Thromboembolic Diseases - Area-c54.it diseases.pdf · Thromboembolic Diseases Incidence, Risk Factors, and Categories Deep venous thrombosis (DVT) and pulmonary embolism (PE), together

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Thromboembolic Diseases

ncidence, Risk Factors, and Categorieseep venous thrombosis (DVT) and pulmonary embolism (PE),

ogether called venous thromboembolism (VTE), remain a seriousealth care problem. Together it has been estimated that there are morehan 900,000 cases per year in this country alone.1 Approximately00,000 individuals die of PE every year and deaths from PE are 5imes more common than deaths from breast cancer, motor vehicleccidents, and AIDS combined. Venous thromboembolism is the thirdost common vascular disease after heart disease and stroke. Addi-

ionally, patients with post-thrombotic syndrome (pain and leg swell-ng after thrombosis) suffer poor quality of life due to chronicymptoms. The incidence of post-thrombotic syndrome is as high as0% over 8 years.2

Acquired risk factors include age, malignancy, surgery and trauma,mmobilization, oral contraceptive use, hormone replacement therapy,regnancy and the puerperium, obesity, neurological disease, cardiacisease, and antiphospholipid antibodies.3 Genetic causes includeeficiencies of antithrombin, proteins C and S, factor V Leiden,rothrombin 20210A, blood group non-O, hyperhomocystinemia,ysfibrinogenemia, dysplasminogenemia, reduced heparin cofactor IIctivity, elevated levels of clotting factors such as factors XI, IX, VII,III, X, and II, and plasminogen activator inhibitor-1.4 Hematologiciseases associated with an increased risk of DVT include dissemi-ated intravascular coagulation (DIC), heparin-induced thrombocyto-enia (HIT), antiphospholipid antibody syndrome, thrombotic throm-ocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), andyeloproliferative disorders (polycythemia vera and essential throm-

ocythemia).5 For venous thrombosis, indications for screening in-lude venous thrombosis in unusual locations (ie, mesenteric venous,ortal venous, etc), idiopathic venous thrombosis, recurrent venoushrombosis, thrombosis on oral contraceptives, and episodes of ag-
ressive superficial thrombophlebitis.
urr Probl Surg 2008;45:844-899.011-3840/2008/$34.00 � 0oi:10.1067/j.cpsurg.2008.08.002

44 Curr Probl Surg, December 2008

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enous Thrombosis PathogenesisThrombosis in the venous circulation involves a combination of stasis,

ndothelial perturbations, and hypercoagulabilities. The inciting eventnvolves thrombus formation from local procoagulant events, such asmall endothelial disruptions at venous confluences, saccules, and valveockets. Neutrophils and platelets then adhere to this thrombus andecome activated, generating inflammatory and procoagulant mediators.hrombus is thus amplified.6 With progression, leukocytes (initiallyeutrophils and later monocytes) extravasate into the vein wall ultimatelyesulting in vein wall inflammation (Fig 1). It appears that a balanceetween proinflammatory and anti-inflammatory cytokines and chemo-ines determine the ultimate vein wall response.7 The earliest elevatedlycoprotein present on endothelial cells and platelets, P-selectin appearso play an important role in thrombogenesis along with the generation ofrocoagulant microparticles.8,9 These microparticles are tissue factor richnd are released from activated leukocytes, platelets, and endothelium.dditionally, tissue factor released from the vein wall also contributes to

hrombosis when direct vein wall injury occurs or when tissue factorecomes exposed to the flowing blood.10

enous Disease Diagnosis

eep Venous ThrombosisThe diagnosis of DVT must be made with confirmatory laboratory

IG 1. Immediately after endothelial cell injury, endothelial cells and platelets are activated promotinghe expression of cell adhesion molecules. This vascular response promotes leukocytes rolling andethering onto the endothelium that initiates an inflammatory event which can lead to thrombosis.Reprinted with permission from Wakefield et al,7 © 2008 Lippincott Williams & Wilkins.)

esting, as patients will be asymptomatic at presentation in up to 50% of

urr Probl Surg, December 2008 845

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ases with DVT. When symptoms are present, patients complain of a dullche or pain in the calf or leg. The most common physical finding isdema, although Wells and colleagues have classified patients into acoring system that emphasizes the physical presentation of patients. Inheir criteria, characteristics that score points include the presence ofctive cancer, paralysis or paresis, recent plaster immobilization of theower extremity, being recently bedridden for 3 days or more, localizedenderness along the distribution of the deep venous system, the entire legeing swollen, calf swelling that is at least 3 cm larger on the involvedide compared with the noninvolved side, pitting edema in the symptom-tic leg, and a history of a previous DVT.11 With extensive proximal DVTn the iliofemoral system, there may be significant swelling, cyanosis, andilated superficial collateral veins.Massive iliofemoral DVT may cause phlegmasia alba dolens (white

wollen leg) or phlegmasia cerulean dolens (blue swollen leg). When theapillaries occlude, venous gangrene may occur. This occurs as therterial inflow becomes obstructed due to the effects of high levels ofenous hypertension. Alternatively, arterial emboli or spasm may occur.he skin blisters and the toes on the involved limb may turn black.enous gangrene must be differentiated from gangrene caused by arterial

nsufficiency. Such differentiation includes the fact that with arterialangrene the limb is pale and cold without significant swelling. Venousangrene is often associated with an underlying malignancy and is alwaysreceded by phlegmasia cerulea dolens. Associated with venous gangrenere amputation rates of 20% to 50%, PE rates of 12% to 40%, andortality rates of 20% to 40% due to the underlying medical conditions

hat have been described.12

Tests for establishing the diagnosis of DVT of historical interest includendirect flow examinations. Duplex ultrasound imaging has replaced theseests and also contrast phlebography due to its high sensitivity, specificity,nd reproducibility. Duplex ultrasound imaging includes a B-mode imagend Doppler flow pattern. Duplex imaging carries sensitivity and speci-city rates greater than 95%.13 According to the grade criteria for thetrength of medical evidence, duplex ultrasound as the test of choice forhe diagnosis of DVT is given a 2C level of evidence13-15 (Table 1).

agnetic resonance imaging (MRI) may be helpful to diagnose centralelvic vein and inferior vena cava (IVC) thrombosis, and spiral computedomography (CT) scanning is also being used more frequently, especiallyhen combined with chest imaging during examination for PE.16 Even at

he calf level, a level in which duplex imaging is felt to be less accurate,
uplex imaging is an acceptable technique in symptomatic patients. Other

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dvantages of duplex imaging include that it is painless, requires noontrast, can be repeated serially, and is safe during pregnancy. This testlso identifies other potential causes of a patient’s symptoms.14 In thesymptomatic patient, screening venous duplex imaging has been asso-iated with varying levels of sensitivity and specificity.Combining clinical characteristics with a D-dimer assay may decrease

he number of negative duplex scans performed.11 Importantly, a singleomplete technically adequate negative duplex scan is accurate enough toithhold anticoagulation with minimal long-term adverse thromboem-olic complications.17 However, this means that all segments of the legave been imaged and evaluated successfully. If the duplex scan isndeterminate, treatment may be based on other factors such as biomar-ers, with the duplex scan repeated in 24 to 72 hours. Also, repeatmaging may be necessary if the patient’s symptoms change or worsen.lthough the use of clinical characteristics and D-dimer levels is useful to

ule out thrombosis, the converse is not true. A positive D-dimerssociation with a positive risk assessment is associated with thrombosisn only approximately 70% of cases, and is not felt good enough to basenticoagulant therapy on.18 We are attempting to establish a panel ofiomarkers that may be used to establish a positive diagnosis of DVTased on the inflammatory response to the thrombotic process and theross-talk between systems.19

Other conditions may be confused with DVT including lymphedema,uscle strain, and contusion. Iliac vein obstruction in the retroperitoneum

eads to unilateral massive leg edema (May-Thurner syndrome), while the

ABLE 1. Evidence-based recommendations for the diagnosis and treatment of venous thromboem-olism15

Test or interventionLevel of evidence(grade criteria)

uplex imaging for DVT diagnosis 2Cpiral CT imaging for PE diagnosis 1AMWH for initial treatment of VTE 1Ariteria for stopping anticoagulation 1Alternative agents for treatment of HIT 1C/2Cse of IVC filters 2Conpharmacological treatment for DVT 1Aombined pharmacological and mechanical VTE prophylaxis 2A

VT, deep vein thrombosis; CT, computed tomography; PE, pulmonary embolism; LMWH, lowolecular weight heparin; VTE, venous thromboembolism; IVC, inferior vena cava; HIT,eparin-induced thrombocytopenia.

resence of a cyst behind the knee may produce unilateral leg pain and


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dema. Other causes of leg swelling (usually bilateral) include systemicroblems such as cardiac, renal, or hepatic abnormalities.

ulmonary EmbolismThe diagnosis of PE involves ventilation-perfusion (V/Q) scanning orulmonary angiography; newer techniques include spiral CT scanningnd MRI. The sensitivity of V/Q scanning is described in a largeandomized multicenter study (PIOPED I) to be 98%, but the specificitys low, at 10%.20 By combining clinical risk factors with V/Q scan,ensitivity and specificity greater than 95% was achieved. With aigh-probability V/Q scan and 2 risk factors for PE, the sensitivity for PEiagnosis was 97%; with 1 risk factor, 84%; and with no risk factors,2%. Similarly, with a normal V/Q scan, the chance of PE was zero,egardless of the risk factor status.21 These results suggest that a normal/Q scan or a high-probability scan provide good diagnostic information.owever, only a small portion of V/Q scans are in 1 of these 2 categories,

nd thus the majority of patients need further testing. Such further testingncludes lower extremity venous duplex ultrasound imaging (venousuplex imaging is positive in approximately 10% of cases in theseatients) and spiral CT scanning. Pulmonary angiography is used infre-uently today. Indications for pulmonary arteriography include acuteassive PE, IVC interruption, and the planning of pulmonary interven-

ional therapy, such as thrombolysis or pulmonary embolectomy.Spiral CT scanning has demonstrated excellent specificity but relatively

ow sensitivity (50% to 65%), despite promising initial results. However,s the technology has improved, the sensitivity and specificity havelso improved, and now emboli at the subsegmental level can bedentified.22 A recent study reported that the sensitivity for isolatedhest CT imaging was 83%, but increased to more than 90% whenlinical analysis was added. Additionally, sensitivity improved whendding a lower extremity imaging study (either CT or ultrasound) tohe chest CT scan.16 Results from this study (PIOPED II) stronglyuggest that if the clinical presentation and spiral CT scan areoncordant, therapies can be recommended safely. However, if resultsre discordant between clinical presentation and spiral CT, then otheronfirmatory tests are necessary. For the diagnosis of PE, spiral CTmaging is given a 1A level of evidence based on PIOPED II (Table). Magnetic resonance imaging has demonstrated excellent promiseor PE diagnosis and is currently being investigated in a multicenter
andomized study (PIOPED III).

