Hematologic products act in the formation, repair, or function of red blood cells. There are four major groups of medications that have hematologic effects. They include the anticoagulants (heparin and warfarin [Coumadin]) and the heparin antagonist protamine sulfate. Thrombolytic agents and antiplatelet factors also have a major influence on blood clotting. Related vitamins and minerals needed for red blood cell development are iron, vitamin K, vitamin B₁₂, and folic acid; these are presented in Chapter 24.

Anticoagulants

One of the body’s protective functions is to clot blood in response to tissue injury. Any damage to the cells starts a series of chemical reactions to protect the body (Figure 20-1). Cellular damage results in the formation of thromboplastin, which then acts on prothrombin to form thrombin. Calcium must be present for this reaction to occur. Thrombin then acts on fibrinogen (a protein found in the blood plasma) to produce fibrin, a netlike substance in the blood that traps red and white blood cells and platelets and forms the matrix, or skeleton, of the clot. Vitamin K must be present to produce prothrombin and other clotting factors that are made in the liver. All anticoagulants prevent the formation of blood clots, or thrombi, by interfering with this complex clotting mechanism of blood and increasing the time it takes for blood to clot. In cases of overdose, protamine sulfate is given to counteract the effect of heparin. In response to some bleeding disorders, vitamin K may be given either orally or parenterally to manufacture prothrombin and serve as an anticoagulant antagonist (see Chapter 24).

FIGURE 20-1 Blood coagulation and clot resolution. *PL,* Phospholipid.

Action

There are two major categories of anticoagulants. The first category, the coumarin and indanedione derivatives, limits formation of blood coagulation factors II, VII, IX, and X in the liver by interfering with vitamin K. These drugs do not destroy existing blood clots; however, they may limit the extension of existing blood clots or thrombi.

The second category, heparin sodium, acts at multiple sites in the normal coagulation system to stop reactions that lead to the clotting of blood and the formation of fibrin clots. It increases the action of antithrombin III (heparin cofactor) on several other coagulation factors, primarily activated factor X (Xa), to slow new clot development. Heparin does not dissolve existing clots either, although thrombolytic agents do. Low-molecular-weight heparin is a special formulation used in special circumstances, such as to prevent deep vein thrombosis (DVT) after surgery.

Uses

As part of the circulatory system, the arterial vessels carry oxygenated blood throughout the body. If these small arteries become plugged with thrombi (clots made of fibrin, platelets, and cholesterol), oxygen cannot get to the tissues, and death may result. Abnormal blood clotting may produce a thrombus in the coronary artery, which nourishes the heart muscle. Emboli (small pieces of a blood clot) may break off from a site of thrombophlebitis (inflammation and blood clot in a vein) in the lower extremities and travel through the bloodstream to block vessels in areas of the heart, brain, or lung. (See Chapter 15, Figure 15-7.) This blockage can cause stroke or death. Drugs that can slow or reduce clotting, then, are very helpful.

Anticoagulant therapy is used to prevent new clot formation or to stop existing clots from growing in size. Anticoagulant therapy is used prophylactically during and after many types of surgery, especially surgery involving the heart or circulation. It is also used in patients with heart valve disease, in patients with some dysrhythmias (irregular heartbeats), and in patients receiving hemodialysis. Any patient on bed rest for a long time is at risk for development of blood clots, especially patients with a history of clotting problems or recent orthopedic, thoracic, or abdominal surgery.

Heparin is the anticoagulant of choice when an immediate effect is needed. For long-term therapy, a coumarin or indanedione derivative is used. The U.S. Food and Drug Administration has classified coumarin preparations as “possibly” effective as part of the therapy for treatment of transient cerebral ischemic attacks. Indanedione derivatives (phenindione) are used to treat pulmonary emboli and as prophylaxis to treat DVT, myocardial infarction, rheumatic heart disease with valve damage, and atrial dysrhythmias. Low-intensity warfarin therapy (prothrombin time [PT] ratio between 1.2 and 1.5) greatly decreases the risk of stroke from nonrheumatic atrial fibrillation and has few side effects.

Adverse Reactions

By far, the most common adverse reactions from heparin and warfarin are excessive bleeding and thrombocytopenia. Early signs of overdose or internal bleeding include bleeding from gums while brushing teeth, excessive bleeding or oozing from cuts, unexplained bruising or nosebleeds, and unusually heavy or unexpected menses in women. These are the “must know” symptoms that suggest the patient needs prompt attention.

