Thrombosis and thromboembolism - part 8 ppt

This initial study has been criticized because objective methods were notused to confirm the diagnosis of recurrent VTE in the majority of patients 6.Nonetheless, these findings suggeste

In ICOPER, the prospective registry of 2454 patients with PE conducted

in 52 hospitals among 7 countries, 304 patients received thrombolytic therapy(1) An amazingly high 3.0% of patients who received thrombolysis sufferedintracranial bleeding Overall, 22% of those receiving thrombolysis had majorbleeding and 12% required transfusions

VII PRACTICAL POINTS

The only FDA-approved contemporary dosing regimen for PE thrombolysis isrt-PA, given in a fixed dose of 100 mg as a continuous infusion over 2 h There

is no need to obtain laboratory tests during the thrombolytic infusion because nodosage adjustments are made rt-PA administered locally within the pulmonaryartery has never been shown to confer any advantage over peripheral administra-tion of the drug (32)

A PE Thrombolysis in Women

Data from 312 patients (144 women and 168 men) included in our group’s PEtrials (21,27–30) were analyzed to determine whether there were gender differ-ences in the efficacy or safety of thrombolytic therapy (33) Our results indicatedthat women and men have a similar benefit and bleeding risk from PE thromboly-

sis These findings suggest that thrombolytic therapy should be considered in themanagement of PE without regard to gender.

B PE Thrombolysis in Cancer Patients

Although the initial angiographic response to thrombolysis is similar in cancerand noncancer patients, the magnitude of improvement among cancer patientsbecomes attenuated on perfusion scanning at 24 h This observation suggests thatcancer patients should receive maximally intensive anticoagulation immediatelyfollowing thrombolysis in order to preserve their initial improvement from ther-apy Fortunately, PE thrombolysis does not appear to be more hazardous in appro-priately selected cancer patients than in patients without cancer (34)

Contemporary PE thrombolysis is safer, more streamlined, and more economicalthan classic PE thrombolysis (Table 3) Contemporary PE thrombolysis is charac-terized by a 2-week ‘‘time window,’’ a brief infusion administered through aperipheral vein, and no special laboratory tests

No ideal thrombolytic agent has yet been developed because of the ing bleeding hazard posed by all lytic drugs However, alternatives to rt-PA havebeen tested and appear in small series to be effective All utilize high concentra-

continu-Table 3 New Concepts in Pulmonary Embolism Thrombolysis

Diagnosis Mandatory pulmonary angio- High-probability lung scan,

pos-gram itive chest CT scan,

echocar-diogram showing isolated, vere right ventricular failure

se-or pulmonary angiogramIndications Systemic arterial hypotension; Hypotension or normotension

hemodynamic instability with accompanying moderate

or severe right ventricular pokinesis

hy-Time window 5 days or less 14 days or less

Route Via pulmonary artery catheter Via peripheral vein

Coagulation tests ‘‘DIC screens’’ every 4–6 h aPTT at conclusion of

thrombo-during infusion lysis

tions of drug administered over a brief duration They include urokinase3,000,000 units over 2 h, with the first 1,000,000 units delivered as a 10-minbolus (29); streptokinase 1,500,000 units over 2 h (35), as well as the myocardialinfarction dosing regimen of ‘‘double bolus’’ reteplase (36).

REFERENCES

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2 Jerjes-Sanchez C, Ramirez-Rivera A, Garcia M de L, Arriaga-Nava R, Valencia S,Rosado-Buzzo A, Pierzo JA, Rosas E Streptokinase and heparin versus heparinalone in massive pulmonary embolism: A randomized controlled trial J ThrombosisThrombolysis 1995; 2:227–229

3 Cannon CP, Goldhaber SZ Cardiovascular risk stratification of pulmonary lism in patients Am J Cardiol 1996; 78:1149–1151

embo-4 Kasper W, Konstantinides S, Geibel A, Tiode N, Krause T, Just H Prognostic nificance of right ventricular afterload stress detected by echocardiography in pa-tients with clinically suspected pulmonary embolism Heart 1997; 77:346–349

sig-5 Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L phy Doppler in pulmonary embolism: Right ventricular dysfunction as predictor ofmortality Am Heart J 1997; 134:479–487

Echocardiogra-6 Goldhaber SZ A contemporary approach to thrombolytic therapy for pulmonaryembolism Vasc Med 2000; 5:115–123

