of heparin to allow clotti
ng to occur

Anticoagulant Use
 Anticoagulant drugs help prevent the development of
harmful clots in the blood vessels by lessening the bl
ood's ability to cluster together
 The function of these drugs is often misunderstood b
ecause they are sometimes referred to as blood thin
ners; they do not in fact thin the blood
 These drugs will not dissolve clots that already have
formed, but it will stop an existing clot from becoming
worse and prevent future clots

Anticoagulant Drugs
 Heparin and warfarin are the two traditional anticoagula
nts
 Anticoagulants are used for acute coronary syndromes,
deep-vein thrombosis (DVT), pulmonary embolism (PE)
, and heart surgery
 Thrombus - A blood clot that forms abnormally within th
e blood vessels
 Embolus - When a blood clot becomes dislodged from t
he vessel wall and travels through the bloodstream
 It is also given to certain people at risk for forming bloo
d clots, such as those with artificial heart valves or who
have atrial fibrillation (AF)

Warfarin
 Warfarin is an oral medication
 It is a synthetic derivative of co
umarin, a chemical found natur
ally in many plants -- it decrea
ses blood coagulation by interf
ering with vitamin K metabolis
m
 It stops the blood from clotting
within the blood vessels and is
used to stop existing clots from
getting bigger (as in DVT) and
to stop parts of clots breaking
off and forming emboli (as in P
E)

Warfarin
 The most common side effects of warfarin are bleedi
ng and bruising
 The bleeding can be in the form of prolonged bleedin
g from cuts; bleeding that does not stop by itself
 Treatment is monitored by regular blood testing usin
g the International Normalized Ratio (INR), which is
a measure of how much longer it takes the blood to c
lot when oral anticoagulant drug is used

Warfarin
 Warfarin inhibits the effective synthesis of biologically acti
ve forms of the vitamin K-dependent clotting factors: II, VI
I, IX and X, as well as the regulatory factors protein C, pr
otein S and protein Z

Dabigatran etexilate
 It was developed by Boehringer Ingelheim
 Dabigatran etexilate is a new oral direct thro
mbin inhibitor and the prodrug of dabigatran
 Dabigatran is a small molecule that reversibl
y inhibits both free and clot-bound thrombin b
y binding to exosite 1 and/or the active site of
thrombin

Rivaroxaban
 Developed by Bayer
 Rivaroxaban is an orally available, small-molecul
e, active site-directed factor Xa inhibitor
 There are no significant interactions between foo
d, antacids, digoxin, aspirin, naproxen and rivaro
xaban have been noted suggesting that dose adj
ustment of rivaroxaban would not be required wh
en these agents are concurrently administered

Anisindione
 Anisindione (brand name Miradon) is a synth
etic oral anticoagulant and an indanedione d
erivative
 Reduces the prothrombin activity of the blood
 It prevents the formation of active procoagula
tion factors II, VII, IX, and X, as well as the a
nticoagulant proteins C and S, in the liver by i
nhibiting the vitamin K–mediated gamma-car
boxylation of precursor proteins

Dicumarol
 It is a potent oral anticoagulant that acts by inhibiting
the synthesis of vitamin K-dependent clotting factors
(prothrombin and factors VII, IX and X) in the liver; it i
s starting to largely replace warfarin
 Dicumarol is produced naturally by conversion of no
ntoxic coumarin in moldy sweet clover hay, lespepez
a hay or sweet vernal hay
 It is used especially in preventing and treating throm
boembolic disease
 Formerly called bishydroxycoumarin

Heparin
 Heparin is given by injection or drip into a vein
(intravenously) or by injection under the skin
(subcutaneously) for treatment and prevention
 It is derived from porcine intestinal mucosa, standardized fo
r anticoagulant activity
 Heparin works by inhibiting the three major clotting factors (t
hrombin, thromboplastin, and prothrombin)
 It slows the process of thromboplastin synthesis, decelerate
s the conversion of prothrombin to thrombin, and inhibits the
effects of thrombin on fibrinogen, blocking its conversion to f
ibrin
 The agent also causes an increase in the number of negativ
ely charged ions in the vascular wall, which helps prevent th
e formation of intravascular clots.

Low-molecular weight heparin
 Low-molecular weight heparin is gradually re
placing heparin for treatment of most patients
with venous thromboembolism and acute cor
onary syndromes because it has more conve
nient and cost-effective
 It has similar results to heparin
 Administered by subcutaneous
injection
 LOVENOX® is an example

Fondaparinux
 Fondaparinux is given via injection once daily
 It is licensed for initial treatment of deep vein thr
ombosis (DVT) and pulmonary embolism (PE) a
nd for venous thromboembolism prevention in p
atients undergoing surgery for hip fracture or hip/
knee replacement

History of Anticoagulants
 In 1960, DW Barritt and SC Jordan performe
d the first randomized trial showing the effica
cy of anticoagulant therapy in the treatment o
f venous thromboembolism. Since then, impo
rtant therapeutic advances have been made i
n the treatment of deep venous thrombosis a
nd pulmonary embolism.

 Warfarin has been the drug of choice for the
prevention and treatment of arterial and veno
us thrombotic disorders for more than 40 yea
rs
 It was initially marketed as a
pesticide against rats and mice,
and is still popular for this purpose

 Ximelagatran was the first oral direct thrombin inhibit
or and had proven efficacy for prevention and treatm
ent of VTE, stroke prevention with AF and recurrent
coronary events after acute myocardial infarction
 It was initially approved for short-term VTE preventio
n in patients undergoing orthopedic surgery in Europ
e
 It was withdrawn by AstraZeneca in 2006 due to lab
works confirming significant damage to the liver

The future for anticoagulants
 Limitations of warfarin have fostered a great i
nterest in the development of novel anticoag
ulants for oral use to potentially replace warf
arin
 The design of specific inhibitors against mole
cular targets that play a pivotal role in the co
agulation cascade are in development

 Molecular targets are factor IIa (thrombin) an
d factor Xa
 The two candidate compounds, one direct thr
ombin inhibitor (dabigatran etexilate) and one
direct factor Xa inhibitor (rivaroxaban) are ho
ping to be approved as new oral anticoagula
nts in the near future

 Factor Xa is an attractive
target for the design of n
ew oral anticoagulants b
ecause of the unique role
factor Xa plays in the coa
gulation cascade as a co
nnection between the ext
rinsic and intrinsic pathw
ays

 Factor Xa also regula
tes thrombin generati
on via binding to fact
or Va followed by acti
vation of prothrombin
to thrombin

 It is hypothesized tha
t anticoagulants targe
ting factor Xa might b
e more effective than
those targeting coagu
lation factors located
lower down in the cas
cade, such as thromb
in

 This concept has bee
n partially proved whe
n the first indirect fact
or Xa inhibitor, fondap
arinux, received FDA
approval for the preve
ntion and treatment of
VTE.

References
 http://science.jrank.org/pages/419/Anticoagulants-How-works.html
 http://www.rxlist.com/cgi/generic/heparin.htm
 http://asheducationbook.hematologylibrary.org/cgi/reprint/2006/1/450
 http://www.medic8.com/healthguide/articles/warfarin.html
 http://www.wikipedia.com
 http://www.drugs.com
 http://www.pharmgkb.org/do/serve

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