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Lilley: Pharmacology and the Nursing Process, 7th Edition

Chapter 26: Coagulation Modifier Drugs

Key Points -

ANATOMY, PHYSIOLOGY, AND PATHOPHYSIOLOGY OVERVIEW

Hemostasis is a general term for any process that stops bleeding. This can be accomplished
by either mechanical or surgical means.
When hemostasis occurs as a result physiologic clotting of blood, it is called coagulation,
which is the process of blood clot formation.
The technical term for a blood clot is a thrombus. A thrombus that is not stationary but
moves through blood vessels is called an embolus.
Normal hemostasis involves the complex interaction of substances that promote clot
formation and substances that either inhibit coagulation or dissolve the formed clot.
Substances that promote coagulation include platelets, von Willebrand factor, activated
clotting factors, and tissue thromboplastin.
Substances that inhibit coagulation include prostacyclin, antithrombin III, and proteins C and
S. In addition, tissue plasminogen activator is a natural substance that dissolves clots that are
already formed.
The coagulation system is called a cascade (or coagulation cascade) because each activated
clotting factor serves as a catalyst that amplifies the next reaction. The result is a large
concentration of a clot-forming substance called fibrin.
Once a clot is formed and fibrin is present, the fibrinolytic system is activated. This system
initiates the breakdown of clots and serves to balance the clotting process.
Hemophilia is a rare genetic disorder in which the previously mentioned natural coagulation
and hemostasis factors are limited or absent. Hemophilia is categorized into two main types
depending on which of the coagulation factors is absent (factor VII, factor VIII, and/or factor
IX). Patients with hemophilia can bleed to death if coagulation factors are not given.




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PHARMACOLOGY OVERVIEW

Drugs that affect coagulation are commonly associated with adverse drug reactions.
Coagulation modifiers work by preventing/promoting clot formation, lysing a preformed clot,
and/or reversing the action of anticoagulants. Coagulation modifiers include anticoagulants,
antiplatelets, thrombolytics, antifibrinolytics, and reversal drugs.
Anticoagulants inhibit the action or formation of clotting factors and therefore prevent clots
from forming.
Antiplatelet drugs prevent platelet plugs from forming by inhibiting platelet aggregation,
which can be beneficial in preventing heart attacks and strokes.
Hemorheologic drugs alter platelet function without preventing the platelets from working.
Sometimes clots form and totally block a blood vessel. When this happens in one of the
coronary arteries, a heart attack occurs, and the clot must be lysed to prevent or minimize
damage to the myocardial muscle.
Thrombolytic drugs lyse (break down) clots, or thrombi, that have already formed.
Antifibrinolytic drugs, also known as hemostatic drugs, have the opposite effect of these
other classes of drugs; they actually promote blood coagulation and are helpful in the
management of conditions in which excessive bleeding would be harmful.

Anticoagulants
Drugs that prevent the formation of a clot by inhibiting certain clotting factors are called
anticoagulants.
Once a clot forms on the wall of a blood vessel, it may dislodge and travel through the
bloodstream as an embolus. If it lodges in a coronary artery, it causes a myocardial infarction
(MI); if it obstructs a brain vessel, it causes a stroke; if it goes to the lungs, it is a pulmonary
embolism; and if it goes to a vein in the leg, it is a deep vein thrombosis (DVT). Collectively,
these complications are called thromboembolic events.
Anticoagulants are also called antithrombotic drugs because they work to prevent the
formation of a clot or thrombus, a condition known as thrombosis. All anticoagulants work in
the clotting cascade but do so at different points.
Heparin works by binding to a substance called antithrombin III, which turns off three main
activating factors: activated factor II (thrombin), activated factor X, and activated factor IX.
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The drug name heparin usually refers to unfractionated heparin, which is a relatively large
molecule derived from various animal sources. Low molecular weight heparins (LMWHs)
are synthetic and have a smaller molecular structure; they include enoxaparin (Lovenox) and
dalteparin (Fragmin).
The LMWHs differ from heparin in that they are much more specific for activated factor X
(Xa) than for activated factor II (IIa, or thrombin).
Warfarin (Coumadin) works by inhibiting vitamin K synthesis by bacteria in the
gastrointestinal tract. This, in turn, inhibits production of clotting factors II, VII, IX, and X,
which are known as vitamin Kdependent clotting factors.
Fondaparinux (Arixtra) inhibits thrombosis by its specific action against factor Xa alone.
Rivaroxaban (Xarelto) is a new oral-acting factor Xa inhibitor approved in 2011.
There are also currently five antithrombin drugs that inhibit the thrombin molecules directly,
one natural and four synthetic. The natural drug is human antithrombin III (Thrombate),
which is isolated from the plasma of human donors. The synthetic drugs are lepirudin
(Refludan), argatroban (Argatroban), bivalirudin (Angiomax), and dabigatran (Pradaxa).
The ability of anticoagulants to prevent clot formation is of benefit in certain settings in
which there is likelihood of clot formation, including MI, unstable angina, atrial fibrillation,
use of indwelling devices such as mechanical heart valves, and conditions in which blood
flow may be slowed and blood may pool, such as major orthopedic surgery or prolonged
periods of immobilization, for example, hospitalization or even long plane rides.
Warfarin is indicated for prevention of any of these events, whereas unfractionated heparins,
LMWHs, direct thrombin inhibitors, and factor Xa inhibitors are used for both prevention
and treatment.
Patients at risk for clots are given medications for DVT prophylaxis while in the hospital and
after major surgery.
LMWHs, especially enoxaparin, are also routinely used as anticoagulant bridge therapy in
situations in which a patient must stop warfarin for surgery or other invasive medical
procedures. Enoxaparin acts as a bridge to provide anticoagulation while the patient must be
without warfarin therapy.
Bleeding is the main complication of anticoagulation therapy, and the risk increases with
increasing dosages. Such bleeding may be localized or systemic.
One particularly notable adverse effect of heparin is heparin-induced thrombocytopenia
(HIT), which is also called heparin-associated thrombocytopenia.
Although the toxic effects of heparin, LMWH, and warfarin are hemorrhagic in nature, the
management is different for each drug. Symptoms that may be attributed to toxicity or an
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overdose of anticoagulants are hematuria, melena (blood in the stool), petechiae,
ecchymoses, and gum or mucous membrane bleeding. In the event of heparin or warfarin
toxicity, the drug is to be stopped immediately.
Stopping heparin alone may be enough to reverse the toxic effects because of the drugs short
half-life (1 to 2 hours). In severe cases, intravenous (IV) injection of protamine sulfate is
indicated.
In warfarin toxicity or overdose, the first step is to discontinue the warfarin. Because
warfarin inactivates the vitamin Kdependent clotting factors and because these clotting
factors are synthesized in the liver, it may take 36 to 42 hours before the liver can
resynthesize enough clotting factors to reverse the warfarin effects. Giving vitamin K
1