7 Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G et al Short-termclinical outcome of patients with acute pulmonary embolism, normal blood pressure,and echocardiographic right ventricular dysfunction Circulation 2000; 101:2817–2822

8 Konstantinides S, Geibel A, Kasper W, Olschewski M, Blumel L, Just H Patentforamen ovale is an important predictor of adverse outcome in patients with majorpulmonary embolism Circulation 1998; 97:1946–1951

9 Chartier L, Bera J, Delomez M, Asseman P, Beregi JP, Bauchart JJ et al floating thrombi in the right heart: diagnosis, management, and prognostic indexes

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10 Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L Pulmonaryembolism: one-year follow-up with echocardiography Doppler and five-year sur-vival analysis Circulation 1999; 99:1325–1330

11 Meyer T, Binder L, Hruska N, Luthe H, Buchwald AB Cardiac troponin I elevation

in acute pulmonary embolism is associated with right ventricular dysfunction J AmColl Cardiol 2000; 36:1632–1636

12 Giannitsis E, Muller-Bardorff M, Kurowski V, Weidtmann B, Wiegand U, mann M et al Independent prognostic value of cardiac troponin T in patients withconfirmed pulmonary embolism Circulation 2000; 102:211–217

Kamp-13 Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI, Schwartz JS,Thompson BT, Popovich J, Jr, Hobbins TE, Spera MA Alavi A, Terrin ML Theclinical course of pulmonary embolism N Engl J Med 1992; 326:1240–1245.

14 Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD,Rauber K, Iversen S, Redecker M, Kienast J Management strategies and determi-nants of outcome in acute major pulmonary embolism: Results of a multicenter regis-try J Am Coll Cardiol 1997; 30:1165–1171

15 Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, sen S, Redecker M, Kienast J, Just H, Kasper W Impact of thrombolytic treatment onthe prognosis of hemodynamically stable patients with major pulmonary embolism:Results of a Multicenter Registry Circulation 1997; 96:882–888

Iver-16 The Urokinase Pulmonary Embolism Trial A national cooperative study tion 1973; 47:1–108

Circula-17 Urokinase-Streptokinase Embolism Trial Phase 2 results A cooperative study.JAMA 1974; 229:1606–1613

18 Sharma GVRK, Burleson VA, Sasahara AA Effect of thrombolytic therapy on monary-capillary blood volume in patients with pulmonary embolism N Engl J Med1980; 303:842–845

pul-19 Sharma GVRK, Folland ED, McIntyre KM, Sasahara AA Long-term benefit ofthrombolytic therapy in patients with pulmonary embolism Vasc Med 2000; 5:91–95

20 Dalla-Volta S, Palla A, Santolicandro A, et al PAIMS 2: Alteplase combined withheparin versus heparin in the treatment of acute pulmonary embolism PlasminogenActivator Italian Multicenter Study 2 J Am Coll Cardiol 1992; 20:520–526

21 Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira

da Silva AM, Come PC, Lee RT, Parker JA, Mogtader A, McDonough TJ, wald E Alteplase versus heparin in acute pulmonary embolism: randomised trialassessing right ventricular function and pulmonary perfusion Lancet 1993; 341:507–511

Braun-22 Nass N, McConnell MV, Goldhaber SZ, Chyu S, Solomon SD Recovery of regionalright ventricular function after thrombolysis for pulmonary embolism Am J Cardiol1999; 83:804–806

23 Parker JA, Drum DE, Feldstein ML, Goldhaber SZ Lung scan evaluation of bolytic therapy for pulmonary embolism J Nucl Med 1995; 36:364–368

throm-24 Daniels LB, Parker JA, Patel SR, Grodstein F, Goldhaber SZ Relation of duration

of symptoms with response to thrombolytic therapy in pulmonary embolism Am JCardiol 1997; 80:184–188

25 Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ Thrombolytic therapyfor pulmonary embolism Frequency of intracranial hemorrhage and associated riskfactors Chest 1997; 111:1241–1245

26 Meyer G, Gisselbrecht M, Diehl JL, Journois D, Sors H Incidence and predictors

of major hemorrhagic complications from thrombolytic therapy in patients with sive pulmonary embolism Am J Med 1998; 105:472–477

mas-27 Goldhaber SZ, Vaughan DE, Markis JE, Selwyn AP, Meyerovitz MF, Loscalzo J,Kim DS, Kessler CM, Dawley DL, Sharma GVRK, Sasahara A, Grossbard EB,

Braunwald E Acute pulmonary embolism treated with tissue plasminogen activator.Lancet 1986; 2:886–889.

