DRUG USED IN

COAGULATION and
BLEEDING DISORDERS
UNIVERSITY OF GULLAS- COLLEGE OF MEDICINE
Thrombosis
• formation of an unwanted clot within a blood vessel
• most common abnormality of hemostasis
• Thrombotic disorders
• acute myocardial infarction (MI)
• deep vein thrombosis (DVT)
• pulmonary embolism (PE)
• acute ischemic stroke
• Bleeding disorders
• Hemophilia
• Vitamin K Deficiency
THROMBUS VS. EMBOLUS
• THROMBUS- A clot that adheres to a vessel
wall

• EMBOLUS- an intravascular clot that floats

in the blood
ARTERIAL THROMBOSIS
• most common cause of acute MI, ischemic stroke and
limb gangrene
• most often occurs in medium-sized vessels rendered
thrombogenic by atherosclerosis
• consists of a platelet-rich clot
VENOUS THROMBOSIS
• triggered by blood stasis or inappropriate activation of
the coagulation cascade
• consist of fibrin-rich clot
• fewer platelets
• Anticoagulant and Thrombolytic drugs are effective in
treatment of both venous and arterial thrombosis

• Antiplatelet drugs are used primarily for treatment of arterial

disease
PLATELET RESPONSE TO INJURY
• Physical trauma initiates a complex series of interactions between
platelets, endothelial cells, and the coagulation cascade
• These interactions lead to hemostasis (cessation of blood loss) from a
damaged blood vessel
• Initially, there is vasospasm of the damaged blood vessel to prevent
further blood loss involves the formation of a platelet–fibrin plug
at the site of the puncture
Mechanism of Hemostasis:
1. Vasoconstriction
• Local autacoid factors from
traumatized tissues and
platelets
-Thromboxane A2(TXA2)
-Endothelin
• Local myogenic spasm
• Nervous Reflexes
2. Primary Hemostasis
• Platelet adhesion
• Platelet activation
• Platelet aggregation
3. Secondary Hemostasis
• Coagulation cascade
PRIMARY HEMOSTASIS
“FORMATION OF PLATELET
PLUG”
SECONDARY
HEMOSTASIS
“FORMATION OF STABLE
FIBRIN CLOT”
RESTING PLATELETS
• Platelets monitoring the
integrity of the vascular
endothelium
• In the absence of injury,
resting platelets circulate
freely
• Chemical mediators, such as
prostacyclin and nitric oxide, are
synthesized by intact endothelial
cells and act as inhibitors of
platelet aggregation
• Prostacyclin (prostaglandin I2)
acts by binding to platelet
membrane receptors that are
coupled to the synthesis of cyclic
adenosine monophosphate
(cAMP)
• Elevated levels of cAMP are
associated with a decrease in
intracellular calcium prevents
platelet activation and release of
platelet aggregation agents
• Platelet membrane contains receptors that can bind
thrombin, thromboxanes, and exposed collagen
• In the intact, normal vessel circulating levels of thrombin
and thromboxane are low, and the intact endothelium covers
the collagen in the subendothelial layers
• Corresponding platelet receptors are unoccupied, and
platelet activation and aggregation are not initiated
When the endothelium is
injured, platelets adhere to
and virtually cover the
exposed collagen of the
subendothelium triggers a
complex series of chemical
reactions, resulting in platelet
activation
• Receptors on the surface of the
adhering platelets are activated
by the collagen of the underlying
connective tissue causes
release of platelet granules
containing chemical mediators,
such as adenosine diphosphate
(ADP), thromboxane A2,
serotonin, platelet activation
factor, and thrombin bind to
receptors in the outer
membrane of resting platelets
circulating nearby
• Previously dormant platelets
become activated and start
to aggregate
• mediated by several
messenger systems that
result in elevated levels of
calcium and a decreased
concentration of cAMP
within the platelet
Local stimulation of the
coagulation cascade by
tissue factors released
from the injured tissue
and by mediators on the
surface of platelets results
in the formation of
thrombin catalyzes the
hydrolysis of fibrinogen to
fibrin
• During clot formation, the
fibrinolytic pathway is locally
activated
• Plasminogenplasmin
(fibrinolysin) by plasminogen
activators in the tissue
• Plasmin limits the growth of
the clot and dissolves the
fibrin network as wounds
heal
PLATELET AGGREGATION
INHIBITORS
ASPIRIN Mechanism of action:
• Nonselective, irreversible COX 1
and COX 2 inhibitor
• inhibits thromboxane A2
• synthesis.
• shifts the balance of chemical
mediators to favor the
antiaggregatory effects of
prostacyclin preventing
platelet aggregation
Therapeutic use:
• prophylactic treatment of transient cerebral ischemia, to reduce the
incidence of recurrent MI, and to decrease mortality in the setting of
primary and secondary prevention of MI
• Complete inactivation of platelets occurs with 75 mg of aspirin daily
• Recommended dose of aspirin ranges from 50 to 325 mg daily
Pharmacokinetics:
• 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.
• Half-life of aspirin ranges from 15 to 20 minutes and for salicylic acid
is 3 to 12 hours
Adverse effects:
• Bleeding time is prolonged by aspirin treatment, causing
complications that include an increased incidence of
hemorrhagic stroke and gastrointestinal (GI) bleeding,
especially at higher doses of the drug
ASPIRIN TOXICITY
• TOXIC DOSE= 150 mg/kg
• 150mg/kg x 70kg/500mg/tab= 21 tabs

