DRUGS USED IN

COAGULATION
DISORDERS

A. Q. Sangalang, MD, FPOGS, RMT

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
 DRUGS USED IN COAGULATION AND BLEEDING
DISORDERS

MECHANISM OF BLOOD COAGULATION

Vascular endothelial cell layer lining blood vessels

• Anticoagulant phenotype
• Blood platelets and clotting factors do not normally adhere to it

In cases of vascular injury

• It undergoes change to a more procoagulant phenotype
● Platelet adherence and activation
● Secretion and synthesis of vasoconstrictors and platelet activating molecules
 DRUGS USED IN COAGULATION AND
BLEEDING DISORDERS

MECHANISM OF BLOOD COAGULATION

Thromboxane
• Synthesized from arachidonic acid within platelets
• Platelet activator and potent vasoconstrictor

Adenosine diphosphate (ADP)Loading...

• Product secreted from platelet granules
• Powerful inducer of platelet aggregation
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MECHANISM OF BLOOD COAGULATION

Serotonin (5 HT)
• Product secreted from platelet granules
• Stimulates aggregation and vasoconstriction

Glycoprotein IIb/IIIa
• Receptor changes its conformation upon activation of platelets enabling it to
bind fibrinogen
• Cross-links adjacent platelets resulting in aggregation and platelet plug
formation
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AND BLEEDING DISORDERS

MECHANISM OF BLOOD COAGULATION

Coagulation system is then activated resulting in thrombin generation and

fibrin clot formation

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 DRUGS USED IN COAGULATION
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MECHANISM OF BLOOD COAGULATION

Tissue factor (TF)
• Main initiator of blood coagulation in vivo
• Expressed outside the blood vessel but not normally expressed in an active
form within the vessel
• Damaged endothelium allows binding of TF to factor VIIa (proconvertin)
forming a complex
DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

BLOOD COAGULATION
CASCADE
 DRUGS USED IN COAGULATION
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MECHANISM OF BLOOD COAGULATION

Fibrinolysis
• Process of fibrin digestion by the fibrin-specific protease, plasmin
DRUGS USED IN COAGULATION
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 DRUGS USED IN COAGULATION
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Primary Groups of Drugs used in Clotting and Bleeding Disorders

• Drugs used in patients at risk for vascular occlusion to decrease clotting or
dissolve clots already present
• Drugs used to increase clotting in patients with clotting deficiencies

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 DRUGS USED IN COAGULATION
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Primary Groups of Drugs used in Clotting and Bleeding Disorders

• Anticlotting drugs
● Myocardial infarction and other acute coronary syndromes
● Atrial fibrillation
● Ischemic stroke
● Deep vein thrombosis (DVT)
● Effective in treatment of both venous and arterial thrombosis
● Used for the treatment of arterial disease
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Primary Groups of Drugs used in Clotting and Bleeding Disorders

• Anticoagulants and thrombolytic drugs
● Effective in treatment of both venous and arterial thrombosis
• Antiplatelet drugs
● Used for the treatment of arterial disease
DRUGS USED IN COAGULATION
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 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

ANTICOAGULANTS
• Classification
• 3 major types of anticoagulants
● Indirect thrombin inhibitors
● Heparin and related product
● Given IV
● Direct thrombin inhibitors
● Given IV
● Coumarin derivatives
● Warfarin
● Orally active
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Chemistry
Unfractionated Heparin (UFH) High Molecular-Weight Heparin (HMWH)
• Large sulfated mucopolysaccharide polymer
• Obtained from animal sources
• Contains molecules of varying size
● Average molecular weight of 5,000-30,000 per batch
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DRUGS USED IN COAGULATION

