How to Diagnose and Treat VTEs

Venous thromboembolic events(VTEs) result from a blood clotthat forms within the venouscirculation and are manifested as deepveinthrombosis (DVT) of the lowerextremity and pulmonary embolism (PE).¹Approximately 50% of patients diagnosedwith DVT have an asymptomaticPE.² DVT has been reported to affect ~2million Americans annually, surpassingthe incidence of myocardial infarctionand cerebral vascular accident.

The 3 major factors that contribute tothe pathogenesis of VTE defined byVirchow's triad include damage to theblood vessel wall, venous stasis, andhypercoagulability.³ These factors can becategorized as hereditary or acquired.Hereditary risk factors include hypercoagulabilitystates such as protein C and Sdeficiency, antithrombin deficiency, ornephrotic syndrome. Acquired risk factorsinclude age, history of VTE, venousstasis due to medical illness, major surgery,long-term immobilization, and drugtherapy such as selective estrogenreceptormodulators or oral contraceptivescontaining estrogen. Anticoagulationis the mainstay of therapy for DVTand PE. Treatment and prevention utilizingunfractionated heparin (UFH) hasbeen ongoing since the 1930s, while warfarinuse dates back to the early 1940s.¹

Diagnosis

The incidence of VTEs is difficult todetermine since clinical signs and symptomsare nonspecific, and screeningtests are not always sensitive enough todetect the disease. The clinical presentationof DVT involves unilateral legswelling, which may reveal a palpablecord (reflecting a thrombosed vein),warmth, ipsilateral edema, superficialvenous dilation, and pain.¹ Laboratorytests will usually reveal elevated serumconcentrations of D-dimer (a by-productof thrombin generation), elevated erythrocytesedimentation rate (ESR), andelevated white blood cell (WBC) count.The diagnosis of DVT may be achieved byeither venography or ultrasonography.The sensitivity and specificity of ultrasonographyranges between 70% and95%, making it the diagnostic test ofchoice for suspected DVT.³ Venography isnot used often because of high cost,invasiveness, technical demands, allergicreactions, and nephrotoxicity.³

The most common signs and symptomsof PE involve dyspnea, pleuriticpain, chest tightness, palpitation, cough,hemoptysis, tachycardia, tachypnea, andpossibly fever.¹ Laboratory tests will usuallyreveal elevated serum concentrationsof D-dimer, ESR, and WBC count.Although pulmonary angiography is consideredthe "gold standard" of PE diagnosis,it is highly invasive and expensive andis associated with an increased risk ofmortality. Ventilation-perfusion (V/Q) andcomputed tomographic (CT) scans arethe most commonly used diagnostictests for PE. V/Q scans measure the mismatchbetween distribution of blood andairflow perfusion in the lungs. CT scansare capable of detecting emboli in thepulmonary arteries.¹

Pharmacologic Therapy

After the diagnosis is confirmed, VTE istreated with UFH, low-molecular-weightheparin (LMWH), or fondaparinux. UFHshould be dosed using a weight-basednomogram (Table 1).⁴ Activated partialthromboplastin time (APTT) should bemeasured 6 hours after the bolus dose.Once a therapeutic APTT is achieved, theAPTT should be evaluated every 24hours. The College of American Pathologists⁵and the American College ofChest Physicians (ACCP)⁴ recommendagainst the use of a fixed APTT therapeuticrange of 1.5 to 2.5 times the controlAPTT. Instead, they recommend basingthe therapeutic range on an antifactor Xaconcentration of 0.3 to 0.7 internationalunits (IU)/mL.

LMWH offers several advantages overUFH (Table 2). Enoxaparin, dalteparin, andtinzaparin are the LMWHs currently availablein the United States. Unlike UFH,routine monitoring is not required. Inselect patients, however, including thosewho are obese or have significant renalimpairment, antifactor Xa can be useful.Antifactor Xa should be measured 4hours after a dose. The therapeutic rangeis 0.6 to 1.0 IU/mL for twice-daily dosing,and 1 to 2 IU/mL for once-daily dosing.⁶Monitoring parameters for both UFH andLMWH include hemoglobin, hematocrit,signs and symptoms of bleeding, bonemineral density with long-term use, andplatelets to avoid heparin-induced thrombocytopenia(HIT).

