High levels of factor XI and the risk of venous thrombosis

T h e N e w E n g l a n d J o u r n a l of M e d i c i n c

HIGH LEVELS OF COAGULATION FACTOR XI AS A RISK FACTOR

FOR VENOUS THROMBOSIS

JOOST C.M. MEIJERS, PH.D., WINNIE L.H. TEKELENBURG, M.Sc., BONNO N. BOUMA, PH.D., ROGIER M. BERTINA, PH.D.,

AND pRITS R. ROSENDAAL, M.D.

ABSTRACT

Background Factor XI, a component of the intrin-sic pathway of coagulation, contributes to the gener-ation of thrombin, which is involved in both the for-mation of fibrin and protection against fibrinolysis. A deficiency of factor XI is associated with bleeding, but a role of high factor XI levels in thrombosis has not been investigated.

Methods We determined factor XI antigen levels in the patients enrolled in the Leiden Thrombophilia Study, a large population-based, case-control study (with a total of 474 patients and 474 controls) de-signed to estimate the contributions of genetic and acquired factors to the risk of deep venous thrombo-sis. Odds ratlos were calculated äs a measure of rel-ative risk.

Results The age- and sex-adjusted odds ratio for deep venous thrombosis in subjects who had factor XI levels above the 90th percentile, äs compared with those who had factor XI levels at or below that value, was 2.2 (95 percent confidence intervai, 1.5 to 3.2). There was a dose-response relation between the fac-tor XI level and the risk of venous thrombosis. Adjust-ment of the odds ratios for other risk factors such äs oral-contraceptive use, homocysteine, fibrinogen, fac-tor VIII, female sex, and older age did not alter the re-sult. Also, when we excluded subjects who had known genetic risk factors for thrombosis (e.g., protein C or S deficiency, antithrombin deficiency, the factor V Lei-den mutation, orthe prothrombin G20210A mutation), the odds ratio remained the same, indicating that the risk of venous thrombosis associated with elevated levels of factor XI was not the result of one of the known risk factors for thrombosis.

Conclusions High levels of factor XI are a risk fac-tor for deep venous thrombosis, with a doubling of the risk at levels that are present in 10 percent of the Population. (N Engl J Med 2000;342:696-701.)

©2000, Massachusetts Medical Society

F

ACTOR XI is a component of the intrmsic

pathway of coagulation. It can be activated in

vitro by contact with a thrombogenic surface,

such äs glass. Whcther surface contact con

tributcs to the activation of factor XI in vivo,

how-cvcr, is unccrtain. Factor XI can also bc activated by

thrombin (Fig. 1), both in the presence and in the

abscncc of negativcly chargcd surfaces.

Through a

fecdback mcchanism, the thrombin level increases,

which is nccessary for the formation of fibrin and for

protection against fibrinolysis.

Thrombin mcdiates

this latter mechanism by activatmg

thrombin-activat-able fibrinolysis Inhibitor,

·

also called

procarboxy-peptidase B

or procarboxypeptidase U." Once

acti-vated, it inhibits fibrinolysis by removing C-termmal

lysine residues from fibrin, which are essential for the

binding and activation of plasminogen.

Factor XI deficiency rcsults in a mild-to-moderate

blccdmg disordcr, especially in tissues with high levels

of local fibrinolytic activity (such äs the urinary tract,

nose, oral cavity, and tonsils).

·

On the basis of the

in vitro data summarized above, the role of factor XI

in hemostasis can be seen äs a combmation of a

pro-coagulant action (the formation of fibrin) and an

antifibrinolytic action (the protection of fibrin).

In a

rabbit model, the lysis of clots was enhanced by the

Inhibition of factor XI.

The role of factor XI in thrombosis m humans is

unclear. We evaluated the effect of high levels of factor

XI on the risk of venous thrombosis äs part of the

Lei-den Thrombophilia Study, a large population-based,

case-control study designed to estimate the

contri-butions of genetic and acquired factors to the risk of

venous thrombosis.