AND BLEEDING DISORDERS

ANTICOAGULANTS
• Indirect thrombin inhibitors
• Chemistry
Unfractionated Heparin (UFH) High Molecular-Weight Heparin (HMWH)
• Highly acidic
• Neutralized by basic molecules (e.g., protamine)
• Given parenterally
● IV or subcutaneously
• Intramuscular injection is avoided
● Risk of hematoma formation
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Chemistry
Low-Molecular-Weight Heparin (LMWH)
• Enoxaparin, dalteparin, tinzaparin
• Have molecular weights of 2000-6000
• Have equal efficacy, greater bioavailability and longer durations of action
than regular heparin
• Can be given less frequently (once or twice a day)
• Given subcutaneously
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Chemistry
Fondaparinux
• Small synthetic drug
• Contains the key pentasaccharide present in unfractionated and LMW heparins
• Administered subcutaneously once daily
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Chemistry
Danaparoid
• LMW heparinoid containing heparan, dermatan and chondroitin sulfates
• Chemically distinct from heparin (no cross-hypersensitivity)
• Can be given intravenously or subcutaneously
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Mechanism and effects
Unfractionated heparin
• Binds to endogenous antitrhrombin II (ATIII) via a key saccharide sequence
• ATIII
● Inhibits clotting factor proteases especially thrombin (IIa), Ixa and Xa
● In the absence of heparin, these reactions are slow
● In the presence of heparin, they are accelerated 1000-fold
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Mechanism and effects
Unfractionated heparin
• Provides anticoagulation immediately after administration
• Monitored with the activated partial thromboplastin time (aPTT) or partial
thromboplastin time (PTT) laboratory test
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Mechanism and effects
LMW heparins and fondaparinux
• Bind to ATIII
• Same inhibitory effect on factor Xa as the regular heparin-ATIII complex
• More selective action because they fail to affect thrombin (IIa)
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Mechanism and effects
LMW heparins and fondaparinux
• Weight-based dosing results in predictable pharmacokinetics and plasma
levels
• Levels are not measured except in renal insufficiency, obesity and pregnancy
• aPTT test does not reliably measure the anticoagulant effect of the LMW
heparins and fondaparinux
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 DRUGS USED IN COAGULATION
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Clinical use
Heparin
• Used when anticoagulation is need immediately (e.g., when starting therapy)
• Common uses
● DVT
● Pulmonary embolism
● Acute myocardial infarction
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Clinical use
Heparin
• Combined with thrombolytics for revascularization
• Combined with glycoprotein IIB/IIIa inhibitors during angioplasty and
placement of coronary stents
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Clinical use
Heparin
• Does not cross the placental barrier
● Drug of choice in pregnancy
• LMW heparins and fondaparinux
● Similar clinical applications
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Toxicity
Increased bleeding

