Anticoagulant & Fibrinolytic Therapy | Copyright © 2008 CEUFast.com

Course Contents

	Purpose    Objectives    Introduction    Safe Practice Recommendations    Anticoagulant Therapy    Aspirin    Warfarin    Heparin    Glycoprotein IIb/IIIa Inhibitors    Antiplatelet Agents    Direct Thrombin Inhibitors    Factor Xa Inhibitors    Thrombolytics and Fibrinolytics    LMWH Products    Patient Education    Conclusion    References    Click any section in the index above to browse to the corresponding course section

Purpose

The purpose of this course is to update healthcare professionals on the use and monitoring of anticoagulant and fibrinolytic medications.

Objectives

Upon completion of this self study module, the participant will be able to:

Introduction

The Institute for Safe Medication Practices (ISMP) issued a warning against concomitant use of low molecular weight heparin (LMWH) and unfractionated heparin (ISMP, 2003). This warning was sent after three deaths were voluntarily reported to the USP ISMP Medication Errors Reporting Program (MERP). LMWH products are used for prophylaxis and treatment of DVT and ischemic complications of unstable angina and non Q wave myocardial infarction (MI) (ISMP, 2003).

The following is a description of the reported deaths (ISMP, 2003). A 62 year old who had unstable angina and died after an initial dose of FRAGMIN (dalteparin) was followed by IV heparin and then a thrombolytic, given when the patient had signs of an acute MI. A 42 year old died from died from intracranial hemorrhage after accidentally prescribed lovenox (enoxaparin) followed by a heparin protocol (ISMP, 2003). The patient presented with an upper extremity thrombosis. An 86 year old woman with a history of atrial fibrillation, hypertension, lethargy and constipation was prescribed enoxaparin subcutaneous every 12 hours. The next day, warfarin was added. The warfarin was later stopped for a colonoscopy and a heparin IV was started; but the enoxaparin was not stopped (ISMP, 2003).

Safe Practice Recommendations

The following basic principals can be used to reduce errors when using fibrinolytics and related drugs (ISMP, 2003):

The ISMP (2003) recommends the following changes to improve safe medication practices:

	Prescribers, pharmacists, and nurses must thoroughly review the patient’s total drug regimen and consider current and recent drug therapy before ordering, dispensing, or administering any heparin products.
	LMWH is often prescribed and administered outside the pharmacy department. Therefore, protocols, guidelines, and standard order forms should prominently remind practitioners to assess all drug therapy, including drugs administered in emergency treatment areas, and avoid concomitant use when indicated (e.g., a heparin infusion should not be started if LMWH has just been administered, etc.)
	For inpatients, a summary of current and discontinued medications (including one time doses) generated from the pharmacy computer system may be helpful if placed on the patient’s chart daily for easy reference.
	A system must be in place to communicate all orders for heparin products to the pharmacy (including those prescribed in emergency treatment areas if patients are admitted) so that screening can occur for unsafe duplication of products and contraindications.
	Be sure that computer alerts for duplicate therapy have not been suppressed.
	Restrict access to heparin products (except flushing solutions) when feasible and dispense these drugs from the pharmacy, as needed.
	Educate nurses about the risks inherent in borrowing high alert medications from other patients’ supplies. If some of these medications must be stored in patient care areas (e.g., emergency department, etc.), display alerts on automated dispensing cabinet screens or affix them to other storage areas.
	Ensure that heparin products stored in automated dispensing cabinets outside emergency treatment areas cannot be removed via override before pharmacy has screened the order.
	Require an independent check by two individuals before administering heparin products. Consider including an independent review of the patient’s entire drug therapy profile and recent laboratory results.

Another way to reduce errors is to limit the fibrinolytic agents on the formulary. Engineered controls can be implemented, like independent double checks or dosing tables to avoid miscalculations. The full generic name for fibrinolytic drugs should be on orders and protocols to avoid confusion. Prompts to remind practitioner to consider the weight for weight based therapy should be incorporated where possible.

Anticoagulant Therapy

Anticoagulants work by interfering with some part of the clotting mechanism. Common indications for the use of anticoagulants include:

	prophylaxis and treatment of venous thrombosis and pulmonary embolism
	preventing thromboembolic complications arising from cardiac surgery, vascular surgery, frostbite and during the acute stage of a MI
	treatment of disseminated intravascular clotting syndrome
	treatment of atrial fibrillation with embolization
	as an anticoagulant during dialysis

Before administering an anticoagulant, coagulation test values must be checked. If they are abnormal, the physician must be notified. Normal ranges prior to anticoagulation therapy are (Skidmore-Roth, 2007):

Patient Education:

	Warn patients to protect themselves from injury and to report any signs of bleeding in the urine, stool (black and tarry), gums or oral mucosa.
	Aspirin, nonsteroidal anti-inflammatory agents (NSAIDs) and steroids will potentiate the action of anticoagulants and should be avoided unless approved by a physician.
	Anticoagulants should be held during active bleeding including menstruation.
	Advise the patient to use a soft-bristle toothbrush to avoid bleeding gums and use an electric razor.
	Carry a medic alert ID that identifies the anticoagulant medication.