METHODS

Patients and Controls

The mcthods by which blood samplcs \\erc obtained and data werc collected havc been dcscubcd clscwheic 16 1<; We enrolled consccutivc patients undei the age of 70 vears who had had a first cpisodc of deep venous thrombosis (objccwely confirmed by im pcdancc plethvsmographv, Doppier ultrasonography, compression ulüasonography, or contrast \enographv) between 1988 and 1993 and who were not known to ha\e cancer The patients were se lectcd from the files of three antieoagulation clmics m the Nether lands (in Leiden, Amstcidam, and Rottadam) These clmics mon itor the antieoagulant treatment of \irtuallv all patients in thice well-defined regions Each patient was asked to find a neighbor or fnend of the samc sex and age (\\ithm fne vears) without deep \cnous thrombosis who A\as \\ilhng to participate äs a control sub ject Partners of patients were also asked to volunteer äs control subjccts If a patient was unable to find a control subject, the first pci son on the list of partners who was the same age and sex äs the patient was asked to participate in the studv A total of 225 of the 474 control subjects (47 peicent) \\cie partneis of other patients The study protocol was appio\cd by the Leiden Umversity ethics committec, and all participants ga\c informed consent

Hom the Thrombosis and HemostaMS Laboratoiv, Dcpaitmcnt of HL matologv, Um\ crsm Mcdieal Ccntci (J C M M , W L H T, B N B ), and tlx Institute of Biomcmbrancs (IC M M , B N B ), Unecht Uimcrsitv, Utrecht and the HemostaMb and IhiomboMS Rcscaich Center (R M B , l· R R l and the Dcpaitmcnt of Clinical Epidcmiolog\ (FR R ) , Leiden Um\crsi!\ Mcdical Ccntci, Leiden — both in the Ncthcrlands Addrcss reprmt a quests to Dr MCIJCIS at the Department of Vascular Mcdlcme, Gl 1-f"1.

Acadcmic Mcdical Ccntci, PO Bo\ 22660, 1100 DD Amsterdam, the Ncthcrlands, 01 at ) c mci]c!s@amc u \ a nl

HIGH LEVELS OF FACTOR XI AS A RISK FACTOR FOR VENOUS THROMBOS1S

Contact-induced activation

i

Xa+Va ·.·.— ••·_·,._.·.·.ρ>lla

TFPI

Fibrinolysis A

Figure 1. Model of Blood Coagulation.

Coagulation is initiated by tissue factor (TF), which binds to factor Vlla. This complex activates factor IX or factor X, which leads to the activation of thrombin (factor lla) and the formation of fibrin. Tissue-factor-dependent Coagulation is rapidly inhibited by tissue-factor-pathway inhibitor (TFPI). Coagulation is maintained through the activation of factor XI by thrombin. Through the intrinsic tenase complex (factors IXa and Villa) and the prothrombinase complex (factors Xa and Va), the additional thrombin required to down-regulate fibrinolysis is generated by the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Activated TAFI (TAFIa) down-regulates fibrinolysis by removing C-terminal lysine residues involved in the binding and activation of plasminogen. Although the contact System is a potent activator of the coagulation System in vitro, it is not a Physiologie activator of Coagulation. The solid arrows indicate activation, and the broken arrows Inhibition. The solid arrow from factor Xa to TFPI indicates that factor Xa has to form a complex with TFPI and that this complex then inhibits TF-Vlla. The increasing width of the arrows indicates the cascade effect. Modified from Bouma et al.1

Laboratory Studies

Blood was collected in tubes containing 0.106 M trisodium cit-rate. Plasma was prepared by centrifugation at 2000 Xj· at room temperaturc and was stored at -70°C. Blood samplcs were ob-tained from patients at käst six months after the thrombotic event and at least thrcc months after the discontinuation of treatment with an oral anticoagulant. Plasma samplcs were available for 473 of the 474 patients and for all 474 controls.

Factor XI antigen was measured by cnzyme-linked immunosor-bent assay with a monoclonal antibody (XI-5)20 used for capture and a rabbit polyclonal antibody2' used for detection. The results are exprcssed äs a percentagc, with 100 percent equivalent to the factor XI antigen Icvel in poolcd plasma samples from 40 healthy volunteers. Each sample was assayed on a single occasion at two di-lutions in duplicate. The intraassay and interassay coefficients of Vari-ation were 4.6 and 7.0 percent in 14 and 70 assays, respectively. All antigen mcasuremcnts were performed during a threc-month period betwecn 1998 and 1999, without knowledge of whether the sample was from a patient or a control subject. Protein C, pro-tein S, and antithrombin were also measured, since deficiencies of these proteins are associated with an increased risk of venous thrombosis.16

Statistical Analysis

We performed two sets of analyses: onc to identify the deter-minants of factor XI Icvels, and the other to establish the contri-bution of high plasma factor XI Icvels to the risk of thrombosis. Dc-terminants of factor XI levels were examined in the controls, since they represented the gencral population. We used a comparison of means and linear regression, and we report means, medians, and regression coefficients, with 95 percent confidence intcrvals for these coefficients.

