Venous thromboembolism (VTE) is a common complication of critical illness that's associated with significant morbidity and mortality.1 For many patients it's also largely preventable with the application of appropriate prophylactic measures. A variety of approaches to VTE prophylaxis exist, but among the most effective, studied, and recommended of these is the administration of heparin preparations. This article reviews these medications and their application toward VTE prophylaxis in the CCU.
Overview of VTE
VTE is a diagnosis that includes deep vein thrombosis (DVT) and pulmonary embolism (PE). An estimated 900,000 Americans develop VTE annually, and approximately two-thirds of these individuals are or were recently hospitalized at the time of diagnosis.2 Most hospitalized patients possess one or more risk factors for VTE. Patients in CCUs also are at risk to develop this complication due to their illnesses and the therapies they require. DVT has been reported in 13% to 31% of critically ill patients patients without prophylaxis.3
Overall, morbidity for patients with VTE is high. Nearly half of patients with a DVT will experience postthrombotic syndrome with signs and symptoms ranging from skin discoloration and varicosities to severe extremity pain and venous ulcers. One-third of patients will develop a recurrent thrombus within 10 years.2 Between 60,000 and 100,000 people in the United States die annually due to VTE, and 25% of patients with PE will present with death as their initial sign.2 One in 10 hospital deaths is attributed to VTE, making it the most preventable cause of death in acute care settings.2
Patients diagnosed with VTE experience a higher morbidity and mortality than those without VTE. DVT specifically is independently associated with a higher number of mechanical ventilator days, longer CCU and hospital stays, increased cost, and an increased risk of death.4 DVT is also a leading cause of PE, a frequently unrecognized and often fatal event in the CCU. This is illustrated by one study, which found that 70% of patients whose autopsy results list PE as the cause of death were never suspected of having PE.5
Thrombus formation
Coagulation is the physiologic response to vascular injury intended to quickly halt blood loss and promote healing. When a clot forms within the lumen of a blood vessel, however, it becomes a pathologic thrombus, resulting in ischemia and infarction. Hemostasis is a multistep process that involves platelets, plasma clotting factors, naturally occurring anticoagulants, and the inherent properties of the endothelial lining of blood vessels.6 (See Understanding hemostasis.)
Coagulation is self-perpetuating through a positive feedback mechanism because many of the molecules that initiate and propagate coagulation are released by cells activated in the coagulation cascade. (see The coagulation cascade.) As a result, the procoagulant processes must be tightly controlled to limit the extent of clotting to the time and place of injury. Regulatory mechanisms of coagulation involve the physical separation of substrates and anticoagulant molecules including protein C, protein S, nitric oxide, thrombomodulin, heparin sulfates, and tissue plasminogen activator, better known as t-PA.7-9
VTE results when pathologic conditions shift the balance between procoagulant forces and anticoagulant forces to favor coagulation.6-8 The conditions that favor this dysregulation are commonly described by using Virchow triad: abnormal blood flow or stasis, vascular wall injury, and hypercoagulability. Many of the common diagnoses treated in the CCU and many of the interventions used to treat them result in the risk factors described by Virchow.9 (See Risk factors associated with venous thrombosis.) Critical illness is often marked by hypoperfusion, hypotension, and prolonged immobility, and each can contribute to venous stasis. Mechanical ventilation, and positive end-expiratory pressure in particular, increases intrathoracic pressure decreasing flow velocity in the vena cava, reducing venous return, and promoting venous stasis. Similarly, elevation of intra-abdominal pressure in excess of central venous pressure decreases venous return from the lower extremities and pelvic and abdominal organs, increasing the risk of thrombosis.5,9,10
Tissue injury related to unintentional trauma or iatrogenic trauma such as surgery results in endothelial damage and inflammation that activate coagulation. Systemic inflammation, severe infection, and sepsis all promote coagulation as well. Even central venous access devices common in the CCU setting can promote coagulation.9 All of these CCU-related VTE risks are in addition to any risk factors that were present prior to admission. Important preexisting risk factors include a previous history of VTE, tobacco use, malignancy, heart failure, chronic obstructive pulmonary disease, obesity, metabolic syndrome, and estrogen therapy.10 The true risk of VTE varies greatly in clinical practice. Risk profiles differ between surgical patients and nonsurgical patients and even within the surgical population where the type of surgical procedure performed can greatly affect risk. Several risk assessment models have been developed to help clinicians determine a particular patient's VTE risk; however, none have been validated for use in critical care. Most critically ill patients should be considered at moderate to high risk for VTE and offered prophylaxis.5,11
VTE prophylaxis