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xillary/Subclavian Vein ThrombosisThrombosis of the axillary/subclavian vein accounts for less than 5% of

ll cases of acute DVT. However, it is associated with PE in up to 10%o 15% of cases and additionally can be the source of significantisability.23 Primary axillary/subclavian vein thrombosis results frombstruction of the vein in the thoracic outlet, the Paget Schrotteryndrome, especially prominent in healthy muscular individuals. It maylso occur in patients with hypercoagulable states who have a tendency tohrombosis. Secondary axillary/subclavian vein thrombosis results usu-lly from indwelling catheters or pacemaker wires. Other less commonauses include mediastinal tumors, malignancy, and medical conditionsuch as congestive heart failure and nephrotic syndrome. Patients withxillary-subclavian venous thrombosis often present with pain, edema,nd cyanosis of the arm. Due to the venous obstruction, superficial venousistension may be apparent over the arm, forearm, shoulder, and anteriorhest wall.Upper extremity venous duplex ultrasound is used for those patientsith suspected axillary-subclavian vein thrombosis. Treatment for docu-ented thrombotic episodes includes anticoagulation. Thrombolysis and

hlebography should be considered. If phlebography is performed, it ismportant that the patient undergo positional phlebography, abducting therm 120 degrees to confirm extrinsic compression of the subclavian veint the thoracic outlet. Venous compromise is further evidenced byrominent collateral veins. A chest radiograph should be obtained toxclude the presence of a cervical rib.

tandard Therapy for VTEThe primary treatment of VTE is systemic anticoagulation, which

educes the risk of PE, extension of thrombosis, and recurrence ofhrombosis. Immediate systemic anticoagulation should be undertaken, ast has been shown that the recurrence rate for VTE is approximately 4- to-fold higher if anticoagulation is not therapeutic in the first 24 hours.24

dequate anticoagulation has been shown to prevent the development ofatal PE both during the initial treatment and after treatment is com-lete.25 However, recurrent DVT may still occur in up to one third ofatients over an 8-year period after adequate appropriate therapy.26

Traditionally, systemic intravenous unfractionated heparin (UFH) haseen undertaken for 5 days, during which time oral anticoagulation withitamin K antagonists (usually warfarin) is instituted. International
ormalized ratios (INRs) therapeutic for 2 consecutive days are usually

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ecommended before stopping heparin.27 However, due to the need forntravenous administration, the need for frequent monitoring, as well ashe bleeding risks of UFH, low molecular weight heparin (LMWH) haseen advanced as primary therapy for VTE. Low molecular weighteparins are derived from the lower molecular weight range of standardeparin. They demonstrate less direct thrombin inhibition and morentifactor Xa inhibition. Low molecular weight heparins have significantmprovement in bioavailability and less endothelial cell and proteininding compared with standard unfractionated heparin. Low moleculareight heparins are at least equivalent to UFH if not slightly superior

egarding thrombus recurrence, with a lower risk for major hemorrhage.28

he list of potential advantages of LMWHs compared with standardnfractionated heparin include a lower risk of bleeding, less antiplateletctivity, a lower incidence of HIT, less interference with protein C andomplement activation, and a lower risk of osteoporosis. Low moleculareight heparins may be administered subcutaneously weight based, anday be administered in the outpatient setting. They do not requireonitoring except in certain circumstances such as renal failure, morbid

besity, and during pregnancy.29 However, the use in the outpatientettings usually requires a team approach and a coordinated effort ofultiple health care providers. There is also mounting evidence thatMWH may decrease the incidence of post-thrombotic syndrome.30

aking all of the evidence together, LMWH is now preferred overtandard UFH for the initial treatment of VTE with a level of evidenceA31 (Table 1).Warfarin should be started only after heparinization is therapeutic torevent warfarin-induced skin necrosis, usually on the first day ofherapy. This condition occurs due to transient hypercoagulability thatccurs for the first few days after warfarin is administered. Warfarinauses inhibition of protein C and protein S before most coagulationactors are inhibited by warfarin. The goal for warfarin dosing is an INRetween 2.0 and 3.0. The recommended duration of anticoagulation afterfirst episode of VTE is 3 to 6 months.32 Calf level thrombi may be

reated with 6 to 12 weeks of warfarin. After a second episode of VTE,he usual recommendation is prolonged warfarin unless the patient is veryoung at the time of presentation or there are other mitigating factors. Theength of time of warfarin usage in other situations is controversial.enous thromboembolism recurrence is increased significantly in theresence of homozygous factor V Leiden and prothrombin 20210Autation, protein C/S deficiency, antithrombin deficiency, antiphospho-

ipid antibodies, and cancer until resolved.3 In these conditions, most


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gree with long-term warfarin therapy especially in circumstances withultiple hypercoagulable states. However, heterozygous factor V Leiden/

rothrombin 20210A does not carry the same risk as their homozygousounterparts, and the length of oral anticoagulation is shortened.Recently, 2 additional criteria have been used to determine the length of

nticoagulation. One involves the amount of scar tissue inside the venousirculation leading to stasis. The second and perhaps better validatedriterion involves D-dimer testing obtained 1 month after warfarin isompleted. If the D-dimer level is elevated above normal, warfarin shoulde continued, as this result suggests that the patient is still prothrom-otic.33-35 One recent study has demonstrated a statistically significantdvantage to resuming coumadin if the D-dimer assay is positiveompared with remaining off coumadin over an average 1.4-year fol-ow-up period (odds ratio [OR] 4.26, P � 0.02).36

Idiopathic DVT is an interesting problem. Most believe that truediopathic thrombosis requires more than 6 months of warfarin, but thectual length is not known. A recent multicenter trial has suggested thator idiopathic DVT, low dose warfarin (INR 1.5-2.0) is superior tolacebo over a 4-year follow-up period with a 64% risk reduction forecurrent DVT after the completion of an initial 6 months of standardarfarin therapy.37 A second study has suggested that full-dose warfarin

INR 2-3) is superior to low-dose warfarin in these same patients withoutdifference in bleeding.38 Thus, the data together suggest that for

diopathic thrombosis, long-term treatment is desirable and an INR of 2.0o 3.0 should be achieved. In aggregate, criteria for discontinuation of oralnticoagulation include thrombosis risk, residual thrombus burden, andoagulation system activation (as suggested by D-dimer measurements).hese criteria are given a level of evidence of 1A33-35,37,38 (Table 1).The most common complication of anticoagulation is bleeding. WithFH, bleeding occurs in approximately 10% of cases over the first 5 days.ith the addition of warfarin at an INR of 2 to 3, the incidence of major

leeding is approximately 6% per year. In treating patients for DVT andE, major bleeding has been reported in 0% to 7% of patients, with fatalleeding in 0% to 2% of patients.39 A meta-analysis showed a rate ofemorrhagic complications estimated at 9.1% for anticoagulation contin-ed beyond 3 months. To decrease bleeding, dose adjustments and use ofnticoagulation clinics are emphasized.Another complication of heparin is HIT. Heparin-induced thrombocy-

openia occurs in 0.6% to 30% of patients in whom heparin is adminis-ered. While historically morbidity and mortality have been high, early
iagnosis and appropriate treatment have decreased the rates.40 Heparin-

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nduced thrombocytopenia usually begins 3 to 14 days after heparin isegun (earlier if the patient has been exposed to heparin in the past) ands caused by a heparin-dependent antibody immunoglobulin that binds tolatelets, activates them, and leads to an increase in thrombocytopenia.41

oth bovine and porcine UFH as well as LMWH have been associatedith HIT, although the incidence with LMWH is less. Arterial and venous

hromboses have been reported, and even small exposures to heparinheparin coating on indwelling catheters) has been known to cause theyndrome. The diagnosis should be suspected in a patient who experi-nces a 50% or more drop in platelet count, when there is a fall in plateletount below 100,000/�L during heparin therapy, or in the presence ofhrombosis during heparin administration.42 The test of choice for makinghis diagnosis is an enzyme-linked immunosorbent assay (ELISA) thatetects the antiheparin antibody in the patient’s plasma. This test is highlyensitive but poorly specific. The serotonin release assay is another testhat can be used, but this test is more specific but less sensitive than theLISA test.43 Cessation of heparin is the most important step in

reatment. Warfarin is contraindicated in this condition until an adequatelternative anticoagulant has been established, to prevent paradoxicalhrombosis. Low molecular weight heparins demonstrate high cross-eactivity with standard heparin antibodies and therefore cannot beubstituted for standard heparin in patients with HIT. The direct thrombinnhibitors hirudin (Lepirudin/Refludan) and argatroban are the treatmentsow approved by FDA, although other agents such as fondaparinux haveeen found to treat this syndrome as well.44,45 The use of these alternativegents is given a 2C and 1C level of evidence42,44,45 (Table 1).