The contribution of an elevated factor XI Icvel to the risk of

venous thrombosis was analyzed by calculating odds ratios äs esti-mates of the relative risk. Since cutoff points for factor XI plasma values are essentially arbitrary, wc used percentiles of the distribu-tion among controls äs cutoff points. We used the 90th and 95th percentiles and also performed an analysis by quartilcs. In all thcsc analyses, the group with the lowest factor XI Icvels (i.e., those at the 90th percentile or below, the 95th percentilc or below, and the 25th percentile or below, respectively) scrved äs the reference category for odds ratios. Ninety-five percent confidence intcrvals were calculated according to the mcthod of Woolf22 or were de-rived from the logistic modcl. We used multivariate modeling by unconditional logistic regression to adjust for sex and age and oth-cr putative confounding variables. Age was analyzed äs a contin-uous variable and äs a dichotomous variable (<30 years, 30 to 50 years, or >50 years). Other variables included in the multivariate model were oral contraceptives (no use or use just before the thrombotic episode), factor V Leiden (noncarrier or carricr [AA and AG]),2·' the prothrombin G20210A mutation (noncarrier or carricr),24 C-reactive protein (continuous variable), hornocysteine (>18.5 /j,mol per liter or =518.5 μηιοί per liter), factor VIII:C (>150 IU per deciliter or =S150 IU per deciliter), and fibrinogen (>4 g per liter [11.8 μιτιοί per liter] or =S4 g per liter). Adjust-ment for thrombophilic abnormalities was performed in a separate analysis. We detcrmined whether the odds ratio increased linearly with incrcasing levels of factor XI by comparing two logistic mod-cls: one that assumcd a linear trend and one that did not (the dummy-variable model). The two models were compared with the likelihood-ratio test, which has a chi-square distribution.

To assess the effect on public health of a high factor XI level äs a risk factor for venous thrombosis, we calculated the population attributable risk. This risk indicates the proportion of all cvents attributable to the risk factor undcr study, on the basis of certain assumptions, including the assumption that the association is caus-al. One can also view the population attributable risk äs the

T h e Nc\\ E n g l a n d J o u r n a l of M c d i c i n e

bcr of c \ c n t s t h a t \ \ i l l bc prcventcd if the nsk factor is rcmo\cd. It LS dcfmed äs the chffcrcnce bctuccn the overall mcidcncc of thc c \ e n t and the mcidcncc m persons « h o do not havc thc nsk fac-tor and is exprcxscd, o s a proportion of thc o \ e n l l mcidcncc Thc population attnhutablc n<k is dem cd f i o m thc relitive nsk and thc prexalcncc of ihc nsk hctor2 1

BJBSULTS

Thc mean .ige of thc patients .ind controls was 45 years, and thc ratio of the males to fcmalcs was ap-proximatcly 3:4 (Tablc 1). Thc mean (±SD) factor XI Icvel in thc control subjccts was 97.0^:19.5 per-ccnt, äs comp.ired \\rith 104.2±22.6 pcrccnt in thc

patients (P<0.001), and was slightly higher in fc-male controls than in fc-male controls (Tablc 2). Figurc 2 shows the distribution of factor XI Icvels in pa-tients and controls. Thc levels wcre normally distrib-utcd and incrcascd with age; thcrc was a 0.19 pcr-cent increase (95 pcrccnt confidcncc interval, 0.07 to 0.30 pcrccnt) with cach addition-il ycar of agc. As Tablc 2 shows, mcan factor XI Icvels in the control subjccts werc 7 pcrcent lowcr in thosc under 30 ycars of agc than in thosc over 50 ycars.

