CHAPTER 50 ANTICOAGULANT, ANTIPLATELET, & THOMBOLYTIC DRUGS

Drugs used to prevent formation of thrombi (intravascular blood clots) and to dissolve
thrombi that have already formed.
- act in several ways: some suppress coagulation
some inhibit platelet aggregation
some promote clot dissolution
- interfere with normal hemostasis, carrying a significant risk of hemorrhage

I. PHYSIOLOGY AND PATHOPHYSIOLOGY OF COAGULATION

A. HEMOSTASIS
- physiologic process by which bleeding is stopped
- occurs in the formation of a platelet plug followed by reinforcement of
the platelet plug with fibrin
- set in motion by blood vessel injury

1. Stage One: Formation of Platelet Plug

- initiated when platelets come in contact with collagen on the
exposed surface of a
damaged blood vessel
- response to contact with collagen, platelets adhere to the site
of vessel injury
- aggregated platelets constitute a plug that stops bleeding
- plug is unstable and must be reinforced with fibrin if
protection is to last

2. Stage Two: Coagulation

- production of fibrin, a protein that reinforces the platelet plug
- produced by way of two convergent pathways:
• intrinsic system – all necessary clotting factors are
present within the vascular system
• extrinsic system – tissue thromboplastin, a factor from
outside the vascular system, is required for operation

B. THOMBOSIS
thrombus – blood clot formed within a blood vessel or within the heart

1. Arterial Thrombosis – formation begins with adhesion of platelets

to the arterial wall
- adhesion is stimulated by damage to the wall or rupture of an
atherosclerotic plaque
- following adhesion, platelets attract additional platelets to
the evolving thrombus
- with continued platelet aggregation, occlusion of the artery
takes place
- as blood flow comes to a stop, the coagulation cascade is
initiated, causing the
 original plug to undergo reinforcement with fibrin
- consequence is localized tissue injury owing to lack of
perfusion

2. Venous Thrombosis – develops at sites where blood flow is slow

- stagnation of blood initiates the coagulation cascade,
resulting in the production of
fibrin, which enmeshes red blood cells and platelets to
form the thrombus
- has a long tail that can break off to produce an embolus
- emboli travel within the vascular system and become lodged
at faraway sites,
frequently the pulmonary arteries
- occurs secondary to embolization at a site distant from the
original thrombus
II. OVERVIEW OF DRUGS USED TO TREAT THROMBOEMBOLIC DISORDERS

Major Categories: anticoagulants – heparin, warfarin

- drugs that disrupt the coagulation cascade,
suppressing production of fibrin
- most effective against venous thrombosis

antiplatelet drugs – aspirin, tirofiban

- drugs that inhibit platelet aggregation
- most effective at preventing arterial thrombosis

thrombolytic drugs – alteplase, streptokinase

- drugs that promote lysis of fibrin, causing dissolution of
thrombi

- these drugs differ in their effects and applications

III. PARENTERAL ANTICOAGULANTS I: HEPARIN AND RELATED DRUGS

- greatly enhance the activity of antithrombin, a protein that inactivates
two major clotting factors:
thrombin and factor Xa
- production of fibrin is reduced, suppressing clotting

A. HEPARIN (UNFRACTIONATED)
- rapid acting anticoagulant administered only by injection
- by promoting the inactivation of thrombin and factor Xa, ultimately
suppresses formation of fibrin
- especially useful for prohpylaxis of venous thrombosis
- effects of heparin develop quickly (within minutes of IV administration)
- preferred anticoagulant for use during pregnancy and in situation that
require rapid onset of
anticoagulant effects, including pulmonary embolism, evolving
stroke, and massive deep vein
 thrombosis (DVT)
- used for patients undergoing open heart surgery and renal dialysis
- low-dose therapy is used to prevent postoperative venous thrombosis
- may also be useful for treating disseminated intravascular coagulation, a
complex disorder in which
fibrin clots form throughout the vascular system and in which
bleeding tendencies may be
present
- used as an adjunct to thrombolytic therapy of acute myocardial infarction
(MI)