28 Goldhaber SZ, Kessler CM, Heit J, Markis J, Sharma GVRK, Dawley D, Nagel JS,Meyerovitz M, Kim D, Vaughan DE, Parker JA, Tumeh SS, Drum D, Loscalzo J,Reagan K, Selwyn AP, Anderson J, Braunwald E A randomized controlled trial ofrecombinant tissue plasminogen activator versus urokinase in the treatment of acutepulmonary embolism Lancet 1988; 2:293–298

29 Goldhaber SZ, Kessler CM, Heit JA, et al Recombinant tissue-type plasminogenactivator versus a novel dosing regimen of urokinase in acute pulmonary embolism:

A randomized controlled multicenter trial J Am Coll Cardiol 1992; 20:24–30

30 Goldhaber SZ, Agnelli G, Levine MN, on behalf of the Bolus Alteplase PulmonaryEmbolism Group Reduced dose bolus alteplase versus conventional alteplase infu-sion for pulmonary embolism thrombolysis An international multicenter random-ized trial Chest 1994; 106:718–724

31 Mikkola KM, Patel SR, Parker JA, Grodstein F, Goldhaber SZ Increasing age is

a major risk factor for hemorrhagic complications following pulmonary embolismthrombolysis Am Heart J 1997; 134:69–72

32 Verstraete M, Miller GAH, Bounameaux H, Charbonnier B, Colle JP, Lecorf G,Marbet GA, Mombaerts P, Olsson CG Intravenous and intrapulmonary recombinanttissue-type plasminogen activator in the treatment of acute massive pulmonary em-bolism Circulation 1988; 77:353–360

33 Patel SR, Parker JA, Grodstein F, Goldhaber SZ Similarity in presentation and sponse to thrombolysis among women and men with pulmonary embolism J Throm-bosis Thrombolysis 1998; 5:95–100

re-34 Mikkola KM, Patel SR, Parker JA, Grodstein F, Goldhaber SZ Attentuation over

24 hours of the efficacy of pulmonary embolism thrombolysis among cancer patients

Am Heart J 1997; 134:603–607

35 Meneveau N, Schiele F, Metz D, Valette B, Attali P, Vuillemenot A, et al tive efficacy of a two-hour regimen of streptokinase versus alteplase in acute massivepulmonary embolism: immediate clinical and hemodynamic outcome and one-yearfollow-up J Am Coll Cardiol 1998; 31:1057–1063

Compara-36 Tebbe U, Graf A, Kamke W, et al Hemodynamic effects of double bolus reteplaseversus alteplase infusion in a massive pulmonary embolism Am Heart J 1999; 138:39–44

Optimal Duration of Anticoagulation

Following Venous Thromboembolism Among Patients With and Without

Inherited Thrombophilia

Gavin J Blake and Paul M Ridker

Brigham and Women’s Hospital and Harvard Medical School,

Boston, Massachusetts

The optimal duration of oral anticoagulation following a venous thromboembolicevent is controversial The goal of therapy is to prevent recurrent events withoutexposing the patient to unnecessary hemorrhagic risk Studies of the long-termclinical course of venous thromboembolism (VTE) suggest a high recurrence rate(1,2) particularly when the index event is idiopathic However, the risk of bleed-ing while on oral anticoagulation is directly related to the length of exposure.Thus, at some point, the risk of treatment may outweigh the potential benefit.Accumulating evidence indicates that VTE is a chronic, multicausal diseasewith genetic and acquired risk factors interacting in a dynamic manner to deter-mine an individual’s risk for VTE (3) Appropriate recommendations on the dura-tion of anticoagulation following VTE should take these risk factors into account.Current recommendations of the American College of Chest Physicians suggest

3 to 6 months of oral anticoagulant therapy with warfarin, adjusted to a targetInternational Normalized Ratio (INR) of 2–3, for the treatment of a first thrombo-embolic event in patients with reversible or time-limited risk factors (4) At least

6 months of therapy is recommended for patients with a first idiopathic event(4)

