Hemostasis is the spontaneous arrest of bleeding from a damaged
blood vessel. Appropriate hemostasis requires normal function of
both the coagulation cascade (Figure 11–3) and platelets. The
coagulation cascade is a series of proteolytic reactions that produce
active proteases and ultimately generate thrombin, which converts
fibrinogen to fibrin, a key structural component of a fibrous clot.
The normal vascular endothelial cell is not thrombogenic, and circulating
blood platelets and clotting factors do not normally adhere to it.
However, when endothelial damage exposes the underlying tissue,
platelets in the vicinity immediately undergo a reaction that causes them
to stick to the exposed collagen (platelet adhesion) and to each
other (platelet aggregation), and the coagulation cascade is activated.
The platelet plug quickly arrests bleeding but must be reinforced
by fibrin for long-term effectiveness. Disorders of hemostasis can
be divided into excessive clotting (thrombosis)
and excessive bleeding (bleeding diathesis).
The drugs used to treat disorders of hemostasis can similarly
be divided into two primary groups (Figure 11–2): (1) anticlotting
drugs used to decrease clotting in patients who either have evidence
of a pathologic thrombus or are at risk for thrombotic vascular
occlusion (anticoagulants, thrombolytics, and antiplatelet drugs);
and (2) drugs used to restore clotting in patients with clotting
deficiencies. The first group includes some of the most commonly
used drugs in the United States. Anticlotting drugs are used in
the prevention and treatment of myocardial infarction and other
acute coronary syndromes, atrial fibrillation, ischemic stroke,
and deep vein thrombosis (DVT). The anticoagulant and thrombolytic
drugs are effective in treatment of both venous and arterial thrombosis,
whereas antiplatelet drugs are used primarily for treatment or prevention
of arterial thrombosis. Drugs in the second group are used to facilitate
clotting in patients with excessive bleeding due to overanticoagulation
or other causes (e.g., hemophilia).
Anticoagulants inhibit the formation of fibrin clots. Three major
types of anticoagulants are available: heparin and
related products, which must be used parenterally; direct thrombin inhibitors, which
also must be used parenterally; and the orally active coumarin derivatives
(e.g., warfarin). The groups differ
in chemistry, pharmacokinetics, and pharmacodynamics. Properties
of the heparins and warfarin are compared in Table 11–1.
Table 11–1. Properties
of Heparins and Warfarin ||Download (.pdf)
Table 11–1. Properties
of Heparins and Warfarin
|Structure||Large polymers, acidic||Small lipid-soluble molecule|
|Route of administration||Parenteral||Oral|
|Site of action||Blood||Liver|
|Onset of action||Rapid (seconds)||Slow, limited by half-lives of factors being replaced |
|Mechanism of action||Activates antithrombin III, which inactivates factors including thrombin and
factor Xa||Impairs posttranslational modification of factors II, VII,
|Monitoring||aPTT1 for unfractionated heparin but not LMW heparins2||PT3|
|Antidote||Protamine for unfractionated heparin but not LMW heparins||Vitamin K, plasma|
|Use||Mostly acute, over days||Chronic, over weeks to months|
|Use in pregnancy||Yes||No|
Heparin is a large sulfated polysaccharide polymer obtained from
animal sources. Each batch contains molecules of varying size, with
an average molecular weight of 15,000 to 20,000. Heparin is highly
acidic. In rare instances of dangerously elevated anticoagulation
with excessive heparin, heparin can be rapidly neutralized by intravenous
administration of the highly basic protein protamine.
Heparin must be given parenterally (intravenously or subcutaneously).
Intramuscular injection is avoided because of the risk of hematoma
Low molecular weight (LMW) fractions of heparin have been developed.
These have molecular weights of 2,000 to 6,000 (e.g., enoxaparin). LMW heparins have greater
and more reliable bioavailability and longer durations of action than
regular heparin; thus, doses can be given subcutaneously less frequently
(e.g., once or twice a day). Fondaparinux is
a small synthetic drug that contains a key pentasaccharide that
also is present in pharmacologically active molecules of unfractionated
and LMW heparins. Fondaparinux is administered subcutaneously once
daily. Danaparoid (not available in
the United States) is a LMW heparinoid, and is chemically distinct
from heparin. This drug is given either intravenously or subcutaneously.
Unfractionated heparin binds to endogenous antithrombin III (ATIII),
a powerful endogenous anticlotting protease. The heparin–ATIII
complex combines with and irreversibly inactivates thrombin (activated
factor II) and several other factors, particularly factor Xa (Figure
11–3). In the presence of heparin, ATIII destroys thrombin
and factor Xa approximately 1000-fold faster than in its absence.
