Agents Used in

Coagulation Disorders

dr. Bayu Lestari, M. Biomed

dr. Elly Mayangsari, M. Biomed
 Terminology
 Extrinsic pathway : Factors in tissues that are important in triggering the clotting
process
 Intrinsic pathway : Factors in the plasma that are activated for clotting, eg, VII, IX,
X, II
 Glycoprotein lIb/IlIa : A large protein complex located on the surface of platelets.
When activated by binding to fibrin or several other ligands, it triggers platelet
aggregation
 Antithrombin III (AT III) : An endogenous anticlotting protein that irreversibly
inactivates thrombin and factor X. Its enzymatic action is markedly accelerated by
heparin
 LMW heparins : preparations of heparin fractions of molecular weight 2000-
6000. Regular heparin has a molecular weight range of 15000-30,000
 Partial thromboplastin time (PTT) : Laboratory test used to monitor the
anticoagulant effect of regular heparin; prolonged when drug effect is adequate
 Prothrombin time (PT) : Laboratory test used to monitor the anticoagulant effect
of warfarin; prolonged when drug effect is adequate
ANTICOAGULANTs
Anticoagulants
 Anticoagulants reduce the formation of fibrin clots.
 Two major types of anticoagulants :
- heparin and its derivatives, which must be used
parenterally
- warfarin  the orally active coumarin derivatives

 Two other anticoagulant proteins :

- lepirudin, a recombinant form of hirudin, a protein
found in leech saliva
- human antithrombin III, a commercial preparation of
an endogenous human anticoagulant.
 HEPARIN - chemistry
 Heparin  a large sulfated polysaccharide polymer
obtained from animal sources, MW : 15,000-20,000
 highly acidic and can be neutralized by basic molecules (eg,
protamine)
 must be given parenterally (IV or SC). Intramuscular
injection is avoided because of the risk of hematoma
formation
 Low-molecular-weight (LMW) of heparin (enoxaparin) 
MW of 2000-5000.
 LMW heparins have greater bioavailability and longer
durations of action  doses can be given less frequently
(once or twice a day)  given SC.
 HEPARIN - mechanism
 Heparin:
- direct anticoagulant (in vitro)
- indirect anticoagulant (in vivo) catalyzes the inhibition of several
coagulation proteases by antithrombin III (AT III).
 The heparin-ATIII complex combines with and inactivates thrombin
(activated factor II) and several other factors, especially factor X
 ATIll inhibits in the intrinsic pathways (with heparin 1000-fold faster)
 Estrogen (oral contraception) can reduce activity of ATIII 
thromboembolism !!!!!
 Others act: Heparin release lipoprotein lipase  hydrolize TG and
VLDL
 The action of heparin is monitored with the activated partial
thromboplastin time laboratory test (aPTT or PTT).
 HEPARIN - mechanism
 LMWH (like regular heparin) bind ATIII :
- has same inhibitory effect on factor X
- the short-chain heparin-ATIII complex has a smaller
effect on thrombin (II).

 The aPTT test does not reliably measure

the anticoagulant
effect of the LMW heparins  problem especially in renal
failure (clearance LMWH may be decreased)

 Lepirudin is a powerful and selective thrombin inhibitor

that can inactivate thrombin within a developing clot
 HEPARIN – clinical uses
 when anticoagulation is needed immediately (eg, when
 its rapid effect
starting therapy)  acute

 Common uses : treatment of deep-vein thrombosis (DVT), pulmonary

embolism, and acute myocardial infarction.
 used in combination with thrombolytics for revascularization and in
combination with glycoprotein inhibitors during angioplasty and placement of
coronary stents.
 it does not cross the placental barrier  DOC used in pregnancy

 LMW heparins have similar clinical applications.

 Lepirudin is used for thrombosis and thrombocytopenia as a result of an
antibody-mediated reaction to heparin
 Antithrombin IIl is used for treatment of patients who resistant to heparin
because of a genetic deficiency in antithrombin III (eg, disseminated
intravascular coagulation)
Intravenously :
 The half-life of heparin in plasma depends on the dose

administered: doses of 100, 400, or 800 units/kg of heparin

are injected intravenously  the half-lives are approximately
1, 2.5, and 5 hours, respectively.

Subcutaneously  the onset of action is delayed 1 to 2 hours.