261

I RANDOMIZED TRIALS OF ANTICOAGULATION

FOLLOWING FIRST VTE

There are surprisingly few randomized trials assessing the optimal duration ofanticoagulation following VTE The Research Committee of the British ThoracicSociety conducted a multicenter comparison of 4 weeks versus 3 months antico-agulation in 712 patients admitted with acute deep venous thrombosis (DVT),pulmonary embolism (PE), or both (5) After 12 months of follow-up, the recur-rence rate was 7.8% in the group randomized to 4 weeks of anticoagulation com-

pared to 4% in the 3-month group ( p⫽ 0.04) Regardless of duration of ulation, there was only one recurrence (0.86%) among 116 patients whodeveloped VTE postoperatively By contrast, among nonsurgical patients, therecurrence rates were higher in the group treated for 4 weeks compared to the

anticoag-group treated for 3 months (9.1 vs 4.7%; p⬍ 0.0002)

This initial study has been criticized because objective methods were notused to confirm the diagnosis of recurrent VTE in the majority of patients (6).Nonetheless, these findings suggested that a short duration of anticoagulationmay be adequate for patients with postoperative venous thrombosis, while alonger course of treatment is necessary for patients without a reversible risk factorsuch as recent surgery

This concept is supported by the work of Levine et al., who conducted arandomized trial of placebo versus warfarin for 8 further weeks in patients whohad completed 4 weeks of anticoagulation for VTE and who had a normal imped-ance plethysmogram at 4 weeks One-hundred-five patients were randomized toplacebo and 109 to warfarin with a target INR of 2–3, and these patients werefollowed for 11 months (7) Patients with two or more VTE, protein C deficiency,protein S deficiency, and antithrombin III deficiency were excluded

During the first 8 weeks after randomization, 9 (8.6%) patients in the cebo group developed VTE compared to 1 (0.9%) patient in the warfarin-treated

pla-group ( p⫽ 0.009) During the 9 months of follow-up beyond 8 weeks, 3 treated patients and 6 warfarin-treated patients developed VTE, so that over thetotal 11 months of follow-up, 12 (11.5%) in the placebo group and 7 (6.8%) in

placebo-the warfarin group developed VTE ( p⫽ 0.3) All seven events in the warfaringroup occurred in patients with continuing risk factors for VTE These resultssuggested that more than 3 months of anticoagulation may be required for patientswith continuing risk factors for VTE

The Duration of Anticoagulation Trial Study Group (DURAC) conducted

a comparison of 6 weeks versus 6 months of oral anticoagulant therapy after afirst episode of VTE (8) Eight-hundred-ninety-seven patients were followed for

2 years, with a target INR of 2–2.85 The recurrence rate was 18.1% in the grouptreated for 6 weeks and 9.5% in the group treated for 6 months, giving an oddsratio for recurrence in the 6-week group of 2.1 There was a sharp increase in

the recurrence rate in the group treated for 6 weeks after anticoagulation wasstopped The rate of recurrence remained nearly parallel for the 18 months there-after, with a linear increase in cumulative risk for both groups, corresponding to

5 to 6% annually (Fig 1)

In the DURAC trial, the overall rate of recurrence after 2 years was muchlower among patients with temporary risk factors than among those with perma-nent risk factors (6.6 vs 18%) Five episodes of major bleeding occurred in the 6-month group and one in the 6-week group, but this difference was not statisticallydifferent Three of these patients were receiving excessive anticoagulation at thetime of admission (INR 4–5.6)

Most recently, Kearon and colleagues randomly assigned 162 Canadianpatients, who had completed 3 months of anticoagulant therapy for a first episode

of idiopathic VTE, to receive either warfarin or placebo for a further 24 months(9) The target INR was 2–3 The trial was terminated early after an averagefollow-up of 10 months The rate of recurrence was 1.3% per patient-year in thewarfarin group and 27.4% per patient-year in the placebo group Warfarin re-sulted in a 95% reduction in the risk of recurrent VTE (Fig 2) There were threeepisodes of major bleeding in the warfarin group and one in the control group.None of the bleeds was fatal

The authors conclude that patients with a first episode of idiopathic VTEshould be treated with anticoagulation for longer than 3 months The optimalduration of anticoagulation, however, remains unclear Extended anticoagulanttherapy is associated with a risk of major bleeding of about 3% per year (10).Although the risk of recurrence is high among patients without reversible riskfactors, fatal pulmonary embolism, the most feared complication, is rare in these

Figure 1 Cumulative probability of recurrent venous thromboembolism after a first sode, according to duration of anticoagulation (Adapted from Ref 8.)