There are a number of other adverse reactions that may occasionally be seen. Warfarin may produce alopecia (hair loss), rash, urticaria (hives), cramping, diarrhea, intestinal obstruction, nausea, paralytic ileus, vomiting, excessive uterine bleeding, hemorrhage with excessive dosage, leukopenia, and fever. Heparin sodium may produce hypertension (high blood pressure); headache; hematoma, irritation, and pain at the injection site; conjunctivitis; tearing of eyes; rhinitis; frequent or persistent erection; hemorrhage; thrombocytopenia; shortness of breath; wheezing; chills; fever; alopecia; and hypersensitivity (allergic) reaction.

Drug Interactions

Other anticoagulants (coumarin or indanedione derivatives), methimazole, and propylthiouracil increase the anticoagulant effect of heparin.

Antihistamines, digitalis, nicotine, and tetracycline decrease the anticoagulant effect of heparin.

Acetylsalicylic acid (ASA), coumarin-derivative anticoagulants, dextran, nonsteroidal antiinflammatory drugs (NSAIDs), and other selected drugs increase the risk of bleeding and hemorrhage in a patient receiving heparin.

ASA, corticotropin, ethacrynic acid, glucocorticoids, and NSAIDs increase the risk of gastrointestinal (GI) bleeding and hemorrhage in a patient receiving heparin.

Allopurinol, ASA, anabolic steroids, antibiotics, androgens, many sedatives, some antacids, dextran, disulfiram, drugs affecting blood elements, glucagon, heparin, narcotics (with prolonged use), phenylbutazone, propylthiouracil, quinidine, quinine, salicylates, thyroid drugs, and vitamin E increase the PT response of patients receiving warfarin.

Adrenocorticosteroids, antacids, antihistamines, barbiturates, contraceptives (oral), estrogens, griseofulvin, haloperidol, meprobamate, primidone, rifam-pin, thiazide diuretics, and vitamin K decrease the PT/International Normalized Ratio (INR) response of a patient on warfarin.

Anticoagulant effects may be increased with acute alcohol intoxication and decreased with chronic alcohol abuse. Oral hypoglycemics taken with anticoagulants may increase the effect of either the hypoglycemic or anticoagulant.

Alkylating agents, antimetabolites, corticosteroids, ethacrynic acid, indomethacin, quinidine, and salicylates increase the risk of bleeding in a patient taking warfarin.

Nursing Implications and Patient Teaching

Patients requiring rapid anticoagulation are commonly hospitalized. Coagulation and PT/INR tests are ordered when the patient is started on anticoagulants. Heparin is usually started for an immediate effect and gradually replaced by oral anticoagulants. Thereafter, the physician or other health care provider orders coagulation and PT/INR tests at regular intervals. When the oral anticoagulant shows proper effect, and the prothrombin activity is in the therapeutic range, heparin therapy may be stopped and the oral anticoagulant therapy continued.

Standard heparin dosing protocols have been controversial for many years. Weight-based dosing is now the standard of care for determining the dosing of heparin. Weight-based dosing uses the patient’s body weight in kilograms, infusing 80 units/kg as an intravenous (IV) bolus. The maintenance infusion is 18 units/kg/hr through an infusion pump. There are indications that weight-based dosing is safer, achieves therapeutic levels in less time than with standard dosing, and results in fewer bleeding complications and a lower rate of thromboembolic recurrences.

The standard tests for determining the general effect of heparin on clotting are the Lee-White coagulation time, the whole-blood activated partial thromboplastin time, and the activated partial thromboplastin time (aPTT). The most commonly used test is the aPTT. The dosage of heparin is considered adequate when the whole blood clotting time is approximately 1.5 to 2.5 times the control value. The recommended method for establishing the unfractionated therapeutic range is by the anti-Xa method. This method is the most specific and is least affected by the variables inherent to the in vitro technique. Samples are collected from patients on unfractionated heparin. The samples are tested with aPTT and anti-Xa assays. The range of aPTT values correlate to anti-Xa levels in a range of 0.3-0.7 U/mL of heparin.

PTs are used to determine the dosage for coumarin preparations. These PT tests are done daily until the results stabilize in the therapeutic range ( to times the normal control value). After stabilization, tests are performed at 1-week to 4-week intervals, depending on patient status. Unfortunately, these test results vary from laboratory to laboratory and from day to day because of variations in the reagent chemical used to perform the test. However, this test is still used in many countries.

To avoid test variation, a system called the International Normalized Ratio (INR) is used to standardize PT reporting so that all laboratory reports are the same. The INR is based on the PT ratio supplied by the drugmaker that would be obtained if a standard reference testing chemical was used. PT numbers are changed to INR measurements by a standard math equation. Laboratories commonly report both numbers (PT/INR) when a PT is ordered.

