Thrombosis and thromboembolism - part 7 potx

In a case-control study at Leiden University, women withthe factor V Leiden mutation who used oral contraceptives were at a 35-foldgreater risk of VTE than controls 40.. Heit JA, Silvers

Data from the Danish National Registry of Patients were used to investigate therisk of a diagnosis of cancer following the detection of VTE not associated with

Venous Thromboembolism 217

Figure 3 Cumulative probability of newly diagnosed cancer after a first VTE episode,according to whether the VTE was idiopathic or nonidiopathic (Reprinted with permissionfrom Ref 35.)

surgery, known cancer, or pregnancy (34) There was a 30% increased risk of adiagnosis of cancer among those with newly detected VTE The risk was substan-tially elevated only during the first 6 months of follow-up and declined rapidlythereafter Of those diagnosed with cancer within 1 year after the initial VTEhospitalization, 40% had distant metastases at the time of the cancer diagnosis.The association between cancer and VTE was most pronounced for cancers ofthe pancreas, ovary, liver (primary hepatic cancer), and brain

In the Swedish Cancer Registry, the risk of diagnosed cancer after a firstepisode of VTE was elevated during at least the following 2 years (35) Thestandardized incidence ratio for newly diagnosed cancer was 3.4 during the firstyear after VTE and remained between 1.3 and 2.2 for the following 5 years Ofthe 854 patients with VTE, 534 had idiopathic VTE occurring in the absence ofsurgery, trauma, temporary immobilization, or oral contraceptive use These werethe patients in whom the association between VTE and the subsequent diagnosis

of cancer was apparent (Fig 3)

A Generations of Oral Contraceptives

First-generation oral contraceptives contained more than 50µg of estrogen andwere associated with an alarming increase in the frequency of VTE, especially

218 Goldhaber

massive PE Second-generation oral contraceptives contain less than 50µg andwere introduced in the United States in 1967 Eventually, in 1989, first-generationpills were withdrawn from the market

Third-generation oral contraceptives utilize the new progestogens, trel or gestodene They cause acne and hirsutism less often and have a morefavorable effect on carbohydrate metabolism and lipid profiles than second-gener-ation pills Ironically, they are associated with a doubling or tripling of the VTErate compared with second-generation oral contraceptives (36,37) The explana-tion for this surprising finding is that third-generation oral contraceptives lead toacquired resistance to activated protein C, thus creating an effect similar to thefactor V Leiden mutation (38)

desoges-Despite the high relative risk of VTE from oral contraceptives, the absoluterisk is low A New Zealand study of oral contraceptives and fatal PE estimatedthe absolute risk of death from PE in current users as 1 per 10.5 million woman-years In this study, the risk of fatal PE was double among those taking third-generation pills (39)

B Oral Contraceptives and Thrombophilia

Oral contraceptives and thrombophilia appear to interact synergistically to crease the risk of VTE In a case-control study at Leiden University, women withthe factor V Leiden mutation who used oral contraceptives were at a 35-foldgreater risk of VTE than controls (40) In a subsequent analysis from the LeidenThrombophilia Study, which included cases with factor V Leiden, protein C or

in-S deficiency, the prothrombin gene 20210 A mutation, and antithrombin-III ciency, the overall risk of developing DVT during the first 6 months of oralcontraceptive use was increased 19-fold in thrombophilic women compared withcontrols (41)

defi-Whether women with a family history of VTE but no personal past history

of VTE should be screened prior to oral contraceptive use is controversial Forwomen with known thrombophilia but no prior VTE, the safest policy is to usealternative forms of contraception However, no definitive ban on using oral con-traceptives can be justified in this setting because the absolute risk of VTE re-mains very low

PE is the leading cause of maternal death in the United Kingdom Beginning inthe 1980s, the number of fatal PEs began to increase, especially following vaginaldelivery In the mid-1990s, about two-thirds of the fatal PEs classified as maternaldeaths occurred postpartum, with cesarean section accounting for approximatelyhalf of these catastrophic events (42)