• LETHAL DOSE= 500mg/kg

• 500mg/kg x 70kg/500mg/tab= 70 tabs
TICLOPIDINE, CLOPIDOGREL,
PRASUGREL, TICAGRELOR
Mechanism of action:
• inhibit the binding of ADP to
platelets receptors reduce
platelet aggregation and inhibit
the activation of the GP IIb/IIIa
receptors required for platelets to
bind to fibrinogen and to each
other
• Ticagrelor binds to the P2Y12 ADP
receptor in a reversible manner.
Therapeutic use:
Clopidogrel:
• patients with a recent MI or stroke
• peripheral arterial disease
• prophylaxis of thrombotic events in acute coronary syndromes
(unstable angina or non–ST-elevation MI)
• prevent thrombotic events associated with percutaneous coronary
intervention (PCI) with or without coronary stenting
Ticlopidine:
• prevention of transient ischemic attacks (TIA) and strokes in patients
with a prior cerebral thrombotic event.
Prasugrel:
• decrease thrombotic cardiovascular events in patients with acute
coronary syndromes (unstable angina, non–ST-elevation MI, and ST-
elevation MI managed with PCI)
Ticagrelor:
• prevention of arterial thromboembolism in patients with unstable
angina and acute MI, including those undergoing PCI
Pharmacokinetics:
• require loading doses for quicker antiplatelet effect
• Food interferes with the absorption of ticlopidine.
• extensively bound to plasma proteins
• undergo hepatic metabolism by the cytochrome P450 (CYP) system to
active metabolites
• Elimination and metabolites occurs by both the renal and fecal routes
• Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on
its active metabolite, which is produced via metabolism by CYP 2C19
Adverse effects:
• cause prolonged bleeding for which there is no antidote
• Ticlopidine is associated with severe hematologic reactions that limit
its use, such as agranulocytosis, thrombotic thrombocytopenic
purpura (TTP), and aplastic anemia
• Clopidogrel causes fewer adverse reactions, and the incidence of
neutropenia is lower
• TTP has been reported as an adverse effect for both clopidogrel and
prasugrel
• Prasugrel is contraindicated in patients with history of TIA or stroke
 Abciximab, eptifibatide, and tirofiban
Mechanism of action:
• Abciximab inhibits the GP IIb/IIIa
receptor complex. By binding to
GP IIb/IIIa, abciximab blocks the
binding of fibrinogen and von
Willebrand factor aggregation
does not occur
• Eptifibatide and tirofiban act
similarly to abciximab, by
blocking the GP IIb/IIIa receptor
Therapeutic use:
• 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
Pharmacokinetics:
• Abciximab is given by IV bolus, followed by IV infusion, achieving peak
platelet inhibition within 30 minutes
• After cessation of abciximab infusion platelet function gradually
returns to normal, antiplatelet effect persisting for 24 to 48 hours
• After cessation of eptifibatide or tirofiban infusion rapidly cleared
from the plasma
• Eptifibatide excreted by the kidney
• Tirofiban excreted unchanged by the kidney and in the feces
Adverse effects:
• Major adverse effect is bleeding, especially if used with
anticoagulants
DIPYRIDAMOLE
• Coronary vasodilator  increases intracellular levels of cAMP by
inhibiting cyclic nucleotide phosphodiesterase resulting in
decreased thromboxane A2 synthesis
• May potentiate the effect of prostacyclin to antagonize platelet
stickiness decrease platelet adhesion to thrombogenic surfaces
• used for stroke prevention and is usually given in combination with
aspirin.
• Patients with unstable angina should not use.
• commonly causes headache and can lead to orthostatic hypotension
CILOSTAZOL
• oral antiplatelet agent that also has vasodilating activity
• inhibit phosphodiesterase type III which prevents the
degradation of cAMP increasing levels of cAMP in platelets
and vascular tissues prevents platelet aggregation and
promotes vasodilation of blood vessels
• alters the lipid profile decrease in plasma triglycerides and
an increase in high-density lipoprotein cholesterol
• reduce the symptoms of INTERMITTENT CLAUDICATION
• metabolized in the liver by the CYP 3A4, 2C19, and 1A2 isoenzymes
• primary route of elimination is via the kidney
• Headache and GI side effects are the most common adverse effects
• contraindicated in patients with heart failure.
ANTICOAGULANTS
• inhibit either the action of
the coagulation factors
(heparin) or
• interfere with the synthesis
of the coagulation factors
(warfarin)
BLOOD COAGULATION
Coagulation process that generates thrombin consists of two
interrelated pathways extrinsic and the intrinsic systems
• Extrinsic system is initiated by the activation of clotting factor VII by
tissue factor (also known as thromboplastin). Response to vascular
injury tissue factor becomes exposed to blood bind and activate
factor VII initiating the extrinsic pathway
• Intrinsic system is triggered by the activation of clotting factor XII.
Blood comes into contact with the collagen in the damaged wall of a
blood vessel
Formation of fibrin
• Both the extrinsic and the intrinsic
systems involve a cascade of
enzyme reactions that transform
plasma factors to their active
forms
• Factor Xa is produced converts
prothrombin (factor II) to
thrombin
• Thrombin converts fibrinogen to
fibrin forms the mesh-like
matrix of the blood clot
Inhibitors of coagulation
• Endogenous inhibitors of coagulation factors:
