Anticoagulants

&
Antiplatelets
NOOR WIJAYAHADI

Terminologies
Antithrombotics = Drugs which
interfere with platelet functions
Anticoagulants = Drugs used to
reduce the coagulability of blood
Thrombolytics (Fibrinolytics) =
Drugs used to lyse thrombin clot
(mainly therapeutic)

The Coagulation and Fibrinolytic Pathways

HEPARIN vs Activated clotting factors

Simplified View of the Coagulation Cascade

Extrinsic

Intrinsic

Common

Prothrombin Time
Extrinsic pathway
Monitor warfarin
INR

Activated Partial
Thromboplastin Time
Intrinsic pathway
Monitor heparin

Clotting Cascade

Thrombosis - Pathogenesis
3 primary
influences
predispose to
thrombus formation
Virchows Triad
(1856):

1.Endothelial Injury
2.Stasis
3.Hypercoagulability

Blood Clotting
Vascular Phase
Platelet Phase
Coagulation Phase
Fibrinolytic Phase

Vascular Phase
Vasoconstriction
Exposure to tissues activate
Tissue factor and initiate
coagulation

Tissue Factor

Platelet phase
blood vessel wall (endothelial cells) prevent

platelet adhesion and aggregation

platelets contain receptors for fibrinogen and von

Willebrand factor
after vessel injury Platelets adhere and

aggregate.
Release permeability increasing factors (e.g.

vascular permeability factor, VPF)

Loose their membrane and form a viscous plug

Coagulation Phase
Two major pathways
Intrinsic pathway
Extrinsic pathway
Both converge at a common point
13 soluble factors are involved in clotting
Biosynthesis of these factors are dependent on Vitamin K1
and K2
Normally inactive and sequentially activated
Hereditary lack of clotting factors lead to

hemophilia -A

Intrinsic Pathway
All clotting factors
are within the blood
vessels
Clotting slower

Activated partial
thromboplastin test
(aPTT)

Extrinsic Pathway
Initiating factor is
outside the blood
vessels - tissue factor
Clotting - faster - in
Seconds
Prothrombin test (PT)

Intrinsic Pathway

Extrinsic Pathway
Tissue Injury

Blood Vessel Injury

Tissue Factor

XIIa

XII

Thromboplastin

XIa

XI

IXa

IX

Xa

Factors affected

VIIa

Prothrombin

By Heparin

Vit. K dependent Factors

Affected by Oral Anticoagulants

Fibrinogen
XIII

VII

X
Thrombin
Fribrin monomer
Fibrin polymer

Functions of Platelet
Plug formation by passive
agglutination and active
aggregation later reinforced
by fibrin
Exposure of PF3 which is clotting
factor III
Mechanical clot retraction
involving platelet actin and
myosin - strengthens clot
Active biochemicals from

Antiplatelet activity in the body

Invivo blockers of platelet
aggregation

Produced in vascular
endothelium
pathway

PGI2* through cAMP*

NO through cGMP pathway

Anticoagulant drugs
Drug Class Prototype
Anticoagulant
Parenteral
Anticoagulant
Oral

Antiplatelet
drugs
Thrombolytic
Drugs

Action

Effect

Heparin

Inactivation of clotting
Factors

Prevent venous
Thrombosis

Warfarin

Decrease synthesis of
Clotting factors

Prevent venous
Thrombosis

Aspirin

Decrease platelet
aggregation

Streptokinase

Fibinolysis

Prevent arterial
Thrombosis
Breakdown of
thrombi

Atherosclerotic Plaque Disruption and Platelet Activation

Mohler E. N Engl J Med 2007;357:293-296

Sites of Action

Schulman, S. P. JAMA 2004;292:1875-1882.

Copyright restrictions may apply.

Antiplatelet

NSAIDS inhibit cyclooxygenase and

decrease TxA2 synthesis (irreversibly with
Aspirin)
Ticlopidine and Clopidogrel ADP induced
platelet aggregation & platelet-fibrinogen
interaction irreversibly blocked
Cilostazol: PDIII inhibitor increases
cytoplasmic cAMP
GP IIb/IIIa blockers : Abciximab,Eptifibatide,
Tirofiban
Dextran : interferes with platelet aggregation

Antiplatelet phamaceuticalscontd
Dipyridamole
# Increases PGI2 release from the endothelium

# Inhibits platelet phosphodiesterase - builds up platelet

cAMP and decreases cytoplasmic Ca2+
# Inhibits RBC uptake of adenosine* which is an
of platelet reactivity

inhibitor

# Inhibits the formation of TxA2 by blocking Tx synthetase

Antiplatelet drugs
Example: Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve
replacement and shunts

Other antiplatelet drugs are - Dipyridamole,

sulfinpyrazone and Ticlopidine

Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the
synthesis of thromboxane 2
(prostaglandins)
Inhibits platelet aggregation