pecial Features of Low Molecular WeighteparinThe safety of LMWH compared with warfarin has led to a considerationf the long-term use of LMWH as a replacement for oral vitamin Kntagonists. Rates of recanalization have been reported to be higher inertain venous segments using LMWH versus traditional oral agents.dditionally the use of LMWH has been found to be improved in canceratients compared with standard heparin or LMWH/warfarin therapyhen used for 6 months without differences in major bleeding.46 Theyave also been found to provide better DVT prophylaxis compared withlacebo for extended 4-week prophylaxis in patients undergoing abdom-nal/pelvic cancer surgery.47

The use of once daily compared with twice daily LMWH dosing has
een assessed in a meta-analysis. Considering more than 1500 patients

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ith VTE, there was a nonsignificant difference in the incidence ofecurrent thromboembolism, thrombosis size, hemorrhagic events, andortality.48 However, there may be instances when twice daily dosing is

till more appropriate. These include patients with marked obesity andhose with cancer.49

lternative/Future Medical Treatments for DVT/PETwo new classes of agents for venous thrombosis treatment includeirect thrombin inhibitors and specific factor Xa inhibitors. Ximelagatrans a direct thrombin inhibitor and showed great promise to replacearfarin. However, ximelagatran caused an elevation in liver function

ests in up to 6% of patients administered the drug and because of this itas not approved in either the United States or Europe. A relative of thisrug, dabigatran etexilate, is currently undergoing phase III studies in thereatment of VTE, and has met a noninflammatory target to enaxoparin inrophylaxis for orthopedic procedures without any elevation in livernzymes or acute coronary events50 (Table 2). Other drugs with similarechanisms of action are currently being evaluated.Fondaparinux and its relative idraparinux are most like LMWH. They

arget factor Xa without inhibiting thrombin by potentiating antithrombinII. These drugs are administered subcutaneously and demonstrate aalf-life of 17 hours for fondaparinux and 80 to 130 hours for idraparinux

ABLE 2. Comparison of properties of rivaroxaban, apixaban, and dabigatran etexilate

Property Rivaroxaban ApixabanDabigatranetexilate

arget Factor Xa Factor Xa Thrombinoute of administration Oral Oral Oralrodrug No No Yesioavailability, % �80 �50 6ime to peak druglevel, h

3 3 2

alf-life, h 9 9-14 14-17requency ofadministration

Once daily Twice daily Once or twice daily

rug interactions Potent CYP3A4 andP-glycoproteininhibitors

Potent CYP3A4 andP-glycoproteininhibitors

Proton pumpinhibitors

enal excretion, % 66 25 80afe in pregnancy No No Nontidote No No No

eprinted with permission from Gross and Weitz,50 © 2008 Lippincott Williams & Wilkins.

compared with 4 hours for LMWH). These agents exhibit no endothelial


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r protein binding. However, no antidote is readily available. Neither ofhese drugs produces thrombocytopenia. Fondaparinux has been tested forhe prophylaxis of major orthopedic surgery. In a meta-analysis involvingore than 7000 patients, there was greater than 50% risk reduction using

ondaparinux begun 6 hours after surgery compared with LMWH begun2 to 24 hours after surgery.51 Although major bleeding was increased,ritical bleeding was not different. Fondaparinux has also been effectiven prophylaxis of general medical patients,52 abdominal surgery pa-ients,53 and for extended prophylaxis after hip fracture.54 Fondaparinuxas also been evaluated in the treatment of both DVT and PE. For DVTt was found equal to LMWH,55 while for PE it was found equal totandard UFH.56 This drug is administered based on body weight: 5 mger body weight �50 kg, 7.5 mg per body weight 50 to 100 kg, and 10g per body weight �100 kg. Treatment at least for 5 days with

oncurrent administration of oral anticoagulation is recommended, untilhe INR is therapeutic at a level of 2 to 3. It has been approved for thereatment of DVT/PE, thrombosis prophylaxis in total hip, total knee, andip fracture patients, and in the extended prophylaxis of hip fractureatients. Idraparinux with the longer half-life in an open label, noninfe-iority trial of 2904 DVT patients and 2215 PE patients was found to meethe noninferiority requirement of DVT, but not for PE.57 Additionally, instudy of long-term treatment in DVT/PE patients, major bleeding wassignificant problem with 3 intracranial bleeding episodes noted.57 Thus

draparinux development has been halted. However, in an attempt to developn antidote, idraparinux is being biotinylated (reversal with avidin) in a drugalled SSR 126517. Phase III trials are currently under way.58

New oral antifactor Xa agents are being developed. Rivaroxaban andpixaban are the 2 agents furthest along in development (Table 2).ivaroxaban has 66% renal excretion, whereas apixaban has only 25%

enal excretion.50,59 Rivaroxaban is in phase II trials showing good resultsn the treatment of DVT regarding symptomatic recurrences and throm-us burden,59 while apixoban is in phase II trials of patients with proximalVT and also phase III trials.50,59

Other antithrombotic agents are being evaluated including oral heparins,ther direct thrombin inhibitors such as lepirudin, bivalirudin, andrgatroban; difibrinating agents such as ancrod; anti-inflammatory agentsuch as P-selectin inhibitors; factor VIIa inhibitors; tissue factor pathwaynhibitor; and activated protein C.60,61 Lepirudin and argatroban haveeen approved for patients with HIT. The use of P-selectin inhibitors is anrea of ongoing research in our laboratory. Such an anti-inflammatory
pproach uses an antithrombotic agent that does not cause direct antico-

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gulant activities and thus the possibility of an agent without bleedingotential.

VC FiltersThe primary indications for the use of IVC filters includes a complica-

ion of anticoagulation, a contraindication to the use of anticoagulation,nd/or failure of that anticoagulation. Protection from PE has been greaterhan 95% using cone-shaped wire-based permanent IVC filters over theast 30 years.62 The success achieved with filters has expanded thendications. These include a free-floating thrombus longer than 5 cm,63

hen anticoagulation risk is excessive (ie, older patient with DVT orollowing major trauma),64 when the risk of PE is felt to be very high (asn certain bone and gastric bypass operations),65 and to allow for the usef perioperative epidural anesthesia. Filters can be permanent or optionalretrievable). If a retrievable filter is left in to become a permanent filter,ts long-term fate has not yet been defined.Filters are usually placed in an infrarenal location. However, filters may

lso be placed in either the suprarenal location or in the superior venaava in special circumstances. Indications for suprarenal placementnclude high-lying clot, pregnancy, or in a women of childbearingotential, or a previous device that has filled with clot or failed. Sepsis isot a contraindication to the use of wire-based filters since the trappedaterial can be sterilized with antibiotics. Although traditionally filters

ave been placed under x-ray guidance, percutaneous techniques for filternsertion using bedside external ultrasound or intravascular ultrasound toeduce exposure to x-rays are now being recommended. Transabdominalxternal ultrasound is ineffective in the face of morbid obesity, if there isverlying bowel gas, or if there are open abdominal wounds. In thesenstances, intravascular ultrasound has been found to be more success-ul.66 Other than 1 randomized prospective study on the use of filters asreatment of DVT (which is not how filters are traditionally used), thevidence for the use of filters is given a 2C level of evidence67 (Table 1).

onpharmacological TreatmentsPain and swelling after an above-the-knee DVT can be decreased by

pproximately 50% by the use of strong compression stockings.68

dditionally walking with good compression does not increase the risk ofE, while significantly decreasing the incidence and severity of pain andwelling after DVT.69,70 It is recommended that once patients areherapeutic on anticoagulants they ambulate while wearing compression
tockings. The use of strong compression and early ambulation after DVT

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reatment is initiated can significantly reduce the long-term morbidity ofain and swelling resulting from the DVT and carries a 1A level ofvidence68,69 (Table 1).In addition to the long-term problems related to DVT and PE, there is

n increased rate of death. In a study involving 665,248 patients from theationwide Inpatient Sample, VTE (DVT or PE) was associated with an

ncreased death rate and unfavorable discharge rate (discharge to reha-ilitation facility, nursing home, or another hospital) in those patientsriginally admitted for myocardial infarction, heart failure, pneumonia, ortroke.71 Venous thromboembolism was also associated with increasedength of stay and increased cost. Thus, VTE appears to confer a significantisk of death in addition to its adverse effects on the legs and lungs.

hrombosis Prophylaxis

ntroduction and Magnitude of the ProblemVenous thromboembolism is an enormous and poorly recognizedroblem that affects thousands of people every year and is associated withore deaths annually than breast cancer, AIDS, and accidental

eaths.72,73 More than 12 million patients, which represents 31% of USospital discharges in 2003, were at risk of VTE.74 Heit and colleaguesave estimated that 296,000 patients die yearly from fatal pulmonarymboli (PE) and one third of these individuals die in a community ratherhan hospital setting. It is noteworthy that this analysis estimated that onehird of the fatal PE events manifested as sudden death, denying anyhysician-related treatment opportunities.75 Venous thromboembolism ishe number one preventable cause of death in hospitalized patients.76

It has been estimated that 200,000 nonfatal PE events occur annuallynd 4% of those patients can be expected to develop chronic pulmonaryypertension.77 This problem may pose quality-of-life issues for thoseffected and is a long-term permanent disability.Nonfatal DVT represents a serious health issue affecting approximately75,000 patients per year.75 These patients require anticoagulants, whichan cause spontaneous bleeding and require frequent blood tests. Patientsay need to limit the intake of certain foods and drink while taking the

nticoagulants, and avoid contact sports or similar activities where injuryay result in excessive bleeding. Many of these patients will require

upport stockings to control symptoms or leg swelling and to help preventhe post-thrombotic syndrome.78 Borow and Goldson studied 500 patientsho underwent surgical procedures lasting 1 hour or more, who were
ver the age of 40 years, and who underwent postoperative fibrinogen