The most comprehensive recommendations for the prevention of VTE come from the American College of Chest Physicians (ACCP), which has published recommendations for prophylaxis since 2001. ACCP guidelines, now in their ninth edition, span hundreds of pages and include specific recommendations for a variety of populations and settings including surgical patients, orthopedic surgical patients, and nonsurgical patients.1 General recommendations for critically ill patients are part of the nonsurgical guidelines and critical care clinicians are encouraged to follow these recommendations. The specifics of prophylaxis should be guided by an assessment of individual patient risk, but VTE prophylaxis is indicated in most critically ill patients. Available methods of prophylaxis against VTE endorsed by the guidelines include mechanical and pharmacologic modalities.12 Mechanical prophylaxis is accomplished with the proper application of graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) devices alone or in combination. These methods of prophylaxis are desirable primarily because they lack the adverse reactions, most notably bleeding, associated with anticoagulation. For patients who are bleeding or at high risk for bleeding, mechanical prophylaxis alone is recommended by ACCP.13 The data to support mechanical prophylaxis alone, however, aren't robust. The available data suggest that mechanical prophylaxis is superior to no prophylaxis, but has lower efficacy than anticoagulants. Compression devices are most beneficial when used in combination, for example, IPC with GCS, or when added to pharmacologic interventions.12
Without evidence of active bleeding or significant risk factors for bleeding, pharmacologic prophylaxis with anticoagulation is indicated for patients with moderate risk for VTE and above. The prophylactic agents of choice are heparins and are available as either unfractionated heparin (UFH) or a variety of low-molecular-weight heparin (LMWH) products. These drugs have demonstrated efficacy in the literature, have a relatively low incidence of complications, and are cost effective for the prevention of VTE.14
Heparins are naturally occurring complex carbohydrate molecules belonging to a group called glycosaminoglycans. They're known to have weak anticoagulant properties, but the understanding of their full role in human physiology continues to evolve. In humans they're produced predominantly in mast cells by assembling repeating units of smaller carbohydrates called disaccharides. The number of disaccharide units in the final molecule varies because as a sugar, no blueprint exists to guide assembly as there would be for a protein. As a result, there isn't a consistent heparin molecule, but rather many versions or heparins, each of which has slightly different properties.13
Pharmaceutical heparin is usually derived and purified from tissue obtained from animal sources, either bovine (cow) lung tissue or porcine (pig) intestine. They're structurally and functionally similar to the heparins described previously. Nurses should consider the source of heparin when delivering culturally competent care because patients with personal, cultural, or religious convictions against consuming products from these animals may object to prophylaxis with these medications.13
Heparins bind to antithrombin, accelerating the rate at which it inactivates thrombin (factor IIa) and other coagulation factors by several thousand times. Heparin also binds with and directly inactivates factor Xa, and to a lesser extent factors IXa, XIa, and XIIa. Much of the anticoagulant properties of heparin result from a specific pentasaccharide region of the sugar that's only active in about one in three naturally occurring molecules. This region is vital to the inactivation of factor Xa. Additional saccharide units extend the length of the molecule and allow heparin to simultaneously bind with both antithrombin and thrombin. This concurrent binding of both molecules is required for the accelerated inactivation of thrombin. Other portions of the molecule are also significant because they bind to proteins and macrophages affecting the bioavailability of the drug. This binding of heparin to cells and proteins results in the dose-response variability observed when heparin is administered at treatment doses with the goal of prolonging activated partial thromboplastin time (aPTT).15
UFH, commonly referred to in practice as simply heparin, contains a heterogeneous mixture of various sizes of heparin molecules with different degrees of anticoagulant effect.15 UFH can be used as both prophylaxis and treatment for VTE. When used prophylactically, lower doses of heparin are generally administered subcutaneously two or three times/day.16 At low doses, heparin's anti-Xa activity serves to blunt the coagulation cascade, downregulating the process and providing prophylactic benefit without therapeutic anticoagulation. Low-dose UFH results in as much as a 60% risk reduction for VTE with only a slight increase in bleeding risk.17 There appears to be no significant difference in VTE events, bleeding events, or mortality between the 8- and 12-hour administration regimen.18 UFH is the preferred anticoagulant in pregnancy because it doesn't cross the placenta and doesn't result in fetal anticoagulation. For patients with renal failure (GFR less than 30mmol/L), UFH is the preferred agent because it undergoes hepatic metabolism and isn't renally eliminated.