Venous Thromboembolism 219

Two-thirds of DVT occur during pregnancy, and the remainder occur partum The risk of DVT is present throughout pregnancy and increases duringthe third trimester Of all antepartum DVT, about one-fifth occur during the firsttrimester, one-third during the second trimester, and almost one-half during thethird trimester (43) After delivery, two of the most important risk factors for VTEare increased maternal age and cesarean section Emergency cesarean section in-creases the VTE risk by about 50% compared with elective cesarean section.Thrombophilia increases the risk of VTE during pregnancy and the puerpe-rium In a control study, the prevalence of factor V Leiden was 44% among womenwith a history of VTE during pregnancy or the puerperium, and the prevalence ofthe prothrombin gene mutation was 17% Compared with controls, the Leiden mu-tation increased the risk of VTE ninefold, and the prothrombin gene mutation in-creased the risk by a factor of 15 The combination of the Leiden and prothrombingene mutations virtually multiplied the risk, estimated to be 107 times greater thancontrol Fortunately, the absolute risk of VTE among carriers of each mutationwas low: 0.2% for Leiden and 0.5% for the prothrombin gene However, amongthose few women with both thrombophilic mutations, the absolute risk soared to4.6% (44) Regardless of factor V Leiden, pregnancy itself causes hypercoagulabil-ity because it induces a relative state of activated protein C resistance

post-Thrombophilia has also been implicated in otherwise unexplained recurrentpregnancy loss The factor V Leiden mutation appears to double the risk of fetalloss, possibly because of an increased frequency of placental vein thrombosis(45,46) In addition to fetal demise, genetic thrombophilia appears to be associ-ated with obstetrical complications, such as preeclampsia, abruptio placentae,fetal growth retardation, and stillbirth (47)

It has been common practice to prophylax with heparin those pregnantwomen who suffered a prior VTE In a prospective study of 125 pregnant womenwith a single prior VTE, antepartum heparin was withheld but postpartum antico-agulation was administered for 4 to 6 weeks (48) Only 3 of the 125 women(2.4%) developed antepartum VTE Thus, VTE during pregnancy may be lesscommon in this population than had been previously thought

The traditional teaching used to be that hormone replacement therapy (HRT)does not predispose to VTE In 1996, this assumption was challenged when threeseparate large data sets implicated HRT as doubling, tripling, or even quadruplingthe risk of VTE (49–51) As with oral contraceptives, the risk of VTE was highestduring the first year of HRT

The Heart and Estrogen/progestin Replacement Study was a randomizedtrial of 2763 postmenopausal women who had a history of coronary heart diseasebut no previous VTE They were allocated to conjugated equine estrogens, 0.625

220 Goldhaber

mg, plus medroxyprogesterone acetate, 2.5 mg, versus placebo In results thatsurprised the medical community, HRT did not reduce the rate of new coronaryevents (52) Furthermore, the rate of VTE tripled among those women receivingHRT (53) Certain subgroups were at especially high risk of increased VTE,including women with lower extremity fractures (18-fold increase), cancer (4-fold increase), postoperative state (5-fold increase), or nonsurgical hospitalization(6-fold increase) Women with factor V Leiden seem to be at especially high risk

of VTE if they take HRT (54)

E Selective Estrogen Receptor Modulators

An alternative to HRT is raloxifene, a selective estrogen receptor modulator thathas estrogenic effects on bone, lipid metabolites, and blood clotting but an estro-gen antagonist effect on breast tissue In a randomized controlled trial of 7705osteoporotic postmenopausal women, raloxifene decreased the risk of breast can-cer by 75% and decreased the rate of vertebral fractures, as had been hoped, but

it tripled the rate of VTE (55)