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canning confirmed with contrast venography. They reported that 66% ofatients who had a history of venous thrombosis developed thrombosisostoperatively. They observed that 50% of the patients with a significantedical history, including previous abdominal or leg surgery, trauma to

he lower abdomen, or leg fracture, developed postoperative venoushrombosis.79,80

One of every 3 patients following a DVT will develop post-thromboticequelae within 2 years; these sequelae are severe in approximately 20%f cases and produce considerable socioeconomic consequences.81 Symp-oms include aching, pain, or leg swelling that progresses during the daynd improves overnight with bedrest. The more severe manifestations ofost-thrombotic syndrome in the legs include skin pigmentation, rashes,r open ulcers.82 This represents a permanent disability and necessitateshe wearing of life-long compression stockings or bandages.83,84

Another important complication of DVT is a paradoxical embolus thatccurs when a clot travels to the right heart, traverses a patent foramenvale, and travels to the brain resulting in a nonhemorrhagic stroke. It haseen documented that 50% of patients presenting with a cryptogenictroke have a patent foramen ovale.85

The focus of thrombosis prophylaxis should be directed toward preven-ion of the many faces of VTE seen in Table 3. Too often clinicians focusurely on preventing clinical and fatal events rather than the entirepectrum of the disease. To evaluate all of the complications of VTE,tudies must be conducted over extended periods of time to see the full

ABLE 3. The many faces of venous thromboembolism

● Prevent fatal pulmonary emboli1% to 5% incidence in patients with �4 risk factors16.7% mortality at 3 months33% of those with pulmonary emboli present as sudden death

● Prevent chronic pulmonary hypertension4% of patients suffering PE

● Prevent clinical venous thromboembolismMorbidity, drugs, tests, hose, changes in lifestyle

● Prevent silent venous thromboembolismRisk of subsequent event doubles that of control population

● Prevent embolic stroke (20% to 30% PFO rate)50% disabled; 20% die; 30% recover

● Prevent the post-thrombotic syndrome33% incidence following DVT and 7% severeMay not be evident for 2 to 5 years

E, pulmonary embolism; PFO, patent foramen ovale; DVT, deep venous thrombosis.

amifications of the disease.86


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isk AssessmentRisk assessment as a guide to thrombosis prophylaxis is necessary since

here is not only a variety of risk factors but the relative risk of each ofhese factors is not the same.87 Heit and colleagues calculated riskstimates for individual factors in a large observational study and foundhe following results: malignant neoplasm 18%, trauma 12%, congestiveeart failure 10%, central venous catheter or pacemaker placement 9%,eurological disease with extremity paresis 7%, and superficial veinhrombosis 5%. Together, 8 risk factors accounted for 74% of all cases ofTE in their study.88 Borow and Goldson have shown that the incidencef VTE increases dramatically to more than 60% with age, or with theength of surgical procedures.79,80 Sugerman and colleagues have ob-erved increasing VTE rates in patients with a body mass index (BMI)reater than 55 and the venous stasis syndrome.89 Kroger and colleaguesave identified risk factors in the cancer patient that are associated withhe development of VTE. Hospitalization, past history of VTE, familyistory of VTE, fever, chemotherapy, and elevated C-reactive proteinCRP) were identified. In the absence of all these factors the predictedTE risk was 2.3%, increasing to 72% if all were present.90 Anderson

nd Spencer have reported that those with 4 risk factors had a 50%ncidence of VTE in their population-based studies, and the incidence was00% in individuals with 5 documented risk factors.91 We have observedhat evidence-based guidelines are applicable only for patients who fit theriteria of the clinical trials. The unique risk pattern of an individual maye such that the prophylaxis appropriate for a particular group may not beppropriate for an individual. A recent Chest consensus document haslso expressed this opinion.92 Kucher and colleagues developed a risktratification schema that identified a high incidence of imaging-provenymptomatic VTE (8.2%) in patients 90 days after hospital discharge. TheTE incidence was reduced to 4.9% using an electronic alert duringospitalization reminding the physician to consider prophylaxis.93 Wemploy a comprehensive risk assessment schema inquiring about a largeumber of risk factors that have been associated with VTE.87 A relativecore for each of these factors has been calculated based on the results ofandomized clinical trials. To simplify the process and maximize com-liance, we ask the patient to complete a straightforward medical historyorm (Fig 2). This is given to the admitting physician, physician assistant,r nurse, and the full risk assessment completed and scored (Fig 3). This
nformation is used to provide a guide to the onset, type, intensity, and

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uration of prophylaxis. The document includes an algorithm for selec-ion of prophylaxis for individual patients. We are in the process ofefining and validating this document. Zakai and colleagues have shownhis system to be valuable in identifying medical patients who are at riskor developing VTE.94

Despite these tools the utilization of prophylaxis is poor, and some feelhat until prophylaxis is mandated the percentage of patients that receive

IG 2. Patient intake risk assessment form.

ppropriate protection will remain suboptimal.


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harmacologic Methods of VTE ProphylaxisLow-dose unfractionated heparin (UFH) was the first pharmacological

gent to be widely investigated for the primary prevention of VTE inatients undergoing surgery. Kakkar demonstrated that LDH significantlyeduced the risk for both DVT and PE in general surgical patients,ncluding fatal PE.95 Thirteen years later another meta-analysis including6,000 patients has compared UFH versus no prophylaxis in surgery. Theesults of this review show that UFH significantly reduced the risk ofVT by 56% compared with no prophylaxis (relative risk [RR] � 0.44;5% confidence interval [CI] 0.37-0.52) and the risk of PE by 30% (RR �.70; 95% CI 0.53-0.93) without significantly increasing the risk ofleeding complications.96 Although no direct comparisons have beenade, in general, UFH should be administered twice daily in moderate-

isk patients, and 3 times daily in high-risk patients according to evidenceresented in the American College of Chest Physicians (ACCP) consen-us document that was just released.97 There is evidence that an increasef wound hematomas from 3.8% to 6.2% could be minimized by avoidingubcutaneous injection of heparin near to the surgical wounds.Unfractionated heparin is very effective for the prevention of DVT andE in general surgery, gynecology, and urology, but suffers from oneotentially serious complication, namely HIT in up to 5% of patientseceiving heparin. This disorder is characterized by the development ofntiplatelet antibodies and characterized by a dramatic drop in the plateletount, usually below 100,000/mm3.98 In 20% of patients suffering fromeparin-related thrombocytopenia there is thrombosis that may lead toschemic complications. One should remember that a 50% drop in thelatelet count is presumptive evidence that HIT is present. The shortalf-life of UFH (0.5-2 hours) is another limitation because it makes morerequent dosing necessary. Yet, this short half-life is an asset when theres a high risk of bleeding complications or in patients with renalmpairment. This drug can be measured with the activated partialhromboplastin time (APTT) and neutralized with protamine sulfate. UFHs widely used for cardiac and vascular surgical procedures and mostvery physician understands the drug and its clinical applications.Low molecular weight heparins (LMWHs) have been developed over

he past 25 years by chemical or enzymatic degradation of UFH resultingn an average molecular weight between 4000 and 8000 D compared with5,000 D for UFH. These LMWHs have improved bioavailability andonger half-life than UFH, and have a more predictable anticoagulant
esponse than UFH. They have become the standard for prophylaxis and

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reatment in a wide variety of clinical settings. As a result once dailynjections can be used for prophylaxis including their use in the outpatientetting. The high and consistent bioavailability coupled with an absencef heparin resistance permit using this drug without routine monitoring.he efficacy of LMWHs for the prevention of postoperative VTE haseen demonstrated in several randomized controlled trials and meta-nalyses comparing LMWHs with placebo and UFH in general sur-ery.99-101 The comparison between the 2 compounds has revealedimilar efficacy, and LMWHs, at appropriate doses, may reduce bleedingomplications in general abdominal surgery. A very large study in 23,078urgical patients demonstrated that either LMWH or UFH was associatedith a 0.15% incidence of fatal PE with a bleeding rate of less than 1.5%

n either group.102 This study coupled with the Kakkar and Collinstudies, which total 20,000 patients, demonstrate the value of UFH orMWH in nearly eliminating fatal PE in surgical patients. We would

ecommend using one of these drugs in most situations including for veryigh-risk patients that do not fit the clinical trial criteria but needrotection.Patients having abdominal operations for cancer have been studied in

everal trials employing 30 days of LMWH compared with 7 days ofrophylaxis. The results indicate a statistically significant reduction inTE in the prolonged prophylaxis groups compared with those receiving

he short course of anticoagulants.47,103

Fondaparinux is a synthetic, injectable pentasaccharide that selectivelynhibits factor Xa producing a conformational change in the antithrombinolecule. This drug has a high bioavailability and long half-life (17

ours). Only 1 case of HIT has been associated with this drug, andsteoporosis has not been observed. This drug is renally excreted andhould not be used in patients with a creatinine clearance of less than 30L/min.104

Fondaparinux has been evaluated in high-risk patients undergoingbdominal surgery and showed equivalent efficacy as the LMWHalteparin with no statistically significant differences in bleeding compli-ations.53

hysical Methods of VTE ProphylaxisPhysical and mechanical methods include graduated elastic stockings

nd intermittent pneumatic compression (IPC) of the calf alone, or calfnd thigh and impulse foot.Elastic compression stockings of the legs reduce the cross-sectional

rea of the veins and, as a result, increase the velocity of blood flow


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n the limb. It has been demonstrated that graduated compressiontockings (GCS) significantly increased the blood velocity around0% at the femoral vein during recumbence as detected by Dopplerltrasound.105 The optimal pressure profile according to these authorsonsisted of 18 mm Hg at the ankle, decreasing to 8 mm Hg in thepper thigh.