Aspirin

Aspirin’s antithrombotic effect is to block the synthesis of thromboxane A2, inhibiting platelet aggregation. The antiplatelet effect of aspirin onset is 20 to 30 minutes and lasts for the life of the platelet (7 – 10 days). The antithrombotic effect requires a much lower does than the anti-inflammatory effect of aspirin; so the usual dosage for the antithrombotic effect is between 80 mg – 325 mg daily (Skidmore-Roth, 2007).

Gastrointestinal side effects may occur with the use of aspirin and may be reduced by lowering the dose. These side effects may include epigastric discomfort, mucosal erosion with gastrointestinal bleeding, or peptic ulceration. Allergic reaction and drug interactions may also occur.

Warfarin

Oral anticoagulation with warfarin (coumadin) is initiated along with heparin therapy to prevent the reoccurrence of thrombi. Because warfarin takes several days to reach a therapeutic concentration, it is usually started several days before heparin therapy is discontinued. A standard beginning dose of 5-15 mg a day is administered and then gradually adjusted until a therapeutic international normalized ratio (INR) of 2:3 is achieved. If the patient has recurrent systemic embolism or a mechanical prosthetic valve, the targeted range is increased to 3:4.5 (Nurse’s Drug Hand Book, 2002). A prothrombin time (PT) is another lab test that may be used to monitor warfarin therapy. Warfarin has a narrow range and the dosage is highly individualized. The elderly or debilitated patients require a lower initial dose.

Warfarin’s anticoagulant effect is the interference with blood clotting by depressing hepatic synthesis of vitamin K dependent coagulation factors II, VII, IX and X. It is used for MI, DVT, pulmonary emboli (PE), atrial dysrhythmias, and post cardiac valve replacement. Vitamin K is the antidote for an overdose of Warfarin.

Warfarin’s anticoagulant effects are easily impacted. Varying vitamin K intake in the diet can affect the action of Warfarin. A normal balanced diet should be maintained. Drastic dietary changes should be avoided. Eliminating all foods high in vitamin K is not recommended. Dosing errors, poor patient compliance, malabsorption and unreliable PT/INR tests may effect the action of Warfarin. Resistance to warfarin may be hereditary or acquired. Other conditions that may effect the action are nephrotic syndrome, hypothyroidism, hyperlipemia, or edema (Skidmore-Roth, 2007).

Gastrointestinal side effects may occur with the use of warfarin. These side effects may include nausea, vomiting, diarrhea, cramps, anorexia, stomatitis, or hepatitis. Hematologic side effects may include hemorrhage, hematuria, leukopenia, eosinophilia, or agranulocytosis (Skidmore-Roth, 2007).

Heparin

Heparin inhibits reactions that lead to blood clotting and formation of fibrin clots and acts at multiple sites in the normal coagulation system. It does not dissolve existing blood clots; but, may prevent clots from becoming large. Heparin has a narrow range and the dosage is highly individualized. Lab test must be closely monitored. Nursing considerations need to include following blood studies: hematuria (Hct), and occult blood in stools.

A continuous heparin infusion is ordered in full anticoagulation doses and administered intravenously (IV). The goal of heparin therapy is to prevent new clots from forming and prevent the extension or growth of an existing thrombus. Heparin does not dissolve existing thrombi but it does block the conversion of fibrinogen to fibrin.

An initial bolus dose of heparin is administered and then maintained by a continuous infusion. IV doses are may be given IV push over 1 minute if dose is less than 1000 U or continuous infusion over 4 to 24 hours (Skidmore-Roth, 2007). The IV peak action is 5 minutes with duration of 2-6 hours. Therapeutic heparin levels can be achieved most effectively when the dosage of heparin is calculated by the patient’s body weight. A standard protocol calls for the administration of a bolus dose of 75 to 100 units per kilogram (u/kg), followed by a continuous infusion of 18u/kg/hr (hour) for at least 5 days (Skidmore-Roth, 2007). All calculations need to be verified by another RN. Inadvertent errors have occurred when the nurse changed the fluids and inadvertently set heparin fluids at mainline rate.

A continuous heparin infusion must be monitored closely. PTT is done 6 hours after the initiation of heparin and then every day. A platelet count should be done every 2-3 days. PTT is also done 6 hours after any change (Skidmore-Roth, 2007). Heparin orders are often written for adjustment of the infusion rate based on the lab results. If not, the physician should be notified if the PTT or APTT is outside of therapeutic range, so the dosage can be adjusted. Therapeutic range of the PTT is 1.5-2.5 times the control value (Smeltzer, 1996). The treatment for overdose is protamine sulfate.