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• Most common adverse effect
• May result in hemorrhagic stroke
Protamine sulfate
● Highly basic peptide that combines with heparin
● Forms a stable complex devoid of anticoagulant activity
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Toxicity
Protamine sulfate
● 1 mg given IV/10 units of heparin left in the patient
● Not to exceed 50 mg in any 10 minute period
● Only partially reverses the effects of LMW heparins
● Does not affect the action of fondaparinux
● Excess danaparoid is removed by plasmapheresis
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Toxicity
Heparin-Induced Thrombocytopenia (HIT)
● Occurs in 1-4% of patients treated for a minimum of 7 days
● Hypercoagulable state
● Produce an antibody that binds to a complex of heparin and platelet factor
● Treated by discontinuance of heparin and administration of a direct
thrombin inhibitor or fondaparinux
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ANTICOAGULANTS
• Indirect thrombin inhibitors
• Toxicity
• LMW heparins, fondaparinux and danaparoid
● Less likely to cause this immune-mediated
thrombocytopenia
• Prolonged use of regular heparin is associated with
osteoporosis and spontaneous fractures
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Chemistry and pharmacokinetics
• Bind directly to the active site of thrombin inhibiting its downstream effect
• Derived from proteins made by Hirudo medicinalis, the medicinal leech
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Chemistry and pharmacokinetics
Hirudin
• Specific irreversible thrombin inhibitor from leech saliva
• Given IV
• Monitored by aPTT
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Chemistry and pharmacokinetics
Lepirudin
• Recombinant form of the leech protein hirudin
• Given IV
• Excreted by the kidneys
● Can accumulate in patients with renal failure
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Chemistry and pharmacokinetics
Bivalirudin
• Modified form of hirudin
• Given IV
• Rapid onset and offset of action
• Clearance is 20% renal and the remainder is
metabolic
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Chemistry and pharmacokinetics
Argatroban
• Small molecule
• Clearance not affected by renal disease
• Dependent on liver function
● Can accumulate in patients with liver disease
• Administered parenterally
• Monitored by aPTT
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Mechanism and effects
Lepirudin and bivalirudin
• Bind simultaneously to the active site of thrombin and to thrombin substrates
Bivalirudin
• Also inhibits platelet activation
Argatroban
• Binds solely to thrombin
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Mechanism and effects
• Inhibit both soluble thrombin and the thrombin enmeshed within developing
clots
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Clinical use
• 3 drugs monitored using aPTT lab test
Lepirudin and argatroban
• Alternatives to heparin in patients with HIT
Bivalirudin
• Used in combination with aspirin during percutaneous transluminal coronary
angioplasty
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Parenteral Direct Thrombin Inhibitors
• Toxicity
• Can cause bleeding
• No reversal agents exist
• Prolonged infusion of lepirudin
● Induce formation of antibodies that form a complex and prolong its
action
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Oral Direct Thrombin Inhibitors
Advantages
• Predictable pharmacokinetics and bioavailability
● Fixed dosing
● Predictable anticoagulant response
• Routine coagulation monitoring is unnecessary
• Do not interact with CP450-interacting drugs
• Rapid onset of action
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ANTICOAGULANTS
• Direct Thrombin Inhibitors
Oral Direct Thrombin Inhibitors
Ximelagatran
• First oral drug approved
• Withdrawn due to hepatic toxicity
Dabigatran
• Equivalent efficacy and safety to LMWH
• Prevention of venous thromboembolism in patients who underwent hip or
knee replacement surgery
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ANTICOAGULANTS
• Coumarin anticoagulants
• Chemistry and pharmacokinetics
Warfarin
• Small, lipid-soluble molecules that are readily absorbed after oral
administration
• Cross the placenta
● Potentially dangerous to the fetus
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ANTICOAGULANTS
• Coumarin anticoagulants
• Chemistry and pharmacokinetics
Warfarin
• One of the most commonly prescribed drugs
• Administered as a sodium salt with 100% bioavailability
• Highly bound to plasma proteins (>99%)
• Half-life of 36h
 DRUGS USED IN COAGULATION
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ANTICOAGULANTS
• Coumarin anticoagulants
• Chemistry and pharmacokinetics
Warfarin
• Racemic mixture
● S-warfarin is 4x more potent than the R-warfarin
• Elimination depends on metabolism by CP450 enzymes
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Warfarin and other coumarins
• Interfere with the normal posttranslational modification of clotting factors in
the liver
● Process that depends on vitamin K
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Warfarin and other coumarins
• Blocks the alpha carboxylation of several
glutamate residues in prothrombin and
factors II, VII, IX, X
• Results in incomplete coagulation
molecules that are biologically inactive
 DRUGS USED IN COAGULATION
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Warfarin and other coumarins
• Half-lives of 8-60 h
● Anticoagulant effect is observed only after sufficient time has passed for
the preformed normal factors to be eliminated
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Warfarin and other coumarins
• Monitored by the prothrombin time (PT or “pro-time”) test
● Should be increased to a level representing reduction of prothrombin
activity to 25% of normal
● Therapeutic range is defined in terms of international normalized ratio
(INR)
● Prothrombin time ratio
● Patient prothrombin time/mean of normal prothrombin time for lab
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Vitamin K-dependent factors
• VII
• IX Half-lives of 6, 24, 40,and 60 h in plasma
• X respectively
• II
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ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Reversal of the action of warfarin
• Stop the drug
• Administer oral or parenteral vitamin K1
● Phytonadione
• Recovery is slow
● Requires the synthesis of new normal clotting factors
● 6-24 h
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Reversal of the action of warfarin
• More rapid reversal can be achieved by transfusion with fresh or frozen
plasma that contains
● Normal clotting factors
● Prothrombin complex concentrates
● Recombinant factor VIIa
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AND BLEEDING DISORDERS