Adverse Effects: hemorrhage = bleeding is the principal complication of

treatment
- monitor closely for signs of blood loss
- symptoms include reduced blood pressure, increased
heart rate, bruises,
petechiae, hematomas, red or black stools, cloudy
or discolored urine,
pelvic pain (suggesting ovarian hemorrhage)
headache or faintness
(suggesting cerebral hemorrhage) and lumbar pain
(suggesting
adrenal hemorrhage)
- risk can be decreased by careful control of dosage so
that not to exceed 2
times the control valve, careful screening of
heparin candidates for risk
factors, and avoiding antiplatelet drugs

heparin-induced thrombocytopenia – potentially fatal

immune-mediated disorder
characterized by reduced platelet counts and
seemingly paradoxical
increase in thrombotic events
- underlying cause is development of antibodies against
heparin platelet protein
complexes
- antibodies activate platelets and damage the
vascular endothelium,
promoting both thrombosis and a rapid loss of
circulating platelets

hypersensitivity reactions – because commercial heparin is

extracted from animal
tissues, these preparation may be contaminated
with antigens that can
promote allergy
 - possible allergic responses include chills, fever, and
urticaria

others – local irritation and hematoma, vasospastic reactions,

osteoporosis

Contraindications: should be avoided both during and immediately

after surgery of the eye, brain,
or spinal cord
lumbar puncture and regional anesthesia

Lab Monitoring: objective of anticoagulant therapy is to reduce blood

coagulability to a level that is low
enough to prevent thromosis, but not so low as to
promote spontaneous
bleeding
goal is difficult and requires careful control of dosage based on
frequent tests of
coagulation
most commonly used test is the Activated Partial
Thromboplastin Time (aPTT)
- normal value is 40 seconds
- at therapeutic levels, heparin increases aPTT by a
factor of 1.5 – 2, making
the aPTT 60 – 80 seconds
- measurement of aPTT should be made frequently
(every 4 – 6 hrs) during the
initial phase of therapy and once daily after
effective dosage is
established

B. LOW MOLECULAR WEIGHT HEPARINS

- enoxaparin (lovenox), dalteparin (fragmin), tinzaparin (innohep)
- simply heparin preparations composed of molecules that are shorter than
those found in
unfractionated heparin
- as effective as unfractionated heparin, can be given on a fixed-dose
schedule and don’t require aPTT
monitoring, can be used at home, and is far less expensive than
unfractionated heparin
- less likely to cause thrombocytopenia
- now considered the first line therapy for prevention and treatment of
established DVT, and DVT
following hip or knee replacement surgery
- administered SC

Adverse Effects: bleeding is the major complication with treatment

can cause immune-mediated thrombocytopenia
 can cause severe neurologic injury, including permanent
paralysis
- risk of serious harm is increased by concurrent use of
antiplatelet drugs
(aspirin) or warfarin

1. Enoxaparin (lovenox)
- approved for prevention of DVT following hip and knee
replacement surgery or
abdominal surgery in patients considered at high risk of
thromboembolic
complications
- approved for prevention of ischemic complications in patients
with unstable angina or
non-Q-wave MI
- administration is by deep SC injection

IV. ORAL ANTICOAGULANTS

- warfarin, anisindione
- used to prevent thrombosis
- have a delayed onset of action, which makes them inappropriate for
emergency use
- well suited for long term prophylaxis
- carry a significant risk of hemorrhage, amplified by the many drug
interactions

A. WARFARIN
- coumadin
- initially used to kill rats and remains one of the most widely used
rodenticides
- suppresses coagulation by acting as an antagonist of vitamin K
- blocks the biosynthesis of vitamin K dependent factors
- specific indications are:
• prevention of venous thrombosis and associated pulmonary
embolism
• prevention of thromboembolism in patients with prosthetic heart
valves
• prevention of thrombosis during a-fib
- also used to reduce the risk of recurrent transient ischemic attacks (TIAs)
and recurrent MI
- due to delayed onset of effects, not useful in emergencies