Thc 90th percentilc of thc factor XI Icvels in thc control group was 120.8 pcrcent. Of the 473 patients, 92 (19 pcrccnt) had valucs that exceedcd this cutoff point, äs comparcd \\'ith 47 of the 474 subjccts in thc control group (10 percont, by defmition). The unadjustcd odds ratio for dcep vcnons thrombosis in patients with a factor XI Icvel .ibovc the 90th pcr-centile (Tablc 3), äs comparcd with thosc who had a lowcr valuc, \\as 2.2 (95 pcrcent confidcncc inter-\-al, 1.5 to 3.2). The scx- and age-adjusted odds ratio

was also 2.2 (95 pcrccnt confidcncc interval, 1.5 to 3.2). VVhen the cutoff point was sct at the 95th per-centilc (130.2 pcrccnt), the odds ratio was 2.3 (95 perccnt confidcnce interval, 1.4 to 3.9).

The relative risk of venous thrombosis associated with a factor XI Icvel above thc 90th percentilc was slightly higher in mcn (odds ratio, 3.2; 95 pcrcent confidcncc interval, 1.7 to 6.3) than in womcn (odds ratio, 1.8; 95 pcrcent confidcnce interval, 1.1 to 2.8); the differcnce was not statistically significant (P~ 0.15). The relative risk was similar in different agc groups: 2.5 (95 pcrccnt confidcnce interval, 0.8 to 7.4) for patients youngcr than 30 ycars of agc, 2.0 (95 pcrcent confidcnce intcrval, 1.1 to 3.4) for thosc bc-twcen 30 and 50 ycars, and 2.4 (95 pcrccnt confidcncc interval, 1.3 to 4.4) for those oldcr t h a n 50 ycars.

To dctcrminc whether thcrc was a dose—rcsponse rclation bctwccn thc factor XI Icvel and thc risk of thrombosis, we stratificd thc subjccts arcording to the factor XI Icvel, and odds ratios werc calculued for vcnous thrombosis in the patients at the higher levels äs compared with thosc at the lowest Icvel. As shown in Figurc 3, thc relative risk of thrombosis incrcascd with thc factor XI levcl, indicating a continuous dosc-responsc relation. Indeed, a b'ne-ir modcl described thc relative risk associated with incrcasing levels of factor

TABLE 1. CH\RAC i m i s n c s 01 P A i i t \ r s

U 11 H Vl \Ol s I'HROMBOSIS A N D ΓΟΧΓΚΟΙ Sl BIK IS

CHARACTERISTIC

AgL (M ) Mcan

Mediän Range Sc\ (M/l·)

Protun C, <0 67 U/ml (no )* Piotem S, <() 67 U/m] (no )* A n t i t h m m b m , <0 80 U/ml (no )* taetoi V Leiden (no )|

Prothiomhin G20210A (no )|

PATIENTS

(N = 473|

CONTROLS

|I\J = 474]

45 0 45 3 14-69 202/271

15 3 5 92 29

4 4 7 45 3 14-72 202/27.

4 6 1 14 11

\ \ i t h t\\o separate *Data ate for abnormal tiAuits of

samplcs fiom e.ich patient

f b i g h t p.Tticnts \\crc homo/\gous (.anicis, and all the

ncrs among the controls \\tit. ht.rero/\goiis

|A11 L a n i c i s \\ere hcrerozxgous

TABLE 2. I - A C I O K XI Li \ n s i\ COMROI S l B f i - C l S ACC ORDINO K) Sl \ \ND AGh

VARIABLE

No OF

SUBJECTS FACTOR XI

Cheull Sex

Male 1-em.lie Agc

<30 \ r 30-50 M >50 \ i

4 7 t

202 2~2

~7 224 173

9 7 0 ± 1 9 5

95 2 ± 1 9 4 98 3±19 5

91 S ± 1 8 9 973±19 1 9 9 0 ± 2 0 0

XI äs well äs a less stringent model with dummy var-iables (P>0.5).

We pcrformed separate anahses adjusted for each of sever.il putative confounding \ ariables. The odds ratio associated with a factor XI level that exceedcd the 90th percentilc was 2.2 (95 pcrccnt confidencc inter-val, 1.5 to 3.3) when adjusted for oral contraccpthe usc, 2.3 (95 pcrcent confidcncc intcnal, 1.5 to 3.3) when adjusted for a homocysteinc level higher than 18.5 μηιοί per liter, 2.1 (95 perccnt confidencc

intcr-\'al, 1.4 to 3.1) when adjusted for a fibrinogen level higher than 4 g per litcr, 1.9 (95 pcrccnt confidencc interval, 1.3 to 2.8) when adjusted for a factor VIII Icvel higher than 150 IU per decüitcr, 2.1 (95 per-ccnt confidence interval, 1.4 to 3.1) when adjusted for the C-rcactive protein levcl, 2.2 (95 percent

HIGH LEVELS OF FACTOR XI AS A RISK FACTOR FOR VENOUS THROMBOSIS

o CD LL

150-,

125-

100-

75-50

Patients Controls

Figure 2. Factor XI Levels in Patients and Control Subjects In each box plot, the Iower and upper bars represent the 10th and 90th percentiles, respectively; the Iower and upper ends of the box represent the 25th and 75th percentiles, respectively, and the Ime inside the box represents the median factor XI level.

