Drugs Used in Disorders of Coagulation

By : Mihret A (B.Pharm, MSC)

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 Hemostasis
• Hemostasis refers to the finely regulated dynamic
process of maintaining
 fluidity of the blood,
 repairing vascular injury, and
 limiting blood loss while avoiding vessel occlusion
(thrombosis) and inadequate perfusion of vital organs.
• Either extreme—excessive bleeding or thrombosis
—represents a breakdown of the hemostatic
mechanism.

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Mechanisms of blood coagulation

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Fibrinolysis
• During clot formation, the fibrinolytic pathway is
locally activated.
• Plasminogen is enzymatically processed to plasmin
(fibrinolysin) by plasminogen activators in the tissue
• Plasmin limits the growth of the clot and dissolves
the fibrin network as wounds heal.

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Key Components of the
Fibrinolytic System

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Endogenous anticoagulants
• Antithrombin (AT)- it inactivates the serine
proteases IIa, IXa, Xa, XIa, and XIIa
• Protein C and protein S attenuate the blood
clotting cascade by proteolysis of the two cofactors
Va and VIIIa.
• Mutation in factor V (factor V Leiden) is the most
common defect in the natural anticoagulant system
• Tissue plasminogen activator activate the
fibrinolytic system

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 Thrombosis
• Thrombosis, the formation of an unwanted clot within a blood vessel,
• It is the most common abnormality of hemostasis.
• Although all thrombi are mixed,
 The platelet nidus dominates the arterial thrombus (white thrombi), and
The fibrin tail dominates the venous thrombus (red thrombi)
• Occlusive arterial thrombi causes ischemia of extremities or vital
organs, and they can result in limb amputation or organ failure.
 acute myocardial infarction (MI),
acute ischemic stroke.
• Deep venous thrombi (DVT) can cause severe swelling and pain of the
affected extremity
• the most feared consequence is pulmonary embolism (PE).

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Management thrombosis
disorders
• These conditions are treated with drugs such as
 Anticoagulant,

 Fibrinolytic, and

 Antiplatelet Agents

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I. Anticoagulants
• Diminishes unwanted thrombus formation.
• These include;
• Heparin
 Unfractionated heparin/HMWH
 Low-molecular-weight heparins (LMWHs) ( enoxaparin,
dalteparin, and tinzaparin)
• Fondaparinux
• Desirudin , lepirudin, argatroban, and bivalirudin
• Warfarin
• Dabigatran ,Apixaban, edoxaban, and rivaroxaban
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Mechanisms of Action of
anticuagulants

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Antithrombin-dependent
anticoagulants
• Antithrombin is a plasma glycoprotein that inhibits
serine protease–clotting enzymes.
• Heparin
 Unfractionated heparin, inactivating thrombin (factor IIa)
and factors IXa and Xa
 Low-molecular-weight heparins (LMWHs) , inhibit mainly
factor Xa.
• Fondaparinux, selective factor Xa inhibitor
• Although the heparin-antithrombin complex is avery
efficient inhibitor of free thrombin, clot-bound
thrombin is resistant to inhibition.
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Direct thrombin inhibitors
• Blocks the effects of free and clot-bound thrombin
• Several parenterally administered agents inhibit
thrombin directly, including
 Desirudin , lepirudin, argatroban, and bivalirudin
• Dabigatran is a synthetic direct oral thrombin
inhibitor

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Direct factor 10a inhibitors
• Apixaban, edoxaban, and rivaroxaban
• are direct oral factor Xa inhibitors.
• Inhibit both free and clot-bound factor Xa, as well
as prothrombinase (factor Xa and factor Va
complex) activity

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Vitamin K epoxide reductase
inhibitors
• Warfarin
• Involves inhibition of vitamin K activity
• Activation of coagulation factors (II, VII, IX, X) and
anticoagulant proteins C and S via the γ-carboxylation
requires vitamin K as a cofactor
• Carboxylation of these vitamin K–dependent coagulation
factors leads to the concomitant oxidation of vitamin K to
its corresponding epoxide.
• The regeneration of vitamin K necessary to sustain the
carboxylation reaction is mediated by vitamin K epoxide
reductase
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Heparin
• Heparin is a linear polysaccharide
• It is administered by IV infusion or subcutaneously
• Heparin is not bound to plasma albumin
• Heparin does not cross the placenta and does not
produce untoward effects in the fetus
• Clotting times for HMWH measured by the
activated partial thromboplastin time (aPTT).
• The t 1/2 of LMWHs is longer than that of the
naturally occurring unfractionated compound.