IG 3. Venous thrombosis risk factor assessment form.

It has been shown that endothelial cracking is associated with venous


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ilation and can be the beginning of a thrombus.106 Venous dilation oftenccurs due to the loss of calf muscle tone with the administration of auscle relaxant during the induction of general anesthesia.107 If the leg is

lso in a dependent position, this aggravates the stasis and can initiate the

IG 3. Continued

eginning of the thrombotic process. It has been shown that GCS can


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revent venous distension that occurs in deep veins of the leg during theourse of operation.108

The efficacy of GCS for VTE prevention has been studied in aeta-analysis involving 11 studies investigating the efficacy of GCS in

800 moderate-risk surgery patients. The results showed a significant8% reduction in the incidence of postoperative DVT in patients withtockings (OR 0.28; 95% CI 0.23-0.48; P � 0.0001).109

Seven additional randomized controlled trials in general, gynecological,rthopedic, and neurosurgical patients revealed the incidence of postop-rative DVT detected by objective diagnostic methods to be significantlyeduced from 29% in the control group to 15% in the GCS group (OR.33; CI 0.26-0.49; P � 0.0001).110 Finally in another systematic reviewf the literature in more than 2400 patients, there was a 66% reduction inhe incidence of DVT, from 21% (133 of 677) in the controls to 8.6% (57f 665) in the GCS group (P � 0.001).111

Although GCS are as effective for DVT prevention in moderate-riskurgical patients, there is a lack of data in high-risk patients includingancer or orthopedic surgery patients. There is no evidence to suggest thatCS prevents pulmonary emboli.There is no conclusive evidence regarding the use of thigh versus calf

ength stockings. Two trials comparing thigh-length and knee-lengthtockings revealed that the incidence of DVT was 8.7% (9 of 104) and.3% (9 of 108), respectively. These results are considered inconclusiveue to the small number of patients and the low DVT rate.112,113

The main limitations of GCS include the lack of international standard-zation of their pressure profiles and the difficulty to fit patients withnusual leg sizes or shapes. Patient compliance may be another limitingssue, especially with thigh-length stockings. Common reasons for non-ompliance included that stockings were not reapplied after cleaning orathing, or were removed because patients complained of itching oreat.112

Intermittent pneumatic compression is the most extensively studied ofhe mechanical methods of prophylaxis and is considered the mostffective of the mechanical methods. These devices may be singlehamber or multiple chamber, and provide uniform or sequential com-ression. One of the available devices indirectly estimates the leg venousressure and adjusts the compression cycle to these changes. Theseevices can compress the leg up to 3 times per minute.114 Anothermportant effect of IPC for VTE prevention is the stimulation ofbrinolysis and coagulation physiological inhibitors by a variety of
hanges in specific fibrinolytic parameters.115-118

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The results of IPC have been variable, but most studies show that IPCeduces the incidence of DVT in a variety of surgical procedures.oderick and colleagues identified 19 trials assessing IPC in 2255atients and showed that IPC significantly reduced the incidence of DVTrom 23.4% (268 of 1147) in the control group to 10.1% (112 of 1108) inhe IPC group, a 66% odds reduction (P � 0.0001).111 There was novidence that sequential compression devices were more protective thanniform compression machines, as their odds reductions were 65% (6rials) and 66% (12 trials), respectively. Another report of 15 trialsnvolving 2200 patients also demonstrated the efficacy of IPC for VTErophylaxis.119 The issue of whether above-knee IPC devices are moreffective than calf-length devices remains unclear in the absence ofarge-scale trials. The choice between both alternatives should be made onractical grounds, depending on their availability and cost.As with GCS, another important issue regarding IPC is compliance and

dequate implementation. Comerota and colleagues have recorded a poorompliance record for these devices and highlighted an urgent need tomprove patient and nursing staff education on the appropriate use of IPCor VTE prophylaxis to optimize implementation.120

ombination of Physical and Pharmacologic MethodsEver since the first description of the factors leading to theevelopment of a venous thrombosis, we have been searching forethods to prevent venous thromboembolism. The combination of

hysical and pharmacologic methods appears ideal as a method ofhrombosis prophylaxis.

ombination of Mechanical Methods andnticoagulantsThere are multiple randomized controlled trials that demonstrate that

he combination of GCS in addition to another prophylactic method wasignificantly more effective than GCS alone. Deep venous thrombosisas encountered in only 2% of the patients in the combined group

ompared with 15% in the control group.110 The Pulmonary Embolismrevention Trial involved a large multinational study that showed that theombination of GCS stockings plus aspirin was effective in lowering theate of fatal PE in hip fracture patients, whereas aspirin alone did not havehe same effect.121 The combination of heparin and GCS in anotherochrane analysis demonstrated superiority compared with heparin alone

ollowing colorectal surgery.122

Most studies using combined modalities involve the use of IPC in


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onjunction with various anticoagulants. Borow and Goldson showedhat using the combination of aspirin, heparin, or coumadin inonjunction with IPC resulted in a 1.5% incidence of DVT in thereated population compared with a 26.8% incidence in the controlroup.123

In one study patients undergoing total hip replacement (THR) wereandomized to IPC alone, IPC plus aspirin, or IPC plus low-dose warfarin.he incidence of ultrasound-detected VTE was 10% in each of theroups.124 Woolsen and Watt showed that the combination was not betterhan IPC although the ultrasonic endpoint and small size of the study (196atients) make it difficult to conclude that combination prophylaxis is notaluable. The effectiveness of the plantar venous plexus foot pumpombined with unfractionated heparin in patients having THR was shownn a study that revealed a 6.6% venographic DVT rate in the combinationroup compared with 27% in the nonpumped group (P � 0.025). Theuthors conclude that chemical prophylaxis plus the use of GCS stockingsnd foot pump reduces the incidence of DVT more than chemicalrophylaxis alone.125 Ramos and colleagues performed a study involving551 patients having coronary artery bypass surgery (CABG) over a0-year period. Patients received either 5000 units of UFH twice daily orn combination with long-leg sequential IPC. The incidence of imaging-roven PE was 4.0% in the heparin group and 1.5% in the combinationrophylaxis group (P � 0.001).126 A study in patients having total jointeplacement involving LMWH in combination with IPC showed 0%ltrasound-detected thrombosis compared with the group receivingMWH and compression stockings where the DVT incidence was 28.6%

40% after total knee replacement [TKR], 14% after THR) (P �.0001).127 A large orthopedic study was done in which patients wereandomized prospectively to receive either LMWH alone or in combina-ion with IPC. In the LMWH group, 15 patients (1.7%) had a DVT,ompared with 4 patients (0.4%) who had a DVT (P � 0.007) in theombined group.128 Low molecular weight heparin or aspirin in combi-ation a foot pump was studied in 275 TKR patients and the incidence ofltrasound DVT was 14.1% using LMWH and the foot pump, and 17.8%ith the aspirin and the foot pump.129 Recently a very large series ofeneral surgical patients was reported that were randomized to receiveither a placebo saline injection daily or 2.5 mg of Fondaparinux, aelective inhibitor of factor Xa, daily for 7 days. Bilateral venography onhe seventh day revealed a 5.3% DVT incidence in the saline group and
.7% in the Fondaparinux group.130 All of this evidence supports the

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oncept that combined modalities provide superior DVT preventionompared with any single thrombosis prophylaxis modality.

urrent Recommendations for Combined ProphylaxisThe newly released 8th ACCP recommends IPC as an option in

onjunction with heparin or LMWH in patients in the highest riskategory for VTE. The combination of mechanical methods and thesenticoagulants is listed as a grade 2A suggestion97 (Table 1).Recently Amin and colleagues performed a database review of data

rom 227 hospitals over a 3.5-year period involving nearly 200,000atients looking at thrombosis prophylaxis rates in US hospitals. Theseuthors found the thrombosis prophylaxis rate was 66.8%, and only3.9% received appropriate prophylaxis according to Chest guidelines.131

t was observed that 26.8% of the patients received mechanical prophy-axis alone in cases in which there was no contraindication because ofleeding. Inappropriate prophylaxis postdischarge was noted in two thirdsf the patients, including 4.7% who received mechanical prophylaxislone.

hrombosis Prophylaxis in the Real WorldSixteen years ago we surveyed 3500 North American general surgeons

nd noted that some form of thromboprophylaxis was used 86% of theime. The most frequently used modalities were IPC, low-dose heparin,nd elastic stockings. A combination of physical and pharmacologicethods was used by one fourth of respondents, and only 50% started

harmacologic prophylaxis before the surgical procedure. The thrombosisisk factors that are most frequently considered by surgeons wheneciding about using prophylaxis are history of VTE, immobility, andength of operation.132 Seven years later a follow-up survey was sent to0,000 general surgeons and 1145 responses were received. ConventionalFH at fixed doses remains the preferred pharmacological agent for VTErevention (74%), followed by 2 LMWHs: enoxaparin (34%) andalteparin (16%). Overall, 52% of surgeons preferred physical methodsver pharmacological methods when used separately and 26% of sur-eons utilize combined physical-pharmacological modalities. A largeultinational cross-sectional study in more than 68,000 patients repre-

enting 352 hospitals in 32 countries was recently published. Theercentage of patients that received appropriate prophylaxis according tovidence-based guidelines was 40% in medical patients and 59% inurgical patients (Table 4).133 The Global Orthopedic Registry recently
ublished by Warwick and colleagues shows more encouraging results.

