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Deep Vein Thrombosis and Pulmonary Embolism

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Author:    Patricia Hartley (RNC, MSN)

Purpose/Goals

This course is designed to educate healthcare professionals to the incidence, risk factors, and appropriate therapy to prevent the silent epidemic of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Objectives

Upon completion of this course, the participant will be able to:

  1. Describe the incidence of DVT and PE.
  2. Describe dietary impact on anticoagulant therapy.
  3. Describe side effects of anticoagulant therapy.
  4. Identify differences in heparin and low-molecular-weight heparins.
  5. Describe essential lab work and normal values for anticoagulant therapy.

Introduction

A deep vein thrombosis (DVT) occurs when a venous thrombosis (blood clot) forms in one of the large veins leading to either partially or completely blocked circulation. This usually occurs in regions of slow or disturbed blood flow, particularly in the lower limbs. A venous thrombosis is an intravascular deposit that is composed of fibrin and red blood cells with a variable platelet and leukocyte component.

There is increasing awareness and evidence that seriously ill, hospitalized medical patients, especially those with heart failure, are at increased risk for sustaining deep venous thromboembolism, in addition to other complications and sequelae associated with left ventricular dysfunction and coronary artery disease. Moreover, the potential costs of complications due to prolonged hospitalization and the morbidity associated with DVT can be significant.

DVT may be clinically silent and hard to diagnose, but this condition may result in health complications if not diagnosed and treated in a timely and effective manner. The first manifestation of DVT may be pulmonary embolism (PE). This can occur when a fragment of a venous thrombosis breaks loose from the wall of the vein, at the site of the DVT, and migrates to the lungs, where it blocks a pulmonary artery or one of its branches. When that venous thrombosis is large enough to completely block one or more vessels that supply the lungs with blood it can result in sudden death. PE may be the most common preventable cause of hospital death. Two-thirds of those individuals who die from PE do so unnecessarily.

Preventing and detecting DVT and PE are essential components of quality nursing care. Before the 1990’s the only effective means of prophylaxis were early mobilization, unfractionated heparin, warfarin sodium (Coumadin), and dextrans. Today, there are several additional options: mechanical stockings, LMWH, and synthetic antithrombotic agents.

Pathophysiology

Anatomists describe the venous drainage of the lower extremity in relationship to the muscle fascia. The superficial veins include the greater and lesser saphenous veins, which drain into the deep system via the perforating or communicating veins. A series of valves direct blood flow toward the heart. The pump action of the thigh and calf muscles powers this flow.

The focus for a venous thrombosis is often a defect in the innermost lining of blood vessels: intimal and endothelial layers. For example, intravenous catheters, irritating medications, or illicit drugs precipitate superficial thrombophlebitis. When a venous thrombosis forms on an Intimal or endothelial defect, the coagulation cascade promotes venous thrombosis growth proximally. Thrombus can extend from the superficial veins into the deep system and become a PE.

Most cases of PE arise from the iliofemoral system. Massive occlusion of the iliofemoral system can be life and limb threatening. While isolated calf thrombi are unlikely to produce significant PE, up to 15-20 percent can later propagate and then embolize. Once a venous thrombosis develops, whether proximal or distal, venous hypertension frequently leads to pain and/or swelling. Extensive deep venous thrombosis can even result in compartment syndrome of the thigh and leg. However, many cases of DVT remain asymptomatic until embolization occurs. Anticoagulation of superficial vein thrombosis remains controversial.

A venous thrombosis is a meshwork of protein strands made of fibrin, normally not found in the circulation. A venous thrombosis results from the coagulation cascade, which is series of enzymatic reactions. Clotting factors in the blood, such as thrombin and Factor Xa, are activated and transformed into fibrin. The coagulation cascade can be launched by the:

  • intrinsic pathway, triggered by things like stress, anxiety, or fear
  • extrinsic pathway, activated by tissue trauma.

Opposing the coagulation cascade is the endogenous fibrinolytic system. After the venous thrombosis organizes or dissolves, most veins will recannualize in several weeks. Residual venous thromboses retract as fribroblast and capillary development lead to intimal thickening. Venous hypertension and residual venous thrombosis may destroy valves, leading to the post-phlebitic syndrome, which develops within 5-10 years. Edema, sclerosis and ulceration characterize this syndrome, which develops in 40-80 percent of patients with DVT. In addition to the chronic changes of the post-phlebitic syndrome, patients also can suffer exacerbations of swelling and pain; probably as a result of venous dilation and hypertension. These exacerbations are clinically indistinguishable from recurrent DVT. Accordingly, episodes of acute swelling and pain should be attributed to the post phlebitic syndrome only after objective tests confirm no recurrence of DVT.

Incidence

Venous thromboembolism is the number-one cause of unexpected hospital death and a major health problem, especially among hospitalized patients. The true incidence is unknown because most DVT is occult.