Because heparin is strongly acidic, it is not compatible with many other medications. Avoid mixing any medication with heparin unless specifically instructed by the pharmacist or the physician. Abrupt withdrawal of heparin can cause increased coagulability (Skidmore-Roth, 2007).

Low-dose heparin is administered subcutaneously (SQ) for prevention and treatment of DVT, in doses of about 5000 units every 12 hours (Skidmore-Roth, 2007). The onset for subcutaneous dose is 20-60 minutes with duration of 8-12 hours. Heparin should be administered the same time each day to maintain steady blood levels by subcutaneous injection with a small gauge needle. Do not massage the area nor aspirate when giving subcutaneous injections. The APTT should be monitored frequently. Heparin is poorly absorbed when administered orally, rectally or sublingually and intramuscular absorption is irregular.

Bleeding is the major adverse consequence of heparin administration, although thrombocytopenia may also occur. Other side effects include fever, chills, diarrhea, nausea, vomiting, anorexia, stomatitis, abdominal cramps, hepatitis, and hematuria. Heparin is contraindicated for patients with hypersensitivity to heparin, hemophilia, leukemia with bleeding, peptic ulcer, thrombocytopenia purpura, severe hepatic disease, blood dyscrasisas, severe hypertension, subacute bacterial endocarditis, or acute nephritis (Skidmore-Roth, 2007)..

Glycoprotein IIb/IIIa Inhibitors

Glycoprotein IIb/IIIa inhibitors may be beneficial for patients with continued unstable angina or acute chest pain and following invasive cardiac procedures to reduce platelet aggregation.

Aggrastat (tirofiban) is a platelet aggregation inhibitor for the treatment of patients with acute coronary syndrome (unstable angina, non Q wave or elevated ST segment MI). Aspirin blocks the synthesis of thromboxane A2, inhibiting platelet aggregation. Despite the absence of thromboxane A2, platelets may be induced to aggregate by triggers such as thrombin, subendothelial collagen, or stainless steel from intracoronary stents. Once platelets are activated, glycoprotein IIb/IIIa receptors that are essential for platelet aggregation appear on the surface of the platelet. Fibrinogen molecules bind to these receptors to form bridges between adjacent platelets, allowing them to aggregate. Glycoprotein IIb/IIIa receptor inhibitors prevent fibrinogen binding and platelet aggregation, regardless of the trigger responsible for platelet aggregation.

Aggrastat combined with heparin and aspirin is effective in reducing the early combined incidence of death, nonfatal MI and other adverse thrombotic events. The recommended infusion dosage of Aggrastat is 50 μg/ml solution administered at an initial rate of 0.4 μg/kg/min for 30 min followed by a continuous infusion of 0.1 μg/kg/min. It may be administered through the same intravenous catheter as heparin. Side effects include bradycardia, dizziness, rash and bleeding. It is contraindicated in hypersensitive patients and those with active internal bleeding, stroke, major surgery, severe trauma, intracranial neoplasm, aneurysm and hemorrhage.

Nursing considerations during therapy should include monitoring of B/P until stable and taken lying and standing since orthostatic hypotension is common. Laboratory monitoring need to include platelet counts, Hct, and hemoglobin (Hgb) done prior to treatment and 6 hours after loading dose then at least daily thereafter during therapy with Aggrastat (or more frequently if there is evidence of significant decline). APTT should be determined before treatment and anticoagulant effects of heparin should be carefully monitored especially when heparin is administered with other products affecting hemostasis (i.e. warfarin).

Antiplatelet Agents

Plavix (clopidogrel) is a platelet aggregation inhibitor that inhibits first and second phases of ADP induced effects in platelet aggregation. It selectively inhibits the binding of ADP to its platelet receptor and subsequent ADP mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. It also inhibits platelet aggregation induced by agonists other than ADP by blocking amplification of platelet activation by released ADP. It acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.

It is useful in reducing the risk of stroke in high risk patients. High risk patients include those with atherosclerosis documented by recent stroke, recent MI or established peripheral arterial disease. It has convenient once daily dosing of one 75 mg tablet, with or without food. When administered with food the gastric symptoms are decreased.

Plavix does not require routine hematological monitoring but may require patients on long term therapy to be followed for liver function (AST, ALT, bilirubin, creatinine) and blood studies (complete blood count [CBC], Hct, Hgb). Common adverse effects include chest pain, headache, diarrhea, rash and purpura. It is contraindicated in patients with active pathologic bleeding such as peptic ulcer or intracranial hemorrhage. As with other antiplatelet agents, Plavix should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or co administration with NSAIDs or warfarin.

Ticlid (ticlopidine) causes a time and dose dependent inhibition of both platelet aggregation and release of platelet granule constituents as well as a prolongation of bleeding time.

It is used to reduce the risk of thrombotic stroke in patients who have experienced stroke precursors and in patients who have had a completed thrombotic stroke. Because of the risk of neutropenia or agranulocytosis, use should be reserved for patients intolerant to aspirin therapy. Dosage is 250 mg TWICE DAILY taken with food.