• protein C
• protein S
• antithrombin III
• tissue factor pathway inhibitor
• The mechanism of action of several anticoagulant agents, including
heparin and heparin-related products, involves activation of these
endogenous inhibitors (primarily antithrombin III)
Heparin and LMWH
• Injectable, rapidly acting anticoagulant used acutely to interfere with
the formation of thrombi. Heparin occurs naturally as a
macromolecule complexed with histamine in mast cells
• Unfractionated heparin is a mixture of straight-chain, anionic
glycosaminoglycans with a wide range of molecular weights. It is
strongly acidic because of the presence of sulfate and carboxylic acid
groups
• Low molecular weight forms of heparin (LMWHs) can also act as
anticoagulants led to the isolation of enoxaparin, produced by
enzymatic depolymerization of unfractionated heparin
Mechanism and effects:
• Unfractionated heparin binds to endogenous antithrombin III (ATIII)
• irreversibly inactivates thrombin and several other factors,
particularly factor Xa
• In the presence of heparin, ATIII proteolyzes thrombin and factor Xa
approximately 1000-fold faster
• heparin provides anticoagulation immediately after administration.
• heparin is monitored with the activated partial thromboplastin time
(aPTT)
LMW heparins and fondaparinux:
• also bind ATIII
• same inhibitory effect on factor Xa.
• Does not require aPTT monitoring
Therapeutic use:
• Heparin and the LMWHs limit the expansion of thrombi by preventing
fibrin formation
• used for the treatment of acute venous thromboembolism (DVT or
PE)
• Heparin and LMWHs are used for prophylaxis of postoperative
venous thrombosis in patients undergoing surgery (hip replacement)
and with acute MI
• anticoagulants of choice for treating pregnant women.
Pharmacokinetics:
• Heparin administered subcutaneously or intravenously.
• LMWHs are administered subcutaneously
• Heparin is often initiated as an intravenous bolus to achieve
immediate anticoagulation followed by lower doses or
continuous infusion of heparintitrating the dose so that
the activated partial thromboplastin time (aPTT) is 1.5- to
2.5-fold that of the normal control
• heparin binds to many proteins that neutralize its activity, causing
unpredictable pharmacokinetics.
• Heparin binding to plasma proteins is variable in patients with
thromboembolic diseases.
• heparin is taken up by the monocyte/macrophage system, and it
undergoes depolymerization and desulfation to inactive products.
• The inactive metabolites, as well as some of the parent heparin and
LMWHs, are excreted into the urine.
• Renal insufficiency prolongs the half-life of LMWHs.
Adverse effects:
• Most common AE is bleeding
• Excessive bleeding may be
managed by discontinuing the drug
or by treating with protamine
sulfate
• Heparin-induced
thrombocytopenia (HIT)
• Osteoporosis has been observed in patients on long-term heparin
therapy
• Possible adverse reactions include chills, fever, urticaria, and
anaphylactic shock
• Heparin and LMWHs are contraindicated in patients who have
hypersensitivity to heparin, bleeding disorders, alcoholism, or who
have had recent surgery of the brain, eye, or spinal cord
ARGATROBAN
• direct thrombin inhibitor
• used for the prophylaxis or treatment of venous thromboembolism in
patients with HIT and approved for use during PCI in patients who
have or are at risk for developing HIT
• metabolized in the liver and has a half-life of about 39 to 51 minutes
• Monitoring includes aPTT, hemoglobin, and hematocrit
• may be used in patients with renal dysfunction but should be used
cautiously in patients with hepatic impairment.
• major side effect is bleeding
Bivalirudin and Desirudin
• parenteral anticoagulants that are analogs of hirudin, a thrombin
inhibitor derived from medicinal leech saliva
• selective direct thrombin inhibitors that reversibly inhibit the
catalytic site of both free and clot-bound thrombin
• Bivalirudin:
• alternative to heparin in patients undergoing PCI who have or are at risk for
developing HIT and also in patients with unstable angina undergoing
angioplasty
• half-life is 25 minutes
• Dosage adjustments are required in patients with renal impairment
• Desirudin is indicated for the prevention of DVT in patients
undergoing hip replacement surgery
• Bleeding is the major side effect
Fondaparinux
• selectively inhibits only factor Xa selectively binding to antithrombin III
• potentiates (300- to 1000-fold) the innate neutralization of factor Xa by
antithrombin III
• approved for use in the treatment of DVT and PE and for the prophylaxis of
venous thromboembolism in the setting of orthopedic and abdominal surgery
• well absorbed from the subcutaneous route
• eliminated in the urine mainly as unchanged drug with an elimination half-life
of 17 to 21 hours
• contraindicated in patients with severe renal impairment
• Bleeding is the major side effect
Dabigatran
Mechanism of action:
• oral direct thrombin inhibitor
• Both clot-bound and free thrombin are inhibited
Therapeutic use:
• approved for the prevention of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation
• may be an alternative to enoxaparin for thromboprophylaxis in
orthopedic surgery.
Pharmacokinetics:
• administered orally
• capsules should be stored in the original container and swallowed