LMWH is prepared by a chemical depolymerization of UFH to fraction longer heparin chains and isolate the active pentasaccharide region. This process improves the predictability of the dose-response relationship considerably, but LMWH has considerably less activity against thrombin. As a result, LMWH acts principally through inactivation of factor Xa. The reduced activity against thrombin doesn't appear to be clinically significant in preventing VTE. Researchers in a large multicenter, open-label study comparing LMWH with UFH for VTE prophylaxis in critical illness found statistically equivalent rates of VTE in patients treated with LMWH or UFH.19
In the United States, two LMWH preparations (enoxaparin and dalteparin) are currently FDA approved for different clinical indications. It's important to note that these preparations aren't interchangeable because each has unique biochemical and pharmacologic properties with specific, weight-based dosing. In addition, LMWH preparations can't be converted unit for unit with heparin.18
Monitoring
Patients receiving heparin preparations for prophylaxis should be monitored for evidence of VTE as well as adverse reactions related to the medications including bleeding and thrombocytopenia. When given at higher therapeutic doses, the anticoagulant effect of UFH must be monitored due to the highly variable bioavailability of the compound. Prophylactic UFH doses, however, don't typically require therapeutic monitoring of anticoagulant effect because these doses aren't expected to prolong the aPTT.20 To monitor prophylactic efficacy, assess patients for evidence of DVT including pain, tenderness to palpation, edema, and discoloration of the extremities, especially in a patient with VTE risk factors. These findings are neither sensitive nor specific for DVT, but may suggest further workup. Acute unexplained tachycardia, hypotension, hypoxemia, and dyspnea may be clinical manifestations of PE and may also prompt additional evaluation of at-risk patients.21
The major concern when considering UFH or LMWH as VTE prophylaxis is an increased risk of bleeding that may be seen without prolongation of the aPTT. Prophylactic dosing of these medications roughly doubles the mean risk of major bleeding events from 0.4% to between 0.6% and 1%, and a similar effect is seen with clinically significant but nonmajor bleeding.19 Patients with the highest bleeding risk include those with a recent history of bleeding, peptic ulcer disease, or a platelet count less than 50,000. Renal failure, hepatic failure, and ICU admission were also shown to increase bleeding risk. Although the increase in risk is small, clinicians should assess a patient's risk for bleeding before initiating pharmacologic prophylaxis.17
Patients receiving any form of heparin should have routine monitoring of platelet counts to aid clinicians in detecting heparin-induced thrombocytopenia (HIT). Patients with previous exposure to heparin should have a platelet count obtained prior to reintroducing heparin, approximately 24 hours after the first dose, then at least every 2 to 3 days for up to 14 days or until therapy is discontinued.22 Two distinct forms of HIT exist and are labeled type I and type II.
HIT type I (HIT I) is a typically benign condition in which the patient experiences a transient drop in platelet counts within the first 2 days of heparin exposure. The mechanism is thought to be related to a direct effect of heparin on platelets causing nonimmune-mediated platelet aggregation that doesn't result in thrombosis formation. Between 10% and 40% of patients treated with heparin will experience this adverse reaction, but there is little clinical significance because platelet counts rarely drop below 100,000 platelets/microliter (mcL) and frequently return to normal without discontinuing heparin.23,24
HIT type II (HIT II) is more serious and less common, affecting 0.5% to 5% of patients receiving heparin preparations.25 Patients develop a significant drop in their platelet counts between 4 and 10 days after the initiation of therapy. In those previously exposed to heparin preparations, HIT II can develop within hours and is mediated by antibodies to platelet factor 4 complexed to heparin, resulting in platelet activation, thrombosis, and consumptive thrombocytopenia.24,26 Absolute thrombocytopenia with counts below 150,000 platelets/mcL or relative thrombocytopenia with thrombocyte reductions of greater than 50% from baseline should raise suspicion for HIT II. Systemic manifestations often precede thrombocytopenia and include thrombosis, fever, chills, chest pain, dyspnea, and skin necrosis at the site of subcutaneous heparin injections.27 Whenever HIT II is suspected, all heparin preparations including UFH and LMWH must be stopped immediately and not restarted unless the diagnosis is excluded. Patients suspected of HIT II can be screened with HIT antibody testing. However, because antibody testing can produce false positives, functional assays such as the serotonin release assay are typically used to confirm the diagnosis. Although HIT II occurs infrequently, it's associated with significant morbidity and clinicians are encouraged to be vigilant for the development of this complication.28 Patients with a confirmed diagnosis require anticoagulation with a nonheparin agent such as argatroban, danaparoid, fondaparinux, or bivalirudin, unless there's a strong contraindication, and should be considered allergic to all heparin preparations for life. The nurse needs to educate the patient, the patient's family, and any caregivers about this.