Contraindications to its use include hypersensitivity to the drug, presence of hematopoietic disorders and presence of hemostatic disorder or active pathologic bleeding (e.g., bleeding peptic ulcer or intracranial bleeding) and patients with severe liver impairment. Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV. Platelet transfusions may also be used to reverse the effect of ticlopidine on bleeding. In most patients, bleeding time and other platelet function tests return to normal within 2 weeks after discontinuation of the drug.

Direct Thrombin Inhibitors

The rationale for clinical use of direct thrombin inhibitors is the inability of the heparin antithrombin complex to inactivate clot bound thrombin. This may be due to the large size of the complex and to masking of the binding sites for heparin and AT on the thrombin molecule following attachment of thrombin to fibrin or arterial wall matrix. In comparison, the direct thrombin inhibitors which are antithrombin independent, inhibit clot bound thrombin because their sites for binding thrombin are not masked by fibrin. Direct thrombin inhibition can also overcome some of the other limitations of standard heparin therapy. These include lack of susceptibility to circulating inhibitors released from activated platelets, including platelet factor 4 (PF4) and lack of diminished activity in states of acquired or inherited antithrombin deficiency. The absence of binding to PF4 is important clinically since antibodies responsible for heparin induced thrombocytopenia (HIT) are provoked by the complex of heparin and platelet factor 4 (PF4) on the platelet surface. It might be expected that a direct thrombin inhibitor can be used to treat HIT. The direct thrombin inhibitors have been studied in a number of different clinical settings, including treatment and prophylaxis of DVT, prevention of embolic stroke in patients with atrial fibrillation and in acute management of patients with unstable angina or MI.

Hirudin is a 65 amino acid protein originally extracted from the salivary gland of the medicinal leech. A recombinant hirudin is also available. Hirudin binds to thrombin via direct interaction with the active site, and the carboxyl tail of hirudin also binds to the exosite I giving rise to very high binding affinity. The anticoagulant activity of hirudin is monitored by the APTT. Its potential disadvantages are cost and the lack of an effective antidote. Hirudin has been primarily evaluated for the treatment of acute coronary syndromes such as unstable angina and MI. These studies suggest that the therapeutic window for hirudin is quite narrow with little added benefit compared to standard heparin. Hirudin may be more effective as prophylaxis in total hip replacement. One study reported significantly lower rates of DVT in patients undergoing total hip replacement which was started 30 minutes before surgery as compared to patients who received enoxaparin that was started the evening before surgery.

Lepirudin is a recombinant hirudin approved for the treatment of HIT. The administration of lepirudin, 0.1 to 0.4 mg/kg bolus followed by 0.1 to 0.15 mg/kg per hour infusion, was associated with a rapid increase in platelet count in 89 percent of patients indicating the absence of crossreactivity with heparin induced antibodies. The incidence of death, amputation and new thromboembolic events was significantly lower. Adequate anticoagulant levels were documented by prolongation of the APTT 1.5 to 3 fold above baseline. Caution should be used in patients with renal insufficiency since the drug is cleared by the kidney and its anticoagulant effect is not easily reversed. Approximately 40 to 70 percent of patients treated with lepirudin for more than five days develop antihirudin antibodies. These are not neutralizing antibodies and may actually enhance drug potency, perhaps by delaying its clearance from the circulation. As a result, the APTT needs to be monitored on a regular basis in such patients.

Argatroban is another direct thrombin inhibitor. It is a small molecule which, in contrast to hirudin, interacts with the active site of thrombin but does not make contact with exosites I or II. It has a short plasma half life, and is monitored by the APTT, although dose dependent changes are also seen in the PT. Dosing precautions are recommended in patients with hepatic dysfunction but dose adjustment is not required in the presence of renal impairment. The drug was approved in June 2000 by the FDA for prophylaxis or treatment of thrombosis in HIT. Argatroban is as an adjunct to thrombolysis in patients with acute MI. Although coronary patency was achieved more often with argatroban than heparin there was no difference in outcomes, at 30 days, of death, recurrent infarction, cardiogenic shock or heart failure, revascularization or recurrent ischemia.

In addition to agratroban, there are currently a number of small molecules, direct thrombin inhibitors under development, some of which are orally active such as ximelagatran (Exanta). It has been tested as prophylaxis and treatment of DVT, prevention of embolic stroke in patients with atrial fibrillation and for secondary prophylaxis following MI. The FDA Advisory Committee recommends against approval based on the high incidence of hepatotoxicity, although this agent was approved for short term use in several European countries. In 2006 the sponsoring company decided to withdraw the agent from the market and terminate its development.

Bivalirudin, previously called hirulog, a direct thrombin inhibitor has been approved by the FDA for use in patients with unstable angina in patients undergoing percutaneous coronary intervention. Bivalirudin may also be of benefit in ST elevation MI, but its role is less well defined.