whole.
• a substrate for P-glycoprotein (P-gp) and is eliminated renally
Adverse effects:
• major adverse effect is bleeding
• should be used with caution in renal impairment or in patients over
the age of 75
• GI adverse effects are common
• Abrupt discontinuation should be avoided
• contraindicated in patients with mechanical prosthetic heart valves
and is not recommended in patients with bioprosthetic heart valves
Rivaroxaban and Apixaban
Mechanism of action:
• oral inhibitors of factor Xa
• bind to the active site of factor Xa preventing its ability to convert
prothrombin to thrombin
Therapeutic use:
• Rivaroxaban is approved for treatment and prevention of DVT and PE
and for the prevention of stroke in nonvalvular atrial fibrillation
• Apixaban is used for stroke prevention in nonvalvular atrial fibrillation
Pharmacokinetics:
• absorbed after oral administration and are highly protein bound
• Food may increase the absorption of rivaroxaban
• Rivaroxaban is metabolized mainly by the CYP 3A4/5 and CYP 2J2
isoenzymes to inactive metabolites
• Apixaban is primarily metabolized by CYP 3A4, with CYP enzymes 1A2,
2C8, 2C9, 2C19, and 2J2 all sharing minor metabolic roles;
approximately 27% is excreted renally
Adverse effects:
• Bleeding is the most serious adverse effect
• As both drugs are eliminated renally declining kidney function can
prolong the effect of the drugs increase the risk of bleeding
• Neither drug should be used in severe renal dysfunction (creatinine
clearance less than 15 mL/min)
WARFARIN
• antagonize the cofactor functions of vitamin K
• only therapeutically relevant coumarin anticoagulant is warfarin
• widely used clinically as an oral anticoagulant
• INR is the standard by which the anticoagulant activity of warfarin
therapy is monitored
• Goal of warfarin therapy is an INR of 2 to 3 for most indications, with
an INR of 2.5 to 3.5 targeted for some mechanical valves and other
indications.
• has a narrow therapeutic index.
Mechanism of action:
• inhibit vitamin K epoxide
reductase
• Warfarin treatment results in the
production of clotting factors
with diminished activity (10% to
40% of normal), due to the lack
of sufficient γ-carboxyglutamyl
side chains
• anticoagulant effects of warfarin are not observed immediately after
drug administration peak effects may be delayed for 72 to 96 hours.
• anticoagulant effects of warfarin can be overcome by the
administration of vitamin K.
Therapeutic use:
• used in the prevention and treatment of DVT and PE, stroke
prevention, stroke prevention in the setting of atrial fibrillation and/or
prosthetic heart valves, protein C and S deficiency, and
antiphospholipid syndrome
• used for prevention of venous thromboembolism during orthopedic
or gynecologic surgery
Pharmacokinetics:
• rapidly absorbed after oral administration
• highly bound to plasma albumin.
• Warfarin readily crosses the placental barrier
• mean half-life of warfarin is approximately 40 hours
• Warfarin is metabolized by the CYP450 system to inactive
components.
• After conjugation to glucuronic acid, the inactive metabolites are
excreted in urine and feces.
• Warfarin has numerous drug interactions that may potentiate or
attenuate its anticoagulant effect
Potentiate anticoagulant effects: Attenuate anticoagulant effects:
• Acute alcohol intoxication • Chronic alcohol ingestion
• Cimetidine • Barbiturates
• Amiodarone • Dicloxacillin
• Fluconazole • Rifampin
• Metronidazole
• Sulfamethoxazole/trimethoprim
Adverse effects:
• principal adverse effect of warfarin is hemorrhage
• Minor bleeding may be treated by withdrawal of the drug or
administration of oral vitamin K1, but severe bleeding may require
greater doses of vitamin K given intravenously
• Whole blood, frozen plasma, and plasma concentrates of blood
factors may also be used for rapid reversal of warfarin
• Warfarin is teratogenic and should never be used during pregnancy.
THROMBOLYTIC DRUGS
Mechanism of action:
• All act either directly or
indirectly to convert
plasminogen to plasmin
cleaves fibrin lysing thrombi
• Clot dissolution and reperfusion
occur with a higher frequency
when therapy is initiated early
after clot formation.
Therapeutic use:
• Mainly for the treatment of MI, ischemic stroke, massive pulmonary
embolism
• administered intravenously
• helpful in restoring catheter and shunt function, by lysing clots
causing occlusions
Adverse effects:
• do not distinguish between the fibrin of
an unwanted thrombus and the fibrin of
a beneficial hemostatic plug
hemorrhage is a major side effect
• contraindicated in pregnancy, in
patients with healing wounds, history of
cerebrovascular accident, brain tumor,
head trauma, intracranial bleeding, and
metastatic cancer
Alteplase, reteplase, and tenecteplase
• Alteplase
• obtained as a product of recombinant DNA technology
• “fibrin selective” at low doses.
• approved for the treatment of MI, massive PE, and acute ischemic stroke
• very short half-life (5 to 30 minutes).
• may cause orolingual angioedema
• Reteplase
• is a genetically engineered, smaller derivative of recombinant tPA
• may be used off-label in DVT and massive PE
• Tenecteplase
• another recombinant tPA with a longer half-life and greater binding affinity
for fibrin than alteplase