Prophylactic use of Aspirin

Low dose daily.
Prevents ischemic attack (ministroke) and MI
335 mg/day reduced the risk of heart attack in
patients over 50
More than 1000 mg/day NO EFFECT
Contraindication - DO NOT give to patients with
glucose 6-PO4 dehydrogenase deficiency

Coagulation Cascade
Three steps:
Initiation Phase:
Starts with VIIa/TF
Ends with formation of IIa

Amplification Phase
Activation of V, VIII, XIII, XI and Fibrinogen by
IIa, if the IIa is not neutralised by ATIII or
Thrombomodulin

Propagation Phase
Refers to the phase during which activated
factors Va, VIIIa, and IXa attach to the platelets
and the platelets release PF3

In-vivo Antithrombotic Mechanisms

Antithrombin III
Inhibits IIa, IXa, Xa, XIa, XIIa, XIIIa and Plasmin by binding to
their active site
When heparin bind to AT III the active sites of the clotting
factors are further compromised
Acquired AT III deficiency: DIC, OCP, sepsis, c/c heparin Rx

Protein C & S
Protein Ca
Va & VIIIa inactivation
IIa + Protein C
Protein S is a co-factor for activated Protein C (Protein C a)

Tissue factor pathway inhibitor (TFPI)

Inhibits VIIa/TF complex and Xa
Circulates in Plasma or contained in Platelets or on
Endothelium
Heparin may release it from the surface of endothelial cells

Fibrinolysis

The Fibrinolytic System

Plasminogen
tPA

Urokinase (endothelium)
PAI-2

PAI-1
Thrombin
(IIa)

Plasmin
(2 antiplasmin) PI
fibrin polymer

Cross-linked

Fibrinogen
fibrin
Polymer

FDP

D-Dimer

Anticoagulant pharmaceuticals
Standard Heparin (Unfractionated Heparin)
(mol.wt 5000- 30,000 Da; av.15,000 Da)
Derived from porcine intestinal mucosa or beef
lung, prepared as Na+ or Ca2+salts
AT III inhibits IIa, IXa, Xa, XIa, XIIa, XIIIa and
Plasmin by binding to their active site. When
heparin binds to AT III the active sites of the
clotting factors are further compromised
Routes: IV, SC, Intra nasal. Never IM or Oral*
Peak plasma levels after SC inj. 2-4 hrs.
Strongly anionic, hence rapidly bound to
proteins.t1/2 90 min

Heparincontd
Complications
Hemorrhageesp. intracranial, intraspinal,
intraocular
Heparin resistanceseen in a/c thrombotic
processes with consumption of AT III. Rx FFP !!
Maternal osteoporosis on c/c use
HIT Syndrome: spectrum
Thrombocytopenia without thrombosis
Hypotension & Transient reversible platelet
aggregation
Irreversible platelet aggregation: White clot
syndrome

Heparin antibodies

LMWH
M.Wt 2000-8000 Da ( avg 4500 Da )- prepared from
SH by fractionation, enzymatic degradation or chem
modifn
Commercial preprn : Enoxaparin, Dalteparin,
Ardeparin, Tinzaparin, Fondaparinux
Routes : SC (OD)
High anti-Xa and low anti-IIa activity greater
antithrombotic and lower anticoag activity
Low anti-IIa activity, hence, aPTT, TT, ACT not ideal
for monitoring. Anti-Xa assay ideal
Less complicated, dose independent clearance and
more predictable anticoagulant response than SH.
Hence lab monitoring not required
Fondaparinux: synthetic, specific inhibitor of Xa,
used for Px in THR & TKR. Long elimination t 1/2 (20
hrs). Renal clearance

Anticoagulation with SH & LMWH

contd

Other uses:

To prevent catheter thrombosis: 2-5 U/ml

If sample collected from indwelling catheter,
blood to be discarded prior to collection of
the sample = 3 times the volume of catheter.
For ABG: 1000 U/ml. Dont exceed 1/10th the
volume of blood, since heparin is itself
acidic. may alter results
Temporary vascular occlusion: 100 U/kg
For CPB & ECMO: 300 U/kg. Monitor ACT.
Reverse with Protamine 1mg / 100 U Heparin

Coumarin derivatives
Dicumarol and Warfarin
Indirect anticoagulants- interfere with hepatic
synthesis of Vit K- dependent clotting factors
Used for Px and Rx in thrombophlebitis, AF,
PTE, AMI, mechanical prosthetic valves and
valvular heart disease
A typical regimen: warfarin started at 5mg/day x
7days, then maintenance dose 2.5 to 7.5 mg OD
depending upon required INR
Monitored using Prothrombin time & INR