Factor Xa Inhibitors

In addition to the direct and indirect thrombin inhibitors, there are a number of direct factor Xa inhibitors that are being developed, such as the tick or leech anticoagulant proteins and their derivatives, and synthetic analogs of the heparin pentasaccharide required for binding to antithrombin. These drugs can be administered orally.

Idraparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin. Idraparinux is a longer acting analogue, able to be given only once per week.

Razxaban is an orally active agent with inhibits factor Xa directly by binding to its active site without requiring the action of antithrombin. Preliminary results of a phase II dose ranging study have indicated increased efficacy compared to LMWH, although doses higher than 25 mg PO twice daily were associated with higher rates of major bleeding.

Rivaroxaban (BAY 59-79-39) is an orally active factor Xa inhibitor. Results of two phase II dose ranging studies for prevention of DVT in patient undergoing major orthopedic surgery have indicate short term efficacy and safety comparable to that of enoxaparin (Lovanox).

Thrombolytics and Fibrinolytics

Thrombolytic therapy is important in cardiovascular care today for a multitude of diagnoses, including acute MI, unstable angina, and other acute coronary syndromes, and acute ischemic stroke. Thrombolytic therapy is also used off label for peripheral arterial occlusive disease, catheter clearance, pulmonary embolism, and DVT. Thrombolytics are used to lyse the clot, limit infarct size and decrease the occurrence of complications, including dysrhythmias, heart failure, thromboembolism and ventricular aneurysm.

A thrombolytic is indicated for patients who have chest pain for at least 30 minutes and who reach the hospital within 12 hours of the onset of symptoms (unless contraindications exist) and whose EKG show new left bundle branch block or ST segment elevation of at least 1 to 2 mm in two or more EKG leads. A thrombolytic is administered within the first 6 hours after the onset of chest pain.

Numerous trials have shown that fibrinolytics have a narrow therapeutic window, which leaves little room for error in dosing calculation. Administering too much drug can increase severe bleeding and intracerebral hemorrhage (ICH) rates. Administering too little drug can result in low patency rates. Medication errors have been shown in several trials to significantly increase mortality. Evidence from several large trials indicated that more complex dosing regimens, weight adjustment, infusion timing, might lead to more medication errors than simpler bolus administration.

Thrombolytic agents are used as part of the following therapeutic interventions:

	Acute or documented evolving MI
	Acute ischemic stroke
	Acute thrombotic or embolic occlusive disease
	Venous thromboembolic disease – specifically for severe or life threatening PE or DVT.

Not all thrombolytic agents have indications for the aforementioned disease states. The routes of administration are via IV infusion, IV bolus over a specified time period, or intra arterial. The route of administration depends on the therapeutic intervention and the individual dosing guidelines for each agent.

Contraindications to thrombolytic therapy include advanced age, older than age 76, recent surgery, pregnancy or recent delivery, cerebrovascular accident within past 3 months, uncontrollable hypertension, major trauma within past 6 months, bleeding disorder, recent organ biopsy, recent CPR, neoplasm and severe renal disease. Bleeding is the most common adverse reaction seen in patients receiving thrombolytic therapy. The types of bleeding events associated with thrombolytic therapy may be broadly categorized as either minor or major. Minor bleeding is observed mainly at invaded or disturbed sites, such as the injection site, or the arterial catheterization site. Major bleeding is defined as internal bleeding, involving gastrointestinal, genitourinary, retroperitoneal, pericardial and intracranial sites. Allergic reactions have been reported, but are extremely rare. Other adverse reaction, include cardiogenic shock, dysrhythmias and reinfarction. It is difficult to associate the use of thrombolytics with these adverse reactions because they can also occur as disease related events.

Retavase (Reteplase recombinant) is a potent fibrinolytic, which is commonly referred to as a clot buster. Retavase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous plasminogen to generate plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action.

It is administered for the treatment of acute myocardial infarction (AMI) in adults for the improvement of ventricular function following the AMI, the reduction of the incidence of congestive heart failure and the reduction of mortality associated with AMI. It helps the body to dissolve the fibrin in the clots that cause blockages in patient’s arteries during heart attacks, thereby improving blood flow to the heart. Retavase speeds up the production of plasmin that degrades the fibrin matrix of the thrombus. It is not currently indicated for pulmonary embolism or acute ischemic stroke. Its unique molecular structure allows it to be safely administered with weight adjustment.

Treatment should be started as soon as possible after the onset of symptoms. Retavase increases the risk of bleeding, including intracranial bleeding, and should be used only in appropriate patients. In addition, fibrinolytic therapy increases the absolute risk of strokes, including hemorrhagic stroke, in patients of advanced age.