Estimated annual incidence of DVT and PE 200,000 up to 600,000 cases

DVT and PE may contribute to 200,000 deaths This is more than breast cancer and AIDS combined

 

Approximately 250,000 patients with DVT require hospitalization for 5-10 days for intravenous heparin therapy. In addition to those with acute thrombosis, millions more suffer from things such as stasis dermatitis and venous ulcers.

To illustrate that the silent epidemic of DVT remains unacknowledged, a recent study in hospitalized patients with DVT, found that 71 percent of patients with DVT did not receive prophylaxis within 30 days prior to diagnosis. Surgical patients were much more likely than non-surgical patients to receive prophylaxis for this condition. These findings indicate that proven regimes for the prevention of DVT are underutilized. Clinical trials and guidelines for prophylaxis and treatment have progressed further and faster than “real-world” preventive efforts and outpatient therapy.

The incongruence between evidence and execution as it relates to DVT prevention amounts to a public health crisis.

Risk Factors

DVT does not discriminate and can occur in anyone. It affects the young, the elderly, the very fit, and public figures, such as former Vice President Dan Quayle. However, certain individuals are at increased risk for developing DVT.

  • Surgery and trauma are responsible for up to 40 percent of all thromboembolic disease
  • Males older than age 60 are more likely to develop DVT
  • In the elderly, DVT is associated with a 21 percent one-year mortality rate, and PE is associated with a 39 percent one-year mortality rate
  • Malignancy is responsible for up to 4 percent of all episodes of DVT
  • Up to 10 percent of patients with new onset DVT develop cancer within six months after the diagnosis of DVT
  • The incidence of DVT and PE is significantly higher in Caucasians and African-Americans than in Hispanics and Asian-Pacific Islanders
  • Ten percent of thromboembolic disease is due to acquired or inherited disorders of coagulation
  • Nearly 25 percent of all patients with superficial phlebitis have involvement of the deep veins.
  • Patients with systemic infection are more likely to develop DVT
  • Up to 26 percent of patients with DVT have had a previous episode

The German pathologist Rudolf Virchow recognized the association between DVT and PE with three common phenomena called Virchow’s triad.

Virchow’s Triad:

venous stasis

hypercoagulability

intimal/endothelial injury

Conditions that cause or contribute to these phenomena increase the risk of venous thromboembolism. Risk factors or triggering events include:

  • Stasis
    • Immobility
      • Four days bed rest
      • Long plane ride (economy class syndrome)
      • Long train or car ride (many hours)
    • Obesity
    • Paralysis – stroke or spinal cord injury
    • Cast on leg
  • Hypercoagulability (underlying disease)
    • Previous thromboembolic disease
    • Malignancy
    • Inflammatory conditions (SLE, IBD, PVD)
    • Nephritic syndrome (loss of antithrombin III)
    • Sepsis
  • Coagulation disorders – inherited vs. acquired
    • Resistance to activated Protein C
    • Protein S deficiency
    • Protein C deficiency
    • Antithrombin deficiency
    • Disorders of fibrinogen or plasminogen
    • Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin)
  • Increased estrogen (causes urinary loss of protein ‘S’ and antithrombin III)
    • Pregnancy
    • Post partum < 3 months
    • Elective abortion or miscarriage
    • Oral contraceptive pills, other exogenous estrogens
  • Intimal damage
    • Intravenous drug abuse
    • Trauma
    • Recent surgery
    • Central lines
  • Multifactoral
    • Trauma
    • Recent surgery
    • Age > 60
    • Cardiac disease
    • Obesity
    • Heart failure
    • Lower limb arteriopathy

The greater the number of risk factors, the greater the potential threat.

 

Number of Risk Factors

Incidence of DVT

Risk Level

0 - 1

< 10 %

Low risk

2

10 – 20 %

Moderate risk

3 - 4

20 – 40 %

High risk

5 or more

40 – 80 %

Highest risk

 

The majority of acute care patients have at lease one risk factor for venous thromboembolism. Even children are at risk for venous thrombosis. Pediatric patients at risk include those with spinal cord injuries, hypercoagulable states, and those with a recent history of central lines.

The principle cause of death related to transatlantic flights is known as the “economy class syndrome.” Venous thrombosis is induced by cramped quarters in an airplane, usually during transoceanic flights.

A cast on the leg also increases venous stasis and impairs the muscle pump mechanism that propels blood into the central circulation. Stasis plays a role in the thrombosis encountered in the morbidly obese and in individuals with cardiac disease. Limb paralysis from stroke or spinal cord injury is associated with a difficult-to-evaluate syndrome of painless or occult thrombosis.