Tamoxifen, another selective estrogen receptor modulator, also acts as anestrogen agonist on bone and an estrogen antagonist on breast tissue In the BritishCancer Prevention Trial of women at high risk of breast cancer, 55 months oftreatment with tamoxifen 20 mg daily halved the rate of breast cancer However,the DVT rate increased by 60%, and the PE rate tripled (56)

In summary, VTE has enormous clinical impact PE has a high mortality ratedespite advances in therapy, and VTE has a high recurrence rate after anticoagula-tion is discontinued DVT is often characterized by leg discomfort and postthrom-botic venous insufficiency that adversely impacts the quality of life Patients withVTE often feel like they have a sword dangling over them because this diseasemay be latent for many years and then recur The etiologies of VTE are multifac-torial, and we have arrived at an exciting juncture where we can identify withincreasing sophistication predisposing genetic, environmental, and hormonal fac-tors that contribute to the risk of this illness

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West-Venous Thromboembolism 221

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9 Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS Clinical risk factorsand timing of recurrent venous thromboembolism during the initial 3 months ofanticoagulant therapy Arch Intern Med 2000; 160:3431–3436

10 Mohr DN, Silverstein MD, Heit JA, Petterson TM, O’Fallon WM, Melton LJ Thevenous stasis syndrome after deep venous thrombosis or pulmonary embolism: apopulation-based study Mayo Clin Proc 2000; 75:1249–1256

11 Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K Cost of long-termcomplications of deep venous thrombosis of the lower extremities: an analysis of adefined patient population in Sweden Ann Intern Med 1997; 126:454–457

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13 Blaszyk H, Bjornsson J Factor V Ieiden and morbid obesity in fatal postoperativepulmonary embolism Arch Surg 2000; 135:1410–1413

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15 Klatsky AL, Armstrong MA, Poggi J Risk of pulmonary embolism and/or deepvenous thrombosis in Asian-Americans Am J Cardiol 2000; 85:1334–1337

16 Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE et

al A prospective study of risk factors for pulmonary embolism in women JAMA1997; 277:642–645

17 Zornberg GL, Jick H Antipsychotic drug use and risk of first-time idiopathic venousthromboembolism: a case-control study Lancet 2000; 356:1219–1223

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22 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens

CH Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.Circulation 1995; 92:2800–2802

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V et al Coexistence of factor V Leiden and Factor II A20210 mutations and recurrentvenous thromboembolism Thromb Haemost 1999; 82:1583–1587

25 De S, V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I et al Therisk of recurrent deep venous thrombosis among heterozygous carriers of both factor

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26 Miles JS, Miletich JP, Goldhaber SZ, Hennekens CH, Ridker PM G20210A tion in the prothrombin gene and the risk of recurrent venous thromboembolism.JACC 2001; 37:1–4

Muta-27 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR High levels

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29 Rosendaal FR Venous thrombosis: a multicausal disease Lancet 1999; 353:1167–1173

30 Hankey GJ, Eikelboom JW Homocysteine and vascular disease Lancet 1999; 354:407–413

31 Langman LJ, Ray JG, Evrovski J, Yeo E, Cole DE Hyperhomocyst(e)inemia andthe increased risk of venous thromboembolism: more evidence from a case-controlstudy Arch Intern Med 2000; 160:961–964

32 Greaves M Antiphospholipid antibodies and thrombosis Lancet 1999; 353:1348–1353

33 Schulman S, Svenungsson E, Granqvist S Anticardiolipin antibodies predict earlyrecurrence of thromboembolism and death among patients with venous thromboem-bolism following anticoagulant therapy Duration of Anticoagulation Study Group

thromboembo-38 Rosing J, Middeldorp S, Curvers J, Thomassen MCLGD, Nicolaes GAF, MeijersJCM, Bouma BN, Bu¨ller HR, Prins MH, Tans G Low-dose oral contraceptives andacquired resistance to activated protein C: A randomized cross-over study Lancet1999; 354:2036–2040.