Giving Retavase is simpler and more convenient than administering tissue plasminogen activator (tPA) or streptokinase (Streptase). Two, 10 unit IV push bolus injections are given over two minute intervals. The second bolus is given 30 minute after the first bolus. Retavase is usually given with heparin and aspirin. Retavase should not be given simultaneously with any other medication through the same IV line. Heparin and Retavase are incompatible. If retavase is to be injected through an IV line previously used for heparin, flush the line with normal saline before and after the retavase injection.

Adverse effects and contraindications are hemorrhage, including intracranial bleeding (risk is greater in older patients and hypertension), bleeding at the injection site, gastrointestinal or genitourinary. Immediately discontinue any heparin that is being administered concurrently and do not give anymore retavase if serious bleeding occurs. Other adverse reactions include rare allergic reactions, nausea, vomiting, hypotension, fever, sinus bradycardia, various dysrhythmias, heart failure, cardiac arrest, and pericarditis. Antiarrhythmic therapy should be available, because dysrhythmias may develop. Retavase is contraindicated in patients who have active internal bleeding, a history of cerebrovascular accident, recent intracranial or intraspinal surgery, trauma, intracranial neoplasm, anteriovenous malformation, aneurysm, known bleeding disorders and severe uncontrolled hypertension.

Any drug that affects platelet function that is given before or after retavase increases the risk of bleeding and warrants close patient monitoring. Drugs that affect platelet function include warfarin heparin, aspirin, ticlopidine, clopidogrel, dipyridamole, and glycoprotein llB/lla inhibitors.

Activase (alterplase, R-TPA) is a t-PA. It produces fibrin conversion of plasminogen to plasmin; able to bind to fibrin, convert plasminogen in thrombus to plasmin, which leads to local fibrinolysis, limited systemic proteolysis.

It is used to lysis obstructing thrombi associated with AMI, and ischemic conditions requiring thrombolysis (PE, DVT, unclotting arteriovenous shunts, acute ischemic CVA). Indications for this drug include the improvement of ventricular function following acute MI, including reducing the incidence of CHF and decreasing mortality, Acute ischemic stroke, after intracranial hemorrhage has been excluded by CT scan and acute pulmonary thromboembolism.

The dose for lysis of thrombi associated with AMI is IV a total of 100 mg; 6-10 mg given IV bolus over 1-2 minutes, 60 mg given over first hour, 20 mg given over second hour, 20 mg given over 3rd hour; or 1.25 mg/kg given over 3 hours for smaller patients.

Dosing for central venous catheter occlusion should be 2 mg in 2 ml or 110% of the internal catheter volume. Thirty minutes of dwell time should be allowed following the initial instillation, and then catheter function should be assessed by attempting to aspirate blood and catheter contents. If catheter function is not restored, 90 additional minutes of dwell time (120 minutes total) should be allowed, and then catheter function should be reassessed. If catheter function restoration fails, this entire process may be repeated one additional time. Once catheter function is restored, the drug and residual clot should be removed by aspirating 4 to 5 ml of blood and the catheter should be gently irrigated with 0.9% sodium chloride. It should not be mixed with any other drugs.

Systematic side effects include GI, GU, intracranial and retroperitoneal bleeding. It may cause sinus bradycardia, ventricular tachycardia, and accelerated idioventricular rhythm. It is contraindicated in hypersensitive patients, those with active internal bleeding, recent CVA, severe uncontrolled hypertension, intracranial/intraspinal surgery/trauma and aneurysm.

Nursing consideration include close monitoring of vital signs and neurologic symptoms at least every 4 hours. A temperature >104º F (40º C) indicates internal bleeding. Monitor the patient closely for bleeding during the first hour of treatment and 24 hours after procedures. Patients may experience hematuria, hematemesis, bleeding from mucous membranes, epistaxis, ecchymosis and occult blood in stools. Heparin therapy after thrombolytic therapy is discontinued.

TNKase (Tenecteplase) is a third generation thrombolytic for thrombolysis associated with AMI. It is a tissue type plasminogen activator. Treatment should be initiated as soon as possible after the onset of AMI symptoms. It can be administered over five seconds, one dose, weight adjusted. It has a lower plasma clearance, longer elimination half life (18 minutes), and may be more resistant to inactivation by plasminogen activator inhibitor as compared to alteplase. Advantages of TNK include ease and rapidity of administration, longer half life, greater fibrin specificity, and lower non cerebral bleeding rates.

The normal dose for thrombolysis in AMI is weight based but should not exceed 50 mg total dose. It has only been administered concomitantly with heparin and aspirin to maintain the APTT of 50 to 75 seconds for 48 to 72 hours. It is contraindicated in active internal bleeding, history of CVA, intracranial or intraspinal surgery in the past 2 months, intracranial neoplasm, arteriovenous malformation or aneurysm, any know bleeding diathesis, severe uncontrolled hypertension and prior hypersensitivity to tenecteplase. Hemorrhage is the major complication. It should be used with caution when administering tenecteplase with drugs that alter platelet function such as aspirin and Plavix. Laboratory monitoring should include APTT, PT and fibrinogen degradation products (FDP)

LMWH Products

LMWH’s are administered SQ, do not require blood coagulation monitoring and can be used as a long-term preventative measure in the home environment.

