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Anticoagulant and Fibrinolytic Therapy
Author: Pamela Dugle

 

Anticoagulant and Fibrinolytic Therapy | Copyright © 2011 CEUFast.com


 

Purpose

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

 

Objectives

After completion of this course the reader will:

  Describe the safe practice recommendations for fibrinolytics
   
  Describe side effects of anticoagulant therapy
   
  Identify differences in heparin and low molecular weight heparins (LMWH)
   
  Identify nursing considerations for anticoagulant and fibrinolytic therapy
   
  Describe essential lab work and normal values for anticoagulant therapy

 

Introduction

Americans have become increasingly sedentary in their lifestyles. Coupled with supersized meals and increased cholesterol intake, Americans are larger than ever before and facing statistics of over one million myocardial infarctions (MI) resulting in 50% deaths. The non-fatal MI is treated with either surgical procedures or pharmaceutical intervention (Farquhar, n.d.).

The fourth leading cause of death in America is Venous Thromboembolism (VTE). 30% of patients with VTE die within 30 days. Patients receiving anticoagulant therapy require a minimum of five days interruption in treatment in order to receive surgical procedures. A study at the mayo Clinic Thrombophilia Center revealed that this temporary interruption of anticoagulant therapy did not have a significant effect on the patient's recovery. This study reviewed a three month cumulative incidence of recurrent thromboembolism, hemorrhage, and death for patients who had VTE and a temporary interruption in treatment. The benefits outweighed the risks and the study showed the threat was low (McBane et al., 2010).

Anticoagulants rank as one of the highest alert medications monitored by the Institute for Safe Medication Practices (ISMP) (High-alert medication feature: Anticoagulant safety takes center stage in 2007, 2007). Multiple warnings have been issued in recent and past years by the ISMP to protect patients against potential harm caused by anticoagulation therapy.

The public became more aware of potential life threatening events associated with anticoagulation therapy after Dennis Quaid and his wife went public with the ordeal they faced in November 2007 after their newborn twins were administered a lethal dose of heparin by mistake. The twins were to have been given a dose of hep-lock to maintain patency of their intravenous catheters but were given an adult dose a thousand times stronger. The twins were given the antidote but spent 12 days in the hospital to regain their normal blood levels (Croft, 2008). This situation could be reflective of an ordeal many people have experienced or known of someone who has experienced it.

The Joint Commission (TJC) studied the effect and adverse effects of anticoagulation therapy for several years. In 2008 TJC recognized the potential for harm with the use of anticoagulants and incorporated them into the 2008 National Patient Safety Goals (NPSG) holding healthcare institutions accountable for improving patient delivery methods and reliability (Jennings et al., 2008).

From the first time nurses are allowed to administer medications they are taught basics of medication administration using the five Rights: Right patient, Right medication, Right route, Right dose, and Right time. Although these five Rights sound basic they are fundamental rights to medication administration. Obviously if all nurses adhered to the five Rights of medication administration, errors would not occur and the Quaid twins would not have been given an adult dose of heparin instead of a hep-lock medication that nearly killed them, nor would TJC deem it necessary to make anticoagulation therapy a NPSG.

Medication reconciliation has become a huge impetus for hospitals and doctors at each visit. With so many possibilities for interaction, providers must anticipate the need for medication reconciliation to maintain patient safety.

 

Safe Practice Recommendations

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

1. Standardize
   
2. Simplify
   
3. Improve access to information
   
4. Restrict access to high alert drugs

The ISMP (unknown, 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. Many pharmaceuticals have look alike and sound alike names. 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).

Platelets 150,000-400,000/mm3
Or 150-400 x 109/L
Activated partial thromboplastin time (APTT) 30-40 sec.
Partial thromboplastin time (PTT) 60-70 sec.
Prothrombin time (PT) 11.0-12.5 sec.

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 dose 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). Aspirin can be administered safely in the one third of the population who are in the lower risk group for stroke (Sullivan, Arant, Ellis, & Ulrich, 2006). A list of anticoagulants can be found in the addendum.

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. Warfarin necessitates having levels monitored regularly in order to maintain a therapeutic level (Ansell et al. 2007). Providers are challenged with the maintenance of therapeutic levels for the patient receiving Warfarin (Davis, Billett, Cohen, & Arnsten, 2005)

Studies indicate that while other countries incorporate different Vitamin K antagonists into their therapeutic regime, the United States primarily relies on Warfarin as the drug of choice (Ansell et al. 2007). A standard beginning dose of 5-15 mg a day is administered and then gradually adjusted until a therapeutic international normalized ratio (INR) of 2.0-3.0 is achieved. If the patient has recurrent systemic embolism or a mechanical prosthetic valve, the targeted range is increased to 3-4.5. A prothrombin time (PT) is another lab test that may be used to monitor Warfarin therapy.

A study by Ansell et al. (2007) reveals that patients in the United States are sub therapeutic 30-36% of the time they are on Warfarin. Warfarin has a narrow range and the dosage is highly individualized. The elderly or debilitated patients require a lower initial dose (unknown, n.d.). The PT was once only capable of being tested by a peripheral lab draw, but now patients can report to Coumadin clinics and within a few minutes have the result through a capillary finger stick and walk out with their new dosing requirements. This has made a tremendous stride towards adjusting dosages since the patient no longer must wait several days for the lab to send the results to the provider for him or her to make adjustments in the doses.

