Background Factor XI, a component of the intrinsic pathway ofcoagulation, contributes to the generation of thrombin, whichis involved in both the formation of fibrin and protection againstfibrinolysis. A deficiency of factor XI is associated with bleeding,but a role of high factor XI levels in thrombosis has not beeninvestigated.
Methods We determined factor XI antigen levels in the patientsenrolled in the Leiden Thrombophilia Study, a large population-based,case–control study (with a total of 474 patients and 474controls) designed to estimate the contributions of geneticand acquired factors to the risk of deep venous thrombosis.Odds ratios were calculated as a measure of relative risk.
Results The age- and sex-adjusted odds ratio for deep venousthrombosis in subjects who had factor XI levels above the 90thpercentile, as compared with those who had factor XI levelsat or below that value, was 2.2 (95 percent confidence interval,1.5 to 3.2). There was a dose–response relation betweenthe factor XI level and the risk of venous thrombosis. Adjustmentof the odds ratios for other risk factors such as oral-contraceptiveuse, homocysteine, fibrinogen, factor VIII, female sex, andolder age did not alter the result. Also, when we excluded subjectswho had known genetic risk factors for thrombosis (e.g., proteinC or S deficiency, antithrombin deficiency, the factor V Leidenmutation, or the prothrombin G20210A mutation), the odds ratioremained the same, indicating that the risk of venous thrombosisassociated with elevated levels of factor XI was not the resultof one of the known risk factors for thrombosis.
Conclusions High levels of factor XI are a risk factor for deepvenous thrombosis, with a doubling of the risk at levels thatare present in 10 percent of the population.
Factor XI is a component of the intrinsic pathway of coagulation.It can be activated in vitro by contact with a thrombogenicsurface, such as glass. Whether surface contact contributesto the activation of factor XI in vivo, however, is uncertain.Factor XI can also be activated by thrombin (Figure 1), bothin the presence and in the absence of negatively charged surfaces.2,3,4,5,6,7Through a feedback mechanism, the thrombin level increases,which is necessary for the formation of fibrin and for protectionagainst fibrinolysis.7 Thrombin mediates this latter mechanismby activating thrombin-activatable fibrinolysis inhibitor,8,9also called procarboxypeptidase B10 or procarboxypeptidase U.11Once activated, it inhibits fibrinolysis by removing C-terminallysine residues from fibrin, which are essential for the bindingand activation of plasminogen.12
Coagulation is initiated by tissue factor (TF), which binds to factor VIIa. This complex activates factor IX or factor X, which leads to the activation of thrombin (factor IIa) 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 VIIIa) 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 physiologic 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–VIIa. The increasing width of the arrows indicates the cascade effect. Modified from Bouma et al.1
Factor XI deficiency results in a mild-to-moderate bleedingdisorder, especially in tissues with high levels of local fibrinolyticactivity (such as the urinary tract, nose, oral cavity, andtonsils).13,14 On the basis of the in vitro data summarizedabove, the role of factor XI in hemostasis can be seen as acombination of a procoagulant action (the formation of fibrin)and an antifibrinolytic action (the protection of fibrin).1In a rabbit model, the lysis of clots was enhanced by the inhibitionof factor XI.15
The role of factor XI in thrombosis in humans is unclear. Weevaluated the effect of high levels of factor XI on the riskof venous thrombosis as part of the Leiden Thrombophilia Study,a large population-based, case–control study designedto estimate the contributions of genetic and acquired factorsto the risk of venous thrombosis.
Methods
Patients and Controls
The methods by which blood samples were obtained and data werecollected have been described elsewhere.16,17,18,19 We enrolledconsecutive patients under the age of 70 years who had had afirst episode of deep venous thrombosis (objectively confirmedby impedance plethysmography, Doppler ultrasonography, compressionultrasonography, or contrast venography) between 1988 and 1993and who were not known to have cancer. The patients were selectedfrom the files of three anticoagulation clinics in the Netherlands(in Leiden, Amsterdam, and Rotterdam). These clinics monitorthe anticoagulant treatment of virtually all patients in threewell-defined regions. Each patient was asked to find a neighboror friend of the same sex and age (within five years) withoutdeep venous thrombosis who was willing to participate as a controlsubject. Partners of patients were also asked to volunteer ascontrol subjects. If a patient was unable to find a controlsubject, the first person on the list of partners who was thesame age and sex as the patient was asked to participate inthe study. A total of 225 of the 474 control subjects (47 percent)were partners of other patients. The study protocol was approvedby the Leiden University ethics committee, and all participantsgave informed consent.