The goal of prolonging the PT to 1.5 to 2.5 times the normal has largely been replaced in the United States and some other countries by specific INR goal recommendations for each clinical indication. The typical INR goal is 2 to 3, except in mechanical cardiac valve replacement, in which a higher INR is necessary to prevent clot formation.

n Assessment

Learn as much as possible about the patient’s health history, including the presence of hypersensitivity, underlying systemic disease, the current nature of the problem, and use of other medications. Inquire about conditions that contraindicate use of some anticoagulants, such as alcoholism; blood dyscrasias; bleeding tendencies of the GI, genitourinary, or respiratory tracts; or malignant hypertension. Patients with congestive heart failure may be more sensitive to coumarin anticoagulants and indanedione derivatives.

Heparin is derived from animal tissue and should be used with caution in any patient with a history of allergy. This drug should be used cautiously in patients with hepatic or renal disease or hypertension, during menses, after delivery, or in patients with indwelling catheters. A higher incidence of bleeding may be seen in women older than the age of 60. Make absolutely sure that female patients taking a coumarin or indanedione derivative are not pregnant or breastfeeding. These drugs are usually not given to children.

Lifespan Considerations

Older Adults

Anticoagulants

Older adults may be more sensitive to the effects of anticoagulants, and a lower maintenance dose is usually recommended for the geriatric patient, along with very close supervision and monitoring. This is particularly true for clients who receive warfarin and may be Vitamin-K deficient because of low intake of green leafy vegetables.

The primary adverse effects of excessive drug dosages are prolonged bleeding from the gums from small shaving cuts or when brushing teeth, excessive or easy skin bruising, blood in urine or stools, and unexplained nosebleeds. There may be early signs of overdose that indicate the need for medical intervention.

Caution patients to wear a MedicAlert bracelet or carry an identification card indicating the use of an anticoagulant. Also, remind patients to always consult the prescriber before starting any new drug (including over-the-counter [OTC] medications and vitamins), if changing a medication dose, or when any drug product is discontinued. Many medications can change the effects of an anticoagulant in the body.

Be aware that when drugs that may cause gastric irritation are given to clients on anticoagulant therapy, the risk for GI bleeding is increased. Drugs such as NSAIDs (e.g., ibuprofen, indomethacin) that are commonly prescribed for the older adult patient often cause GI effects.

Alcohol consumption can alter the effect of anticoagulants in the body. Patients should be instructed to avoid alcohol or at the least limit their alcohol intake to one alcoholic drink a day. Alcohol may cause liver damage and minor GI bleed-ing, both of which increase the individual’s sensitivity to anticoagulants.

The nurse should be aware that diet can interfere with the anticoagulant effect. In a previously stabilized person, vitamin C deficiency, chronic malnutrition, diarrhea, or other illness may result in an increased anticoagulant effect. Increased intake of green leafy vegetables (e.g., broccoli, cabbage, collard greens, lettuce, spinach) or consumption of a nutritional supplement or multivitamin containing vitamin K can result in decreased anticoagulant effectiveness.

Modified from McKenry LM, Tessier E, Hogan MA: Mosby’s pharmacology in nursing, ed 22, St Louis, 2006, Mosby.

n Diagnosis

There are many medical and surgical contraindications to the use of anticoagulant drugs, particularly in patients who have recently had surgery, trauma, or obstetric complications. Review the patient’s problems and make certain that none of these contraindications exist.

n Planning

The dosages listed for heparin are given in United States Pharmacopeia heparin units. Heparin is not effective if given orally and should be given by IV injection, IV infusion, or deep subcutaneous (intrafat) injection. Heparin should not be given via intramuscular (IM) injection because these injections produce hematomas, irritation, and pain at the injection site. Use a small (25-gauge) needle and a tuberculin syringe for the subcutaneous intrafat injection.

Clinical Pitfall

Planning for Safety

Patients who are anticoagulated and require dental or surgical procedures may need to discontinue the medication before surgery to avoid problems with bleeding. Patients should be encouraged to tell the dentist, physician, or surgeon they are taking anticoagulants. Surgical procedures may be a particular risk if patients have a traumatic injury or require emergency surgery.

n Implementation

Anticoagulant drugs should not be used if good laboratory facilities are not available, or if the patient is not compliant in taking medications or keeping appointments for laboratory and health assessment. Coumarin derivatives should not be used in a patient undergoing diagnostic or therapeutic procedures with risk for uncontrolled bleeding.