Trauma, surgery and invasive procedures disrupt venous integrity. Surgery and trauma contributes to both a hypercoagulable state and immobility. These insults activate the clotting cascade, causing the indices of thrombosis and fibrinolysis rise rapidly. In particular, surgery of the hip and lower extremities can incite thrombosis.

Malignancy also accelerates the coagulation cascade. Activation of the extrinsic pathway via tissue factors plays an important role in venous thrombosis generation. Breast and prostrate cancer are common precipitants. Recurrent migratory superficial thrombophlebitis caused by malignancy (usually solid tumors) is called Trousseau’s syndrome. This condition is resistant to warfarin therapy and may require long-term heparin prophylaxis.

Increased estrogen predisposes to thrombosis due to a fall in protein ‘S’ and cigarette smoking significantly enhances this tendency. Increased estrogen occurs during all stages of pregnancy, the first three months postpartum after elective abortion, and during treatment with oral contraceptive pills (OCPs). Low-dose estrogen OCPs are not associated with an increased risk of DVT. Women with congenital resistance to activated protein ‘C’ are especially susceptible to thrombosis due to OCPs. Progesterone only pills and Norplant may slightly increase the risk of thrombosis.

Thromboembolic disease may be due to acquired or inherited disorders of coagulation. Three of the most common disorders include deficiencies of protein ‘S’, protein ‘C’ and antithrombin III. While most patients inherit these conditions they may also be acquired. Because the nephritic syndrome results in urinary loss of antithrombin III, this diagnosis should be considered in children presenting with thromboembolic disease. Antiphospholipid antibodies accelerate coagulation and include the lupus anticoagulant and anticardiolipin antibodies. Paradoxically nearly half of these patients have a prolonged PTT on laboratory testing despite being hypercoaguable. Antiphospholipid antibodies should be suspected when thrombosis occurs in young patients with no other risk factors. This syndrome is especially likely if the patient has arterial thrombosis or venous thrombosis in unusual locations, such as the mesentery or solid organs. Inflammatory processes, such as systemic lupus erythematosus, sickle cell disease, and inflammatory bowel disease also predispose to thrombosis presumably due to hypercoagulability.

Iatrogenic causes of venous thrombosis are increasing due to the widespread use of central venous catheters; particularly subclavian and internal jugular lines. These lines are an important cause of upper extremity DVT, particularly in children. Femoral lines also generate thrombus in 14 percent of patients canulated.

Diagnosis

As many as half of all DVT episodes produce minimal symptoms or are completely silent.

 

Symptomatic patients typically complain of lower extremity pain or swelling. They may report a sense of fullness, which increases with standing or walking. Some individuals may complain of pain in the lower extremity when coughing or sneezing, which is different from electric type pain with cough or sneeze that is associated with sciatica. Venous involvement is usually unilateral unless the vena cava occludes, which is a rare and catastrophic event. In one study, DVT never occurred in the patients with bilateral symptoms. However, bilateral involvement can occur.

Clinical examination alone is able to confirm only 20 to 30 percent of cases of DVT; so, DVT and PE may be difficult to diagnose without specific tests. Differential diagnosis of a swollen painful leg is broad. Other conditions that display symptoms similar to those of DVT include muscle strains, skin infections, and phlebitis (inflammation of veins). Many conditions can cause bilateral leg edema, secondary to either hypoproteniemia or an increase in venous or lympathatic pressure. Lymphedema may also produce unilateral leg swelling. A lack of discrepancy in calf size does not rule out DVT. Asymmetry of the calves of 1 cm or more is abnormal but does not definitively distinguish thromboembolic disease. Asymmetric calf swelling of greater than 3 cm is almost always a significant finding.

It is important to determine the time course of symptoms and to elicit a history of recent events. Venous thrombosis usually occurs over several days. Sudden, severe pain is more compatible with muscle rupture or injury.

Homans’ sign is positive when there is pain in the posterior calf or knee with forced dorsiflexion of the foot. However, Homan’s sign is inaccurate and unreliable as a test for DVT because it is often present with sciatica.

Temperatures can help distinguish cellulitis from DVT. Patients with DVT may have a low grade fever due to the systemic inflammatory process this fever rarely exceeds 102oF.

The presence of risk factors for DVT must decrease the threshold for obtaining imaging studies. Nearly all patients with complaints compatible with venous thrombosis and who do not have typical alternative diagnosis require an imaging study. Patients with suspected DVT who complain of chest pain or shortness of breath should have a VQ CT scan to expedite the diagnosis.

Associated symptoms are also important, especially the presence of chest pain or shortness of breath that may suggest PE. The medical history should be used to assess risk factors for thromboembolic disease. A history of prior DVT is important.