 HEPARIN – adverse effect & toxicity
 the most common adverse effect of regular and
LMW heparins  increased bleeding (in
hemorrhagic stroke), thrombocytopenia

 Tx: stop heparin  antidote : protamin sulfate IV

1mg/100 unit heparin
 WARFARIN - chemistry
 The coumarin anticoagulants (eg, warfarin) are
small, lipid-soluble molecules  readily absorbed
after oral administration.
 They cross the placental barrier readily 
potentially dangerous to the fetus.
 Warfarin is highly bound to plasma proteins (>99%),
and its elimination depends upon metabolism by
hepatic cytochrome P450.
 WARFARIN - mechanism
 Warfarin interfere synthesis of clotting factors in the liver  vitamin
K antagonist  indirect anticoagulant (in vivo)

 The vitamin K- dependent factors : II (thrombin), VII, IX, X

 The action of warfarin can be reversed with vitamin K  requires the

synthesis of new normal clotting factors  slow (6-24 hours)

 rapid reversal  by transfusion with FFP (contains normal clotting

factors)

 The effect of warfarin is monitored by prothrombin time (PT) test

 T1/2 : 40hr
 WARFARIN – clinical uses
 Warfarin is used for chronic anticoagulation except
in pregnant women.
 Long-term prophylaxis of thrombosis
 WARFARIN – adverse effect & toxicity
 Adverse effect : bleeding (in colon)
 Contraindicated in pregnancy
 Antidote : vitamin K

 warfarin has a narrow therapeutic window 

dose !!
WARFARIN – interaction
INCREASING EFFECT
 Interaction with
amiodarone, cimetidine,
disulfiram (inhibitor) 
reduce warfarin's clearance
and increase the
anticoagulant effect
 Deficiency vitamin K
 Liver disease
 Aspirin/NSAID  increase
warfarin effect
DECREASING EFFECT
 Interaction with
barbiturates,
carbamazepine, phenytoin
(inducer)  increase
warfarin's clearance and
reduce the anticoagulant
effect
 Nephrotic sydrome
 Pregnant (fx VII, VIII, IX 
>>)
ANTIPLATELET DRUGs
 Antiplatelet
 Platelet aggregation plays a central role in the
clotting process  coronary and cerebral artery
occlusion.
 Platelet aggregation is facilitated by thromboxane,
adenosine diphosphate (ADP), fibrin, serotonin, etc
 Prostacyclin and increased intracellular cAMP 
change thrombotic reaction  inhibit aggregation.
 Antiplatelet drugs :
- aspirin and other NSAIDs
- dipyridamole
- inhibitors of ADP receptors (ticlopidine and
clopidogrel)
- glycoprotein llb/IIIa receptor inhibitors
(abciximab, tirofiban, and eptifibatide)

 These drugs increase bleeding time

 Mechanism
 Aspirin and other NSAIDs inhibit thromboxane synthesis by
blocking the enzyme cyclooxygenase.
 Thromboxane A2 is a potent stimulator of platelet
aggregation.
 Aspirin is particularly effective because it irreversibly
inactivates the enzyme  inhibition by aspirin persists until
new platelets are formed (several days).
 Other NSAIDs cause a less persistent antiplatelet effect
(hours).
 Sulfinpirazon: not inhibit platelet aggregation, but inhibit
platelet adhesion
Prothrombotic Effects of COX-2 Selective
Inhibitor
 Mechanism
 Prostasiklin (Epoprostenol) : potent inhibitor of platelet aggregation 
t1/2 : short  bypass operation

 Ticlopidine's and clopidogrel's mechanism of action involvesirreversible

inhibition of the ADP-receptor  inhibition of ADP-mediated platelet
aggregation.

 Abciximab is a monoclonal antibody that reversibly inhibits the binding of

fibrin and other ligands to the platelet glycoprotein IIb/IIIa receptor
 Eptifibatide and tirofiban also reversibly block the glycoprotein IIb/IIIa
receptor.

 The mechanism of dipyridamole is not well understood  may increase

cAMP in platelets by inhibiting phosphodiesterases  vasodilator
 Clinical uses
 Aspirin is used to prevent further infarct, to reduce the incidence
of first infarcts, to prevent transient ischemic attacks (TIAs),
ischemic stroke, and other thrombotic events.