The sites of intrafat injections of heparin should be rotated to avoid formation of hematomas. (See Chapter 10, Figure 10-16, for rotation site suggestions.) Because of the adverse effects if inaccurate doses are given, once the heparin is drawn into the syringe, double check the dose with another nurse. There are several things to remember about heparin injection that make the process unique. First, do not attempt to pull back on the plunger or aspirate blood before injection. Second, the nurse must be extra careful to not move the needle while the heparin is being injected. Third, injection sites should not be massaged before or after injection. Patients receiving heparin are not good candidates for IM injections of other medications, because hematomas and bleeding into nearby areas may occur.

If the heparin solution is discolored or contains a precipitate (solid at the bottom), it must not be used. Heparin is strongly acidic and is chemically incompatible with many other medications in solution, so it must not be piggybacked with other drugs into an infusion line. Never mix any drug with heparin in a syringe when bolus therapy is given.

If intermittent IV therapy is being given, blood for partial thromboplastin time determination should be drawn hour before the next scheduled heparin dose. Blood for partial thromboplastin times can be drawn anytime after 8 hours of continuous IV heparin therapy. However, blood should not be drawn from the tubing of the heparin infusion line or from the vein being used for infusion. Blood should always be drawn from the arm not being used for heparin infusion.

If heparin is being given at the same time as a coumarin or an indanedione derivative, blood should not be drawn for PTs within 5 hours of IV heparin administration or 24 hours if heparin is given subcutaneously. IV heparin infusions should be checked frequently, even if pumps are in good working order, to make sure the proper dose is being given.

If anticoagulant therapy is started with heparin and continued with a coumarin or indanedione derivative, it is recommended that both drugs be given until the PT or INR results indicate an adequate response to the coumarin or indanedione derivative.

A summary of anticoagulants is provided in Table 20-1.

Clinical Pitfall

Internal Bleeding

Signs suggesting internal bleeding include abdominal pain or swelling, back pain, bloody or tarry stools, bloody or cloudy urine, constipation (resulting from paralytic ileus or intestinal obstruction), coughing up blood, dizziness, severe or continuous headaches, and vomiting blood or “coffee-ground” substance.

Table 20-1

Anticoagulants and Other Drugs Affecting the Blood

GENERIC NAME	TRADE NAME	COMMENTS
Anticoagulants
Coumarin and Indanedione Derivatives
warfarin (sodium)	Coumadin	Dosage individualized for patient and problem. Usual initiation dose is 2-5 mg/day, with dosage adjustments based on the results of INR and/or PT ratio determinations. Store tablets at 59° F to 86° F, and protect from air and light.
Heparin
heparin	Heparin	Dosage is adjusted according to patient’s coagulation time. q4h
Low-Molecular-Weight Heparins
dalteparin sodium	Fragmin	Given SQ for DVT prophylaxis and treatment for DVT/PE, MI.
enoxaparin	Lovenox	Given SQ for DVT prophylaxis and treatment for DVT/PE, MI.
tinzaparin	Innohep	Given for DVT/PE treatment.
Heparin Antagonist
protamine sulfate	Protamine Sulfate	The onset of action for protamine sulfate is 0.5-1 min. The duration of action is 2 hr. Adults and children: 1 mg of protamine sulfate for every 90 USP units of beef lung heparin or for every 115 USP units of porcine intestinal mucosa heparin to be neutralized. Administer IV at a slow rate over 1-3 min (limit is 50 mg given in 10 min). Additional doses may be given if need is indicated by coagulation studies.
Thrombolytic Agents
Tissue Plasmogen Activators
alteplase, recombinant	Activase	For lysis of coronary artery thrombi (accelerated infusion): Best results if given IV within 6 hr of onset of symptoms of MI. Dosage is determined by patient weight. An IV bolus is given first followed by IV infusion over 60 min. May be slightly more effective but costs 10 times more than other products. Pulmonary embolism or acute ischemic stroke: Must administer within 3 hr after onset of symptoms. 10% of the total dose is given as an IV bolus over 1 min then the remaining dose is administered over 60 min.
reteplase	Retavase	Given as a double bolus with first bolus IV over 2 min then another IV bolus 30 min later.
tenecteplase	TNKase	Dose is weight based. Do not give more than 50 mg; by IV administration only. Do not exceed recommended volume per 5 sec when giving as IV bolus.
Antiplatelet Agents
abciximab	ReoPro	Give IV bolus administered 10-60 min before the start of PTCA, followed by a continuous IV infusion for 12 hr.
acetylsalicylic acid	ASA	Give 325-650 mg PO (chewed) stat with first indication of MI. Do not give ASA in addition to coumarin anticoagulants.
anagrelide	Agrylin	Used in treating essential thrombocythemia to reduce elevated platelet count and the risk of thrombosis. Give daily for about 1 wk and then adjust to lowest effective dosage required to reduce and maintain platelet count, 600,000/mL.
cilostazol	Pletal	For intermittent claudication, give daily approximately 30 min before or 2 hr after breakfast and dinner. May need a smaller dose if concurrent administration of some CYP3A4 drugs.
clopidogrel	Plavix	Give with or without food. No adjustment necessary for older adult patients or those with renal disease.
dipyridamole	Persantine	Give daily as adjunct to warfarin therapy.
ticlopidine	Ticlid	Give with food.
Other Miscellaneous Products
antihemophilic factor	Hemofil M/E Koate-HPMonoclate P	Used in treating patients with hemophilia A. Individualize dosage based on needs of patient.
antiinhibitor coagulant complex	Autoplex T/E Feiba VH	Individualize dosage based on needs of patient.
antithrombin III	Thrombate III	Used in treating patients with hereditary antithrombin III deficiency. Individualize dosage based on needs of patient.
eptifibatide	Integrilin	Give IV bolus as soon as possible after diagnosis of acute coronary syndrome, followed by continuous infusion of 2 mcg/kg/min until hospital discharge or CABG surgery.
hydroxyurea	Droxia	Antisickling agent. The patient’s CBC count must be monitored every 2 wk.
pentoxifylline	Trental	Used in intermittent claudication from chronic occlusive arterial disease and in cerebrovascular insufficiency. Give with meals. Decrease dosage if GI side effects develop.
tirofiban	Aggrastat	Used with heparin in the treatment of acute coronary syndrome, including patients who are to be managed medically and those with PTCA. Can be administered in the same IV catheter as heparin. Give for 48-108 hr, including during surgical procedure and after. Medication must be diluted and administered according to the patient’s weight.