Monitoring: evaluated by monitoring prothrombin time (PT) – coagulation

test that is especially
sensitive to alterations in vitamin K dependent
fators
 - average PT value is 12 seconds
- warfarin treatment prolongs PT
results are reported in terms of an international normalized
ratio (INR)
- determined by multiplying observed PT ratio by a
correction factor specific to
particular thromboplastin preparation employed
for the test
objective of treatment is to raise the INR to appropriate valve
- INR of 2 – 3 is appropriate for most patients, although
for some the target INR
is 3 – 4.5
- if INR is below recommended range, warfarin
dosage is increased
- if INR is above recommended range, warfarin
dosage is reduced
- INR cannot be altered quickly
- PT must be determined frequently during therapy
- daily during the first 5 days
- twice a week for the next 1 – 2 weeks
- once a week for the next 1 – 2 months
- every 2 – 4 weeks thereafter
- blood should be drawn no sooner than 5 hours after an
IV injections and no
sooner than 24 hours after an SC injection

Adverse Effects: hemorrhage - bleeding is the major complication

- can occur at any site
- severe overdose can be treated with vitamin K
- patients should be encouraged to carry identification
(Medic Alert bracelet) to
inform emergency personnel of warfarin use
- given detailed verbal and written instructions
regarding signs of
bleeding, dosage size and timing, and
scheduling of PT tests
- advises to record administration of each dose,
rather than relying on
memory

fetal hemorrhage & teratogenesis during pregnancy –

warfarin can cross the placenta
and effect the developing fetus
- fetal hemorrhage and death can occur
- can cause gross malformation, central nervous system
(CNS) defects and
optic atrophy
- FDA Risk Category X: risks to the developing fetus
outweigh any possible
 benefits of treatment
- if pregnancy occurs, possibility of termination should be
discussed
- heparin, which does not cross the placenta,
should be employed if
necessary

during lactation – warfarin should be advised against while

breast feeding

Warnings and Contraindications – not for patients with severe

thrombocytopenia or uncontrollable
bleeding, lumbar puncture, regional anesthesia, surgery of the eye,
brain, or spinal cord,
hemophilia, increased capillary permeability, dissecting aneurysm,
GI ulcers, severe
hypertension, and women anticipating abortion

Vitamin K1 for Warfarin Overdose: vitamin K1 antagonizes warfain’s actions

and can thereby reverse
warfarin-induced inhibition of clotting factors synthesis
- vitamin K may be given orally or IV
- should be diluted and infused slowly before IV administration
due to causing severe
anaphylactoid reactions (flushing, hypotension, and
cardiovascular collapse)
- if vitamin K fails, levels of clotting factors can be raised quickly by
infusing fresh whole blood,
fresh-frozen plasma, or plasma concentrates of vitamin K-
dependent clotting factors

V. ANTIPLATELET DRUGS
- agents that suppress platelet aggregation
- indication is prevention of thrombosis in arteries

A. ASPIRIN
- suppresses platelet aggregation
- proven applications: primary prevention of MI (prevention of a first MI)
secondary prevention of MI (prevention of reinfarction in
patients who have
already had an MI)
prevention of stroke in patients with a history of TIAs
- although it lowers the risk of MI, it does not reduce the risk of death
- cardiovascular risk is based on age, gender, cholesterol levels,
blood pressure, and smoking
status
Adverse Effects: increases the risk of GI bleeding and hemorrhagic
stroke
B. ADENOSINE DIPHOSPHATE RECEPTOR ANTAGONISTS
- clopidogrel (plavix)
- cause irreversible blockade of ADP receptors on the platelet surface,
preventing ADP stimulated
aggregation
- effects begin 2 hrs after initial dose and plateau after 3 – 7 days of
use
- platelet function and bleeding time return to baseline about 7 – 10
days after treatment is
stopped
- approved for secondary prevention of ischemic stroke, MI, and other
vascular events in patients with
atherosclerosis documented by recent MI, recent stroke, or
established peripheral arterial
disease
- administered orally, with or without food
- dosage does not have to be changed for elderly or those with renal
dysfunction
- can cause potentially fatal hematologic effects