 Clopidogrel and ticlopidine are effective in preventing transient

ischemic attacks and ischemic strokes, especially in patients who
cannot tolerate aspirin
- prevent thrombosis in patients who have recently received a
coronary artery stent.

 The glycoprotein IIb/IIIa inhibitors

prevent restenosis after
coronary angioplasty and are used in acute coronary syndromes
(eg, unstable angina and non-Q wave acute myocardial infarction).
Role of Aspirin and CPG
on ACS (Acute Coronary
Syndrome) Patients
 Adverse effect & Toxicity
 All antiplatelet drugs significantly enhance the
effects of other anticoagulant agents.
 Aspirin and other NSAIDs cause gastrointestinal
bleeding and CNS effects
 Ticlopidine causes bleeding and severe
neutropenia
 Clopidogrel may be less hematotoxic.
 The major toxicities of the glycoprotein Ilb/IIIa
inhibitor drugs are bleeding and thrombocytopenia
(chronic uses)
THROMBOLYTIC /FIBRINOLYTIC
AGENTs
 Thrombolytic/Fibrinolytic
 The thrombolytic drugs :
- urokinase
- streptokinase
- alteplase and reteplase (forms of tissue
plasminogen activator, t-PA)
-anistreplase

 All are given intravenously.

Fibrinolytic system
 Mechanism
 Plasmin is the normal endogenous fibrinolytic enzyme.
 By splitting fibrin into fragments, plasmin promotes the
breakdown and dissolution of clots

 Urokinase is extracted from cultured human kidney cells.

Like t-PA, this human enzyme directly converts
plasminogen to plasmin

 Streptokinase is obtained from bacterial cultures.

It forms a complex with endogenous plasminogen 
catalyzes the rapid conversion of plasminogen to plasmin.
 t-PA is a large human protein that directly converts fibrin-bound plasminogen to
plasmin.
- This selectivity for plasminogen that has already bound to fibrin (ie, a clot) 
greater selectivity and less danger of spontaneous bleeding
- t-PA's selectivity appears to be quite limited.

 AIteplase is normal human plasminogen activator.

 Reteplase is a mutated form of human t-PA with similar effects but a slightly
faster onset of action and longer duration of action.

 Anistreplase  anisoylated plasminogen-streptokinase activator complex

(APSAC) is a prodrug.
- hydrolyzed in vivo (a slow, spontaneous process)
- streptokinase-activated plasminogen is released and converts endogenous
plasminogen to plasmin.
- slow release  long half-life
 Clinical uses
 The major application of the thrombolytic agents is
in the emergency treatment of coronary artery
thrombosis.
 also used in cases of multiple pulmonary emboli.
 Contraindication : cerebral hemorrhage
 Adverse effect & Toxicity
 Adverse effect : bleeding
 Cerebral hemorrhage is the most serious
manifestation

 Streptokinase, a bacterial protein  antigenic 

induces severe allergic reactions
 Human proteins (urokinase and t-PA) and
anistreplase are much more expensive than
streptokinase and not much more effective.
 DRUGS USED IN
BLEEDING DISORDERs
 Inadequate blood clotting may result from vitamin K deficiency ,
cause :
- genetically determined errors of clotting factor synthesis (eg,
hemophilia)
- a variety of drug-induced conditions
- thrombocytopenia.

 Treatment :
- administration of vitamin K
- preformed clotting factors
- antiplasmin drugs

Thrombocytopenia may be treated by administration of platelets.

 Vitamin K
 a fat-soluble vitamin
 Deficiency of vitamin K  common in new borns and in older
individuals with abnormalities of fat absorption.

 Treated with oral or parenteral vitamin K supplements using :

 K1 (phytomenadione) from chlorophyllous plants

 K2 from gut bacteria

 K3 (menadione) synthesized chemically.

 Large doses of vitamin K1 are used to reverse the

anticoagulant effect of excess warfarin.
 Clotting factors
 Agent : fresh plasma and purified human blood
clotting factors, especially factor VIII and factor IX
 Function : to treat hemophilia

 These products are extremely expensive and carry a

risk of infection (due to contamination by blood-
borne pathogens) and immunologic reactions.
 Antiplasmin agents
 Antiplasmin agents  management of acute
bleeding episodes in hemophiliacs and others with
bleeding disorders.
 Aminocaproic acid and tranexamic acid are orally
active agents that inhibit fibrinolysis by inhibiting
plasminogen activation