ANTICOAGULANTS
• Coumarin anticoagulants
• Mechanism and effects
Reversal of the action of warfarin
• Disappearance of excessive effect
● Not correlated with warfarin concentration
● Reestablishment of normal clotting activity
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ANTICOAGULANTS
• Coumarin anticoagulants
• Clinical use
• Chronic anticoagulation in all of the clinical situations described previously
for heparin
• Contraindicated in pregnant women
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ANTICOAGULANTS
• Coumarin anticoagulants
• Toxicity
Bleeding
• Most important adverse effect of warfarin
Early in therapy
• Hypercoagulability with subsequent dermal vascular necrosis can occur
● Due to deficiency in protein C
● Endogenous vitamin K dependent anticoagulant
● Very short half-life
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

ANTICOAGULANTS
• Coumarin anticoagulants
• Toxicity
• Can cross the placenta
● Hemorrhage in the developing fetus
● Abnormal bone formation
• Has a narrow therapeutic window
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ANTICOAGULANTS
• Coumarin anticoagulants
• Drug interactions
• Cytochrome P450-inducing drugs
Increase warfarin’s clearance
Reduce the anticoagulant effect of a given dose
Barbiturates, carbamazepine, phenytoin, rifampin
 DRUGS USED IN COAGULATION
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ANTICOAGULANTS
• Coumarin anticoagulants
• Drug interactions
• Cytochrome P450 inhibitors
Reduce warfarin’s clearance
Increase the anticoagulant effect of a given dose
Amiodarone, SSRI, cimetidine
 DRUGS USED IN COAGULATION AND BLEEDING DISORDERS

PROPERTIES OF HEPARINS AND WARFARINS

Property Heparins Warfarin

Structure Large polymers, acidic Small lipid-soluble molecule

Route of administration Parenteral Oral

Site of action Blood Liver

Slow, limited by half-lives of factors being
Onset of action Rapid (seconds) replaced
Activates antithrombin III, which Impairs post translational modification of
Mechanism of action proteolyses factors including thrombin and factors II, VII, IX, X
factor Xa
aPTT for unfractionated heparin but not
Monitoring PT
LMW heparins
Protamine for unfractionated heparin but
Antidote not LMW heparins Vitamin K, plasma

Use Mostly acute, over days Chronic, over weeks to months

Use in pregnancy Yes No

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ANTIPLATELET DRUGS
Platelet aggregation
• Plays a central role in the clotting process
• Important in clots that form in the arterial circulation
• Facilitated by thromboxane, ADP, fibrin, serotonin and other substances
• Agents that increase intracellular cyclic adenosine monophosphate (cAMP)
● Prostacyclin
● Inhibit platelet aggregation
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ANTIPLATELET DRUGS
A. Classification and prototypes
• Increase bleeding time
COX inhibitors
• Aspirin and other NSAIDs
Inhibitors of phosphodiesterase 3
• Dipyridamole and cilostazol
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ANTIPLATELET DRUGS
A. Classification and prototypes
Antagonists of ADP receptors
• Ticlopidine and clopidogrel
Glycoprotein IIb/IIIa receptor inhibitors
• Abciximab, tirofiban, eptifibatide
 DRUGS USED IN COAGULATION
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ANTIPLATELET DRUGS
A. Classification and prototypes
• Increase bleeding time
● Test used to monitor their effects
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ANTIPLATELET DRUGS
A. Mechanism of action
Aspirin and other NSAIDs
• Inhibit thromboxane synthesis by blocking the enzyme cyclooxygenase