Laboratory Studies
Blood was collected in tubes containing 0.106 M trisodium citrate.Plasma was prepared by centrifugation at 2000xg at room temperatureand was stored at –70°C. Blood samples were obtainedfrom patients at least six months after the thrombotic eventand at least three months after the discontinuation of treatmentwith an oral anticoagulant. Plasma samples were available for473 of the 474 patients and for all 474 controls.
Factor XI antigen was measured by enzyme-linked immunosorbentassay with a monoclonal antibody (XI-5)20 used for capture anda rabbit polyclonal antibody21 used for detection. The resultsare expressed as a percentage, with 100 percent equivalent tothe factor XI antigen level in pooled plasma samples from 40healthy volunteers. Each sample was assayed on a single occasionat two dilutions in duplicate. The intraassay and interassaycoefficients of variation were 4.6 and 7.0 percent in 14 and70 assays, respectively. All antigen measurements were performedduring a three-month period between 1998 and 1999, without knowledgeof whether the sample was from a patient or a control subject.Protein C, protein S, and antithrombin were also measured, sincedeficiencies of these proteins are associated with an increasedrisk of venous thrombosis.16
Statistical Analysis
We performed two sets of analyses: one to identify the determinantsof factor XI levels, and the other to establish the contributionof high plasma factor XI levels to the risk of thrombosis. Determinantsof factor XI levels were examined in the controls, since theyrepresented the general population. We used a comparison ofmeans and linear regression, and we report means, medians, andregression coefficients, with 95 percent confidence intervalsfor these coefficients.
The contribution of an elevated factor XI level to the riskof venous thrombosis was analyzed by calculating odds ratiosas estimates of the relative risk. Since cutoff points for factorXI plasma values are essentially arbitrary, we used percentilesof the distribution among controls as cutoff points. We usedthe 90th and 95th percentiles and also performed an analysisby quartiles. In all these analyses, the group with the lowestfactor XI levels (i.e., those at the 90th percentile or below,the 95th percentile or below, and the 25th percentile or below,respectively) served as the reference category for odds ratios.Ninety-five percent confidence intervals were calculated accordingto the method of Woolf22 or were derived from the logistic model.We used multivariate modeling by unconditional logistic regressionto adjust for sex and age and other putative confounding variables.Age was analyzed as a continuous variable and as a dichotomousvariable (<30 years, 30 to 50 years, or >50 years). Othervariables included in the multivariate model were oral contraceptives(no use or use just before the thrombotic episode), factor VLeiden (noncarrier or carrier [AA and AG]),23 the prothrombinG20210A mutation (noncarrier or carrier),24 C-reactive protein(continuous variable), homocysteine (>18.5 µmol perliter or 18.5 µmol per liter), factor VIII:C (>150IU per deciliter or 150 IU per deciliter), and fibrinogen (>4g per liter [11.8 µmol per liter] or 4 g per liter). Adjustmentfor thrombophilic abnormalities was performed in a separateanalysis. We determined whether the odds ratio increased linearlywith increasing levels of factor XI by comparing two logisticmodels: one that assumed a linear trend and one that did not(the dummy-variable model). The two models were compared withthe likelihood-ratio test, which has a chi-square distribution.