epi-Figure 2 Cumulative probability of recurrent venous thromboembolism in patients with

a first episode of idiopathic thrombosis who were assigned to warfarin or placebo after

an initial 3 months of anticoagulation (Adapted from Ref 9.)

patients providing they are not confined to bed Schulman et al reported onlyone fatal PE among 450 patients with idiopathic VTE, and Levine et al reportednone among 301 patients (7,8) Thus, there are insufficient data at this time torecommend lifelong anticoagulation to all patients with first idiopathic venousthrombosis

FOLLOWING RECURRENT VTE

The DURAC group have also conducted a trial comparing 6 months of oral coagulation with indefinite anticoagulation in 227 patients with a second episode

anti-of VTE (11) The target INR was again 2–2.85 and the patients were followedfor 4 years The rate of recurrent VTE in the group treated for 6 months was20.7% compared to 2.6% in the group treated indefinitely (Fig 3) The relativerisk for recurrence in the 6-month group was 8.0

None of the recurrent episodes in the group assigned to indefinite ulation actually occurred during anticoagulation; all three patients had discon-

anticoag-Figure 3 Cumulative probability of recurrent venous thrombosis in patients with a ond episode, according to the duration of assigned anticoagulation therapy (Adapted fromRef 11.)

sec-tinued their anticoagulation therapy prematurely; 8.6% of the group assigned toindefinite anticoagulation suffered a major hemorrhage compared to 2.7% of the

6 month group This difference was not statistically significant ( p⫽ 0.08) Themonthly incidence of major hemorrhage while on anticoagulation therapy was0.20%, which compared favorably with older studies reporting major bleedingrates of 0.6 to 0.7% on oral anticoagulation

This study showed that a target INR of 2–2.85 is effective in preventingrecurrent VTE in individuals with a prior history of at least two events Theauthors calculated that for every 100 patients with recurrent VTE receiving warfa-rin indefinitely compared to 6 months, 0.43 episodes of recurrent VTE would beaverted per month at a cost of 0.2 major bleeds per month Thus it would be ofvalue to determine whether a lower intensity of anticoagulation could eliminatethe risk of bleeding while still offering the same protective effect This issue isbeing evaluated in the ongoing Prevention of Recurrent Venous Thromboembo-lism (PREVENT) trial, which will be discussed later in this chapter (12)

In view of the above data, it seems clinically appropriate to consider fying patients into those with low, intermediate, or high risk for recurrent VTE(13) The low-risk group, with temporary reversible risk factors for VTE such

strati-as trauma or surgery, can probably be treated for 4 to 6 weeks after the risk factor

is removed The intermediate-risk group, with a history of a first idiopathic event,should receive maintenance therapy with warfarin for at least 6 months Indefiniteanticoagulation should be reserved for the high-risk group, including those whoalready have recurrent VTE

III MULTICAUSAL MODEL FOR VENOUS

THROMBOEMBOLIC RISK

Accumulating evidence suggests that VTE is a multicausal disease with gene–gene and gene–environment interactions playing a dynamic role Rosendaal hasrecently proposed that a more precise model of VTE risk can be attained byconsidering the lifelong risk due to inherited defects along with a dynamicallyincreasing risk with age (3) Superadded events such as pregnancy, trauma, orsurgery may cause an individual to transiently exceed his or her thrombosisthreshold and precipitate an acute event In contrast, stopping oral contraception,increasing exercise, or folate supplementation may tip the balance away fromthrombosis, and keep thrombosis-prone individuals below their thrombosisthreshold

However, several questions remain As more genetic and acquired risk tors for VTE are discovered, which patients will be deemed intermediate or highrisk? Should we screen for genetic risk factors in all patients with a first VTE?Could low-dose warfarin achieve the same beneficial effects in reduction of VTErisk without the accompanying risk of hemorrhage? The rest of this chapter willfocus on these issues

Surgery Factor V Leiden

Trauma Prothrombin G20210A mutationImmobilization Antithrombin deficiencyObesity Protein C deficiency

Pregnancy Protein S deficiency

Oral contraception Dysfibrinogenemia

Hormone replacement therapy Dysfunctional thrombomodulinCancer HyperhomocysteinemiaNephrotic syndrome

Antiphospholipid antibody syndromes

Hyperhomocysteinemia

Table 2 Estimated Prevalence of Inherited Risk Factors for Venous Thrombosis

in the General Population, Among Those with a History of Thrombosis, and AmongThose with Familial Thrombophilia