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here were 15,000 patients in the registry and 95% of these individualseceived anticoagulant or mechanical prophylaxis following joint replace-ent procedures. LMWH prophylaxis was popular outside of the Unitedtates and combined with IPC 11% to 17% of the time. This combinationas used in nearly 25% of American patients. Warfarin use was rareutside the United States; however, it was combined with IPC approxi-ately 33% of the time in the United States.134 Amin and colleagues have

eported a database review from 227 hospitals involving 200,000 patientsooking at thrombosis rates in American hospitals.131 Overall thesenvestigators found the thrombosis prophylaxis rate was 66.8%, with only3.9% conforming to Chest guidelines. This study highlights two remain-ng serious problems regarding thrombosis prophylaxis. There are stillery substantial numbers of patients not being protected and even whenome form of prophylaxis is used, it does not conform to evidence-baseduidelines.

ggressive Therapies for Acute DVT and PEThe term “aggressive treatment” gives the connotation that it is out of

he ordinary or unusual. For the purpose of this discussion, aggressive isefined as adopting a strategy of thrombus removal before long-termnticoagulation, rather than accepting the existing venous thrombosis ormbolic pulmonary occlusion and treating the patient with anticoagula-ion alone, thereby accepting all of the post-thrombotic or embolicorbidity that accompanies iliofemoral DVT and pulmonary embolism

PE).Studies have shown that patients with post-thrombotic syndrome have a

ignificant reduction in their quality of life.135,136 The severity of thecute venous thrombotic event is predictive of the degree of post-hrombotic morbidity. This is especially true in patients with iliofemoralVT.Iliofemoral DVT is a clinically relevant subset of patients with acuteenous thrombosis who suffer severe post-thrombotic morbidity.137-139

ABLE 4. ENDORSE Registry133

Medical Surgical

No. of patients 37,356 30,827At risk for VTE 42% 64%Receiving ACCP Tx 40% 59%

TE, venous thromboembolism; ACCP, American College of Chest Physicians; Tx, treatment.

inety percent of iliofemoral DVT patients who are treated with


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nticoagulation alone will have ambulatory venous hypertension, result-ng in severe chronic venous insufficiency. Up to 40% will haveymptoms of venous claudication, and within 5 years, 15% developenous ulceration. The adverse impact on quality of life is evident. Thisiscussion reviews the body of evidence demonstrating that a strategy ofhrombus removal is the preferred management for patients with iliofem-ral DVT and offers the best long-term outcome.140,141

In general, avoiding pathophysiology or minimizing pathophysiologicisturbances offers patients the best chance of a favorable outcome. Theathophysiology of post-thrombotic venous disease is ambulatory venousypertension, defined as an elevated venous pressure during exer-ise.142,143 Nicolaides and colleagues143 and Welkie and colleagues144

ave demonstrated that ambulatory venous pressure is directly linked tohe clinical manifestations observed with chronic venous disease, such aswelling, pigmentation, and lipodermatosclerosis. Long-standing venousypertension has a significant effect on the microcirculation, which canesult in dermal breakdown.Two pathologic anatomic components contribute to ambulatory venousypertension: venous valvular incompetence and obstruction of the veinumen. The most severe post-thrombotic morbidity is associated with theighest venous pressures, which occur in patients with combined valvularncompetence and luminal obstruction.142,143,145 It is intuitive that ifhrombus is removed and patency restored, obstruction cannot be part ofhe underlying pathophysiology. Long-term studies of acute DVT haveemonstrated that early thrombus resolution preserves valve function.146

herefore, early thrombus removal in patients with extensive venoushrombosis eventually eliminates the underlying pathologic conditionseading to ambulatory venous hypertension and has the potential ofaintaining normal venous physiology.

vidence Supporting an “Aggressive” ApproachThere is a spectrum of evidence supporting a strategy of thrombus

emoval in patients with acute DVT. Although small segmental thrombiay be well tolerated in many patients without significant post-throm-

otic morbidity, typically in the femoral vein of the mid thigh, patientsith extensive DVT, especially those with iliofemoral thrombosis, willave severe post-thrombotic morbidity if treated with anticoagulationlone. Data are available from experimental observations in animalodels,147,148 long-term follow-up studies in patients with acute DVT

reated with anticoagulation alone,146,149,150 clinical reports of large
atient series,151-153 and randomized trials.154-157 The aggregate data

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verwhelmingly demonstrate that patency can be restored, vein wall andalvular function can be maintained, and post-thrombotic morbidity cane reduced if thrombus is successfully eliminated, intrinsic vein pathol-gy (stenosis) corrected, and long-term therapeutic anticoagulation main-ained to avoid rethrombosis.

trategies of Thrombus RemovalStrategies of thrombus removal have not been widely accepted by theedical community. In large part, this is the result of international

uidelines recommending against catheter-directed thrombolysis andperative venous thrombectomy.158 Unfortunately, authors of these in-uential guidelines focused on outdated information published manyecades earlier and overlooked contemporary randomized trials.Treatment approaches that have adopted venous thrombectomy and

atheter-based thrombolytic therapy have demonstrated significantly bet-er outcomes compared with patients treated with anticoagulation alone.The underlying principles are similar whether one employs an operativer percutaneous approach. The initial goal is to eliminate all acutehrombus followed by correction of underlying venous pathology andherapeutic anticoagulation to avoid rethrombosis.

reatment Options and Patient EvaluationAn important part of the initial evaluation of patients with iliofemoralVT is a CT scan of the head, chest, abdomen, and pelvis. Martinez andomerota159 reported their CT scan findings in patients presenting with

liofemoral DVT. In addition to finding asymptomatic pulmonary embolin 50% of patients and assessing the proximal extent of thrombus, theyound an undiagnosed malignancy in 79% of patients with idiopathicliofemoral DVT. Since iliofemoral DVT is generally the result of anggressive thrombotic stimulus, it is not surprising that a large proportionf idiopathic patients are found to have an underlying malignancy.lthough chest, abdomen, and pelvic CT scans have been a routine partf the evaluation of iliofemoral DVT patients at Jobst Vascular Center forhe past several years, a head CT is now added to rule out intracranialathology.Contemporary venous thrombectomy is generally available to allatients where vascular surgeons practice. There are few contraindica-ions to operative thrombectomy, especially when the thrombus is lesshan 10 days old. Treatment goals are straightforward: to removehrombus in the iliofemoral and infrainguinal venous segments and
estore unobstructed venous return into the vena cava. Knowing the full

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xtent of thrombus preoperatively and having good imaging intraopera-ively is imperative for a well-planned and successful procedure.Catheter-directed thrombolysis is the preferred treatment option forost patients who have no contraindications to thrombolytic therapy.djunctive mechanical techniques are becoming increasingly popular and

end to shorten treatment time and reduce the dose of plasminogenctivator.A frequent concern of physicians is the risk of procedure-related PE.he patients at highest risk of procedure-related PE are those withonocclusive thrombus in their vena cava. Therefore, it is important tomage the proximal and distal extent of thrombus and particularly themount and level of vena caval involvement. This will assist in theecision whether vena caval filtration or other forms of embolic protec-ion (eg, balloon occlusion) are used (Fig 4).The traditional contraindications to the use of thrombolytic agents are

oftened by direct intrathrombus infusion and the use of adjunctiveechanical techniques. If the dose of lytic agent can be reduced and the

uration of therapy shortened, the risk of a systemic lytic effect iseduced, since circulating plasminogen activator inhibitors and antiplas-ins neutralize the effect of plasminogen activators and plasmin that

scape into the systemic circulation.

perative Venous ThrombectomyContemporary venous thrombectomy for iliofemoral venous thrombosisas been shown to be effective in both the short and the longerm.154,155,160 The largest report of operative venous thrombectomyailed to show fatal PE and reported only 1 operative death.161 Theong-term benefits of venous thrombectomy relate to its ability to achieveroximal patency and maintain distal valve competence. Both outcomesre influenced by the initial technical success and the avoidance ofecurrent thrombosis. Therefore, attention to operative detail in terms ofomplete thrombus removal, correcting underlying venous stenoses, andaintaining therapeutic anticoagulation postoperatively are crucial.ooled data from a number of contemporary reports on iliofemoralenous thrombectomy (Table 5154,162-173) demonstrate that early andong-term patency of the iliofemoral venous segment is 70% to 80%ompared with 30% of patients treated with anticoagulation alone.139

emoropopliteal venous valve function is preserved in the majority ofatients. The Scandinavian investigators reported their randomized trialutcomes of operative venous thrombectomy versus anticoagulation
lone in patients with iliofemoral venous thrombosis.154-156 Patients

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nderwent complete follow-up evaluation at 6 months, 5 years, and 10ears. They showed that those randomized to venous thrombectomy hadmproved iliac vein patency (P � 0.05), lower venous pressures (P �

IG 4. A young man with an acute gastrointestinal bleed from Crohn’s colitis developed a painful,wollen left leg with bluish discoloration (phlegmasia cerulea dolens). Venous duplex documentedcute thrombus extending from the distal femoral vein into the external iliac vein. A contralateral

liocavagram was performed to evaluate the vena cava, which demonstrated a sizable amount ofonocclusive thrombus extending into the vena cava (A). In preparation for his operative venoushrombectomy, a caval occlusion balloon was positioned under fluoroscopy from the right commonemoral vein and was inflated during the iliocaval thrombectomy (B, C). The entire proximal and distalhrombus was removed intact (D, E). (Reprinted with permission from Comerota and Gale.174) (Colorersion of figure is available online.)