D-dimer is a blood test that has a predictive value for DVT. A normal D-dimer in a patient with no risk factors for thrombosis makes proximal DVT extremely unlikely. D-dimer is a specific degradation product of cross-linked fibrin. Because concurrent production and breakdown of venous thrombosis characterize thrombosis, patients with thromboembolic disease have elevated levels of D-dimer. A D-dimer less than 500 mcg/L rules out PE in 98% - 100% of cases. It is also important to note that any process that activates the coagulation cascade and fibrinolytic system can cause D-dimer levels to rise.

Preliminary tests for suspected PE should include a chest X-ray and electrocardiogram (EKG). The chest X-ray may be normal or abnormal but is helpful in diagnosing other conditions that mimic PE. The EKG will help rule out cardiac ischemia. And since the most common EKG finding in PE is sinus tachycardia, PE should be considered whenever unexplained tachycardia occurs.

Coagulation studies rarely are required as part of the initial evaluation of venous thrombosis. Occasionally it may be valuable after Doppler demonstrates an acute venous thrombosis and in patients who develop a venous thrombosis while on warfarin.

Venous ultrasonography of the venous system is obtained with high-resolution equipment to produce two-dimensional images of reflected signals from an array of ultrasound sources, including the common femoral vein in the groin and the popliteal vein, which connects to the femoral vein. Gentle pressure is applied to the probe to determine whether the vein under examination is compressible. The most accurate ultrasonic criterion for diagnosing venous thrombosis is non-compressibility of the venous lumen under gentle probe pressure. The test is inexpensive, noninvasive, and widely available. Changes in flow that occur with respiration and from calf compression differentiate obstructing from non-obstructing thrombi.

Ultrasound has clinical limitations. High sensitivity testing requires sophisticated diagnostic equipment. Scans are very reader dependent and some facilities do not achieve optimal accuracy because of a lack of radiographic expertise. During the second half of pregnancy, ultrasound becomes less specific because the gravid uterus compresses the inferior vena cava, thereby changing Doppler flow in the lower extremities.

Impedance plethysmography (IPG) is performed by placing two sets of electrodes around the patient’s calf and an oversized blood pressure cuff around the thigh. The electrodes sense a change in blood volume (increased blood volume decreases electrical impedance) in the calf veins, which is recorded on a strip chart. Changes in venous filling are produced by inflating the thigh cuff to obstruct venous return and then reestablishing blood flow by deflating the cuff and assessing the time taken for venous volume in the calf to return to baseline. If a venous thrombosis is present in the popliteal or more proximal veins, venous emptying is delayed. IPG is very operator dependent and the literature shows that the sensitivity of IPG is generally around 65 percent. Because any impairment of venous outflow affects the plethysmography results, many false positives occur. Post-phlebitic syndrome, abdominal tumors, pregnancy, and congestive heart failure can produce inaccurate results.

Venography is performed by injecting radiographic material into a superficial vein on the top of the foot. The contrast material mixes with the blood and flows through the leg. An x-ray image of the leg and pelvis will show the calf and thigh veins, which drain into the external iliac vein. A venous thrombosis is diagnosed by the presence of an intraluminal filling defect, an abrupt cut-off of the contrast material on the x-ray. Venography is considered the most accurate in terms of diagnosing a venous thrombosis.

Venography is contraindicated in patients with renal insufficiency or dye allergy. Some radiologists disagree on interpretation in at least 10 percent of cases and 5 to 15 percent of all studies are technically inadequate. Because it is more invasive than other tests, it is usually reserved for special cases when the diagnosis is unclear, for example, when the patient has a high clinical probability of thrombosis and a negative ultrasound.

Pulmonary angiogram is the gold standard for diagnosing PE. However, it is expensive, invasive, and not without risk; so, it is not ordered often. A pulmonary angiogram is a good choice for unstable patients because it eliminates the need for other tests that could yield inconclusive results.

Spiral-helical-CT is a relatively new technique for visualizing the pulmonary arteries. It provides a view of the entire thorax, but it requires contrast dye and must be interpreted by an experienced radiologist.

Magnetic resonance angiography (MRA) is fairly new procedure for diagnosing PE. It is minimally invasive and uses gadolinium, a contrast material with no known adverse effects. It may not be suitable for claustrophobic or massively obese patients, or for patients with pacemakers or other metallic devices. It is also expensive.

Prevention and Treatment

Routine use of simple, well-established and effective methods of DVT prevention would save the lives of thousands of Americans each year.

Unfortunately the management of PE has been characterized by a failure to use preventive measures or prophylaxis. Only one-third of hospitalized patients with risk factors for venous thromboses receive preventive treatment. Three quarters of primary care physicians do not realize that the major vessels of the lower extremities are deep veins and neglect to anticoagulate the patient when these veins are involved.

Without preventive treatment, up to 60 percent of patients who undergo total hip replacement surgery may develop DVT. Cancer patients undergoing surgical procedures have at least twice the risk of postoperative DVT and more than three times the risk of fatal PE than non-cancer patients undergoing similar procedures.

