Describe important elements in the physiology of hemostasis and thrombosis.

  Discuss possible consequences of blood clotting disorders.

  Compare and contrast heparin and warfarin in terms of indications for use, onset and duration of action, route of administration, blood tests used to monitor effects, and nursing process implications.

  Discuss antiplatelet agents in terms of indications for use and effects on blood coagulation.

  Discuss direct thrombin inhibitors in terms of indications and contraindications for use, routes of administration, and major adverse effects.

  Describe thrombolytic agents in terms of indications and contraindications for use, routes of administration, and major adverse effects.

  Identify the prototype drug for each drug class.

  Describe systemic hemostatic agents for treating overdoses of anticoagulant and thrombolytic drugs.

  Understand how to use the nursing process in the care of patients receiving anticoagulant, antiplatelet, and thrombolytic agents.

KEY TERMS

Anticoagulants: drugs that prevent formation of new clots and extension of clots already present; do not dissolve formed clots

Antiplatelets: drugs that prevent one or more steps in the prothrombotic activity of platelets

Embolus: object that migrates through the circulation until it lodges in a blood vessel, causing occlusion; may be a thrombus, fat, air, amniotic fluid, a bit of tissue, or bacterial debris

Essential thrombocythemia: chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the absence of another cause

Fibrinolysin: enzyme that breaks down the fibrin meshwork that stabilizes blood clots; also referred to as plasmin

Hemostasis: prevention or stoppage of blood loss from an injured blood vessel and is the process that maintains the integrity of the vascular compartment

Heparin-induced thrombocytopenia (HIT): immune-mediated prothrombotic reaction resulting in a decrease in platelet count associated with heparin administration in patients with detectable HIT antibodies

Plasmin: enzyme that breaks down the fibrin meshwork that stabilizes blood clots; also referred to as fibrinolysin

Plasminogen: inactive protein found in many body tissues and fluids

Prothrombotic reaction: adverse effect that leads to thrombogenesis

Thrombogenesis: formation of a blood clot

Thrombolysis: breakdown or dissolution of blood clots

Thrombolytics: drugs that dissolve blood clots

Thrombosis: formation of a blood clot

Thrombus: blood clot

Introduction

Anticoagulant, antiplatelet, and thrombolytic drugs are used in the prevention and management of thrombotic and thromboembolic disorders. Thrombogenesis (or thrombosis), the formation of blood clots, is a normal body defense mechanism to prevent blood loss. Thus, this process may be lifesaving when it occurs as a response to hemorrhage; however, it may be life-threatening when it occurs at other times, because the thrombus, or blood clot, can obstruct a blood vessel and block blood flow to tissues beyond the clot either at the site of clot formation or to another part of the body. To aid understanding of drug therapy for thrombotic disorders, normal hemostasis, endothelial functions in relation to blood clotting, platelet functions, blood coagulation, and characteristics of arterial and venous thrombosis are described.

Overview of Coagulation Disorders

Physiology

Hemostasis

Hemostasis is the process that maintains the integrity of the vascular compartment. It involves activation of several mechanisms, including vasoconstriction, formation of a platelet plug (a cluster of aggregated platelets), sequential activation of clotting factors in the blood (Fig. 7.1), and growth of fibrous tissue (fibrin) into the blood clot to make it more stable and to repair the tear (opening) in the damaged blood vessel. Overall, normal hemostasis is a complex process involving numerous interacting activators and inhibitors, including endothelial factors, platelets, and blood coagulation factors (Box 7.1).

Clot Lysis

When a blood clot is being formed, plasminogen, an inactive protein present in many body tissues and fluids, is bound to fibrin and becomes a component of the clot. After the outward blood flow is stopped and the tear in the blood vessel is repaired, plasminogen is activated by plasminogen activator (produced by endothelial cells or the coagulation cascade) to produce plasmin. Plasmin (also called fibrinolysin) is an enzyme that breaks down the fibrin meshwork that stabilizes the clot; this fibrinolytic or thrombolytic action dissolves the clot.

Etiology

Normally, thrombi are constantly being formed and dissolved, but the blood remains fluid and flow is not significantly obstructed. If the balance between thrombogenesis and thrombolysis, dissolution of blood clots, is upset, thrombotic or bleeding disorders ensue. Thrombosis may occur in both arteries and veins. Arterial thrombosis is usually associated with atherosclerotic plaque, hypertension, and turbulent blood flow. These conditions damage arterial endothelium and activate platelets to initiate the coagulation process. Arterial thrombi cause disease by obstructing blood flow. If the obstruction is incomplete or temporary, local tissue ischemia (deficient blood supply) occurs. If the obstruction is complete or prolonged, local tissue death (infarction) occurs.