TABLE 3. RISK o? THROMBOSIS ACCORDINC, το FAC IOR XI Livn

FACTOR XI* (N = 473)PATIENTS CONTROLS (N=474) (95% Cl)t ODDS RATIO

s90th Perccnole >90th Pcrccntilc =595th Pcrccntilc >95th Perccntilc

381 92

423 50

427 47

451 23

1 0 2 2 (1 5-32)

1 0 2 3 (1 4-39)

*The 90th and 95th percentiles of factor XI lexcls in control subjccts wcre 120 8 and 130 2 percent, re spcctivch, with 100 pcrctnt eqimalcnt to the factor XI antigen levcl in poolcd plasma samples from 40 hcalthv voluntccrs

fThe odds ratio is for the higher pcrccntilc äs com pared \\ith tht lo\\er puccntilc CI dcnotcs confi dcncc intcrval

fidence interval, 1.5 to 3.2) when adjusted for factor V Leiden, and 2.3 (95 percent confidence interval, 1.6 to 3.3) when adjusted for prothrombin G20210A. All these odds ratios were also adjusted for age and sex. When patients with known genetic risk factors for thrombosis (i.e., protein C deficiency, protein S defi-ciency, antithrombin defidefi-ciency, the factor V Leiden mutation, or the prothrombin G20210A mutation) were excluded from the analysis, the odds ratio for venous thrombosis m patients with factor XI levels exceeding the 90th percentile remained 2.2 (95 per-cent confidence interval, 1.5 to 3.3).

co er

(Λ

TD T3

O

Quartile

Figure 3. Odds Ratio for Thrombosis Accordmg to the Factor XI Level.

The patients and control subjects were stratified in quartiles ac-cording to the factor XI level (first quartile, =s83.3 percent, sec-ond quartile, «94.8 percent; third quartile, «110 0 percent; and fourth quartile, >110.0 percent), with 100 percent equivalent to the factor XI antigen level m pooled plasma samples from 40 healthy volunteers. Odds ratios for thrombosis were calculated in the patients m the second, third, and fourth quartiles, äs com pared with those m the first quartile. The 95 percent confidence mtervals were 0.8 to 1.8 for the second quartile, 1.0 to 2 2 for the third, and 1.7 to 3.3 for the fourth.

In the most fully adjusted modcl (adjustcd for age, sex, a high level of factor VIII, a high fibrinogcn lev-el, hyperhomocysteinemia, use of oral contraceptives, factor V Leiden, the prothrombin 20210A allclc, and the C-rcactive protein levcl), the odds ratio associatcd with a factor XI level that excceded 120.8 percent (90th percentile) was 1.9 (95 percent confidence in-terval, 1.3 to 2.9). This result indicated that the risk of thrombosis associated with a high level of factor XI was not the result of one of these underlymg abnor-malitics.

DISCUSSION

Wc found that a high lc\cl of factor XI (defined äs a value above the 90th percentile of the distribution of valucs in control subjects) was a risk factor for venous thrombosis, with a relative risk of 2.2 (95 per-cent confidence interval, 1.5 to 3.2) äs compared with Iower levels. Our findings were not due to the cffects of oral-contraccptive use, sex, or age. Also, known ge-netic risk factors, such äs protein C deficiency, pro-tein S deficiency, antithrombin deficiency, the factor V Leiden mutation, or the prothrombin G20210A

T h e N e w E n g l a n d J o u r n a l of M c d i c i n c

mutation, did not explain the incrcascci risk of throm-bosis associated with a high levcl of factor XI. High factor XI levels werc associated with a slightly higher relative risk of thrombosis for mcn than for women. Sincc therc is 110 obvious biologic mcchanism for such a sex-specific difference in the effect of factor XI on the risk of thrombosis, wc think this finding may well havc been due to chance.