To assess the effect on public health of a high factor XI levelas a risk factor for venous thrombosis, we calculated the populationattributable risk. This risk indicates the proportion of allevents attributable to the risk factor under study, on the basisof certain assumptions, including the assumption that the associationis causal. One can also view the population attributable riskas the number of events that will be prevented if the risk factoris removed. It is defined as the difference between the overallincidence of the event and the incidence in persons who do nothave the risk factor and is expressed as a proportion of theoverall incidence. The population attributable risk is derivedfrom the relative risk and the prevalence of the risk factor.25
Results
The mean age of the patients and controls was 45 years, andthe ratio of the males to females was approximately 3:4 (Table 1).The mean (±SD) factor XI level in the control subjectswas 97.0±19.5 percent, as compared with 104.2±22.6percent in the patients (P<0.001), and was slightly higherin female controls than in male controls (Table 2). Figure 2shows the distribution of factor XI levels in patients and controls.The levels were normally distributed and increased with age;there was a 0.19 percent increase (95 percent confidence interval,0.07 to 0.30 percent) with each additional year of age. As Table 2shows, mean factor XI levels in the control subjects were7 percent lower in those under 30 years of age than in thoseover 50 years.
Figure 2. Factor XI Levels in Patients and Control Subjects.
In each box plot, the lower and upper bars represent the 10th and 90th percentiles, respectively; the lower and upper ends of the box represent the 25th and 75th percentiles, respectively; and the line inside the box represents the median factor XI level.
The 90th percentile of the factor XI levels in the control groupwas 120.8 percent. Of the 473 patients, 92 (19 percent) hadvalues that exceeded this cutoff point, as compared with 47of the 474 subjects in the control group (10 percent, by definition).The unadjusted odds ratio for deep venous thrombosis in patientswith a factor XI level above the 90th percentile (Table 3),as compared with those who had a lower value, was 2.2 (95 percentconfidence interval, 1.5 to 3.2). The sex- and age-adjustedodds ratio was also 2.2 (95 percent confidence interval, 1.5to 3.2). When the cutoff point was set at the 95th percentile(130.2 percent), the odds ratio was 2.3 (95 percent confidenceinterval, 1.4 to 3.9).
Table 3. Risk of Thrombosis According to Factor XI Level.
The relative risk of venous thrombosis associated with a factorXI level above the 90th percentile was slightly higher in men(odds ratio, 3.2; 95 percent confidence interval, 1.7 to 6.3)than in women (odds ratio, 1.8; 95 percent confidence interval,1.1 to 2.8); the difference was not statistically significant(P= 0.15). The relative risk was similar in different age groups:2.5 (95 percent confidence interval, 0.8 to 7.4) for patientsyounger than 30 years of age, 2.0 (95 percent confidence interval,1.1 to 3.4) for those between 30 and 50 years, and 2.4 (95 percentconfidence interval, 1.3 to 4.4) for those older than 50 years.
To determine whether there was a dose–response relationbetween the factor XI level and the risk of thrombosis, we stratifiedthe subjects according to the factor XI level, and odds ratioswere calculated for venous thrombosis in the patients at thehigher levels as compared with those at the lowest level. Asshown in Figure 3, the relative risk of thrombosis increasedwith the factor XI level, indicating a continuous dose–responserelation. Indeed, a linear model described the relative riskassociated with increasing levels of factor XI as well as aless stringent model with dummy variables (P>0.5).
Figure 3. Odds Ratio for Thrombosis According to the Factor XI Level.
The patients and control subjects were stratified in quartiles according to the factor XI level (first quartile, 83.3 percent; second 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 in pooled plasma samples from 40 healthy volunteers. Odds ratios for thrombosis were calculated in the patients in the second, third, and fourth quartiles, as compared with those in the first quartile. The 95 percent confidence intervals 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.
We performed separate analyses adjusted for each of severalputative confounding variables. The odds ratio associated witha factor XI level that exceeded the 90th percentile was 2.2(95 percent confidence interval, 1.5 to 3.3) when adjusted fororal contraceptive use, 2.3 (95 percent confidence interval,1.5 to 3.3) when adjusted for a homocysteine level higher than18.5 µmol per liter, 2.1 (95 percent confidence interval,1.4 to 3.1) when adjusted for a fibrinogen level higher than4 g per liter, 1.9 (95 percent confidence interval, 1.3 to 2.8)when adjusted for a factor VIII level higher than 150 IU perdeciliter, 2.1 (95 percent confidence interval, 1.4 to 3.1)when adjusted for the C-reactive protein level, 2.2 (95 percentconfidence interval, 1.5 to 3.2) when adjusted for factor VLeiden, and 2.3 (95 percent confidence interval, 1.6 to 3.3)when adjusted for prothrombin G20210A. All these odds ratioswere also adjusted for age and sex.