All hospitalized patients should be evaluated upon admission for risk factors. Both mechanical and pharmacological prophylactic regimens should be started on all patients at risk. Mechanical prophylaxis includes elastic stockings and intermittent pneumatic compression. Pharmacological prophylaxis includes low-molecular weight heparin, heparin, heparinoids and warfarin (perioperative). Ideally prophylactic agents should be efficacious, easy to administer and monitor, cost effective, perfectly matched to the patient, and free of adverse reactions and complications.

Patients with DVT need prompt treatment to prevent complications; those with PE need it stat. Patients with PE who have normal blood pressure and right ventricular function may be adequately treated with anticoagulation or inferior vena cava (IVC) filter placement. Those with hemodynamic instability, moderate to severe right ventricular dysfunction, or elevated troponin levels warrant more aggressive treatment either embolectomy or thrombolysis. Embolectomy is no longer merely a last ditch effort for PE. Thanks to prompt diagnosis and triage, careful patient selection, and improved surgical technique survival rates run about 89% more than a month after surgery.

DVT is usually treated with anticoagulation (typically, some form of heparin followed by warfarin). An IVC filter is indicated for patients when anticoagulant therapy has failed or is contraindicated, such as patients who have recently undergone surgery.

Thorough review of the patient’s total drug regimen is key to the safe use of all forms of heparin. Many times, LMWH is  prescribed and administered in the emergency department. 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 (e.g., a heparin infusion should not be started if LMWH has just been administered)

Anticoagulation Therapy

LMWH are approved for the treatment of acute DVT with or without PE. LMWH has several advantages over unfractionated heparin. It has a more predictable dose response, a longer plasma half-life and is less likely to cause heparin-induced thrombocytopenia. There is no need to track activated clotting time (ACT) or partial thromboplastin time (PTT) to monitor anticoagulation effect. Plasma anti-X levels can be used to monitor anticoagulation effect.

Unfractionated heparin, given intravenously, is still a viable option for treating DVT. Most often, it is ordered for proximal or catheter-related DVT.

DVT or PE patients usually go home on warfarin after being treated with either LMWH or unfractionated heparin as a bridge to warfarin. A typical course of anticoagulation lasts three to six months, though no one knows for sure how long anticoagulation must continue in order to prevent recurrence. As many as one in three people who complete warfarin therapy develop another DVT or PE within five years.

LMWH

LMWH is administered according to body weight once or twice daily, both during the high-risk period when prophylaxis for DVT is recommended and also when waiting for oral anticoagulation to take effect in the treatment of DVT. The activated partial thromboplastin time (aPTT) does not need to be monitored, and the dosage does not need to be adjusted. LMWH binds less strongly to protein, has enhanced bioavailability, interacts less with platelets, and yields a very predictable dose response, eliminating the need to monitor aPTT. LMWH, like standard heparin, binds to antithrombin III; however, LMWH inhibits thrombin to a lesser degree and Factor Xa to a greater degree than standard heparin.

Lovenox (enoxaprin) is one of the LMWH. It is obtained by “breaking up” unfractionated porcine heparin into smaller molecules. These agents exert their anticoagulant effect by inhibiting clotting factor Xa. LMWH only slightly affect thrombin and aPTT or prothrombin time. Although enoxaprin has been used for the prevention of deep vein thrombosis for quite some time, recent studies show it also prevents the ischemic complications of unstable angina and non-Q-wave MI when administered concurrently with aspirin.

Do not give the enoxaprin by the IM or IV route and do not use it interchangeably – unit for unit – with other LMWH. Recommended dosing is 30 mg subcutaneous every 12 hours or 40 mg per day. The medication should be given for a minimum of two days and continued until the patient is clinically stable. The usual duration of treatment is two to eight days. When giving enoxaprin, alternate between the left and right anterolateral and left and right posterolateral sections of the abdomen. Insert the entire length of the needle into a skin-fold so that it reaches into the abdominal fat, holding the syringe between the thumb and forefinger and keeping the skin-fold in your fingers throughout the injection. To minimize bruising, don’t rub the site after completing the injection.

As you would expect, bleeding is the most common reaction. Watch for injection site ecchymosis and hematomas, nosebleeds, oozing from surgical wounds, and all catheter sites. As with other anticoagulants, there have also been rare cases of spinal column hematomas reported with the concurrent use of enoxaprin and spinal or epidural anesthesia. The risk of such reactions, which can result in long-term or permanent paralysis, may be heightened in patients with post operative epidural catheters. With these reactions in mind, be sure to look for a bleeding site if an unexpected drop in hematocrit or blood pressure occurs.