Thromboxane A2
• Potent stimulator for platelet aggregation

• Potent stimulator for platelet aggregation

 DRUGS USED IN COAGULATION
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ANTIPLATELET DRUGS
A. Mechanism of action
Aspirin
• Irreversible enzyme inhibitor
• Particularly effective
• Inhibition persists until new platelets are
formed (several days)
• Other NSAIDs cause less persistent
antiplatelet effect (hours)
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ANTIPLATELET DRUGS
A. Mechanism of action
Ticlopidine and clopidogrel
• Irreversible inhibition of the ADP receptor
• Inhibition of ADP-mediated platelet
aggregation
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ANTIPLATELET DRUGS
A. Mechanism of action
Abciximab
• Monoclonal antibody
• Reversibly inhibits the binding of fibrin
and other ligands to the platelet
glycoprotein IIb/IIIIa
● Glycoprotein IIb/IIIIa
● Cell surface protein that is involved
in platelet cross-linking (“final
common pathway”)
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ANTIPLATELET DRUGS
A. Mechanism of action
Tirofiban and eptifibatide
• Reversibly block the glycoprotein IIb/IIIa receptors
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ANTIPLATELET DRUGS
A. Mechanism of action
Dipyridamole and cilostazol
• Dual mechanism of action
● Prolong platelet-inhibiting action of intracellular cAMP inhibiting
phosphodiesterase 3
● Phosphodiesterase 3
● Enzyme that degrades cAMP
● Prevent the uptake of extracellular adenosine
● Acts through platelet adenosine A2 receptors to increase platelet cAMP
● Inhibits platelet aggregation
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ANTIPLATELET DRUGS
A. Clinical use
Aspirin
• Prevents further infarcts in individuals who had one or more myocardial
infarcts
• May reduce the incidence of first infarcts
• Used extensively to prevent transient ischemic attacks (TIA), ischemic
stroke, and other thrombotic events
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ANTIPLATELET DRUGS
A. Clinical use
Clopidogrel and Ticlopidine
• Effective in preventing TIAs and ischemic strokes, especially in patients who
cannot tolerate aspirin
• Prevent thrombosis in patients who have recently received a coronary artery
stent
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ANTIPLATELET DRUGS
A. Clinical use
Glycoprotein IIb/IIIa inhibitors
• Prevent restenosis after coronary angioplasty
• Used in acute coronary syndromes
● Unstable angina, and non-Q wave acute myocardial infarction
Dipyridamole and cilostazol
● Used to treat intermittent claudication
● Manifestation of peripheral arterial disease
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ANTIPLATELET DRUGS
A. Toxicity
Aspirin and other NSAIDs
• Cause GI and CNS effects

All antiplatelet drugs

• Significantly enhance the effects of other anticlotting agents
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ANTIPLATELET DRUGS
Ticlopidine
• Bleeding in up to 5% of patients
• Severe neutropenia in about 1%
• Rare thrombotic thrombocytopenic purpura (TTP)

Clopidogrel
• Less hematoxic
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ANTIPLATELET DRUGS
• Toxicity
Glycoprotein IIb/IIIa receptor blocking drugs
• Bleeding
• Thrombocytopenia (with chronic use)

Dipyridamole and cilostazol

• Headaches
• Palpitations
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THROMBOLYTIC AGENTS
• Classification and Prototypes
Tissue plasminogen activator (t-PA)
• Alteplase, tenecteplase, and reteplase
Anistreplase
Urokinase
Streptokinase
• All are given IV
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THROMBOLYTIC AGENTS
• Mechanism of action
Plasmin
• Normal endogenous fibrinolytic enzyme
• Promotes the breakdown and dissolution of clots
• Thrombolytic enzymes
● Catalyze the activation of the inactive precursor, plasminogen to plasmin
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THROMBOLYTIC AGENTS
• Mechanism of action
• Tissue plasminogen activator
• t-PA
• Large human protein
• Directly converts fibrin-bound plasminogen to plasmin
• Selectivity is quite limited
• Less danger of spontaneous bleeding

Alteplase
• Normal human plasminogen activator

Tenecteplase
• Mutated form of t-PA with a longer half-life
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THROMBOLYTIC AGENTS
• Mechanism of action
• Tissue plasminogen activator
Reteplase
• Mutated form of human t-PA with similar effects
• Slightly faster onset of action and longer duration of action