Venous thrombosis is usually associated with venous stasis. When blood flows slowly, thrombin and other procoagulant substances present in the blood become concentrated in local areas and initiate the clotting process. With a normal rate of blood flow, these substances are rapidly removed from the blood, primarily by Kupffer’s cells in the liver. A venous thrombus is less cohesive than an arterial thrombus, and an embolus can easily become detached and travel to other parts of the body. This embolus may be a thrombus, fat, air, amniotic fluid, tissue, or bacterial debris.

Venous thrombi cause disease by two mechanisms. First, thrombosis causes local congestion, edema, and perhaps inflammation by impairing normal outflow of venous blood (e.g., thrombophlebitis, deep vein thrombosis [DVT]). Second, embolization obstructs the blood supply when the embolus becomes lodged. The pulmonary arteries are common sites of embolization.

Pathophysiology

Atherosclerosis is the basic disease process that often leads to pathologic thrombosis. Atherosclerosis begins with accumulation of lipid-filled macrophages (i.e., foam cells) on the inner lining of arteries. Foam cells develop in response to elevated blood lipid levels and eventually become fibrous plaques (i.e., foam cells covered by smooth muscle cells and connective tissue). Advanced atherosclerotic lesions also contain hemorrhages, ulcerations, and scar tissue.

Atherosclerosis can affect any organ or tissue but often involves the arteries supplying the heart, brain, and legs. Over time, plaque lesions become larger and extend farther into the lumen of the artery. Eventually, a thrombus may develop at plaque sites and partially or completely occlude an artery. In coronary arteries, a thrombus may precipitate myocardial ischemia (angina or infarction) (see Chap. 26); in carotid or cerebral arteries, a thrombus may precipitate a stroke; in peripheral arteries, a thrombus may cause intermittent claudication (pain in the legs with exercise) or acute occlusion. Thus, serious impairment of blood flow may occur with a large atherosclerotic plaque or a relatively small plaque with superimposed vasospasm and thrombosis. Consequences and clinical manifestations of thrombi and emboli depend primarily on their location and size.

Thrombotic disorders occur much more often than bleeding disorders and are emphasized in this chapter. Bleeding disorders may result from excessive amounts of drugs that inhibit clotting.

Clinical Manifestations

Clinical manifestations of thrombosis vary depending on the size and location (arterial or venous system) of the thrombus. Symptoms are the result of decreased perfusion to an area due to the restriction or cessation of blood flow. Arterial blood clots in the cerebral, pulmonary, or cardiac system can produce a cerebrovascular accident, pulmonary embolism, or myocardial infarction, respectively. Venous blood clots may lead to DVT; classic symptoms include leg swelling and pain on palpation in the calf or thigh. However, half of all affected patients do not have any symptoms of DVT. Additional discussion of clinical manifestations is found in The Nursing Process, Assessment.

Drug Therapy

Drugs given to prevent or treat thrombosis alter some aspect of the blood coagulation process (Table 7.1; see Fig. 7.1). Anticoagulant drugs, which prevent formation of new clots and extension of already existing clots, do not dissolve clots that have already formed. Widely used in thrombotic disorders, they are more effective in preventing venous thrombosis than arterial thrombosis. Antiplatelet drugs are used to prevent arterial thrombosis. Thrombolytic drugs are used to dissolve thrombi and limit tissue damage in selected thromboembolic disorders.

Anticoagulant Drugs

There are three types of anticoagulants: heparins, vitamin K antagonists, and direct thrombin inhibitors (DTIs).

Heparins

Heparin is a pharmaceutical preparation of the natural anticoagulant produced primarily by mast cells in pericapillary connective tissue, and it is the prototype anticoagulant. Endogenous heparin is found in various body tissues, most abundantly in the liver and lungs. Exogenous heparin is obtained from bovine lung or porcine intestinal mucosa and standardized in units of biologic activity. See below for a discussion of low-molecular-weight heparins (LMWHs).