Because it acts on existing blood components, heparin provides anticoagulation
immediately after administration. The action of heparin is monitored
with the activated partial thromboplastin time (aPTT) or partial
thromboplastin time (PTT) laboratory tests (Table 11–1).
LMW heparins and fondaparinux bind ATIII, and these complexes
have the same inhibitory effect on factor Xa as the regular heparin–ATIII
complex. However, LMW heparin–ATIII and fondaparinux–ATIII
complexes provide a more selective action because they fail to affect
thrombin. The aPTT test does not reliably measure the anticoagulant
effect of the LMW heparins and fondaparinux. Because the LMW heparins
and fondaparinux have fairly reliable pharmacokinetic properties,
their use usually precludes the need for laboratory monitoring of
the coagulation effect. However, the lack of a readily available
test for monitoring drug effect is a potential problem in special
circumstances such as in patients with impaired renal function who
may exhibit reduced drug clearance.
Because of its rapid effect, heparin
is used when anticoagulation is needed immediately (e.g., when starting
anticoagulation therapy). Common uses include treatment of DVT,
pulmonary embolism, and acute myocardial infarction. Heparin is
used in combination with thrombolytics for revascularization and
in combination with glycoprotein IIb/IIIa inhibitors during
angioplasty and placement of coronary stents. Because heparin does
not cross the placental barrier, it is the drug of choice when an
anticoagulant must be used in pregnancy. LMW heparins and fondaparinux
have similar clinical applications.
Increased bleeding is the most
serious adverse effect of heparin and the related molecules; the
bleeding may result in hemorrhagic stroke. If excessive unfractionated
heparin has been given, protamine can be used as an antidote to lessen
the risk of hemorrhage. Protamine only partially reverses the effects
of LMW heparins and does not affect the action of fondaparinux.
Regular heparin causes moderate transient thrombocytopenia in many
patients and severe thrombocytopenia and paradoxic thrombosis in
a small percentage of patients. The latter individuals produce an
antibody that binds to a complex of heparin and platelet factor
4. LMW heparins, fondaparinux, and danaparoid are less likely to
cause this immune-mediated thrombocytopenia. Prolonged use for 3
to 6 months or longer of full doses of regular heparin is associated
Direct thrombin inhibitors are derived from proteins made by Hirudo medicinalis, the medicinal
leech. Lepirudin is the recombinant
form of the leech protein hirudin, and bivalirudin is
a modified form of hirudin. Argatroban is
a small, nonprotein molecule. All three drugs are administered parenterally.
Lepirudin can accumulate in patients with renal failure, whereas
argatroban can accumulate in patients with liver disease.
These drugs inhibit coagulation
by binding directly to thrombin, thus avoiding the need for endogenous
antithrombin III. Unlike the heparins, these drugs inhibit both
soluble thrombin and the thrombin enmeshed within clots. Bivalirudin
also inhibits platelet activation.
Lepirudin and argatroban are used
as alternatives to heparin in patients who require anticoagulation
and who also have a history of heparin-induced thrombocytopenia.
Bivalirudin is used in combination with aspirin during percutaneous
transluminal coronary angioplasty. Like unfractionated heparin,
the action of these drugs is monitored with the aPTT laboratory
Like other anticoagulants, the
direct thrombin inhibitors can cause bleeding. No reversing agents
are available. Prolonged infusion of lepirudin can induce formation
of antibodies that form a complex with lepirudin and prolong its action.
The coumarin anticoagulants (e.g., warfarin)
are small, lipid-soluble molecules that are readily absorbed after
oral administration. Because they cross the placenta and have teratogenic
effects, they are not used in pregnancy. Warfarin is highly bound
to plasma proteins (>99%), and its elimination depends
on metabolism by cytochrome P450 enzymes. Warfarin is the only member
of the group used in the United States.
Warfarin and other coumarins interfere
with the normal posttranslational modification of clotting factors
in the liver, a process that requires vitamin K. The vitamin K–dependent
factors include factors II (thrombin), VII, IX, and X (Figure 11–2).
Because these factors have half-lives of 8 to 60 hours in the plasma,
an anticoagulant effect is observed only after sufficient time has
passed for the existing functional factors to be eliminated. The
action of warfarin can be reversed with vitamin K, but recovery
requires the synthesis of new functional clotting factors and is therefore
slow, requiring 6 to 24 hours. More rapid reversal can be achieved
by transfusion with fresh or frozen plasma that contains normal
clotting factors. The effect of warfarin is monitored by the prothrombin
time (PT) corrected by means of the International Normalization
Ratio (INR) (Table 11–1).
and Adverse Effects
Warfarin is used for chronic anticoagulation
in all of the clinical situations described previously for heparin
except those that occur in pregnant women. Bleeding is the most
important adverse effect of warfarin. Early in therapy, a period
of hypercoagulability with subsequent dermal vascular necrosis can
occur. This is most commonly due to reduced synthesis of protein
C, an endogenous vitamin K–dependent anticoagulant with
a relatively short half-life. Warfarin can cause bone defects and
hemorrhage in the developing fetus and is contraindicated in pregnancy.