(phytonadione) can hasten the return to normal coagulation.
Drug interactions involving the oral anticoagulants are profound and complicated. The main
interaction mechanisms responsible for increasing anticoagulant activity include enzyme
inhibition of metabolism, displacement of the drug from inactive protein-binding sites,
decrease in vitamin K absorption or synthesis by the bacterial flora of the large intestines,
and alteration in the platelet count or activity.

Antiplatelet Drugs
Antiplatelet drugs work to prevent platelet adhesion at the site of blood vessel injury, which
actually occurs before the clotting cascade.
A platelet plug that has formed at a site of vessel injury is not stable and can be dislodged.
The clotting cascade is then stimulated to form a more permanent fibrin plug (blood clot).
Aspirin is widely used for its analgesic, antiinflammatory, and antipyretic (antifever)
properties, but it also has antiplatelet effects.
Dipyridamole, another antiplatelet drug, also works to inhibit platelet aggregation by
preventing the release of adenosine diphosphate (ADP), platelet factor IV, and thromboxane
A
2
(TXA
2
), all substances that stimulate platelets to aggregate or form a clot.
Clopidogrel is a drug that belongs to the class of antiplatelet drugs called ADP
inhibitors. It inhibits platelet aggregation by altering the platelet membrane so that it can no
longer receive the signal to aggregate and form a clot.
Glycoprotein (GP) IIb/IIIa inhibitors work by blocking the receptor protein by the
same name that occurs in the platelet wall membranes.
Aspirin has many therapeutic effects, but many of them vary depending on the dosage.
Aspirin is officially recommended for stroke prevention by the American Stroke Society.
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Clopidogrel is given to reduce the risk for thrombotic stroke and is used for prophylaxis
against transient ischemic attacks as well as for post-MI prevention of thrombosis.
Dipyridamole is used as an adjunct to warfarin in the prevention of postoperative
thromboembolic complications and to decrease platelet aggregation in various other
thromboembolic disorders.
The GP IIb/IIIa inhibitors are used to treat acute unstable angina and MI and are given
during percutaneous coronary intervention procedures, such as angioplasty.
Pentoxifylline is indicated for peripheral vascular disease, whereas cilostazol is
indicated specifically for intermittent claudication.
Cilostazol has been shown to be superior to pentoxifylline in improving exercise tolerance in
elderly patients.
The potential adverse effects of the various antiplatelet drugs can be serious, and they all
pose a risk for inducing a serious bleeding episode.
The use of dipyridamole with clopidogrel, aspirin, and other nonsteroidal antiinflammatory
drugs (NSAIDs) produces additive antiplatelet activity and increased bleeding potential. The
combined use of steroids or nonaspirin NSAIDs with aspirin can increase the ulcerogenic
effects of aspirin.