The relative risk associated with a high factor XI lev-el did not vary according to age. Venous thrombosis is strongly associated with age, with annual incidcnce rates increasing from less than l case per 10,000 young adults to nearly l per 100 elderly persons.26

Whcn a similar relative risk is applied to these inci-dence rates, the result, in absolute terms, is a larger ef-fect of a high level of factor XI in the elderly. This effect is compounded by the increase in factor XI lev-els with increasing age.

The relative risk of 2.2 associated with a factor XI level present in 10 pcrcent of the population leads to the conclusion that a high factor XI level is an impor-tant contributor to the overall bürden of vcnous thrombosis. On the basis of diese data, the popula-tion attributable risk of thrombosis is 11 percent (i.e., 11 percent of all cascs of thrombosis in the gen-eral population may be attributable to high factor XI levels).25

Our understanding of the role of factor XI in he-mostasis has changed considerably ovcr the past 20 years. Initially, factor XI was thought to be involvcd in the Initiation of coagulation, äs a component of die contact systcm. The contact System consists of fac-tor XI, facfac-tor XII, prckallikrcin, and high-molecular-weight kiiiiiiogen, and the System is activated in vi-tro when these proteins are exposed to a negatively charged surface such äs glass. However, the role of the contact System in coagulation in vivo is doubtful, because of the absence of blceding complications in patients with defidencies of contact factors other than factor XI and the absence of a physiologic activating surface.

Factor XI deficiency results in a wide ränge of bleed- l ing manifestations, from asymptomatic blecding to ! injury-rclated bleeding that requires multiple trans-fusions.27'28 Unlike hemophilia A or B, factor XI de- j

ficiency is rarely manifested äs spontancous bleeding; | the associated bleeding usually occurs after trauma, t surgcry, or other ehallenges to hemostasis.29 This

find-ing indicates that factor XI is activated durfind-ing coag-ulation by one or more enzymes other than factor · Xlla. The finding that thrombin can activate factor XI2·3 has led to a revised model of coagulation3·30 in l

which factor XI contributcs to the secondary gener-ation of thrombin (in contrast to the pnmary genera-tion of thrombin that is due to the extrinsic pathway of coagulation). This revised modcl explains the par-ticularly severe bleeding complications in patients with a deficiencv of factor VIII or IX, because these

fac-tors are involved in both pnmary and secondary thrombin generation. However, this model does not explain the predominance of bleeding in tissues with high levels of local fibrinolytic activity (the urinary tract, nose, oral cavity, and toiisils) in patients with faetor XI deficiency.1314 The location of the bleeding

may be explained, howcver, by the role of secondary thrombin generation in the regulation of fibrinoly-sis7 through the activation of thrombin-activatable

fi-brinolysis inhibitor.8·9

The role of factor XI in coagulation is twofold: by generating thrombin, it both contributes to the for-mation of fibrin and helps protect fibrin from rapid proteolysis.1 It was therefore our hypothesis that with

high levels of factor XI, the secondary generation of thrombin would be enhanced or sustaiiied, leading to a prolonged down-regulation of fibrinolysis and there-fore a risk of thrombosis. The risk of thrombosis asso-ciated with high le\'els of factor XI may be explained by the role of factor XI in the down-rcgulation of fi-brinolysis. The Km for the activation of factor XI by

thrombin is 50 nM,3 which is within the ränge of the

plasma level of factor XI (30 to 60 nM).3 This suggcsts

that, at least kinetically, an increase in the factor XI level should lead to an increased rate of activation.

The first abiiormalitics in the clottiiig System that were found to be associated with an increased risk of venous thrombosis were deficiencies of antithrombin, protcin C, and protein S. These deficiencies are gen-erally the result of major genetic disruptions that lead to loss of the protein's natural anticoagulant activity. Prothrombotic abnormalities that are the result of more subtle genetic alterations and a gain of function include factor V Leiden (a mutated factor V, which is less sensitive to inactivation)31 and increased levels

of three clotting factors (factor VIII,18 prothrombin,24

and fibrinogen32). Until now, the prothrombotic

cf-fects of elevated levels of these coagulation proteins were thought to be due to prolonged formation of fi-brin äs a result of excessive generation of thrombin. At least in the case of factor VIII and prothrombin, however, an alternative explanatioii may be that the sustained generation of thrombin results in prolonged down-regulation of fibrinolysis through the activa-tion of thrombin-activatablc fibrinolysis inhibitor.