Many factors contribute to both the success and failure of Warfarin therapy. Aspects such as diet and drug interactions, non-compliance by the patient, individual metabolism of the drug, knowledge deficit, and lifestyle interruption due to frequent monitoring are a few of the factors that impact successful therapeutic treatment (Davis, Billett, Cohen, & Arnsten, 2005).

Although Warfarin is used for other treatment modalities, the use for atrial fibrillation in those patients at high risk for stroke is the primary reason for the drug (Sullivan, Arant, Ellis, & Ulrich, 2006). "Atrial fibrillation is the most common sustained cardiac arrhythmia" (Sullivan, Arant, Ellis, & Ulrich, 2006). The incidence of Atrial Fibrillation increases with age causing an increased risk for stroke for the elderly population.

Reaching a therapeutic level of anticoagulation takes longer trying to use oral anticoagulants alone. Therefore, frequently the patient will receive Warfarin concomitantly with heparin. For example, a 67 year old male patient was admitted to the hospital and diagnosed with having thromboses. In an effort to reach maximum anticoagulation his provider ordered both a weight based heparin protocol with oral Warfarin. Through repeated lab tests the provider was able to discharge the patient in three days with instructions for follow up clinic testing. Close monitoring allowed the provider to administer the required medication to reach the therapeutic level and reduce the potential for adverse events and patient harm from the medication.

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 affect the action of Warfarin. Resistance to warfarin may be hereditary or acquired. Other conditions that may affect 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

Recent statistics reveal that one third of all patients hospitalized each year will have exposure to heparin. Unfortunately with this large number of patients receiving heparin the number increases for the potential development of heparin induced thrombocytopenia (HIT). HIT is a severe drug reaction that can occur at any time in any patient receiving heparin. HIT can develop as early as day five or sooner if patients had earlier heparin exposure regardless of the route of administration. The patient develops antibodies and thrombin generation increases (unknown, n.d.).

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: complete blood count 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. Another problem with heparin administration occurs if the nurse piggybacks an IV fluid into the heparin at a higher rate than the heparin. This creates mini bolus infusions. Therefore, heparin should have a separate line to prevent this. The IV tubing should also be labeled with the name of the drug infusing.

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 4-6 hours after any change depending on the facility protocols (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. 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 SQ 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.

In 2009 the ISMP released a notification to healthcare providers regarding the new reference standards for heparin. This notification included the testing methods to best establish potency of the heparin and the ability to distinguish impurities. The ISMP anticipated a 10% reduction in potency. The notification advised providers that closer monitor would be necessary to reach the desired therapeutic level. While this notification applied to the new monograph. Bearing this in mind, there would still be "old" heparin available and most manufacturers agreed to label the "new" with an "N" before the lot number (unknown, 2009).

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, hematocrit (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 such as complete blood count (CBC), Hct, and 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.

Ticlid causes allergic reactions in many patients. The patients develop a rash similar to red man syndrome. The rash can appear over the entire body.

 

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 cross reactivity 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 (Lovenox).

 

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 the past three months, uncontrollable hypertension, major trauma within past six 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 >104° F (40° 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:

  Enoxaparin (Lovenox)
   
  Tinzaparin (Innohep)
   
  Ardeparin (Normiflo)

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 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 onetime dose. Practitioners should be reminded to assess all drug therapy especially in 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.

Danaparoid an alternative anticoagulant that can be used in patients with HIT and acute DVT. Danaparoid 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 danaparoid 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 cross reactivity between danaparoid 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 danaparoid.

There are several potential disadvantages to danaparoid 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.

After having surgery a female nurse noticed she had developed a severe left calf pain regardless of the fact she had made special effort to walk a minimum of hourly as directed by her surgeon. She contacted her provider and had an ultrasound to her left lower extremity. She was diagnosed with a thrombophlebitis of the lateral aspect and a DVT to the medial aspect. After consulting with her surgeon the primary provider developed a plan of care that involved twice daily injections of Lovenox. The prescription was written and the patient proceeded to the pharmacy to discover the drug was very expensive and the instructions were very sketchy. She asked the pharmacist and was told that everything she needed to know was in the drug insert. Using all the training she had obtained in nursing school about administration of medication from a syringe, she immediately expelled the air bubble from the syringe. She began developing extreme bruising after a few days and had difficulty finding an injection site. A nurse practitioner friend suggested there was something special about the air bubble. A search ensued and after contacting the manufacturer, the patient was able to discover that the air bubble should not be expelled and the massive bruising she incurred was due to the air bubble being expelled. After polling many nurses she discovered that they had all taken the same training as she had to expel the air from the syringe. For improved quality of delivery of care, when administering Lovenox, one must not use any injection sites other than the abdomen and the air bubble must remain in the syringe and expelled into the tissue after the medication to serve as a barrier to prevent the medication from leaking out of the tissue.

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 is 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.