.05), less leg edema (P � 0.05), and fewer patients with post-thrombotic


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yndrome (P � 0.05) compared with patients treated with anticoagulationlone. Table 6 briefly summarizes the general aspects of the contemporaryenous thrombectomy. Specific operative detail has been published byomerota and Gale.174,175

atheter-Directed ThrombolysisEarly attempts of pharmacologic clot dissolution of acute venous

hrombosis used systemic delivery of plasminogen activators. Althoughhe results demonstrated reduced post-thrombotic morbidity, the highoses of plasminogen activators resulted in higher rates of bleeding

ABLE 5. Long-term results of venous thrombectomy with arteriovenous fistula: iliac vein patency andemoral-popliteal valve competence

No. of reports PatientsFollow-up

(mos) (mean)Iliac veinpatency

Femoral-poplitealvalve competence

1154,162-171 702 41 78% —154,163,165,169,170,172,173 352 45 — 63%

ABLE 6. Technique of contemporary venous thrombectomy

1. Identify etiology of extensive venous thromboembolic processa. Complete thrombophilia evaluationb. Rapid CT scan of head, chest, abdomen, and pelvis

2. Define full extent of thrombusa. Venous duplex examinationb. Contralateral iliocavagram, MRV, or spiral CT

3. Prevent pulmonary embolism (numerous techniques)a. Anticoagulationb. Vena caval filter (if nonocclusive caval clot)c. Balloon occlusion of vena cava during thrombectomyd. Positive end-expiratory pressure during thrombectomy

4. Perform complete thrombectomya. Iliofemoral (vena cava) thrombectomyb. Infrainguinal venous thrombectomy (if required)

5. Ensure unobstructed venous inflow to and outflow from thrombectomized iliofemoralvenous systema. Infrainguinal venous thrombectomy (if required)b. Correct iliac vein stenosis (if present)

6. Prevent recurrent thrombosisa. Construct arteriovenous fistula (3.5- 4 mm)b. Continuous therapeutic anticoagulationc. Catheter-directed postoperative anticoagulation (if infrainguinal venous

thrombectomy is required)d. Extended oral anticoagulation

RV, magnetic resonance venography; CT, computerized tomography.eprinted with permission from Comerota and Gale.175

omplications.176 Many patients in these studies were treated for infrain-


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ABLE 7. Review of studies of catheter directed thrombolysis for acute DVT

Author, year

Total no.of patients

(limbs) Intervention

emba et al,180 1994 21 (27) CDT with UK, angioplasty/stenting forresidual stenosis

emba et al,181 1996 32 (41) CDT with UK, angioplasty/stenting forresidual stenosis

erhaeghe et al,182 1997 24 CDT with rt-PA, stenting for residual stenosisjarnason et al,151 1997 77 (87) CDT with UK, angioplasty, stenting,

thrombectomy, bypass for residualstenosis

ewissen et al,152 1999 287 (312) CDT with UK, stenting for residual stenosis;systemtic lysis (n � 6)

omerota et al,153 2000 54 CDT with UK or rt-PA, thrombectomy forresidual stenosis

orne et al,183 2000 10 CDT with rt-PAasirajan et al,184 2001 9 CDT with UK, rt-PA, or rPAbuRahma et al,185 2001 51 CDT w/UK or rt-PA, stents/18 Hep/33

edantham et al,186 2002 20 (28) CDT with UK, rt-PA, or rPA, thrombectomy,stenting

lsharawy et al,157 2002 35 CDT w/SK, angio, stent/18 Hep/17

astaneda et al,187 2002 15 CDT with rPArunwald et al,188 2004 74 (82) CDT with UK, tPA, or rPA, angioplasty,

stentingaiho et al,189 2004 32 CDT with rt-PA/16

Systemic lysis with rt-PA/16illesen et al,190 2005 45 CDT with rt-PA, angioplasty, stentingackson et al,191 2005 28 CDT with UK or rPA, stentinggawa et al,192 2005 24 CDT with UK/10

CDT with UK � IPC/14im et al,193 2006 37 (45) CDT with UK/23

CDT � PMT/14in et al,194 2006 93 (98) CDT with rPA, rt-PA, or UK, angioplasty,

stenting/46PMT with rPA, rt-PA, or UK, angioplasty,

stenting/52rotack et al,195 2007 69 CDT with UK, tPA, retavase, pulse-spray,

mechanical thrombectomy, stenting, IVCfilters

oldenberg et al,196 2007 22 CDT and/or systemic lysis with mechanicalthrombectomy/9

Anticoagulation alone/13

DT, catheter-directed thrombolysis; Hep, heparin; IPC, intermittent pneumatic compression;VC, inferior vena cava; NR, not reported; rPA, recombinant plasminogen activator; PMT,harmacomechanical thrombolysis; rt-PA, recombinant tissue plasminogen activator; tPA,issue plasminogen activator; UK, urokinase.
eprinted with permission from Comerota and Gravett.140

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Results Complications

Significant/completeresolution

(%)

Partialresolution

(%)

Noresolution

(%)

Bleeding

Minor(%)

Major(%) PE

Death dueto Rx (%)

18 (72) 5 (25) 2 (8) 1 (4) 0 (0) None None

21 (32) 9 (28) 2 (6) 0 (0) 0 (0) None None

19 (79) 5 (21) 0 (0) 0 (0) 6 (25) None None69 (79) 0 (0) 18 (21) 11 (14) 5 (6) 1 None

96 (31) 162 (52) 54 (17) 15 (28) 54 (11) 6 2 (�1)

14 (26) 28 (52) 6 (11) 8 (15) 4 (7) 1 None

9 (90) 1 (10) 0 (0) 3 (30) None 2 (20) None7 (78) 1 (11) 1 (11) NA NA NA NA

15 (83)1 (3)

NRNR

NRNR

3 (17)3 (9)

2 (11)2 (6)

None2 (6)

NoneNone

23 (82) NR NR None 3 (14) None None

13 (72)2 (12)

5 (28)8 (47)

0 (0)7 (41)

NoneNone

NoneNone

NoneNone

NoneNone

15 (100) NR NR None None None None54 (73) 26 (32) NR 6 (8) 4 (5) None None

8 (50) 5 (31) NR 4 (25) 2 (13) 2 (13) None5 (31) 8 (50) NR 6 (38) 1 (6) 5 (31) None

42 (93) NR NR 4 (8) None 1 (2) None5 (18) 20 (72) NR 2 (7) None None None0 (0) 10 (100) None None None None None5 (36) 9 (64) None None None None None

21 (81) 3 (11) 2 (8) 1 (4) 2 (7) 1 (4) None16 (84) 3 (16) None None 1 (5) 1 (5) None32 (70) 14 (30) 5 (11) 2 (4) 1 (2) None None39 (75) 13 (25) 4 (8) 2 (4) None None None

40 (63) 19 (30) 4 (6) None None None None

8 (89) NR NR 1 1 None None5.5 (42) NR NR


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uinal DVT; therefore, even when lytic therapy was successful, thelinical benefits were not as apparent as with patients with iliofemoralenous thrombosis.However, important observations were made in randomized trials.atients successfully treated with intravenous thrombolytic therapy had aignificantly better chance of preserving normal vein valve function andnjoyed reduced post-thrombotic morbidity.177-179

Delivery of thrombolytic agents into the thrombus results in higher ratesf clot dissolution, shorter treatment times, and reduced bleeding com-lications. Many reports have documented good outcomes of catheter-irected thrombolysis for acute DVT. Most of these reports are listed inable 7,151-153,157,180-196 which also includes pharmacomechanical tech-iques used as adjuncts to catheter-directed thrombolysis. Generally,uccess rates in the 75% to 90% range can be anticipated. Bleedingomplications have been reported in up to 11%; however, in the majorityf the reports published within the past 6 years, bleeding complicationsre 5% or less. Symptomatic PE during thrombolytic infusion is uncom-on and fatal PE is a rarity.The National Venous Registry is the largest report to date of patients

reated with lytic therapy for acute DVT. It is hampered with theeficiencies of nonrandomization and the biases of patient selection.owever, the authors reported a significant correlation of thrombus-free

urvival with the results of initial therapy (P � 0.001). At 1 year, 78% ofatients who initially had complete clot resolution had patent veinsompared with only 37% of patients who had less than 50% lysis. Inatients with first-time iliofemoral DVT who had initially successful clotysis, 96% remained patent at 1 year. Initial lytic success also correlatedith valve function at 6 months. Sixty-two percent of patients with less

han 50% thrombolysis had venous valve incompetence, whereas 72% ofatients who had complete lysis had normal valve function (P � 0.02).A quality-of-life (QOL) study was published demonstrating that suc-

essful thrombolysis for patients with iliofemoral DVT resulted in aignificantly improved quality of life compared with a control cohort ofatients treated with anticoagulation alone.153 A randomized trial per-ormed by Elshawary and Elzayat157 compared catheter-directed throm-olysis with anticoagulation alone in patients with iliofemoral DVT.atients treated with thrombolysis had considerably better outcomes at 6onths, demonstrating improved patency and vein valve function.The above data are a compelling argument for catheter-directed throm-olysis. Larger randomized trials are required to establish definitive
ecommendations for care. Fortunately, 2 large trials are under way that

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ill randomize patients with acute DVT to catheter-directed thrombolysisersus anticoagulation alone,197,198 evaluating anatomic, physiologic, andlinical endpoints.

harmacomechanical ThrombolysisAlthough good results have been reported with catheter-directed throm-olysis, treatment times are often long and doses of plasminogenctivators often high to successfully complete a course of therapy. Thisas dampened the enthusiasm of many physicians. Sillesen and col-eagues190 reported that 93% of their patients were successfully treatedith catheter-directed thrombolysis and that 90% of their patients whoere discharged with patent veins had normal venous valve function at 1ear. However, they reported an average treatment time for catheter-irected thrombolysis of 71 hours. This duration of acute care isogistically difficult for many practitioners and medical centers. Thessociated cost of care is high, especially when considering that all

IG 5. A 32-week pregnant woman presented with left leg pain and swelling of 3 days’ duration. Aenous duplex examination suggested external iliac and common iliac vein thrombosis, confirmedith ascending phlebography (A). Isolated segmental pharmacomechanical thrombolysis waserformed with a Trellis catheter using 3 mg recombinant tissue plasminogen activator (rt-PA). The

hrombus was eliminated, demonstrating stenosis of the left common iliac vein (May-Thurner). The leftommon iliac vein was dilated and stented (B), resulting in unobstructed venous drainage into the venaava (C). The patient subsequently delivered a healthy infant boy and was asymptomatic with normalenous function 1 year later.

atients receiving lytic therapy are monitored in intensive care units.