• Reteplase and Tenecteplase

• approved for use in acute MI
• have longer half-lives
STREPTOKINASE
• an extracellular protein purified
from culture broths of group C β-
hemolytic streptococci.
• forms an active complex with
plasminogen converts
uncomplexed plasminogen to the
active enzyme plasmin
hydrolysis of fibrin plugs
• also catalyzes the degradation of
fibrinogen, clotting factors V and
VII
UROKINASE
• produced naturally in the body by the kidneys
• Therapeutic urokinase is isolated from cultures of human kidney cells
and has low antigenicity
• directly cleaves the arginine–valine bond of plasminogen to yield
active plasmin
• only approved for lysis of pulmonary emboli
• Off-label uses include treatment of acute MI, arterial
thromboembolism, coronary artery thrombosis, and DVT
DRUG USED TO TREAT BLEEDING
Aminocaproic acid and Tranexamic acid
• Fibrinolytic states can be controlled by the administration of these
agents
• Competitively inhibit plasminogen activation by inhibiting tPA
• synthetic, orally active, excreted in the urine
• Tranexamic acid is 10 times more potent than aminocaproic acid
• potential side effect is intravascular thrombosis
Protamine Sulfate
• antagonizes the anticoagulant effects of heparin
• derived from fish sperm or testes and high in arginine content.
• positively charged protamine interacts with the negatively charged
heparin forming a stable complex without anticoagulant activity
• Adverse effects include hypersensitivity as well as dyspnea, flushing,
bradycardia, and hypotension when rapidly injected
VITAMIN K1(phytonadione)
• stops bleeding problems due to warfarin.
• administered via the oral, subcutaneous, or intravenous route
• The response to vitamin K1 is slow, requiring about 24 hours to
reduce INR (time to synthesize new coagulation factors)
• Fresh frozen plasma for immediate hemostasis