Because warfarin has a narrow therapeutic window, its involvement
in drug interactions is of major concern. Cytochrome P450–inducing
drugs (e.g., barbiturates, carbamazepine, phenytoin) increase clearance
of warfarin and reduce the anticoagulant effect of a given dose.
Cytochrome P450–inhibitors (e.g., amiodarone, selective
serotonin reuptake inhibitors, cimetidine) reduce clearance of warfarin
and increase its anticoagulant effects. Variations in dietary vitamin
K can also alter the anticoagulant effects of warfarin. Increases
in vitamin K in the diet decrease the anticoagulant effect of warfarin,
and decreases in vitamin K have the opposite effect. A major source of
vitamin K is leafy green vegetables.
Platelet aggregation plays a central role in the clotting process
and is especially important in clots that form in the arterial circulation,
including those responsible for coronary and cerebral artery occlusion.
Platelet aggregation is facilitated by thromboxane, adenosine diphosphate
(ADP), fibrin, serotonin, and other endogenous substances. Endogenous
substances that increase the formation of cyclic adenosine monophosphate
(cAMP) in platelets (e.g., prostacyclin) inhibit platelet aggregation.
Antiplatelet drugs include aspirin, antagonists of ADP receptors
(clopidogrel and ticlopidine), glycoprotein IIb/IIIa receptor
inhibitors (abciximab, tirofiban, and eptifibatide) and inhibitors
of phosphodiesterase 3 (dipyridamole and cilostazol). The antiplatelet
drugs increase bleeding time, which is the basis of a laboratory
test that is sometimes used to monitor their effects.
other nonsteroidal anti-inflammatory drugs (NSAIDs) are discussed
in Chapter 34. These drugs inhibit the formation of all prostaglandins,
including thromboxane, by inhibiting the enzymecyclooxygenase (COX). Although
all NSAIDs impart an increased risk of bleeding, particularly in
the gastrointestinal tract, only aspirin is used therapeutically
as an antiplatelet drug. Aspirin is particularly effective because
of its irreversible inhibition of COX. In blood vessels, there is
a delicate balance between the inhibitory effect on platelet function
of prostacyclin, which is produced by endothelial cells, and the
platelet-activating effect of thromboxane, which is released by
previously activated platelets. Platelets, which lack the machinery
for synthesis of new proteins, are unable to escape the inhibitory
effect of aspirin on thromboxane formation. In contrast, endothelial cells,
which contain a nucleus and the capacity to synthesize proteins,
continue to produce some COX and prostacyclin. Aspirin therapy,
therefore, tips the prostacyclin/thromboxane balance toward
prostacyclin and inhibition of platelet function. Since all of the
other NSAIDs inhibit COX reversibly, they have a less selective
antiplatelet effect. In fact, if other NSAIDs are administered concomitantly,
they may decrease the antiplatelet effect of aspirin.
The mechanism of antiplatelet action of ticlopidine and clopidogrel involves irreversible
inhibition of the ADP receptor, resulting in inhibition of ADP-mediated platelet
aggregation. Because these drugs irreversibly modify the platelet
ADP receptor, platelets are affected for the remainder of their
lifespan, which is about 10 days (as is the case with aspirin).
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. Glycoprotein
IIb/IIIa, a member of the integrin family of adhesion molecules,
is the most abundant receptor on the surface of activated platelets.
The binding of fibrinogen (the primary ligand) and other ligands
(e.g., von Willebrand factor) to the glycoprotein IIb/IIIa
receptor cross links platelets, resulting in platelet aggregation and
formation of the platelet plug.
Dipyridamole and the newer drug cilostazol exert their antiplatelet
activity by inhibiting phosphodiesterase
3, an enzyme that inactivates cAMP, and also by inhibiting
the uptake of adenosine, which increases platelet cAMP through activation
of adenosine receptors. These two
molecular effects act in concert to boost the intracellular concentration
of cAMP, an inhibitor of platelet activation. Activation of adenosine
A2 receptors acts through Gs to stimulate adenylyl
cyclase. Blockade of adenosine uptake by dipyridamole or cilostazol increases
the local concentration of adenosine and thereby increases the rate
of production of cAMP in platelets. At the same time, the inhibition
of the enzyme that inactivates intracellular cAMP prolongs the duration
of action of this second messenger.
Aspirin is used to prevent future
infarcts in individuals who have had one or more myocardial infarcts.