Thrombolytic Drugs
Thrombolytics are coagulation modifiers that lyse thrombi in the coronary arteries. If the
blood flow is reestablished early, the heart muscle and left ventricular function can be saved.
Tissue plasminogen activator (t-PA) and anisoylated plasminogen streptokinase activator
complex (APSAC) are two of these drugs.
The use of thrombolytics has largely been replaced by interventional cardiologic
procedures, such as percutaneous coronary intervention, but are still a viable option in
hospitals that do not offer percutaneous coronary intervention.
The newer thrombolytics have chemical specificity for fibrin threads and work primarily at
the site of a clot. They still carry some bleeding risk.
The indications for thrombolytic therapy include acute MI, arterial thrombosis, DVT,
occlusion of shunts or catheters, pulmonary embolism, and acute ischemic stroke.
The most common undesirable effect of thrombolytic therapy is internal, intracranial, and
superficial bleeding. Other problems include hypersensitivity, anaphylactoid reactions,
nausea, vomiting, and hypotension. These drugs can also induce cardiac dysrhythmias.
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Treatment for toxicity is symptomatic and supportive because thrombolytic drugs have a
relatively short half-life and no specific antidotes.

Antifibrinolytic Drugs
These drugs prevent the lysis of fibrin; in doing so, they actually promote clot formation. For
this reason, they are also called hemostatic drugs.
Three synthetic antifibrinolytics are availableaminocaproic acid, tranexamic acid, and
desmopressin.
There are three drugs used for the treatment of hemophilia produced by recombinant DNA
technology, which eliminates the risk associated with obtaining them from human blood.
Products currently available include rVII, rVIII, and rIX.
Antifibrinolytics are useful in both the prevention and treatment of excessive bleeding
resulting from systemic hyperfibrinolysis or surgical complications. They have also proved
successful in arresting excessive oozing from surgical sites such as chest tubes as well as in
reducing the total blood loss and the duration of bleeding in the postoperative period.
Desmopressin may also be used in patients who have hemophilia A or type I von Willebrand
disease.
Recombinant factors VII, VIII, and IX are used to treat hemophilia or to stop the bleeding
from excessive warfarin therapy.
When drugs such as estrogens or oral contraceptives are used concurrently with
aminocaproic acid or tranexamic acid, increased coagulation may occur.

NURSING PROCESS
Coagulation modifiers have a variety of uses, including the following: (1) prevention or
elimination of clotting in a peripherally inserted catheter, (2) maintenance of patency
(without clotting) of central venous catheters, (3) clot prevention in coronary artery bypass
grafting, (4) prevention of clotting after major vessel injury, (5) treatment of
thrombophlebitis to prevent venous and/or arterial thromboembolism, and (6) prevention of
clotting with use of prosthetics (e.g., heart valve replacements) and in atrial fibrillation.
Perform a thorough patient assessment to identify the presence of risk factors.
It is also important to assess the skin, oral mucous membranes, gums, urine, and stool for any
evidence of bleeding. Assess patients for any blood in the urine or stool, easy bruising,
excessive bleeding from toothbrushing or shaving, or unexplained nosebleeds while
receiving these medications, and report any such findings.
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It is crucial to patient safety to remember that heparin is not interchangeable unit for unit
with drugs in another class of anticoagulants, the LMWHs. Heparin sodium contains benzyl
alcohol; therefore, assess for allergy to this additional component.
With antiplatelet drugs, obtain a thorough nursing history and medication history, and
perform a physical assessment before beginning drug therapy.
Aspirin is not to be used in children and teenagers, in patients with any bleeding disorder,
in pregnant or lactating women, or in patients with vitamin K deficiency or peptic ulcer
disease.
Before use of thrombolytics, assess for a history of hypotension and cardiac dysrhythmias.
Antifibrinolytics require the same skillful assessment of baseline parameters and laboratory
testing; however, there are additional concerns for patients with dysrhythmias, hypotension,
bradycardia, convulsive disorders, nausea, vomiting, and abdominal pain or diarrhea.
Routinely monitor vital signs, heart sounds, peripheral pulses, and neurologic status in all
patients during and immediately after anticoagulant therapy.
The antidote to hemorrhage or uncontrolled bleeding resulting from heparin or LMWH
therapy is protamine sulfate.
Therapeutic levels of anticoagulants and other clotting-altering drugs or coagulation modifier
drugs are also monitored by laboratory studies such as activated partial thromboplastin time
(aPTT), prothrombin time (PT), and international normalized ratio (INR.)
Some of the therapeutic effects include decreased chest pain and a decrease in dizziness as
well as in other neurologic symptoms.
Adverse effects of anticoagulants include bleeding and hematoma formation (heparin);
thrombocytopenia (heparin and LWMHs); bleeding, dizziness, shortness of breath, and fever
(direct thrombin inhibitors); bleeding, hematoma, dizziness, and gastrointestinal distress
(selective factor Xa inhibitors); and bleeding, lethargy, and muscle pain (warfarin). Early
signs of drug overdose for any of the clotting-altering drugs (i.e., anticoagulants) include
bleeding of the gums during toothbrushing, unexplained nosebleeds or bruising, and heavier-
than-usual menstrual bleeding.