General Patients FamilialFactor population with thrombosis thrombophiliaProtein C deficiency ⬍0.5 3 5Protein S deficiency ⬍0.5 2 5Antithrombin deficiency ⬍0.5 1 3Factor V Leiden 5 20 50Prothrombin G20210A 3 6 20Hyperhomocysteinemia 5 10 15

of antithrombin, protein C and protein S, and the antiphospholipid syndromewere the only established thrombophilic syndromes These deficiencies together,however, account for only 5 to 10% of familial VTE (3) Two recently discoveredgenetic defects, the factor V Leiden mutation and the prothrombin gene mutation,appear to account for a far greater proportion of thrombophilic syndromes (Table2)

A Factor V Leiden

In 1993, Dahlbach first described resistance to breakdown by activated protein

C which appeared to be characteristic of selected patients with VTE (14) Thisabnormality is caused by a single adenine for guanine point mutation in the genecoding for factor V, which leads to the substitution of glutamine for arginine atposition 506, one of three cleavage sites on factor V for activated protein C (15).Thus, this mutation, known as factor V Leiden, makes factor V relatively resistant

to degradation by protein C

The significance of factor V Leiden as a risk factor for VTE was shown

in the Leiden Thrombophilia study, a population-based study of 301 patients lessthan 70 years of age who had a first episode of VTE not related to malignancy(16) Resistance to protein C was detected in 21% of cases compared to 5% ofage- and sex-matched controls (odds ratio 6.6) Subsequent analysis showed that80% of the patients resistant to protein C were either heterozygous or homozy-gous for factor V Leiden Factor V Leiden has since been shown to be the mostcommon genetic mutation associated with VTE (17)

The association between factor V Leiden and risk of VTE was confirmed

in a large prospective study of healthy U.S males enrolled in the Physicians’Health Study (PHS) (18) The prevalence of the mutation was significantly higher

among men who developed VTE than among controls (11.6 vs 6%; p⫽ 0.02).

In adjusted analysis, the relative risk (RR) for VTE among men with the mutation

was 2.7 ( p⫽ 0.008) The increased risk was seen in 63 patients with primary

VTE (RR 3.5) but not in 58 patients with secondary VTE (RR1.7; p ⫽ 0.3)

In men older than 70 years of age, the risk of primary VTE increased fold

seven-The association between age, factor V Leiden, and the risk of VTE wasanalyzed in a further study from the PHS For men⬍50 years old, those withthe mutation had no increased risk of VTE compared to controls, but with increas-ing age the risk conferred by the mutation also increased (19) Incidence ratedifferences between affected and unaffected men were 1.23 for those aged 50 to59; 1.61 for those aged 60 to 69; and 5.97 for those aged 70 or older This trendwas most pronounced for primary VTE (Fig 4) No significant relationship wasfound for secondary events

These findings strongly suggest that the pathogenesis of VTE is rial and requires interactions between both inherited and acquired risk factors.One such interaction appears to be between factor V Leiden and homocysteine

multifacto-In a further analysis from the PHS, it was shown that high homocysteine levels(⬎95th percentile) alone were not associated with a significantly increased risk ofVTE but that, when present along with factor V Leiden, hyperhomocysteinemiaconferred a 20-fold increased risk of idiopathic VTE (Fig 5) (20)

Factor V Leiden also enhances the risk of VTE in patients with other bophilic states In a study of patients with symptomatic protein C deficiency, theprevalence of factor V Leiden was 14% (21) In a study of seven families affected

throm-by both protein S deficiency and Factor V Leiden, 72% of individuals with bothabnormalities had a thrombotic event compared to 19% of those with protein Sdeficiency alone and 19% of those with factor V Leiden alone (22)