Fondaparinux, a selective factor Xainhibitor, can also be used to treat VTE.Fondaparinux does not require routinecoagulation testing, as it does not alterthe APTT/prothrombin time. The primaryadverse effect is bleeding. Fondaparinuxdoes not cause HIT, nor does it demonstratecross-sensitivity in vitro. Sincethere is a lack of data regarding its use inpregnancy, lactation, and pediatrics, UFHand LMWH remain the agents of choicefor VTE in these populations.

Warfarin therapy should be started onday 1 of VTE treatment at 5 to 10 mgdaily, and dose-adjusted according to theinternational normalized ratio (INR)results.⁷ Concomitant therapy with UFHor LMWH can be stopped after 4 to 5days of combined therapy when the INR>2.0 for a 2-day period.^6,7 Anticoagulationwith warfarin in a patient with a firstepisode of VTE should be continued forat least 3 months at a target INR range of2.0 to 3.0. If the patient has a history ofHIT, direct thrombin inhibitors, lepirudinand argatroban, are used in place of UFH,LMWH, or fondaparinux.

Warfarin Therapy

Patients taking vitamin K antagonistssuch as warfarin must make lifestylechanges to ensure medication effectivenessand safety. A major lifestyle factor isdiet, specifically vitamin K consumption,since vitamin K plays a role in the body'sclotting process and is inhibited by warfarin.Vitamin K is found in many foodgroups, predominantly green leafy vegetablessuch as broccoli, cabbage, collardgreens, lettuce, and spinach, and in certainoils. It is essential for the patient tomaintain consistent eating habits, consistingof small portions of vitamin K-containingfoods, in order to avoid fluctuations inthe INR. It is important to note that nutritionalsupplements such as Ensure andBoost contain high amounts of vitamin K;therefore, the amount of intake of theseproducts must be consistent throughoutwarfarin therapy. Ethanol may alter warfarinmetabolism and should be consumedin moderation.

Patients must also be educated toavoid high-risk activities that may resultin bleeding or bruising. Even simple dailyactivities, such as shaving or brushingteeth, require caution; a soft-bristletoothbrush or an electric shaver shouldbe used to avoid potential bleeding.

Patients must inform all otherhealth care providers in regardsto warfarin therapy, since certaindental and surgical proceduresmay require that warfarin bestopped for a period of time toprevent potential bleeding.Equally important is avoidingcertain drug combinationswhich may potentially interferewith the metabolism of warfarin,resulting in INR fluctuations.Women must also be advised touse appropriate measures toprevent pregnancy, since warfarinis teratogenic.

Conclusion

VTEs, specifically DVT and PE, aredebilitating diseases that may result inmortality if untreated. Diagnosis of VTE isoften completed with noninvasive proceduressuch as ultrasonography and V/Qscans. Although venography and pulmonaryangiography are standard in DVTand PE diagnosis, respectively, both aretoxic to the kidneys and have been associatedwith a high rate of mortality.

Pharmacists practicing in inpatient andoutpatient settings, including communitypractice, should be familiar with theguidelines published by the ACCP andthe appropriate use of UFH, LMWH, andwarfarin treatment in order to appropriatelycounsel patients, maximize drug-therapyeffectiveness, and minimizeadverse effects. Treatment with warfarininitially requires extensive INR monitoringto ensure that the appropriate dose isbeing utilized. Once the INR is stabilized,INR monitoring may be extended tomonthly intervals. It is essential thatpharmacists understand the risk factors,common diagnostic procedures, potentialdrug and food interactions, and pharmacologicand nonpharmacologic treatmentregimens, in order to educatepatients so they may live longer, healthierlives.

Dr. Lieberman is a pharmacy practiceresident at the James J. PetersVeterans Affairs Medical Center inBronx, NY. Dr. Plakogiannis and Dr.Pham are both assistant professorsof pharmacy practice at Arnold &Marie Schwartz College of Pharmacyand Health Sciences, Long IslandUniversity, in Brooklyn, NY.

For a list of references, send a stamped, self-addressedenvelope to: References Department,Attn. A. Rybovic, Pharmacy Times, AscendMedia Healthcare, 103 College Road East,Princeton, NJ 08540; or send an e-mailrequest to: arybovic@ascendmedia.com.