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Adverse effects of heparin
• Bleeding
• Thrombocytopenia
 Associated with arterial or venous thrombosis
• Bleeding induced by heparin can be rapidly
reversed with protamine sulfate

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Warfarin
• Administered as the sodium salt and has 100% oral bioavailability.
• Over 99% of racemic warfarin is bound to plasma albumin,
• Has Small volume of distribution
• metabolized in the liver by CYP2C9.
• It has long half-life in plasma (36 hours), and
• The lack of urinary excretion of unchanged drug.
• Effective for the primary and secondary prevention of arterial and
venous thromboembolism.
• The full anticoagulant effect of warfarin is typically reached within 4–7
days.
• Prothrombin time (PT), is used to measure their anticoagulant effects
• Warfarin therapy prolongs the PT and increases the INR

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Adverse Effects of warfarin
• Bleeding
• Teratogen
 include nasal bridge deformities and abnormal bone
formation.
• Rapid reversal of the effect of warfarin can be
achieved only by transfusion of plasma containing
clotting factors or prothrombin complex
concentrates (PCC).
• Oral or IV use of vitamin K1 (phytonadione) are an
antidote
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Direct oral anticoagulants
• The DOACs have predictable responses using fixed
doses without coagulation monitoring.
• Absorption after oral administration is rapid
• Metabolism occurs in the liver
• Renal excretion is the major route of elimination for
DOACs
• DOACs have reduced drug-drug interactions
compared to warfarin

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II. Antiplatelet Drugs
• Aspirin
• Thienopyridines:
 Clopidogrel, prasugrel, ticlopidine
• Dipyridamole
• Aggrenox
• GP IIb/IIIa blockers
 abciximab, eptifibatide, and tirofiban,
• Vorapaxar

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 Aspirin

• Inhibits the synthesis of thromboxane A2 by irreversible acetylation of a

serine residue on the active site of COX-1
• The inhibitory effect is rapid
• suppression of platelet aggregation last for the life of the platelet,
which is approximately 7 to 10 days.
• Aspirin is used in the prophylactic treatment of
o transient cerebral ischemia,
o to reduce the incidence of recurrent MI, and
o to decrease mortality in the setting of primary and secondary prevention of MI.
• Complete inactivation of platelets occurs with 75 mg of aspirin given
daily.
• The recommended antiplatelet dose of aspirin ranges from 50 to 325
mg daily.

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Pharmacokinetics and adverse
effects of asprin
• When given orally, aspirin is absorbed by passive
diffusion and quickly hydrolyzed to salicylic acid in
the liver.
• Salicylic acid is further metabolized in the liver and
some is excreted unchanged in the urine.
• The half-life of aspirin ranges from 15 to 20 minutes
and for salicylic acid is 3 to 12 hours.
• Higher doses of aspirin increase incidence of
hemorrhagic stroke and gastrointestinal (GI)
bleeding
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Thienopyridines
• Clopidogrel, Ticlopidine, prasugrel, ticagrelor, and cangrelor
• All of these agents are administered orally, with the exception of
cangrelor, approved for IV use
• Clopidogrel, Ticlopidine,and prasugrel irreversibly block the ADP
P2Y12 receptor on platelet
• Ticagrelor and cangrelor bind to the P2Y12 ADP receptor in a
reversible manner.
• The maximum inhibition of platelet aggregation is achieved in
o 2 minutes with intravenous (IV) cangrelor,
o 1 to 3 hours with ticagrelor,
o 2 to 4 hours with prasugrel,
o 3 to 4 days with ticlopidine, and
o 3 to 5 days with clopidogrel.

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Clopidogrel
• Is a prodrug metabolized by cytochrome CYP2C19 to its active
metabolite
• Clopidogrel in combination with aspirin is approved for
patients with
 unstable angina or non-ST-elevation acute myocardial infarction
(NSTEMI);
 ST-elevation myocardial infarction (STEMI); or
 recent myocardial infarction, stroke, or established peripheral
arterial disease.
• The antithrombotic effects of clopidogrel are dose dependent
• The duration of the antiplatelet effect is 7–10 days.
• Thrombotic thrombocytopenic purpura

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Prasugrel
• Prasugrel, similar to clopidogrel, is approved for
patients with acute coronary syndromes
• In contrast to clopidogrel, cytochrome P450
genotype status is not an important factor in
prasugrel pharmacology
• Prasugrel carry black box warnings for bleeding.
• Prasugrel is contraindicated in patients with history
of TIA or stroke.