In the case of prothrombin, the risk of thrombosis is associated with a mutation in the genc (G20210A) that may act through elevated levels.24 We are

cur-rcntly investigating whether elevated levels of factor XI may also be gcnetically determined.

In conclusion, an elevated factor XI level is a risk factor for venous thrombosis. We postulate that a high level of factor XI causes thrombosis through sus-tained generation of thrombin, \vhich leads to the protection of fibrin from proteolysis.

Suppoitcd in part b\ giants f i o m the Xcthcrlands Hcart Foundation (89063 and D96Ü21)

HIGH LEVELS OF FACTOR XI AS A RISK FACTOR FOR VENOUS THROMBOSIS

Wc an, ititicbud to Di<; FJ \I l an ritt Wen (Anticoatjulatton Leideti) LP Colh (Anticoaefulatwn thmc AnutLi Acitn) and PH h und ins (Anticoanulatiim Clmit Rottet dam) foi tbm assiitanci, toMis A Schitij > foi data manajft.meiit and to Mi A

Wmqwiitcmd Vfi i Vit ci fm a< iftana n ith tht labinaton studu.s

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14 Berliner S Horo\\itz I Martmovi itz U Bicnncr B Schgsohn U Den tal surger) in paticnts \\ith sc\crc factor XI dcficicncv \\ithout phsma ic placcmcnt Blood Coagul Fibnnohsis 1992 3 46S 8

15 Mmncma MC Fncdcnch PW Le\i M et al Enhancement of rabbit

j u i., u hi \cin thromboKsii b\ iicuti ih/itioi oi fictc r \I in \ i \ o c\idcncc foi i iolc of Hctoi \I is in inti hbnnohtic fictoi I ( Im Imcst 1998 101 10 4 [ F r n t u n J ( Im Imcst 1998 101 9 I " J

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17 kostci I Rosend-ul FR de Rondc H Briet F \nuicnbiouekc JP Bcrtina RA·! \ e n o u s thiombosis duc to pooi intieoiguhnt icsponse tt ie ti\ ited piotei i C Leiden Ihiombophiln Stud\ I incct 199τ 342 1ι03 6 18 Koste r l Bhnn \T> Bnet l \ m d c n b r o u e l e J P R o s e n d n l F R Role of elottnik fietot VIII in eflect of \on Willtbnnd he toi on oeeurrenec of dccp \ u n thiombosis I inect 199S 34τ 152 5

19 Vindcnbrouckc JP Kostci l Buct E Rutsim PH Bertini RM Rosendnl FR Incrcascd rtsk of \cnous thiombosis m oril eontriceptnc uscrs \\ho arc cairiers of fietor V I cidcn mutition Lmcct 1994 344 1453 7

20 Wuillemin WA Minnema M McijcisJCM et al Irnctuation oi faetoi XIi in human plismi isscssed b\ mcasunnL, factor XIa proicisc mhibitoi eomplcxes mijor rolc for Gl mhibitoi Blood 199S 85 1517 26 21 Boumi B\ Vloos\\i]k RAA Griffin JH Inimiinolot^ic studics of hu min coagulition fietoi XI md its compie\ \\ith hi^ii molccular \\cit,ht ki nmogen Blood 1983 62 1123 31

22 WoolfB On cstinntniL, thcrchtion h t\\ccn blood ^roup and diseist. Arm Hum Gcnct 195ö 19 251 3

23 RoscndaalFR Kostcr T Vindcnbrouckc JP Rcitsmi PH Hi^hnskoi

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1504 8

24 Poort SR RoscncliillR Rcitsmi PH Bcrtmi RM A eommon ge

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25 Rothnnn KJ Modern cpidemiolot,\ Boston I ittle Bio\\n 19S6 3i 40

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29 Idtm t-ieto! XI dcheicnc\ Ihromb Hicmost 1993 70 68 71 30 Di\ie l W Fu)iki\\i K Kisicl \\ Ihc coit,uUtion ciseide mit ition mamtcnmcc md icguhtion Biochcmistn 1991 3010363 70 31 Bcrtmi RM Ködern m BPC Kostci l et Ί! Mutition in blood et iL,uhtion factor V assoenled \\ith icsistmcc to icti\ ucd piotcm ( N atme 199436964 7

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