Pharmacokinetics

It is necessary to give heparin intravenously or subcutaneously, because the gastrointestinal (GI) tract does not absorb the drug. After intravenous (IV) injection, it acts immediately. After subcutaneous injection, it acts within 20 to 30 minutes. Metabolism takes place in the liver and the reticuloendothelial system. Excretion, primarily in the form of inactive metabolites, occurs in the urine. Hemodialysis does not remove it.

Action

Heparin combines with antithrombin III (a natural anticoagulant in the blood) to inactivate clotting factors IX, X, XI, and XII; inhibit the conversion of prothrombin to thrombin; and prevent thrombus formation (see Fig. 7.1). After thrombosis has developed, heparin can inhibit additional coagulation by inactivating thrombin, preventing the conversion of fibrinogen to fibrin and inhibiting factor XIII (fibrin-stabilizing factor). Other effects include inhibition of factors V and VIII and platelet aggregation.

Use

Prophylactically, patients at risk for certain disorders take low doses of heparin prophylactically to prevent DVT and pulmonary embolism. These disorders include

Therapeutically, patients receive heparin for management of acute thromboembolic disorders (e.g., DVT, thrombophlebitis, pulmonary embolism). In these conditions, the aim of therapy is to prevent further thrombus formation and embolization. Another use is in disseminated intravascular coagulation (DIC), a life-threatening condition characterized by widespread clotting, which depletes the blood of coagulation factors. The depletion of coagulation factors then produces widespread bleeding. The goal of heparin therapy in DIC is to prevent blood coagulation long enough for clotting factors to be replenished and thus be able to control hemorrhage. In addition, clinicians use heparin to prevent clotting during cardiac and vascular surgery, extra-corporeal circulation, hemodialysis, and blood transfusions, and in blood samples to be used in laboratory tests. Heparin does not cross the placental barrier and is not secreted in breast milk, making it the anticoagulant of choice for use during pregnancy and lactation.

Table 7.2 presents the dosage information for the heparins.

TABLE 7.2

DRUGS AT A GLANCE: Anticoagulants

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; PTCA, percutaneous transluminal coronary angioplasty or atherectomy; sec, seconds.

Use in Children

Little information about the use of anticoagulants in children is available. When children take heparin for systemic anti-coagulation, weight is the basis for determination of dosage (~50 units/kg). It is essential to use extreme caution to ensure that the vial concentration of heparin is correct. Fatalities in infants involving heparin overdoses have occurred. In addition, premature infants should not take heparin solutions containing benzyl alcohol as a preservative; fatal reactions have resulted.

QSEN Safety Alert  

Several major adverse events have resulted from the use of heparin, and it is classified as a high-alert drug. Nurses demonstrate consistent practice in administrating heparin by their heightened individual awareness of the risks and by advocating for systems to account for human error such as bar coding and “smart” pumps. Effective standardized practices to support safety and quality include special safeguards to reduce the risk of errors that may harm the patient.

Use in Older Adults

Older adults often have atherosclerosis and thrombotic disorders, including myocardial infarction, thrombotic stroke, and peripheral arterial insufficiency, for which they receive an anticoagulant drug. They are more likely than younger adults to experience bleeding and other complications associated with this therapy. With standard heparin, general principles for safe and effective use apply. With LMWHs, elimination may be delayed in older adults with renal impairment, and the drugs should be used cautiously.

Use in Patients With Renal Impairment

People with renal impairment may take heparin in usual dosages. However, the half-life of the drug may increase.

Use in Patients With Hepatic Impairment

Likewise, people with hepatic impairment may take heparin in usual dosages. However, the half-life of the drug may increase or decrease.

Use in Patients With Critical Illness

Heparin is often used in patients who are critically ill. However, the risk of bleeding is increased in the presence of other coexisting conditions. People who are critically ill have a high risk of DVT and pulmonary embolism, as well as a higher morbidity and mortality, including an increase in length of hospital stay, the need and duration of mechanical ventilation, and death. Effective prevention and treatment of thrombosis is necessary and typically includes LMWHs. In addition, it is essential to consider intermittent pneumatic compression devices and other measures to prevent DVT or pulmonary embolism.

Use in Patients Receiving Home Care

Patients may take standard heparin at home using the subcutaneous route, and use of LMWHs for home management of venous thrombosis has become standard practice. Daily visits by a home care nurse may be necessary if the patient or a family member is unable or unwilling to inject the medication. It is essential to take platelet counts before therapy begins and every 2 to 3 days during heparin therapy. If the platelet count falls below 100,000 platelets per microliter of blood or to less than half the baseline value, it is necessary to discontinue the heparin.