Enoxaprin is contraindicated in patients with hypersensitivity to the drug, to regular heparin, or to pork products. It should also be avoided in those with active major bleeding. Use the drug with extreme caution in patients with a history of heparin-induced thrombocytopenia. In such cases, you will have to closely monitor for even mild thrombocytopenia, if the patient’s platelet count falls below 100,000/mm3, discontinue the drug, as ordered. Enoxaparin should also be used with extreme caution in patients who have an increased risk of hemorrhage, including those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration, and hemorrhagic stroke. The elderly and those with renal insufficiency are likely to eliminate enoxaparin more slowly from their systems, so use the drug cautiously in these patients as well. Drugs that can affect hemostasis, including oral anticoagulants and platelet inhibitors, should be discontinued prior to therapy with enoxaparin. 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 or the prevention of DVT in abdominal surgery patients. The dosage is 200 IU/kg every day or 100 IU/kg bid. The average dose is 2500 IU administered subcutaneous for 5 to 8 days. The peak response is achieved in 2 to 4 hours. Drugs that effect hemostasis should be discontinued prior to initiation of therapy with Fragmin. APTT and 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. Fragmin is contraindicated in patients with hemophilia, leukemia with bleeding, thrombocytopenia purpura, cerebrovascular hemorrhage, cerebral aneurysm, severe hypertension, and other sever cardiac disease. There is an increased risk of bleeding when used with aspirin, anticoagulants, and platelet inhibitors. It is administered subcutaneously, not IM or IV. Protamine sulfate is given for overdose.

Normiflo (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 sub-q and not IM (which may cause muscular hematoma). The dosage is 50 antifactor 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 LMWH drugs that affect hemostasis should be discontinued prior to initiation of therapy.

Heparin

Heparin is an anticoagulant used to decrease the clotting ability of the blood and help prevent harmful venous thrombosis from forming in the blood vessels. This medicine is sometimes called a blood thinner, although it does not actually thin the blood. Unfractionated heparin binds with antithrombin factor III, a protein in the blood, to produce an anticoagulant effect. The heparin-antithrombin III complex inactivates certain coagulation enzymes. Patient response is usually monitored with aPTT or ACT. Heparin will not dissolve venous thromboses that have already formed, but it may prevent the formation of new venous thromboses or of venous thromboses from becoming larger.

Dosage is based on weight and the protocol is usually 5000-10,000 units every 4 hours, then titrated to PTT or ACT level. It is not adequately absorbed when administered orally, rectally, or sublingually. Intramuscular absorption is irregular.

IV doses may be given IV push over 1 minute if the dose is less than 1000 Units or by continuous infusion over 4 to 24 hours. IV peak action is 5 minutes with a duration of 2-6 hours.

All IV heparin calculations should be verified by another RN.

Inadvertent errors have occurred when nurses change the fluids and set heparin fluids at mainline rate.

 

The onset for a subcutaneous dose is 20-60 minutes with a duration of 8-12 hours. The medication should be administered the same time each day to maintain steady blood levels by subcutaneous injection with small gauge needle. Do not massage the area nor aspirate when giving subcutaneous injections.

Side effects include fever, chills, diarrhea, nausea, vomiting, anorexia, stomatitis, abdominal cramps, hepatitis, hemorrhage, and hematuria. It is contraindicated in those with hypersensitivity to heparin products, hemophilia, leukemia with bleeding, peptic ulcer, thrombocytopenia purpura, severe hepatic disease, blood dyscrasisas, severe hypertension, subacute bacterial endocarditis, and acute nephritis.

Nursing considerations need to include blood studies (Hct, occult blood in stools). PTT should be done 6 hours after the initiation of heparin and then every day. The results should be 1.5-2 ´control between 31.5 and 36 seconds. PTT is also done 6 hours after any change. A platelet count should be done every 2-3 days. Thrombocytopenia may occur on the 4th day of treatment. Treatment for overdose is protamine sulfate.

Coumadin (Warfarin)

Coumadin (Warfarin) is an anticoagulant that interferes with blood clotting by indirect means. Coumadin inhibits the synthesis of coagulation factors that are dependent on vitamin K. It depresses hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, and X). It is used for DVT, PE, MI, atrial dysrhythmias, and post cardiac valve replacement.

The usual dosage is 10-15 mg/day X 3 days, then titrated to PT and INR. The degree of suppression is dose-dependent. Warfarin is rapidly absorbed from the GI tract. The oral onset of effect is 12-24 hours with a peak effect in 1 ½ - 3 days, and duration 3 – 5 days. Coumadin is started on the first or second day of therapy with LMWH. Once the INR is between 2 and 3, the LMWH is discontinued. Vitamin K reverses warfarin’s anticoagulant effects.