ASA, Acetylsalicylic acid; CABG, coronary artery bypass grafting; CBC, complete blood cell; DVT, deep vein thrombosis; INR, international normalized ratio; IV, intravenous; MI, myocardial infarction; PE, pulmonary embolism; PO, by mouth; PT, prothrombin time; PTCA, percutaneous transluminal coronary angioplasty; SQ, subcutaneous.
Indicates “Must-Know Drugs,” or the 35 drugs most prescribers use.

n Evaluation

If heparin is given by continuous IV infusion, the coagulation time should usually be determined every 4 hours in the early stages of treatment. Many medical centers have adopted evidenced-based protocols that indicate heparin dosing based on previous aPTT results and when the next aPTT should be drawn.

Watch for signs of overdose of anticoagulants and internal bleeding as therapy progresses. This might include bleeding gums when brushing teeth, blood in the urine, or coughing up blood.

Determine whether the patient understands why he or she is taking the medicine and the symptoms of overdose. Have the patient explain to the nurse if he or she notices signs of bruising or easy bleed-ing. More accurate patient monitoring of antico-agulant response is a Joint Commission National Patient Safety Goal, and many hospitals are adopting new protocols for required patient teaching and clinical monitoring.

n Patient and Family Teaching

Tell the patient and family the following:

• The patient should take the oral medication only as directed. If a dose is missed, it should be taken as soon as possible, but not if it is almost time for the next dose. The doses should not be doubled. The patient should keep a record of all missed doses.

• The patient will need regular PT/INR time or coagulation blood tests, and regular visits to the physician to ensure that blood clotting stays within the narrow therapeutic range. The dosage may require changes from time to time, based on results of laboratory tests.

• The patient should not take other medications without checking with the health care provider; this includes aspirin or any OTC medicines.

• The patient should wear a MedicAlert bracelet or necklace, or carry a medical information card stating the name of the anticoagulant.

• The patient should inform all nurses, physicians, dentists, podiatrists, and other health care providers about being on anticoagulant therapy.

• The patient should use caution in brushing teeth, trimming nails, and shaving. (An electric razor should be used when possible.)

• Pressure should be used to stop bleeding from accidental cuts or scrapes; if bleeding persists after 10 minutes, the health care provider should be contacted.

• The patient should not engage in contact sports or other activities that could lead to injuries.

• The patient should eat a normal, balanced diet, but should avoid eating excessive amounts of foods high in vitamin K (tomatoes, onions, dark leafy greens, bananas, or fish).

• The patient should avoid alcohol.

• The patient should know the possible side effects of anticoagulants: active bleeding or signs of bleeding such as tarry stools, blood in the urine, bleeding gums, nosebleeds, dizziness, coughing up blood, abdominal or joint pains, unexplained bruising, or unusually heavy or unexpected menstrual periods in women.

• After anticoagulation therapy has been stopped, the patient should use caution until the body recovers its blood-clotting abilities.