Aspirin may also reduce the incidence of first infarcts. The drug
is used extensively to prevent transient ischemic attacks (TIAs),
ischemic stroke, and other thrombotic events. Clopidogrel and ticlopidine
are useful in preventing TIAs and ischemic stroke, especially in
patients who cannot tolerate aspirin. Clopidogrel is also used to
reduce thrombosis in patients who have recently received a coronary
artery stent. The glycoprotein IIb/IIIa inhibitors (abciximab,
eptifibatide, and tirofiban) prevent restenosis after coronary angioplasty
and are used in acute coronary syndromes (e.g., unstable angina
and non-Q-wave acute myocardial infarction). Dipyridamole and cilostazol are
used to treat intermittent claudication (muscle pain on exercise),
a manifestation of peripheral arterial disease.
Aspirin causes gastrointestinal,
renal, and CNS effects, as discussed in more detail in Chapter 34.
All antiplatelet drugs significantly enhance the effects of other
anticlotting agents. However, their inhibitory effects on hemostasis cannot
be monitored with the aPTT or PT anticoagulation tests. Ticlopidine
causes bleeding in up to 5% of patients, severe neutropenia
in about 1%, and very rarely thrombotic thrombocytopenic
purpura, a serious condition characterized by hemolysis and end-organ
damage. Clopidogrel is less hematotoxic. The major toxicities of
glycoprotein IIb/IIIa receptor-blocking drugs (abciximab,
eptifibatide, and tirofiban) are bleeding and, with chronic use,
thrombocytopenia. The most common adverse effects of dipyridamole
and cilostazol are headaches and palpitations.
The thrombolytic drugs currently available are alteplase, tenecteplase,
and reteplase (forms of tissue plasminogen activator [t-PA]),
urokinase, and streptokinase (Table 11–2). All are given
Table 11–2. Properties
of Thrombolytic Enzymes ||Download (.pdf)
Table 11–2. Properties
of Thrombolytic Enzymes
|Agent||Source||Duration of Action (min)||Comments|
|Alteplase, reteplase, tenecteplase||Recombinant human proteins||2–10||Active tissue plasminogen activator, (t-PA); converts plasminogen
to plasmin; intravenous infusion (alteplase) or bolus doses (reteplase, tenecteplase). Most
expensive. Reteplase and tenecteplase are longer acting than alteplase.|
|Streptokinase||Bacterial product||20–25 ||Streptokinase combines with plasminogen; the combination
converts plasminogen to plasmin; intravenous infusion required. Least expensive.|
|Urokinase||Human kidney cell culture||<20 ||Active plasminogen activator|
Plasmin is an endogenous fibrinolytic
enzyme. By splitting fibrin into fragments, plasmin promotes the breakdown
and dissolution of clots (Figure 11–4). Thrombolytic enzymes
catalyze the conversion of the inactive precursor, plasminogen,
Diagram of the fibrinolytic system. The useful thrombolytic
drugs are shown on the left. Aminocaproic acid and tranexamic acid
inhibit plasmin formation, while aprotinin inhibits plasmin’s enzymatic
t-PA is a large human protein that directly converts fibrin-bound
plasminogen to plasmin (Figure 11–4). Alteplase is
normal human plasminogen activator produced by recombinant DNA technology. Reteplase is a mutated form of human
t-PA with similar effects, but a slightly faster onset of action
and longer duration of action. Tenecteplase is
another mutated form of t-PA with a longer half-life.
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. Although not
itself an enzyme, streptokinase forms a complex with endogenous
plasminogen. The complex catalyzes the rapid conversion of plasminogen
The major application of the
thrombolytic agents is in the emergency treatment of acute myocardial
infarction when emergency coronary angioplasty is either not available
or contraindicated. Under ideal conditions in which treatment is
initiated within 12 hours of the thrombotic event, these agents
can cause prompt recanalization (restoration of the lumen) of the
Alteplase is also approved for the treatment of acute ischemic
stroke with the caveats that drug therapy must be initiated within
3 hours of the onset of symptoms, and only after hemorrhagic stroke
has been ruled out by an imaging procedure. The thrombolytic agents
are also used in cases of pulmonary embolism with hemodynamic instability,
severe DVTs, and ascending thrombophlebitis of the iliofemoral vein
with severe lower extremity edema.
Bleeding is the most important
hazard and occurs with approximately the same frequency with all of
the thrombolytics. Cerebral hemorrhage is the most serious manifestation.
Streptokinase, a bacterial protein, often evokes the production
of antibodies and loses its effectiveness or induces severe allergic
reactions on subsequent therapy. Patients who have had streptococcal
infections may have preformed antibodies to the drug. Because they
are human proteins, urokinase, t-PA, and variants of t-PA are not
subject to this problem, but they are much more expensive than streptokinase
and not much more effective.