Coumadin is a narrow range (index) drug and treatment of each patient is a highly individualized matter. The dosing must be individualized dosage based on the patient’s sensitivity to the drug as indicated by prothrombin time (PT) and International Normalized Ratio (INR). Use of large dosing may increase the incidence of hemorrhage and other complications and may give a false sense of full anticoagulation in early treatment. Use of a large loading does not offer more rapid protection against thrombi formation and is not recommended. Low initiation doses are recommended for elderly and debilitated patients.

Dietary factors, specifically the vitamin K content of certain foods, play an important role in therapy with Coumadin. If a patient eats excessive amounts of foods high in vitamin K content the effect of Coumadin could be antagonized. Conversely reduction of vitamin K intake could increase the effect of Coumadin. Recommended daily allowance of vitamin K is .05 – 1.0 mg/kg of body weight. Patients should eat a normal balanced diet maintaining a consistent amount of vitamin K. Drastic changes in dietary habits should be avoided. Patients should not eliminate all foods containing vitamin K from their diets.

Numerous factors alone or in combination may affect the response to Coumadin. Patients exhibiting a decreased response to Coumadin should be evaluated to determine the cause and thus direct therapy. Factors that alone or in combination may be responsible for a decreased PT and INR response:

  • Edema
  • Hereditary or acquired Coumadin resistance
  • Hyperlipemia
  • Hypothyroidism
  • Nephrotic syndrome
  • Diet high in vitamin K
  • Potential drug interactions (heparin, thyroid supplements, antibiotics etc.)
  • Unreliable PT and INR determinations
  • Malabsorption
  • Patient compliance
  • Medication dosing error

Gastrointestinal side effects include diarrhea, nausea, vomiting, anorexia, stomatitis, cramps, and hepatitis. Hematologic effects may include hematuria, hemorrhage, leukopenia, eosinophilia, and agranulocytosis.

Thrombolitics

Thrombolytic therapy is important for DVT/PE prevention. Numerous trials have shown that thrombolytics and fibrinolytics have a narrow therapeutic window, which leaves little room for error in dosing calculation. Administering too much of the drug can increase severe bleeding and intracerebral hemorrhage (ICH) rates. Administering too little of the 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, involving weight adjustment and infusion timing, may lead to more medication errors than simpler bolus administration. Route of administration is 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.

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, arrhythmias, and infarction. It is difficult to associate the use of thrombolytics with these adverse reactions because they can also occur as disease-related events.

 

Cautions

Three deaths reported voluntarily to the USP-ISMP Medication Errors Reporting Program (MERP) in the first 6 months of 2001 prompted the Institute for Safe Medication Practices (ISMP) to warn healthcare professionals against concomitant use of LMWH and unfractionated heparin.

The first reported death involved a 62-year-old patient with unstable angina who died after receiving an initial dose of Fragmin in the emergency department, and then IV heparin along with a thrombolytic when he exhibited signs of an acute myocardial infarction.

In another case a 42-year-old patient with an upper extremity thrombosis died from intracranial hemorrhage after a physician accidentally prescribed enoxaprin and initiated a heparin protocol.

The third case led to the death of a hospitalized 86-year-old woman with a history of atrial fibrillation, hypertension, lethargy, and constipation. A consulting cardiologist prescribed enoxaprin 60 mg every 12 hours subcutaneously. On the following day, warfarin was added to the drug regimen. Later in the week a gastroenterologist recommended a colonoscopy to rule out colorectal cancer. Warfarin was discontinued and a heparin infusion was ordered. However, enoxaprin administration continued every 12 hours and the order was never faxed to the pharmacy. To administer the bolus and begin the infusion, the nurse borrowed a vial of heparin and a premixed solution that the pharmacy had dispensed for another patient. Several hours later, the patient’s aPTT was supratherapeutic at greater than 90 seconds. The heparin infusion was decreased to 900 units/hour. By morning, the patient’s aPTT was still elevated, her hemoglobin and hematocrit had dropped, and there was evidence of internal bleeding. Heparin and enoxaprin were discontinued immediately, but the patient died despite aggressive treatment.

Patient Education

Medical experts say that it is critical to warn patients about the risk of DVT and PE and to educate them about preventative measures. Most Americans are unaware of DVT, its symptoms, and its risk factors according to a nationwide survey conducted on behalf of the American Public Health Association (APHA). Acclaimed journalist David Bloom died as a result of DVT while on assignment in Iraq. His death raised awareness and questions among the public health about DVT.

Thorough education for patient and family on the importance of preventing DVT includes encouraging patients to get up and move around as early and frequently as possible and getting prophylaxis as needed. Whenever possible, written and verbal information explaining the physiology of blood flow to and from the heart should be provided. Patients should be instructed when to notify the healthcare provider for worsening symptoms or medication side effects any sign of bleeding (gums/teeth with brushing/flossing, tarry stools, nosebleeds, blood in urine etc), back or stomach pain, bleeding in the eye, poor circulation, skin rash or peeling, and difficulty breathing.