Adverse Effects: generally well tolerated

abdominal pain, dyspepsia, diarrhea, rash and GI bleeding
can cause TTP, usually during the first 2 wks of treatment

C. GLYCOPROTEIN LLB/LLA RECEPTOR ANTAGONISTS

- sometimes called “super aspirins”
- mot effective antiplatelet drugs
- administered IV, usually in combination with aspirin and low-dose heparin
- treatment is expensive

1. Abciximab (reopro)
- purified fragment of a monoclonal antibody
- binds to platelets and prevents receptor from binding
fibrinogen
- in conjunction with aspirin and heparin, approved for IV
therapy of acute coronary
syndromes (ACSs) and patients undergoing balloon or
laser angioplasty (PCIs)
- can accelerate revascularization in patients undergoing
thrombolytic therapy for acute
MI
- effects persist for 24 – 48 hours after stopping infusion

Adverse Effects: doubles the risk of bleeding

may cause GI, urogenital, and retroperitoneal
bleeds
 does not increase the risk of fatal hemorrhage or
hemorrhagic stroke

2. Eptifibatide (integrilin)
- small peptide that causes reversible and highly selective
inhibition of GP IIb/IIIa
receptors
- approved for use in ACSs and patients undergoing PCIs
- effects reverse by 4 hrs after stopping infusion
- bleeding is primary adverse effect

3. Tirofiban (aggrastat)
- neither an antibody nor a peptide, modeled after a platelet
inhibitor isolated from the
venom of the sawscaled viper, a snake indigenous to
Africa
- used to reduce ischemic events associated with ACSs and PCi
- platelet function returns to baseline within 4 hrs of stopping
the infusion
- bleeding is primary adverse effect

V. THROMBOLYTIC DRUGS
- also known as fibrinolytics (and formally as clot busters)
- given to remove thrombi that have already formed
- all carry a risk of serious bleeding and should be administered only by
clinicians skilled in their use
- employed acutely and only for severe thrombotic disease

A. ALTEPLASE (TPA)
- activase
- also known as tissue plasminogen activator (tPA)
- commercial preparations are identical to naturally occurring human tPA,
an enzyme that promotes
conversion of plasminogen to plasmin, an enzyme that digests the
fibrin matrix of clots
- low therapeutic doses produce selective activation of plasminogen that is
bound to fibrin in thrombi
- activation of plasminogen in the general circulation is minimized
- bleeding tendencies are equivalent to those seen with other thrombolytic
drugs
- risk of intracranial bleeding is higher
- does not cause allergic reactions or induce hypotension
- short half-life (about 5 minutes) owing to rapid hepatic inactivation
- indicated for acute MI, pulmonary embolism and treating ischemic stroke
- expensive
 - given by an “accelerated” or “front-loaded” schedule
- for patients who weigh over 67 kg, total dose for treating acute MI
is 100 mg
- administration is divided into 3 phases: a 15 mg bolus
followed by 50 mg infused over 30
minutes
followed by 35 mg infused over 60
minutes

B. TENECTEPLASE (TNKASE)
- variant of human tissue plasminogen activator (tPA, alteplase)
- approved for treating patients undergoing acute MI
- just as safe and effective as tPA, but much easier to use - - given by bolus
injection
- thrombolysis develops faster and emergency room personnel are
spared the work of monitorin
a prolonged infusion
- has the potential to allow dosing before the patient reaches a
hospital
- dosage is based on body weight
- no one is given more than 50 mg
- cost is identical to tPA (activase)