Common LMWH agents include:

For SQ injections of LMWH, use a fatty layer of the abdomen in the area just above the iliac crest; use a 25/26 gauge, 1/2 or 5/8 inch needle (Skidmore-Roth, 2007). Do not withdraw on the plunger to check for blood return. This may cause tissue injury or hematoma. Apply gentle pressure to the puncture site for 5-10 seconds but do not massage. Systematically rotate sites and record appropriately.

LMWH (LMWH) products offer effective prophylaxis and treatment against DVT and are useful in preventing ischemic complications in unstable angina and non Q wave MI. As a prophylactic, LMWH is as effective as standard heparin or warfarin and does not require monitoring of the APTT or the INR. It is a good option for patients with a first episode of DVT, no risk factors for bleeding and the ability to administer injections with or without help of a visiting nurse or family member. Based on the results of large clinical trials LMWH and heparinoids (danaparoid sodium) are at least as effective and safe as unfractionated heparin (UFH) for the treatment of patients with acute proximal DVT and for the prevention of DVT in patients who undergo surgery. LMWHs have the advantage of a longer half life and a more predictable dose response then UFH. LMWHs are more expensive than UFH, but given the advantages listed above, the clear cut evidence of their efficacy in nonpregnant patients, and the fact that they are safe for the fetus, they are also suitable for routine clinical use in pregnant patients who require anticoagulant therapy. It is also used in low doses to prevent the formation of blood clots in certain patients, especially those who must have certain types of surgery or who must remain in bed for a long time.

Thorough review of the patient’s total drug regimen is key to safe use of all forms of heparin. Many times, LMWH is prescribed and administered in the emergency department (ED). Consequently, those orders are rarely communicated to the pharmacy or screened for safety. In addition communication of drug therapy administered in the ED may not be standardized and may not appear on the patient’s drug therapy profile after admission, especially if it was a one time dose. Practitioners should be reminded to assess all drug therapy (including the ED) and avoid concomitant use when indicated.

The advantages of LMWH are predictability, dose dependent plasma levels, a long half life, and less bleeding for a given antithrombotic effect. LWMH has a lower risk of heparin induced osteoporosis.

LMWH is given according to body weight once or twice daily, during the high risk period when prophylaxis for DVT is recommended and when waiting for oral anticoagulation to take effect.

LMWH is derived from standard heparin through chemical or enzymatic depolymerization. Standard heparin has a molecular weight of 5,000 to 30,000 daltons, LMWH have a molecular weight of 1,000 to 10,000 daltons. LMWH binds less strongly to protein, has enhanced bioavailability, interacts less with platelets, yields a very predictable dose response, and eliminates the need to monitor APTT. LMWH binds to antithrombin III; however, LMWH inhibits thrombin to a lesser degree and Factor Xa to a greater degree than standard heparin.

Danaproid an alternative anticoagulant that can be used in patients with HIT and acute DVT. Danaproid is a LMWH, consisting of a mixture of a heparin sulfate, dematan sulfate and chondroitin sulfate. Its anticoagulant effect is mediated by inhibition of thrombin via combination of heparin cofactor I and heparin cofactor II, plus some undefined endothelial cellular mechanism. The net effect is a more selective factor Xa inhibitor than LMWH, with a ratio of anti-factor Xa to antithrombin activity of 28:1 compared to 3:1 with LMWH.

Therapy with danaproid is monitored by an anti-factor Xa assay, not by the APTT. Monitoring is particularly important in patients with renal insufficiency since danaparoid is cleared by the kidneys. There is a 10 percent crossreactivity between danaproid and the antibody responsible for HIT in vitro, but the clinical significance of this is uncertain given the apparent therapeutic benefit in such patients. In one study thrombocytopenia without thrombosis was noted in patients with classical HIT who were switched from heparin to danaproid.

There are several potential disadvantages to danaproid therapy. These include expense (approximately $1000 per day at full anticoagulant dose), very long half life (25 plus or minus 100 hours) and the absence of a reversing agent if bleeding occurs.

Lovenox (enoxaparin) is a LMWH that exerts an anticoagulant effect by inhibiting clotting factor Xa. LMWH only slightly affect thrombin and APTT or prothrombin time. Although enoxaparin is used for DVT prophylaxis and prevention of ischemic complications of unstable angina and non Q wave MI when administered concurrently with aspirin. Enoxaparin is given subcutaneously and should not be given IM or IV. Subcutaneous injections should be alternated between the left and right anterolateral and left and right posterolateral sections of the abdomen. The needle should be inserted the entire length into a skin fold so that it reaches into the abdominal fat. Do not rub the site after completing the injection.