Prophylactic heparin preparations can be a source of patient dissatisfaction because they can only be administered by subcutaneous injection. Currently, no oral anticoagulant exists that's appropriate for use in the CCU. Warfarin, a vitamin K antagonist, is approved for VTE prophylaxis; however, it's rarely used in the critical care setting because the anticoagulant effect is delayed, not occurring until 36 to 72 hours after administration. Hospitalized patients may also have cormobidities such as impaired liver function, which can disrupt the anticoagulant effect.29 In recent years, new oral agents have become available and show promise as possible alternatives for parenteral medications. These agents include an oral direct thrombin inhibitor and direct factor Xa inhibitors and have been approved for VTE prophylaxis in select populations outside of the CCU, including orthopedic surgery and atrial fibrillation.27 Their use in critically ill patients is currently limited by a lack of available reversal agents and numerous case reports of severe bleeding. Evidence supporting these agents for VTE prophylaxis in critical illness is also lacking.26
Implications for nursing practice
Critical illness independently confers moderate to high risk for VTE, and most patients in the CCU should have appropriate VTE prophylaxis. Assess every patient for VTE risk factors and advocate for VTE prophylaxis when indicated. As a Joint Commission Core Measure, VTE prophylaxis provides nurses caring for patients in the CCU an additional incentive to partner with prescribers to ensure the delivery of optimal patient care. Mechanical methods of thromboprophylaxis require consistent use by clinicians educated in their proper application.30
Prior to the administration of pharmacologic VTE prophylaxis, assess patients for a history of HIT, recent bleeding, and bleeding associated with prior heparin exposure. If these conditions are present, the use of heparin preparations should be questioned.
A baseline complete blood cell count, platelet count, and coagulation profile should be obtained prior to initiation of pharmacologic prophylaxis; request additional lab testing at intervals appropriate to each patient. Thrombocytopenia, as well as other abnormalities, should be immediately communicated to the prescriber. Heparins for VTE prophylaxis should be administered by subcutaneous injection. To avoid the loss of drug when using the prefilled LMWH syringes, the air bubble shouldn't be expelled. The preferred site for administration is the abdomen above the iliac crests, but the thighs also are used. Avoid I.M. injection because it can result in injury to underlying vasculature, leading to clinically significant bleeding. Rotate injection sites between doses and don't massage or use injection sites for administration of other medications.31
Following the initiation of therapy, monitor patients for signs of overt or occult bleeding including hemoptysis, hematuria, melena, hematochezia, anemia, tachycardia, and hypotension. Report findings to the prescriber because they may warrant discontinuation of heparin. For patients undergoing procedures where bleeding is likely, review the need for alternative prophylaxis with the prescriber.
Conclusion
Heparin preparations, including UFH and LMWH, are safe and effective for VTE prophylaxis. Nurses are ideally positioned to advocate for prophylaxis, as well as to monitor its effects. Nurses are encouraged to develop an understanding of the indications and contraindications for these medications.
The coagulation cascade6
The terminal steps in both the intrinsic and extrinsic coagulation pathways are the same. Calcium, factor X, and platelet phospholipids combine to form prothrombin activator, which then converts prothrombin (II) to thrombin (IIa). This interaction causes conversion of fibrinogen (I) into the fibrin (Ia) strands that create the insoluble blood clot.
Risk factors associated with venous thrombosis
Venous stasis
Bed rest
Immobility
Spinal cord injury
Acute myocardial infarction
Congestive heart failure
Shock
Venous obstruction
Hypercoagulable states
Genetic factors
Stress and trauma
Pregnancy
Childbirth
Oral contraceptives and menopausal hormone therapy
Dehydration
Cancer
Antiphospholipid syndrome
Hyperhomocysteinemia
Vascular trauma
Indwelling venous catheters
Surgery
Massive trauma or infection
Hip fractures
Orthopedic surgery
*Many of these risk factors involve more than one mechanism.
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