Adverse Effects

Hemorrhage is the major side effect of heparin therapy, hypersensitivity to the drug has occurred, and local irritation with subcutaneous injections of heparin can cause erythema and mild pain. Heparin-induced thrombocytopenia (HIT) (type II) is a potentially life-threatening complication of heparin administration, leading to a decrease in platelet count and detectable HIT antibodies. This condition occurs in 1% to 3% of people receiving heparin at therapeutic levels for 4 to 14 days, sometimes sooner in those who have previously received heparin. HIT is one of the most common immune-mediated adverse drug reactions. All patients exposed to any heparin at therapeutic or prophylactic doses or minute amounts in heparin flushes or on heparin-coated catheters, as well as those receiving LMWH, are at risk. If HIT occurs, it is necessary to discontinue all heparin and manage anticoagulation with a DTI such as argatroban.

Contraindications

Contraindications include GI ulcerations (e.g., peptic ulcer disease, ulcerative colitis), intracranial bleeding, dissecting aortic aneurysm, blood dyscrasias, severe kidney or liver disease, severe hypertension, polycythemia vera, and recent surgery of the eye, spinal cord, or brain. Caution is necessary in patients with hypertension, renal or hepatic disease, alcoholism, history of GI ulcerations, drainage tubes (e.g., nasogastric tubes, indwelling urinary catheters), threatened abortion, endocarditis, and any occupation with high risks of traumatic injury.

Nursing Implications

Preventing Interactions

Many medications interact with heparin, increasing or decreasing its effect (Box 7.2). Some herbs and foods increase the effects of the drug (Box 7.3). No herbs or foods that decrease the effects of heparin have been identified.

IV, Intravenous: PT prothrombin time.

Administering the Medication

Traditional anticoagulants have two major limitations: a narrow therapeutic window of adequate anticoagulation without bleeding and a highly variable individual dose-response that requires monitoring by laboratory testing. Prescribers use the activated partial thromboplastin time (aPTT), which is sensitive to changes in blood clotting factors, except factor VII, to regulate heparin dosage. Thus, normal or control values of aPTT indicate normal blood coagulation, and therapeutic values of adequate anticoagulation indicate low levels of clotting factors and delayed blood coagulation. During heparin therapy, the aPTT should be maintained at approximately 1.5 to 2.5 times the control or baseline value. The normal control value is 25 to 35 seconds; therefore, therapeutic values of adequate anticoagulation are 45 to 70 seconds, approximately. With continuous IV infusion, blood for the aPTT may be drawn at any time; with intermittent administration, blood for the aPTT should be drawn approximately 1 hour before a dose of heparin is scheduled. It is not necessary to monitor aPTT with low-dose standard heparin given subcutaneously for prophylaxis of thromboembolism or with the LMWHs (e.g., enoxaparin).

The nurse should be aware that heparin has disadvantages: parenteral injection is necessary, and the drug has a short duration of action, which means that there is a need for frequent administration.

Assessing for Therapeutic Effects

The nurse assesses for the absence or reduction of signs and symptoms of thrombotic disorders (e.g., less edema and pain with DVT, less chest pain and respiratory difficulty with pulmonary embolism, absence of uncontrolled bleeding). It is also necessary to ensure that aPTT values are within the therapeutic range.

Assessing for Adverse Effects

The nurse assesses the patient for signs of overt bleeding or HIT. Protamine sulfate, which is discussed in more detail later in the chapter, is an antidote for standard heparin and LMWHs. Protamine is typically given for bleeding that may not respond to merely withdrawing the heparin.

Patient Teaching

Education related to bleeding risk is essential for patients receiving heparin. The nurse reinforces instructions for safe use of the drug and related anticoagulants, reminding patients to obtain laboratory tests, and teaching how to observe for signs and symptoms of bleeding. Additional patient teaching guidelines for anticoagulants, including heparins, are outlined in Box 7.4.

Other Drugs in the Class

Standard heparin is a mixture of high and low molecular weight fractions, but most anticoagulant activity is attributed to the low molecular weight portion. LMWHs contain the low molecular weight fraction and are as effective as IV heparin in treating thrombotic disorders. Indications for their use include prevention or management of thromboembolic complications associated with surgery or ischemic complications of unstable angina and myocardial infarction. Currently available LMWHs (dalteparin, enoxaparin) differ from standard heparin and each other and are not interchangeable.