In some reports, factor V Leiden has been associated with an increased risk

of recurrent VTE (23) This would be an important finding as it would potentiallyidentify patients who might benefit from prolonged anticoagulation In the PHS,for example, 77 patients with idiopathic VTE were followed prospectively for

an average of 68 months Eleven patients (14.3%) developed recurrent VTE;seven cases (11.1%) among 63 patients who were not carriers of the mutationand four cases (28.6%) among 14 who were carriers of factor V Leiden Theincidence rate was 7.46 per 100 person-years among carriers and 1.82 per 100

person-years among those without the mutation The crude RR was 4.1 ( p ⫽

0.04) and the age- and smoking-adjusted RR was 4.7 ( p⫽ 0.047) Among zygous men, 76% of recurrent events were attributable to the mutation.This initial finding that factor V Leiden carries an increased risk for recur-rent VTE is supported by a larger European study that followed 251 patientswith VTE for up to 8 years (24) The recurrence rates were 39.5% in the group

hetero-Figure 4 Estimated age-specific incidence rates for venous thromboembolism amongmen with (dashed lines) and without (solid lines) factor V Leiden mutation Left: Anyvenous thromboembolism Middle: Idiopathic venous thromboembolism Right: Venousthromboembolism associated with cancer or surgery (Adapted from Ref 19.)

heterozygous for factor V Leiden, and 18.3% in those who were not carriers ofthe mutation, giving a relative risk of 2.4 for carriers of the mutation Of note,factor V Leiden predicted risk of recurrence of both idiopathic and secondaryVTE in this study

Not all studies agree, however, that being a carrier for factor V Leidenconfers an increased risk of recurrent VTE Rintelen and colleagues conducted

a retrospective study of Austrian patients with VTE and found that the risk ofrecurrence was increased only in those homozygous for factor V Leiden (9.5%per patient per year) (25) Those heterozygous for factor V leiden had a similarrecurrence rate to controls (4.8% per patient per year and 5% per patient peryear, respectively)

Workers in Milan have recently reported data regarding the frequency of

Figure 5 Interrelations of factor V Leiden mutation and hyperhomocysteinemia on risk

of venous thromboembolism (⫹, present; ⫺, absent) (Adapted from Ref 20.)

recurrent VTE in 112 carriers of the factor V Leiden mutation alone, 17 patientsheterozygous for both factor V Leiden and the prothrombin mutation, and 283patients who had neither mutation (2) The cumulative incidence of recurrentVTE was 30% among carriers of factor V Leiden alone and 30% among patientswith neither mutation The cumulative incidence was 65% among the carriers ofboth factor V Leiden and the G20210A prothrombin mutation (RR 2.6) Whenonly spontaneous recurrences were considered, the relative risk for carriers ofboth mutations was 3.7 No difference in recurrence rates was observed betweenpatients heterozygous for factor V Leiden alone and those without either muta-tion The authors conclude that a finding of heterozygosity for both factor VLeiden and the prothrombin mutation should prompt lifelong treatment with anti-coagulants

Thus, there remains disagreement whether factor V Leiden is associatedwith an increased risk of recurrent VTE This issue merits further study as it has

a potentially large impact on clinical practice

B Prothrombin Gene Mutation

Poort and colleagues have described a single point mutation in the prothrombingene (G-to-A transition at position 20210) that appears to be associated withincreased prothrombin levels (26) The G20210A allele is observed in 3–7% ofcases and 1–3.9% of healthy subjects (27–30)

The association between the heterozygous state and VTE is controversial

A Swedish study from the DURAC group reported an odds ratio of 4.6 for firstVTE in 28 carriers of the mutation, and other small studies have suggested asimilar risk of VTE in heterozygous carriers of the mutation (27,28,31)

In contrast, a large American study of over 2000 men found only a weakassociation between the G20210A mutation and overall risk of VTE (30) The

relative risk was 1.7 ( p ⫽ 0.08) The relative risk for idiopathic VTE was 1.9

( p⫽ 0.1) These effects were smaller in magnitude than those associated withfactor V Leiden (RR 3 for overall VTE, RR 4.5 for primary VTE) (Fig 6).Other recent studies have sought to address the key question of whetherpatients who carry the G20210A transition are at increased risk of recurrent VTE

If this is the case, then carriers of the mutation who present with a first episode

of VTE should be considered for more long-term anticoagulation

Figure 6 Relative risks of developing future venous thromboembolism (VTE) amongparticipants in the Physicians’ Health Study according to presence or absence of prothrom-bin or factor V Leiden mutations Data are shown for any VTE and for events not associ-ated with cancer, surgery, or trauma (idiopathic VTE) (Adapted from Ref 30.)