The recommended dose for angina and MI patients is 1mg/kg subcutaneously every 12 hours with 100-325 mg of oral aspirin once a day. The treatment duration is two to eight days. If the patient is having a vascular procedures, like cardiac catheterization, the next scheduled dose should be delayed for six to eight hours after sheath removal.

The common adverse effect is hemorrhage. Monitoring of blood clotting times is not needed and the dosage is not adjusted. Enoxaparin is contraindicated in patients who are hypersensitive to enoxaparin, heparin, or pork. It is contraindicated for those with active major bleeding. Enoxaparin should be used cautiously in patients with and increase risk of hemorrhage, uncontrolled hypertension, endocarditis, or a history of HIT and should be discontinued if the patient’s platelet count falls below 100,000/mm3. Patients with renal insufficiency and the elderly eliminate enoxaparin more slowly, so enoxaparin should be used cautiously. Drugs that can affect hemostasis, including oral anticoagulants and platelet inhibitors, should be discontinued before using enoxaparin, because concomitant use may increase the risk of hemorrhage.

Fragmin (dalteparin) prevents conversion of fibrinogen to fibrin and prothrombin to thrombin by enhancing inhibitory effects of antithrombin III. It is used in the treatment of unstable angina and non Q wave MI. May also be used in the prevention of DVT in abdominal surgery patients.

The dosage is 200 IU/kg every day or 100 IU/kg twice daily. It is administered subcutaneous for 5 to 8 days. Peak response is achieved in 2 to 4 hours. Drugs that effect hemostasis should be discontinued prior to initiation of therapy with Fragmin. APTT or ACT are not considered useful for monitoring Fragmin effects. Plasma anti-factor Xa concentrate should be monitored in patients with renal insufficiency. Patients on long term therapy should have monitoring of platelet counts, Hct, Hgb, stool for occult blood, plasma lipids and liver and renal function studies.

Side effects include hypersensitivity to this drug, heparin or other anticoagulants. It is contraindicated in patients with hemophilia, leukemia with bleeding, thrombocytopenia purpura, cerebrovascular hemorrhage, cerebral aneurysm, severe hypertension and other sever cardiac disease. There is increased risk of bleeding when use with aspirin, anticoagulants and platelet inhibitors. It is administered subcutaneously not IM or IV. Protamine sulfate is given for overdose.

Nomiflow (ardeparin) prevents conversion of fibrinogen to fibrin and prothrombin to thrombin by enhancing inhibitory effects of antithrombin III. It is used in the prevention of DVT after knee replacement surgery. The activity is expressed in anti-factor Xa units.

It should be administered deep intra-fat subcutaneous and not IM (which may cause muscular hematoma) Dosage is 50 antifactors XaU/kg every 12 hours until the patient is fully ambulatory or for 2 weeks. Peak level usually is achieved in 3 hours. PTT is not useful for monitoring the effectiveness of therapy. Side effects include intracranial bleeding, fever, hemorrhage and thrombocytopenia. It is contraindicated in patients with hypersensitivity to this drug, pork products, heparin or other anticoagulants. As with other low molecular weight heparins, drugs that affect hemostasis should be discontinued prior to initiation of therapy.

Patient Education

The patient should be monitored for signs and symptoms of bleeding problems, such as bleeding gums or presence of blood in stool. Nurses should reduce the number of punctures and apply pressure to puncture sites. Thrombolytics should only be administered in settings in which the patient can be closely monitored.
The patient should be educated on medication administration. The patient and family should be educated about necessary precautions when taking anticoagulants, such as using as a soft toothbrush and an electric razor, returning for routine laboratory tests, avoiding aspirin and ibuprophen and informing other physicians and dentists about anticoagulant therapy.

Conclusion

More than six million people in the United States suffer from angina pectoris and seven million have had a MI. It is no surprise that clinicians are desperately searching for new, more efficient ways to bring coronary artery disease (CAD) under control. Stroke affects about 450,000 in the U.S. each year. Aspirin, warfarin and IV heparin are anticoagulants used as therapy to prevent further strokes and AMI but they are not without risks. These anticoagulants have a narrow therapeutic window of adequate anticoagulation without bleeding, and a highly variable dose response relation among individuals that require monitoring of lab values.

Anticoagulants are used to treat and prevent clotting disorders such as DVT, phlebitis, pulmonary embolus, peripheral vascular disease and disorders arising from prolonged bed rest. Thrombolytics are used in emergent situations such as dissolving clots in coronary arteries, pulmonary arteries and deep veins, and prevention of acute MI.

Nursing implications include monitoring of lab values prior to initiation and throughout therapy. This should include a platelet count, hemoglobin and/or hematocrit, serum creatinine and APTT. APTT should be maintained between 50 and 70 seconds. The lab will call the nurse if the level is >68 for PTT and a prothrombin >27. ACT between 300 and 350 seconds is desired. PTT is collected 4.5 cc in a blue top tube. Specimen must be transported within 1 hour to the lab and refrigerated if unable to spin and separate. Tubes must be full due to dilution factor.

References

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