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IG 6. Treatment algorithm for patients with iliofemoral deep venous thrombosis. (Color version of
gure is available online.)
ABLE 8. Evidence-based recommendations for the aggressive treatment of patients with iliofemoralVT15,201

Recommendation Grade

n patients with extensive (iliofemoral) DVT, operative venous thrombectomy maybe used to reduce acute symptoms and post-thrombotic morbidity

2B

ollowing venous thrombectomy, the same duration and intensity ofanticoagulation should be used as in those who do not undergothrombectomy

1C

n patients with extensive proximal DVT and low risk for bleeding, CDT can beused to reduce acute symptoms and post-thrombotic morbidity

2B

harmacomechanical thrombolysis should be considered in preference to CDTalone

2C

ollowing CDT, underlying venous lesions should be corrected 2Collowing CDT, the same intensity and duration of anticoagulation should beused as those who are not treated with CDT

1C

atients with acute DVT should be treated with a 30-40 mm Hg compressionstocking to reduce post-thrombotic morbidity

1A

VT, deep venous thrombosis; CDT, catheter-directed thrombolysis.


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IG 7. Patient being treated for a gastrointestinal bleed with sudden shortness of breath, tachycardia,nd drop in blood pressure (A). Pulmonary arteriogram showed large PE of the left main pulmonaryrtery. Following treatment with pulse-spray infusion of thrombus with 6 mg of recombinant tissuelasminogen activator (rt-PA) and catheter-based fragmentation, patient’s clinical condition improved,
xygenation improved, and subsequent cardiac echo was normal (B).urr Probl Surg, December 2008 879

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Percutaneous mechanical techniques alone or in combination withhrombolysis have been developed to more rapidly clear the venousystem. Vedantham and colleagues198 evaluated the effectiveness ofechanical thrombectomy alone or in combination with pharmacologic

hrombolysis in 28 limbs of patients with acute DVT. They used a varietyf mechanical devices and catheters. They found that mechanical throm-ectomy alone was successful for removing thrombus that developedntraprocedurally (which is generally gelatinous and not cross-linked withbrin). However, in the remaining patients, only 26% of the thrombusas removed by mechanical thrombectomy. The addition of a plasmin-gen activator solution to the mechanical technique removed 82% of thehrombus. This underestimates the benefit to patients with acute DVT,ince these authors included patients with chronic occlusions who did notespond to treatment.Several reports have recently surfaced documenting the benefits of

ombined pharmacomechanical thrombolysis. Martinez and colleagues199

eported the outcome of patients with iliofemoral DVT treated initiallyith isolated segmental pharmacomechanical thrombolysis (ISPMT)ersus catheter-directed thrombolysis. Isolated segmental pharmacome-hanical thrombolysis was associated with better success rates, shorterreatment times, and lower doses of plasminogen activators (Figs 4, 5).Lin and colleagues194 reported their 8-year experience with rheolytic

hrombectomy. Patients treated with the AngioJet catheter had signifi-antly fewer phlebograms, shorter intensive care unit (ICU) stays, shorterospital stays, and fewer blood transfusions. A smaller group of patients

ABLE 9. Review of studies of mechanical thrombectomy catheters for PE

Catheter typeTotal no.patients

ConcurrentCDT (%)

Results

Completeresolution

(%)

Partialresolution

(%)

Noresolution

(%)

reenfield219-227 108 19 (18) 82 (76) 8 (7) 9 (8)

heolytic (AngioJet)228-234 70 29 (41) 65 (93) 0 2 (3)igtail235-248 175 169 (97) 156 (89) 1 (0.6) 0mplatz249-251 15 7 (47) 14 (93) 0 0ydrolyser252-254 20 20 (100) 19 (95) 0 0rrow-Trerotola255 15 0 0 1 (7) 0ang256 3 0 0 3 (100) 0otals 406 244 (60) 336 (83) 13 (3) 11 (3)

E, pulmonary embolism; MI, myocardial infarction; CDT, catheter-directed thrombolysis.

reated by Kasirajan and colleagues184 reported that rheolytic thrombec-


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omy alone was less effective than combined pharmacomechanicalhrombolysis.Parikh and colleagues200 reported their initial clinical experience withltrasound-accelerated thrombolysis in both upper and lower extremityVT. Complete lysis was observed in 70% of patients and overall lysis

n 91%. The median infusion time was 22 hours and 4% had majoromplications. These results, compared with historical controls of cath-ter-directed thrombolysis, suggest an advantage to ultrasound-acceler-ted thrombolysis. It is this author’s opinion that each device may have aarticular advantage in a given clinical situation and that a combination ofechniques may be required in a given patient’s scenario.

ummary: Iliofemoral DVTThe aggregate information on operative venous thrombectomy, cathe-

er-directed thrombolysis, and pharmacomechanical thrombolysis forliofemoral DVT demonstrate substantial benefits for patients treated withstrategy of thrombus removal. A treatment algorithm for patients with

liofemoral DVT is presented in Fig 6.The recent ACCP consensus conference on antithrombotic therapy forenous thromboembolic disease has reviewed the existing evidence forhe management of patients with iliofemoral DVT and incorporatedecommendations for care. These evidence-based recommendations areummarized in Table 8.201

ggressive Treatment for Pulmonary EmbolismAnticoagulation is the recommended management for the majority of

Complications

Bleeding

Other DescriptionDeath due to

Rx (%)Minor (%) Major (%)

0 1 (0.9) 16 (15) Renal failure, pulmonary infarct, MI,pleural effusion, thrombocytopenia

8 (7)

0 10 (14) 4 (6) Heart block, thrombocytopenia 8 (11)2 (1) 2 (1) 2 (1) Cardiac arrest, catheter problems 6 (3)0 0 0 00 0 0 2 (10)0 0 0 00 0 0 02 (0.5) 13 (3) 22 (5) 24 (6)

atients with acute PE. However, patients with large pulmonary emboli


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8

ausing hemodynamic instability or pulmonary hypertension associatedith right heart abnormalities benefit considerably by restoring normalutflow from the right ventricle.202 Ideally, the goal of therapy in patientsith large pulmonary emboli is to improve/restore normal cardiopulmo-ary hemodynamics, thereby avoiding chronic thromboembolic pulmo-ary hypertension with its associated morbidity and mortality. Pengo andolleagues77 reported that within 2 years of a first episode of PE, almost% of patients developed chronic thromboembolic pulmonary hyperten-ion. Unquestionably, this percentage will increase in patients with largeulmonary emboli. Chronic thromboembolic pulmonary hypertension isssociated with recurrent PE, younger age at onset, large perfusionefects, and idiopathic PE. Pulmonary emboli that cause right ventricularysfunction are associated with a 6-fold increase in hospital mortality and.4-fold increase in 1-year mortality following discharge.203 Surgicalulmonary embolectomy can reduce thromboembolic pulmonary hyper-ension. The operative mortality rate for pulmonary thromboembolectomyor massive PE has diminished, with contemporary reports indicating thathere remains a definitive role for operative pulmonary embolectomy inatients who do not have other options to open their occluded pulmonaryrteries.204,205

Intravenous infusion of thrombolytic agents decreases mortality, im-roves right ventricular function, improves pulmonary function, andecreases chronic thromboembolic pulmonary hypertension as well aseducing recurrent venous thromboembolic disease206-217 (Fig 7). Gold-aber and colleagues202 showed rapid improvement in right ventricularunction, reduction in end diastolic right ventricular area, improvedulmonary perfusion, and reduction in recurrent PE when patients werereated with recombinant tissue plasminogen activator (rt-PA) comparedith heparin. Konstantinides and colleagues218 reported the results of a

arge international PE registry and showed that 30-day mortality wasower in patients receiving lytic therapy and that primary thrombolysisas the only independent predictor of survival on multivariate analysis.owever, not all patients with major pulmonary emboli are candidates for

ystemic thrombolytic therapy. Several authors have recently reportedmproved outcomes in patients treated with catheter-based thrombusspiration, maceration, fragmentation, and power-pulse infusion of plas-inogen activators175,219-256 (Table 9).Improvements in catheter-based techniques, with power-pulse infusionf plasminogen activators into proximally occluding pulmonary emboliith mechanical fragmentation, rapidly reduce pulmonary hypertension,

hereby improving patient oxygenation and cardiopulmonary hemody-


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amics (Fig 8). Lower doses of plasminogen activators pulsed into thehrombus promote subsequent lysis of the fragmented thrombus trappedn the proximal pulmonary artery as a result of the plasminogen activatorinding to fibrin-bound plasminogen.

ummary: Pulmonary EmbolismPatients with pulmonary emboli that raise pulmonary artery pressures to

he point of affecting right ventricular function have a markedly increasedarly and long-term mortality, increased risk of recurrence, and increasedisk of chronic thromboembolic pulmonary hypertension. All patientsith PE should undergo cardiac echocardiography to assess pulmonary

rtery pressure and right heart function. Patients with abnormalities ofight heart function should be considered for systemic thrombolytic

IG 8. Treatment algorithm for patients with pulmonary embolism. (Color version of figure is availablenline.)

herapy or catheter-based fragmentation with thrombolysis or operative


p(

8

ulmonary embolectomy, as suggested by the PE management algorithmFig 8).201

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Thromboembolic Diseases - Area-c54.it diseases.pdf · Thromboembolic Diseases Incidence, Risk Factors, and Categories Deep venous thrombosis (DVT) and pulmonary embolism (PE), together