Factors affecting coumarin potency

INCREASE PT
Reduced clearance
Disulfiram
Metronidazole
cotrimoxazole

Reduced albumin
binding
Phenylbutazone

Additive hemostatic
effect
Aspirin, Heparin
Liver disease,
Vit. K deficiency

Incresed turnover of
Vit.K
Clofibrate,
Hypermetabolic state

DECREASE PT
Accelerated clearance
Barbiturates
Rifampin

Reduced absorption
Cholestyramin

Coumarin resistance

Fibrinolytics
Plasminogen activators
Preparations:

Anistreplase (t 100 minutes)

Streptokinase (t 83 minutes)
Urokinase (t 20 minutes)
Reteplase (t 15 minutes)
Alteplase (t 3 minutes)

Streptokinase:
bacterial enzyme
indirect activator of plasminogen: SK first forms a complex with
Plasminogen. It is this complex which activates subsequent
plasminogen.
Dose in AMI: 1.5 million units I.V over 1 hour

Urokinase:
product of renal tubular cell
direct activator of plasminogen.

Fibrinolyticscontd..

Major problem: hemorrhage

Causes:
NOT related to residual activity
Defective fibrin polymerisation due to FDPs: can be a
problem upto 24 hrs despite t1/2 of 3 hrs
Platelet aggregation inhibition by FDPs
Decreased concentration of factors I,V & VIII

Rx of hemorrhage due to fibrinolytics:

Discontinue administration
Antagonise residual effect: Aprotinin or EACA
After residual effect wanes: FFP / Cryoppt

Fibrinolyticscontd..

Some basic facts to be remembered:

Heparin should be added in the post-thrombolytic
pd. till hospitalised followed by warfarin therapy till
3 months, as Plasminogen is most effective if it lies
within the fibrin matrix during clot formation. Clots
formed during the period of thrombolysis are
resistant to subsequent thrombolysis.
Reperfusion arrhythmia: so must repeat an ECG
post-thrombolysis
Avoid coughing, straining, HTN post-thrombolysis
No IM inj.
Sampling through indwelling catheters
Lower limb BP cuffs: risk of embolisation of
dissolving clots
Local infusions of thrombolytics may have major
systemic effects: Do Not Underestimate !

Fibrinolyticscontd..
Contraindications:
Absolute

Cerebrovascular hmg at any time

Non hmgic stroke or other CVA within past year
SBP >180mmHg; DBP >110 mmHg
Suspicion of Aortic dissection
Active internal bleeding (excluding menses)

Relative

INR 2 on current anticoagulant

Recent (< 2 wk.) history of surgery or invasive procedure
Prolonged ( > 10 min )CPCR
Known bleeding diathesis
Pregnancy
Hmgic ophthalmic condition (eg. hmgic diabetic
retinopathy)
Active peptic ulcer
history of severe HTN, now adequately controlled
history of having received SK within 5 days to 2 years

Neuraxial block along with

anticoagulants: Recommendations
Antiplateles

NSAIDs alone and NAB are compatible

The effect of ticlopidin and clopidogrel should be
allowed to dissipate (7 days) before NAB
GPIIb/IIIa inhibitors: NAB 8 hrs after tirofiban and
eptifibatide, and 48 hrs after abciximab
Concurrent use of SH, LMWH, or anticoagulants
increase the risk of bleeding (holds true for all
subsequent anticoagulants)

Fibrinolytics

NAB not recommended upto 10 days

If NAB is undertaken, monitor neurologically atleast
q2h
Confirm adequate fibrinogen and low FDP levels
before removing the catheters

contd..
Oral anticoagulants
Stop anticoagulants and allow normalization of INR
prior to performance of NAB
Preop warfarin: if initial dose >24 hrs earlier or a
second dose was given, check INR before NAB
Warfarin @ 5mg/day for >36 hrs and receiving
epidural analgesia should have INR checked daily
and before catheter removal
If epidural catheter present, withold / reduce
warfarin if INR > 3
Remove catheter if INR < 1.5
If INR > 1.5 and catheter removed, monitor
neurologically for at least 24 hrs.

Contd..
Standard heparin
Minidose, SC
No CI to performance of NAB
Consider delaying initiation of heparin till after
institution of the NAB
After 4 days of SH confirm whether HIT has occurred

I.V Heparin for intraop anticoagulation

A gap of 4-6 hrs required between heparin and NAB
Consider minimal concentrations of local anesthetics to
permit early detection of neurological changes
Delay initiating heparin till 1 hr after needle placement
for NAB
Remove epidural cath 1 hr before any subsequent i.v
dose of heparin (assuming 12 hrly dosing ) or 4 hr after
the last dose of heparin
Difficult needle placement / bloody tap not an indication
for cancellation, but frequent postop monitoring of
neurological status mandatory

contd..