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Ticlopidine
• Is approved for prevention of stroke in patients with a
history of
 a transient ischemic attack (TIA) or thrombotic stroke in
patients with a prior cerebral thrombotic event, and
 in combination with aspirin for prevention of coronary stent
thrombosis.
• However, due to life-threatening hematologic adverse
reactions, ticlopidine is generally reserved for patients
who are intolerant to other therapies.
• Adverse effects of ticlopidine include
 nausea, dyspepsia, and diarrhea, hemorrhage , thrombotic
thrombocytopenic purpura , and leukopenia
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Glycoprotein IIb/IIIa inhibitors
• Abciximab, Eptifibatide, and tirofiban
• These agents are given intravenously, along with
heparin and aspirin, as an adjunct to PCI for the
prevention of cardiac ischemic complications.
• Abciximab is also approved for patients with
unstable angina not responding to conventional
medical therapy when PCI is planned within 24
hours.
• The major adverse effect of these agents is
bleeding, especially if used with anticoagulants.
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Additional antiplatelet-directed
drugs
• Dipyridamole is a phosphodiesterase inhibitor
o increases intracellular levels of cAMP ,
o thereby resulting in decreased thromboxane A2
synthesis.
• Dipyridamole is used for stroke prevention and is
usually given in combination with aspirin.

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Fibrinolytics /Thrombolytic
drugs
• Are drugs that activate the conversion of plasminogen to
plasmin, a serine protease that hydrolyzes fibrin.
• Are clot-dissolving medications
 both protective hemostatic thrombi and target
thromboemboli are broken down.
• Clot dissolution and reperfusion occur with a higher
frequency when therapy is initiated early
• Thrombolytic agents are usually administered
intravenously.
• These drugs are also given intra-arterially, especially for
peripheral vascular disease
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Cont’d
• These include:
• Endogenous plasminogen activators
o Tissue plasminogen activator (t-PA) and
o Urokinase plasminogen activator (u-PA).
• Recombinant human t-PA
o Alteplase
o Reteplase and
o Tenecteplase
• Streptokinase

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Mechanism of action

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Therapeutic use

• Administration of fibrinolytic drugs by the

intravenous route is indicated in cases of
o pulmonary embolism with hemodynamic instability,

o severe deep venous thrombosis

o acute myocardial infarction

o acute ischemic stroke within 3 hours of symptom onset.

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 Alteplase
• Alteplase is formerly known as tissue plasminogen activator or tPA
• It is a serine protease originally derived from cultured human
melanoma cells.
• It is now obtained as a product of recombinant DNA technology.
• Alteplase has a low affinity for free plasminogen in the plasma,
o fibrin selective at low doses.
• It rapidly activates plasminogen that is bound to fibrin in a thrombus
or a hemostatic plug.
• Alteplase is approved for the treatment of MI, massive PE, and acute
ischemic stroke.
• Alteplase has a very short half-life (5 to 30 minutes),
a portion of the total dose is injected intravenously as a bolus, and the
remaining drug is administered over 1 to 3 hours,

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Reteplase and tenecteplase,
• Reteplase and tenecteplase are as effective as
alteplase,
• But they have
 simpler dosing schemes because of their longer half-
lives
 greater binding affinity for fibrin than alteplase.
• Approved for use in acute MI and in acute
ischemic stroke within 3 hours of symptom onset.

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 Streptokinase
• Is a protein (but not an enzyme in itself) synthesized by
streptococci
• Streptokinase complexes with and activates free
plasminogen molecules to form plasmin.
• It is administered by intravenous infusion
• streptokinase is highly immunogenic and cannot be used
repeatedly
• Patients with antistreptococcal antibodies can develop
fever, allergic reactions, and therapeutic resistance.
• Streptokinase has been associated with increased bleeding
risk in acute ischemic stroke
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Adverse effects of Thrombolytic agents
• Hemorrhage is a major adverse effect
• Are contraindicated in
o pregnancy
o patients with healing wounds,
o a history of cerebrovascular accident,
o brain tumor,
o head trauma,
o intracranial bleeding, and
o metastatic cancer.

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