• Urokinase
• Extracted from cultured human kidney cells
• Directly converts plasminogen to plasmin
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THROMBOLYTIC AGENTS
• Mechanism of action
• Streptokinase
• Obtained from bacterial cultures
• Not an enzyme
• Forms a complex with endogenous
plasminogen
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THROMBOLYTIC AGENTS
• Mechanism of action
• Anistreplase
• Anisoylated plasminogen-streptokinase activator complex (APSAC)
• Prodrug
• Anisoyl group is hydrolyzed in vivo
● Slow spontaneous process
• Streptokinase-activated plasminogen is released and converts plasminogen to
plasmin
● Long half-life
 DRUGS USED IN COAGULATION AND BLEEDING DISORDERS

PROPERTIES OF THROMBOLYTIC AGENTS

Agent Source Duration of Action Comments

Active tissue plasminogen

activator (t-PA); converts
plasminogen to plasmin;

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Alteplase, reteplase, intravenous infusion (alteplase)
Recombinant human proteins 2 – 10 min
tenecteplase or bolus doses (reteplase,
tenecteplase). Most expensive.
Reteplase and tenecteplase are
longer acting than alteplase.

Prodrug: streptokinase plus Slowly relases streptokinase-

activated plasminogen; single
Anistreplase recombinant human 1–2h
bolus administration provides
plasminogen
long duration of action

Streptokinase combined with

plasminogen; the combination
Streptokinase Bacterial product 20 – 25 min converts plasminogen to
plasmin; intravenous infusion
required. Least expensive

Urokinase Human cell kidney culture <20 min Active plasminogen activator
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THROMBOLYTIC AGENTS
• Clinical use
• Emergency treatment of coronary artery thrombosis
● Under ideal conditions (within 6 h)
● Prompt recanalization of the occluded vessel
● Very prompt use (within 3 h of the first symptoms) in patients with
ischemic stroke
● Significantly better clinical outcome
● Used in cases of multiple pulmonary emboli
DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

THROMBOLYTIC AGENTS
• Toxicity
Bleeding
• Most important hazard
• Same frequency with all drugs
Cerebral hemorrhage
• Most serious manifestation
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

THROMBOLYTIC AGENTS
• Toxicity
Urokinase, t-PA, variants of t-PA
• Human proteins
• Do not evoke the production of antibodies
• Together with anistreplase
● Much more expensive
● Not much more effective
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

Inadequate blood clotting
• May result from
● Vitamin K deficiency
● Genetically determined errors of clotting factor synthesis
● Hemophilia
● Variety of drug-induced conditions
● Thrombocytopenia
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

Treatment
• Vitamin K
• Preformed clotting factors
• Antiplasmin drug
• Platelets for thrombocytopenia
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

• Vitamin K
• Fat-soluble vitamin
• Dietary requirement is low
● Additionally synthesized by bacteria that colonize the human intestine
• Two natural forms
● Vitamin K1 (phytonadione), found in food
● Vitamin K2 (menaquinone), synthesized by intestinal bacteria
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

• Vitamin K
• Deficiency of vitamin K
● Common in newborns and in older individuals with abnormalities of fat
absorption
● Treated with oral or parenteral vitamin K supplements
● Phytonadione (K1)
• Large doses are used to reverse the anticoagulant effect of excess warfarin
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

• Clotting Factors
• Most important agents used to treat hemophilia
● Fresh plasma
● Purified human blood clotting factors, especially factor VIII and Factor
IX
● Purified from blood products or produced by recombinant DNA
technology
● Extremely expensive
● Carry a risk of infection (because of contamination by blood-borne
pathogens for factors purified from blood products) and immunologic
reactions
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

• Antiplasmin Agents
• Management of acute bleeding episodes in hemophiliacs and others with
bleeding disorders
Aminocaproic acid and tranexamic acid
• Orally active
• Inhibit fibrinolysis by inhibiting plasminogen activation
 DRUGS USED IN COAGULATION
AND BLEEDING DISORDERS

DRUGS USED IN BLEEDING DISORDERS

• Antiplasmin Agents
Aprotinin
• Serin protease inhibitor (serpin)
• Inhibits fibrinolysis by free plasmin
• Associated with increased risk of renal failure, heart attack and stroke