LMWH
A gap of 24 hrs required between Fondaparinux administration
and NAB. For catheter removal same interval recommended
A gap of 12 hrs required between LMWH and performance of
NAB. In renal failure the interval should be longer (16-18 hrs)
Remove epidural cath 24 hr after last dose of LMWH and do not
administer subsequent dose for next 2 hr
Difficult needle placement / bloody tap not an indication for
cancellation, but important to delay subsequent dose of LMWH
for 24 hrs
Consider minimal concentrations of local anesthetics to permit
early detection of neurological changes
Consider single dose SAB

Prompt recognition of epidural hematoma is confirmed

by CT or MRI followed by emergency decompressive
laminectomy within 8 hrs

Anticoagulants and periop

considerations

Advantages of stopping an anticoagulant should

outweigh the risks
Postop bleeding due to warfarin administration is
rarely fatal or associated with major morbidity
whereas the consequences of venous or arterial
embolism may be fatal
Anticoagulation decreases the risk of VTE by 80%,
the risk of arterial TE in patients with mechanical
heart valves by 75%, and risk of ATE in patients with
nonvalvular AF by 66%
Rebound hypercoagulation state may develop by
discontinuing warfarin, super-added by the
prothrombotic effect of surgery .
Surgery increases risk of VTE but not ATE in patients
with AF or mechanical heart valves

Patients on warfarin periop

In cases where change over to alternative anticoagulant not
done before sx:
INR 2-3: 4 scheduled doses of warfarin withheld to allow
INR to fall to 1.5 before sx
INR measured day before sx to see response
If INR 1.8 at this time, inj. Vit. K SC (not IM)
If INR 1.5 perform surgery
After surgery:
Warfarin takes 3-4 days to reach INR to 2. So Rx started
soon after surgery
With the above regimen patients can have subtherapeutic
levels for 2 days before and after surgery. Yet these levels
can still provide partial protection against thromboembolism

Patient on warfarin for VTE

During first 30 days:

Elective surgery should be avoided

If not possible, substitute with I.V Heparin before and after
surgery while INR <2
If PTT within Rxic range, stop heparin 4-6 hrs prior to
surgery
Restart Heparin 4-6 hrs after surgery, but do not infuse @
greater than the maintenance rate for about 12 hrs. Should
be delayed even longer if evidence of surgical bleed
PTT rechecked 12 hrs after restarting heparin

After 30 days:

Discontinue warfarin 4 days prior

Need not start I.V Heparin preop
I.V Heparin must be started postop and continued till
warfarin takes effect and INR 2.0

Mechanical Px should be combined

Patients on other anticoagulants

Clopidogrel: should be stopped 7
days before surgery. Aspirin can
be substituted safely
GPIIb/IIIa inhibitors:
contraindicated upto 6 wks after
major trauma or surgery
Fondaparinux: administered 6
hrs after surgery

What if?
Emergency surgery ?
Aspirin- not much bleeding
Clopidogrel- platelet concentrates.
UFH poses not much problem- can
be stopped 4 hrs prior. May be
reversed with protamine. FFP may
be administered
LMWH: needs to be stopped 12 hrs
earlierwhat if accompanied by
renal failure?
Warfarin: now u have a problem. Vit
K starts to act within 8-12 hrs
what route will u give? Menadione

Stead L and Judson K. N Engl J Med 2006;355:e7

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

Fibrinolysis
Exogenously administered drugs
Streptokinase - bacterial product
- continuous use - immune reaction

Urokinase - human tissue derived

no immune response

Tissue plasminogen activator (tPA) - genetically

cloned
no immune reaction
EXPENSIVE

Drug preparations : To reduce

clotting
Heparin (generic, Liquaemin sodium)
Parenteral - 1000 - 40,000 U/ml

Warfarin (generic , Coumadin)

Oral : 2 - 20 mg tablets

Dipyridamole (Persantine)
Oral : 25,50,75 mg tablets

Drug preparations : to lyse clots

Alteplase recombinant (tPA, Activase)
20, 50 mg Lyophilized powder - reconstitute
for iv

streptokinase (Kabikinase, streptase)

Parenteral : 250000 - 1.5 million units per
vial . Lyophilized powder. Reconstitute for iv

Urokinase ( Abbokinase)
Parenteral : 250000 units per vial. Powder to
reconstitute to 5000 u/ml for injection

Drug preparations: clotting

deficiencies
Vitamin K ( Phytonadione (K1), Mephyton
Oral : 5 mg tablets

Plasma fractions - for hemophilia

Antihemophilic factor ( VIII, AHF)
Parenteral

Factor IX complex (konyne HT, proplex T)

Parenteral : in vials

Drug preparations : to stop

bleeding
Systemic use : aminocaproic acid (Amicar);
Tranexamic acid (cyclokapron),Vitamin K
Local adsorbable drugs

Gelatin sponge (Gelfoam)

Gelatin film
Oxidized cellulose ( Oxycel)
Microfibrillar collagen (Avitene)
Thrombin