 

Complication of Anticoagulant Therapy

The rate of major bleeding in patients treated with UFH and warfarin therapy is approximately 2% when used for the treatment of DVT. In addition, adjusted dose subcutaneous UFH can cause a persistent anticoagulant effect that may persist up to 28 hours after the last injection of adjusted dose subcutaneous heparin as indicated by a prolonged APTT. The mechanism for this prolonged effect is unclear. In pregnancy the APTT response to heparin is often attenuated because of increased levels of factor VIII and fibrinogen. Bleeding complications appear to be very uncommon with LMWH.

Approximately 3% of patients receiving UFH develop immune; IgG mediated thrombocytopenia that is frequently complicated by extension of preexisting VTE or new arterial thrombosis. This should be differentiated from an early, benign, transient thrombocytopenia that can occur with initiation of UFH therapy. Diagnosing immune thrombocytopenia is often difficult because definitive platelet activation assays are not widely available and turnaround times are slow. It should be suspected when the platelet count falls to < 100 X 109/L or < 50% of the baseline value 5 to 15 days after commencing heparin therapy, or sooner with recent heparin exposure. In pregnant women who develop HIT and require ongoing anticoagulant therapy, use of the heparinoid, danaparoid sodium, is recommended because it has much less cross reactivity with UFH and, therefore, less potential to produce recurrent HIT than LMWH.

Long term heparin therapy has been reported to cause osteoporosis in both laboratory animals and humans. A number of studies have attempted to quantify the risk of osteoporosis when heparin is administered for periods > 1 month. In general, symptomatic vertebral fractures have been reported to occur in about 2 to 3% of the patient population and significant reductions is bone density have been reported in up to 30% of patients receiving long term UFH therapy. Several lines of evidence now suggest that LMWHs have a lower risk of osteoporosis than heparin. Studies using an animal model of heparin induced osteoporosis support the hypothesis that LMWHs cause less osteoporosis than UFH.

Anticoagulants (Berry et al. 2010)

Generic Name Brand Name Half Life Administration Indication Special Considerations

Alteplase (tissue plasminogen activator)

Activase Less than 10 minutes IV Thrombi lysis, acute PE, acute CVA  Administer within 3 hours of onset of acute CVA
Argatroban   39-51 minutes IV Thrombosis in HIT • Check activated PTT 2 hours after administration

• Monitor for signs of hemorrhage
Aspirin Ecotrin, Bayer 15-20 minutes PO Rectal MI, USA, TIA  
Bivalirudin Angiomax 25 minutes IV USA with PTCA,PCI @ risk for HIT Don't give IM
Clopidogrel bisulfate Plavix 8 hours PO MI, PAD, CVA Platelet aggregation returns to normal approximately 5 days after drug stopped
Enoxaparin Lovenox 4.5 hours SQ DVT, PE after surgery • Don't expel air from prefilled syringe
• Antidote is protamine sulfate
• Don't give IM
• Give in abdomen only
Heparin Sodium Heparin 1-2 hours IV, SQ DVT, M, PE, MI Antidote-Protamine Sulfate
Refludan Lepirudin 0.8-2 hours IV Recombinant Hirudin  
Retaplase Retavase 13-16 minutes IV Acute MI  
Streptokinase Streptase 1st phase 18 minutes, 2nd phase 83 minutes IV AV cannula occlusion, Embolism, lysis after MI Most beneficial within 4 hours of onset
Tenecteplase TNKase 20 minutes to 2 hours IV MI Can develop reperfusion arrhythmias
Tinzaparin sodium Innohep 3-4 hours SQ DVT Do not administer IM or IV
Tirofiban Hydrochloride Aggrastat 2 hours IV ACS, PTCA, Atherectomy • Protect from light
• Discard after 24 hours
• Administer with ASA and heparin
Warfarin Coumadin 20-60 hours PO
IV
PE, DVT, MI, Atrial Fibrillation Antidote-oral or parenteral vitamin K

 

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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Davis, N. J., Billett, H. H., Cohen, H. W., & Arnsten, J. H. (2005). Impact of adherence, knowledge, and quality of life on anticoagulation control. The Annals of Pharmacotherapy, 39, 632-636.

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High-alert medication feature: Anticoagulant safety takes center stage in 2007. (2007, January 11). Retrieved April 30, 2010, from http://www.ismp.org

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McBane, R. D., Wysokinski, W. E., Daniels, P. R., Litin, S. C., Slusser, J., Hodge, D. O., et al. (2010). Periprocedural anticoagulation management of patients with venous thromboembolism. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(3), 442-448.

Safeguards needed to avert fatal errors from concomitant use of heparin products (2003). Institute for Safe Medication Practices.

Skidmore-Roth, L. (2007). Mosby's 2007 nursing drug reference. Philadelphia: Mosby.

Sullivan, P. W., Arant, T W., Ellis, S. L., & Ulrich, H. (2006). The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US. Pharmacoeconomics, 24(10), 1021-1033.

Unknown. (n.d.). Heparin-induced thrombocytopenia: One of the most important immunohematologic problems in clinical medicine. Retrieved April 30, 2010, from http://www.argatroban.com

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