39 Parkin L, Skegg DCG, Wilson M, Herbison GP, Paul C Oral contraceptives andfatal pulmonary embolism Lancet 2000; 355:2133–2134

40 Vandenbroucke JP, Koster T, Brie¨t E, Reitsma PH, Bertina RM, Rosendaal FR.Increased risk of venous thrombosis in oral-contraceptive users who are carriers offactor V Leiden mutation Lancet 1994; 344:1453–1457

41 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP Higherrisk of venous thrombosis during early use of oral contraceptives in women withinherited clotting defects Arch Intern Med 2000; 160:49–52

42 Greer IA Thrombosis in pregnancy: maternal and fetal issues Lancet 1999; 353:1258–1265

43 Ray JG, Chan WS Deep vein thrombosis during pregnancy and the puerperium: Ameta-analysis of the period of risk and the leg of presentation Obstet Gynecol Surv1999; 54:265–271

44 Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann

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throm-45 Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA Factor

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or pulmonary angiography (suspected PE) may also be required.

Today venous compression ultrasonography (US) is the key diagnostic tool inpatients with a first episode of clinically suspected DVT The sensitivity andspecificity exceed 90% for proximal DVT (1) The corresponding values aredefinitely less (50% or less) for isolated distal DVT Although these results may

be superior in experienced hands, they clearly highlight the need for integratingthe US result in a comprehensive approach

A crucial issue in this regard is clinical assessment, which can be madeeither by means of a standardized Wells score (2) or in an empirical way (3).These two means have been compared in the case of suspected DVT (4) Boththe Wells score and the empirical evaluation can triage patients into a low, inter-mediate, or high clinical probability category However, the empirical methodperformed slightly better in categorizing patients in the high-probability class,while the Wells score categorized more patients in the low-probability class

225

pre-Ventilation/perfusion lung scanning has been investigated in the large PED study (6), which defined clear interpretation categories Briefly, while anormal/near-normal perfusion scan virtually rules out PE, a high-probabilityventilation/perfusion pattern allows one to diagnose PE Low-probability andintermediate-probability categories were also defined, but are considered in mostcenters as nondiagnostic patterns.

PIO-In recent years, interest has developed in using spiral computed tomography(CT) for PE diagnosis Two systematic reviews have independently and simulta-neously concluded that this new technique has not been adequately evaluated(7,8) and that additional research is required to establish its place in clinicalpractice In particular, sensitivity of spiral CT to the presence of PE appears to

be lower than anticipated from the initial studies, especially if the embolus islocated in subsegmental vessels

Gold standards for DVT and PE diagnosis are ascending venography andpulmonary angiography, respectively Both exams are invasive, costly, and notdevoid of risk Moreover, their interpretation may be equivocal, as interob-server agreement is far from optimal The aim of any diagnostic strategy is toreduce the number of invasive exams without increasing the number of falsediagnoses

Table 1 Comparison of Three Rapid DD Tests for Diagnosing DVT and/or PE

Patients with DVT Sensitivity Specificity

of venous thromboembolism On the other hand, this trend means that the ity of patients referred to a diagnostic center for evaluation will have the disorderexcluded rather than confirmed Second, because DVT and PE are now recog-nized as two clinical manifestations of a single disease, treatment algorithms anddiagnostic protocols have been streamlined.

major-As a consequence of these two observations, the first diagnostic step shouldideally be highly sensitive in order to detect the disease in a substantial proportion

of suspected patients On the other hand, diagnosing DVT in a patient suspected

of PE suffices to rule in venous thromboembolism and to indicate anticoagulanttreatment

The evaluation of a diagnostic tool or strategy culminates in managementtrials or outcome studies in which the overall clinical strategy is applied Theoutcome at 3 or 6 months of follow-up is subsequently surveyed to determinethromboembolic events that might have occurred in patients in whom anti-coagulant treatment had been withheld on the basis of a negative diagnosticworkup (9)