A report from Austria found no association between the G20210A mutationand risk of recurrent VTE (27) Of 492 patients with documented VTE, 8.5%were carriers of the mutation The recurrence rate was 7% in carriers versus 12%

in those without the mutation Similarly, a report from the DURAC group found

no increased risk of recurrence in carriers of the prothrombin mutation (oddsratio 0.9) (31) In this study, the heterozygote state for factor V Leiden was notassociated with an increased risk of recurrent VTE (17.8% in carriers vs 17.6%

in noncarriers) Those homozygous for the factor V Leiden, however, had a edly increased risk of recurrence (odds ratio 4.8) By contrast, in the PHS, theprothrombin mutation was associated with an increased risk of recurrent events,particularly when coinherited with factor V Leiden

mark-How is this apparent discrepancy between risk for first and subsequent VTEexplained? The average risk of a second episode of VTE is approximately 3 to5% annually for all VTE patients, which is severalfold higher than the risk forcarriers of the G20210A mutation for first VTE Thus coexisting or unrecognizedrisk factors for recurrent VTE may overshadow the risk generated by this muta-tion alone Recent data suggest that, when combined with other genetic mutations,the prothrombin gene mutation may greatly increase the risk of recurrent VTE.The Milan group reported a fourfold increased risk of recurrent idiopathic VTE

in carriers of both factor V Leiden and the prothrombin gene mutation (2)

CONTRACEPTION, AND PREGNANCY

Patients who carry factor V Leiden may be at increased risk of VTE when takingthe oral contraceptive pill In a case control study of women aged 15 to 49 fromthe Netherlands, the risk of VTE associated with the oral contraceptive pill (OCP)was 3.8, and with factor V Leiden was 7.9 (32) The risk of thrombosis for thosewith both risk factors increased by more than 30-fold

Further evidence of gene–gene and gene–environment interactions comesfrom a recent study of VTE in pregnant women (33) Factor V Leiden was found

in 43.7% of cases, compared to 7.7% of controls (RR 9.3), and the prothrombingene mutation was found in 16.9% of cases and 1.3% of controls (RR 15.2).Remarkably, both abnormalities were detected in 9.3% of cases compared to none

of the controls (estimated odds ratio 107)

There appears to be a relationship between the prothrombin gene mutationand pregnancy-related changes in fibrinolysis and coagulation, as the risk con-ferred by this mutation in pregnant women is greater than that observed in non-pregnant populations Assuming an incidence of one thromboembolic event in

1500 pregnancies, the calculated probability of thrombosis among carriers of

fac-tor V Leiden was 0.25%, among those with the prothrombin mutation was 0.5%,and among those with both abnormalities was 4.6% This finding has led to thecontroversial recommendation that all pregnant women with a personal or familyhistory of VTE should be screened for these genetic abnormalities (34).

Patients with congenital forms of homozygous homocystinuria can have cally elevated plasma levels of homocysteine and are at markedly increased riskfor both venous and arterial thrombosis However, such severe forms of congeni-tal hyperhomocysteinemia are rarely encountered in clinical practice By contrast,modest elevations of plasma homocysteine (⬎17 µmol/L) are common, occurring

dramati-in approximately 5% of the general population Plasma homocystedramati-ine levels flect both dietary intake of folic acid as well as inherited defects in the homocyste-ine metabolic enzymes cystathionineβ-synthase and methylene-tetrahydrofolatereductase (MTHFR) Specifically, a common thermolabile (tl)-MTHFR variantcaused by a C to T mutation at nucleotide 677 has been associated with elevatedplasma homocysteine levels

re-A recent metanalysis of nine clinical studies found that individuals withhomocysteine levels in excess of the 95th percentile had an overall threefoldincrease in risk of VTE (Fig 7) (35) As discussed above, risks associated withhyperhomocysteinemia are further increased in the presence of other inheriteddefects such as factor V Leiden

VII FACTOR XI

Factor XI is a component of the intrinsic pathway that contributes to thrombingeneration A recent study from the Leiden Thrombophilia group showed highplasma levels of factor XI are associated with an increased risk of VTE (36).Patients with factor XI levels above the 90th percentile were associated with anadjusted odds ratio of 2.2 for VTE when compared to those with levels belowthe 90th percentile This risk was maintained when patients with known geneticrisk factors for thrombosis were excluded There was a linear relationship be-tween increasing factor XI levels and risk of VTE

The relative risk associated with factor XI did not vary according to age.The risk of VTE, however, is strongly associated with age, with an annual inci-dence of approximately 1 per 10,000 in the young increasing to nearly 1 in 100

in the elderly Thus, in absolute terms, the effect of high factor XI levels is likely

to be most important in the elderly