LMWHs are given subcutaneously and do not require close monitoring of blood coagulation. These characteristics allow outpatient anticoagulant therapy, an increasing standard. The drugs are also associated with less thrombocytopenia than standard heparin. However, monitoring of platelet counts during therapy is necessary.

Vitamin K Antagonists

Warfarin (Coumadin) is the most commonly used oral anticoagulant and is the prototype vitamin K antagonist. Table 7.2 presents dosage information for warfarin.

Pharmacokinetics

Warfarin is well absorbed after oral administration. Administration with food may delay the rate but not the extent of absorption. The drug is highly bound to plasma proteins (98%), mainly albumin. Metabolism takes place in the liver. Excretion, primarily as inactive metabolites, occurs in the kidneys. Renal impairment does not affect drug metabolism but may decrease excretion of the drug.

Action

Warfarin acts in the liver to prevent synthesis of vitamin K– dependent clotting factors (i.e., factors II, VII, IX, and X). Similar to vitamin K in structure, warfarin therefore acts as a competitive antagonist to hepatic use of vitamin K. Conversely, vitamin K serves as the antidote for warfarin. Warfarin has no effect on circulating clotting factors or on platelet function, so the anticoagulant effects do not occur for 3 to 5 days after warfarin is started because clotting factors already in the blood follow their normal pathway of elimination.

Use

Warfarin is most useful in long-term prevention or management of venous thromboembolic disorders, including DVT, pulmonary embolism, and embolization associated with atrial fibrillation and prosthetic heart valves. In addition, warfarin therapy after myocardial infarction may decrease reinfarction, stroke, venous thromboembolism, and death. The smaller doses used now are equally effective as ones used formerly, with similar antithrombotic effects and decreased risks of bleeding.

Use in Children

After cardiac surgery, children receive warfarin to prevent thromboembolism, but there are no established doses and guidelines for safe, effective use. Accurate drug administration, close monitoring of blood coagulation tests, safety measures to prevent trauma and bleeding, avoiding interacting drugs, and informing others in the child’s environment (e.g., teachers, babysitters, health care providers) are necessary.

Use in Older Adults

Warfarin metabolism may be altered in older adults. As patient age increases, a lower dose of warfarin is usually required to produce a therapeutic effect.

Use in Patients With Hepatic Impairment

Warfarin is more likely to cause bleeding in patients with hepatic disease because of decreased synthesis of vitamin K and decreased plasma proteins. In addition, only the liver eliminates warfarin; thus, it may accumulate in people with hepatic impairment, and dosage adjustment may be necessary.

Use in Patients With Critical Illness

Because the anticoagulant and antithrombotic effects of warfarin take several days to occur, patients who are critically ill require concurrent treatment with other anticoagulants, such as heparin or LMWHs. Heparin is usually continued until the international normalized ratio (INR) is the therapeutic range.

Use in Patients Receiving Home Care

For prevention of DVT, warfarin is usually self-administered at home, with periodic office or clinic visits for blood tests and other follow-up care. For home management of DVT, warfarin may be self-administered, but a nurse usually visits, performs a fingerstick INR, and notifies the prescriber, who then prescribes the appropriate dose of warfarin. Precautions to decrease risks of bleeding are necessary. However, the risk of bleeding has decreased in recent years because lower doses of warfarin are now used. In addition, medical conditions other than anticoagulation may cause bleeding during warfarin therapy.

Adverse Effects

The primary adverse effect associated with warfarin therapy is hemorrhage. Additionally, nausea, vomiting, abdominal pain, alopecia, urticaria, dizziness, and joint or muscle pain may occur.

Contraindications

Contraindications to warfarin include GI ulcerations, blood disorders associated with bleeding, severe kidney or liver disease, severe hypertension, and recent surgery of the eye, spinal cord, or brain. Caution is warranted in patients with mild hypertension, renal or hepatic disease, alcoholism, history of GI ulcerations, drainage tubes (e.g., nasogastric tubes, indwelling urinary catheters), and occupations with high risks of traumatic injury. Warfarin, a pregnancy category X medication, is contraindicated during pregnancy because it crosses the placenta and may produce fatal fetal hemorrhage. The Food and Drug Administration (FDA) has issued a BLACK BOX WARNING ♦ for warfarin due to its risk of causing major or fatal bleeding.

Nursing Implications

Preventing Interactions

Many medications and herbs interact with warfarin, increasing or decreasing its effect (Boxes 7.5 and 7.6).