Table 2 compares four recently proposed management strategies (2,3,10,11) OneItalian study relies on serial US (10) (i.e., repetition of compression US after 1week in all patients with no DVT on the initial exam) A second Italian studyrelies on serial US restricted to patients with a normal initial US and an abnormal

DD result (rapid latex test) (11) In the third strategy, serial US was restricted

to patients with a non-low-prior clinical probability (PCP) (2) In the fourth rithm, a single US was performed in patients with a DD result above the criticalcutoff (rapid ELISA method) (3), with PCP allowing the identification of patientsrequiring venography (those with a high PCP, a positive DD, and a negative US).These four strategies were assessed in management trials with long-term(at least 3-month) follow-up In the three trials in which DD (11), PCP (2), orboth (3) were added to the initial US exam, the proportion of patients requiring

algo-a repealgo-at US exalgo-am algo-at 1 week walgo-as reduced from 76% in the study relying on US

DD test — Instant-IA — Vidas DD Patients with US 1702 (100%) 946 (100%) 593 (100%) 346 (73%)

VTE, venous thromboembolism; DVT, deep vein thrombosis; FU, follow-up; US, compression sonography; RUS, repeat US (Instant-IA and Vidas DD are D-dimer tests marketed by Stago, As- nie`res, France, and bioMe´rieux, Lyon, France, respectively.)

ultra-alone (10) to 9% when adding DD latex test (11), 28% when adding PCP (2),

or 0% when adding DD ELISA test and PCP assessment (3) (Table 2).Compression venous US appears to be the key diagnostic tool in outpatientsclinically suspected of DVT However, because the prevalence of DVT in thesuspected population is quite low (approximately 20%), using a highly sensitive

DD (ELISA) test as an initial screening would reduce the number of initial USexams by one-fourth to one-third Alternatively, PCP or DD may be used todiminish the number of repeat US However, the principle of repeat US after 1week to pick up undiagnosed distal DVT that would have extended proximally,albeit very attractive at a first glance, has a low yield and is not cost effective(12) Last, the 3-month thromboembolic risk in these four studies (13) (Table 2)was low and comparable to the 1.9% (95% CI; 0.4–5.4%) observed in clinicallysuspected patients followed up after a negative venogram (14) Of note, theseresults were obtained by means of a compression US technique limited to theexamination of the common and superficial femoral and popliteal veins This atleast questions the affirmation by some investigators that a complete, more time-consuming venous US examination (from the calf to the inferior vena cava)should be performed in all patients clinically suspected of DVT (15)

Venous Thromboembolism 229

Recently, two sequential, mainly noninvasive strategies were applied in largecohorts of patients with suspected PE (3,16) They are based on PCP, assessedempirically (3) or by means of a clinical model (16); on a rapid DD ELISA test(3); on venous compression US (3,16); on a V/Q lung scan (3,16); and, in somecases, on pulmonary angiography These strategies are depicted in Figures 1 and

Figure 1 Diagnostic algorithm for suspected pulmonary embolism PE, pulmonary bolism; US, lower limb venous ultrasonography; DVT, deep vein thrombosis; PCP, priorclinical probability; near-N, near-normal; Rx, treatment; no Rx, no treatment (FromRef 3.)

em-230 Bounameaux

Figure 2 Diagnostic algorithm for suspected pulmonary embolism PE, pulmonary bolism; US, lower limb venous ultrasonography; DVT, deep vein thrombosis; PCP, priorclinical probability; near-N, near-normal; Rx, treatment; no Rx, no treatment (FromRef 16.)

em-2 The 3-month thromboembolic risks that were associated with these algorithmswere 0.9% (95% CI; 0.2–2.7%) (3) or 0.5% (95% CI; 0.1–1.3%) (16), respec-tively Pulmonary angiography had to be performed in 11% (3) or 4% (16) ofpatients These strategies allow the management of the majority of patients withwidely available, noninvasive diagnostic tools In a third, smaller Dutch study,

a sequential strategy of ventilation/perfusion lung scan, rapid whole-blood DDtest SimpliRED, US, and pulmonary angiography was used The 3-month throm-boembolic risk was 2.5% (95% CI; 0.5–7.1%) in the 121 patients in whom antico-agulant treatment had been withheld on the basis of a normal perfusion or anondiagnostic lung scan pattern associated with a negative SimpliRED DD test.(17)