Patients need to be reminded that drinking lots of fluids is helpful in preventing venous thrombosis. They should cut back on salt which includes limiting canned, dried, packaged, and fast foods. They should season foods with herbs instead of salt.

Vegetables such as asparagus, chickpeas, avocado, broccoli, and cabbage are high in vitamin K, which helps the blood to clot. Eating more or less of these foods can affect the way the Coumadin works. They should limit fats to 2 to 4 tablespoons a day. Teas that contain sweet clover, sweet woodruff, or Tonka beans should be avoided.

If walking is contraindicated, mechanical devices for active and passive lower extremity activity should be ordered. This activity should include flexion and extension of ankles, knees, and hips Patients should be cautioned to avoid any constricting clothing that might decrease venous flow to the legs and to avoid sitting with knees bent or crossed for long periods of time. It is important to provide graduated compression stockings for all at-risk patients, unless their use is contraindicated because of ischemic vascular disease.

Patients must be alerted to drug interactions with any of the medications that may be prescribed for prophylaxis or treatment of DVT or PE. For example:

  • Aspirin
  • Anti-inflammatory drugs such as ibuprofen
  • Omega-3 fatty acid supplements (fish oil)
  • Herbal products
    • Feverfew
    • Garlic
    • Ginger
    • Gingko
    • Horse chestnut

It is recommended that patients receiving treatment for DVT or PE should wear med-alert jewelry or carry an identification card containing their name, name and dose of medications being used, and name and phone number of their healthcare provider.

Summary

As knowledge of venous thromboembolism grows, the role of nursing in preventing and managing this life-threatening condition continues to grow. Understanding the mechanism by which thromboembolism occurs will help nurses to assess patients for risk factors on admission and throughout the hospital stay. Seriously ill medical patients, as well as surgical and trauma patients are at risk. Orders of DVT prophylaxis must be obtained when indicated in these patients. Basic nursing must focus on maximal mobility, including range of motion and walking, when appropriate. Nurses must remain alert to signs and symptoms of DVT and PE.

Anticoagulant medication must be given on time, at the same time each day. Monitor blood work to adjust the dosage if needed. Watch for and instruct patients to be alert for signs and symptoms of bleeding and heparin-induced thrombocytopenia. Since many of the drugs used to manage DVT are metabolized by the liver and excreted by the kidneys, hepatic and renal function should be monitored particularly in the elderly and those who are critically ill. Even with best efforts not all cases of venous thromboembolism will be eliminated but identifying patients at risk and providing prophylaxis will help to reduce the incidence of this silent epidemic and save lives.

References

Anand, SS et al. (1998) Does This Patient Have Deep Vein Thrombosis, JAMA 279:1094-1099.

Booth, S.L., Sadowski, J. A., Weibraush, J.R., and Ferland, G., Vitamin K Content of Food – A Provisional Label; Journal of Food Comp. Anal. 1993; 6:109-20.

Bosker, Gideon, Emerman, Charles, and Volthuro, Gregory, (2002) DVT Prophylaxis in Patients with Heart Failure: The Evolving Standard of Care for the Hospitalized Patient, Clinical Cardiology Consensus Report, American Health Consultants.

Cannon, C.P.; (2000) Am. J. Cardiology; Safety First…Examining Thrombolytic Medication Errors, 85: 17C – 22C.

Chase, Sandra L.; The Newest Critical Care Drugs, Part 1, RN; Vol. 62, No. 5 (May 1999) pp. 34 – 48.

Chase, Sandra L.; The newest Critical Care Drugs, Part 2; RN; Vol. 62, No. 6, (June 1999) pp. 36 – 40.

Dalen, J.E., Hirsh, J., Introduction: Antithrombotic Therapy – A comprehensive Update: Chest 1998; 114:439-440.

Geerts, W.H. et al., Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytics Therapy, Chest, Sept. 2004; 126 (3-supplement) 3385 – 4005.

Institute for Safe Medication Practices, Huntington Valley, PA. Sept. 8, 1999, Hespan and heparin mix-ups - reduce the risk by using generic name and product.

Institute for Safe Medication Practices, Huntington Valley, PA. Feb. 26, 2001 Safeguards needed to avert fatal errors from concomitant use of heparin products.

Krames Patient Education, 2005 Preventing Deep Vein Thrombosis, The StayWell Company, Yardley, PA.

Morris, Beverly A., Morrison, Ruth, Yetsko, Cheryl, Venous Thromboembolism: Prevention and Treatment, RN Oct. 2002.

Quinlan, D.J. et al., (2004) LMWH as Effective as Heparin in Preventing Pulmonary Embolism. Ann Intern Med, 140: 175-83

Rydberg, Eric J., Westfall, John M., Nicholas, Richard A., Low-Molecular-Weight Heparin in Preventing and Treating DVT; March 15, 1999.