Finally, in a secondary analysis of a database of 1034 consecutive patientsreferred to a diagnostic center with clinically suspected PE, the diagnosis could

be ruled out by the combination of a low clinical probability and a nondiagnosticlung scan (i.e., abnormal but non-high-probability pattern), provided no proximalDVT had been detected on US exam This combination was present in 175 pa-tients of the cohort (22%), and was safe to rule out PE since the 3-month thrombo-embolic risk was only 1.7% (95% CI; 0.4–4.9%) (18)

Venous Thromboembolism 231

Because these strategies have a similar efficacy, the less resource-intensivestrategy depicted in Figure 2 (3) is likely to be the most cost-effective one How-ever, formal cost-effectiveness studies comparing them are not yet available

INTEGRATED APPROACH

The strategies described above can be combined in a single, integrated algorithm(Fig 3) that is, however, suitable for patients with clinical symptoms and/orsigns of venous thromboembolism who are referred to an outpatient clinic or anemergency ward for ruling in/out the disease It is not suited for patients whoare hospitalized in medical or surgical wards for longer periods of time, nor is

Figure 3 Integrated diagnostic algorithm for suspected venous thromboembolism PE,pulmonary embolism; US, lower limb venous ultrasonography; DVT, deep vein thrombo-sis; PCP, prior clinical probability (From Ref 3.)

232 Bounameaux

it suitable for patients who present with hemodynamic instability In the lattercase, the problem is therapeutic rather than diagnostic; moreover, emergencytreatment (e.g., thrombolysis or embolectomy) must be considered in these pa-tients without delay Thus, echocardiography and/or spiral CT may be first-linediagnostic tools, because in this situation signs of right heart dysfunction or pres-ence of proximal emboli are very likely to be present

On the other hand, patients who are hospitalized in medical or surgicalwards for more than 24 h are unlikely to present with DD concentrations belowthe critical cutoff due to comorbidities Thus, in a diagnostic study of suspected

PE in hospitalized patients, the yield of a negative DD result was very low (about5%) (19), which at least questions its utility in this category of patients.Last, age considerably influences the performance of all diagnostic tools(20) In an analysis of two large outcome studies that enrolled 1029 consecutiveoutpatients presenting in the emergency ward with clinically suspected pulmo-nary embolism (prevalence of pulmonary embolism 27%), the prevalence of pul-monary embolism increased progressively from 12% below age 40 to 44% aboveage 80 The positive predictive value of a high clinical probability of pulmonaryembolism was higher in the elderly (71 to 78% above 60 vs 40 to 64% below60) Sensitivity of DD testing was 100% in all age subgroups, but specificitydecreased markedly with age, from 67% below age 40 to 10% above age 80.The diagnostic yield of lower limb venous compression US was higher in theelderly [46% (95% CI; 26–67%) below 40 vs 56% (95% CI; 44–68%) above80] The proportion of diagnostic (normal/near-normal or high probability) lungscans also decreased from 68% to 42% with increasing age This variable should

be kept in mind in the diagnostic approach of this disease

Diagnosing DVT and PE has improved over the past 15 years primarily due tothe development of venous compression ultrasound of the lower limbs and D-dimer measurement If carefully applied, these strategies can reduce the need forvenography and pulmonary angiography to less than 10% of patients evaluatedand thus are likely to be cost effective These newer diagnostic strategies shouldthus be implemented in daily practice, taking into account local facilities andexpertise (21) In the near future, spiral CT might be included in the diagnosticapproach of PE, but its exact place remains to be determined

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Venous Thromboembolism 233

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