When patients with known genetic risk factors for thrombosis(i.e., protein C deficiency, protein S deficiency, antithrombindeficiency, the factor V Leiden mutation, or the prothrombinG20210A mutation) were excluded from the analysis, the oddsratio for venous thrombosis in patients with factor XI levelsexceeding the 90th percentile remained 2.2 (95 percent confidenceinterval, 1.5 to 3.3).
In the most fully adjusted model (adjusted for age, sex, a highlevel of factor VIII, a high fibrinogen level, hyperhomocysteinemia,use of oral contraceptives, factor V Leiden, the prothrombin20210A allele, and the C-reactive protein level), the odds ratioassociated with a factor XI level that exceeded 120.8 percent(90th percentile) was 1.9 (95 percent confidence interval, 1.3to 2.9). This result indicated that the risk of thrombosis associatedwith a high level of factor XI was not the result of one ofthese underlying abnormalities.
Discussion
We found that a high level of factor XI (defined as a valueabove the 90th percentile of the distribution of values in controlsubjects) was a risk factor for venous thrombosis, with a relativerisk of 2.2 (95 percent confidence interval, 1.5 to 3.2) ascompared with lower levels. Our findings were not due to theeffects of oral-contraceptive use, sex, or age. Also, knowngenetic risk factors, such as protein C deficiency, proteinS deficiency, antithrombin deficiency, the factor V Leiden mutation,or the prothrombin G20210A mutation, did not explain the increasedrisk of thrombosis associated with a high level of factor XI.High factor XI levels were associated with a slightly higherrelative risk of thrombosis for men than for women. Since thereis no obvious biologic mechanism for such a sex-specific differencein the effect of factor XI on the risk of thrombosis, we thinkthis finding may well have been due to chance.
The relative risk associated with a high factor XI level didnot vary according to age. Venous thrombosis is strongly associatedwith age, with annual incidence rates increasing from less than1 case per 10,000 young adults to nearly 1 per 100 elderly persons.26When a similar relative risk is applied to these incidence rates,the result, in absolute terms, is a larger effect of a highlevel of factor XI in the elderly. This effect is compoundedby the increase in factor XI levels with increasing age.
The relative risk of 2.2 associated with a factor XI level presentin 10 percent of the population leads to the conclusion thata high factor XI level is an important contributor to the overallburden of venous thrombosis. On the basis of these data, thepopulation attributable risk of thrombosis is 11 percent (i.e.,11 percent of all cases of thrombosis in the general populationmay be attributable to high factor XI levels).25
Our understanding of the role of factor XI in hemostasis haschanged considerably over the past 20 years. Initially, factorXI was thought to be involved in the initiation of coagulation,as a component of the contact system. The contact system consistsof factor XI, factor XII, prekallikrein, and high-molecular-weightkininogen, and the system is activated in vitro when these proteinsare exposed to a negatively charged surface such as glass. However,the role of the contact system in coagulation in vivo is doubtful,because of the absence of bleeding complications in patientswith deficiencies of contact factors other than factor XI andthe absence of a physiologic activating surface.
Factor XI deficiency results in a wide range of bleeding manifestations,from asymptomatic bleeding to injury-related bleeding that requiresmultiple transfusions.27,28 Unlike hemophilia A or B, factorXI deficiency is rarely manifested as spontaneous bleeding;the associated bleeding usually occurs after trauma, surgery,or other challenges to hemostasis.29 This finding indicatesthat factor XI is activated during coagulation by one or moreenzymes other than factor XIIa. The finding that thrombin canactivate factor XI2,3 has led to a revised model of coagulation3,30in which factor XI contributes to the secondary generation ofthrombin (in contrast to the primary generation of thrombinthat is due to the extrinsic pathway of coagulation). This revisedmodel explains the particularly severe bleeding complicationsin patients with a deficiency of factor VIII or IX, becausethese factors are involved in both primary and secondary thrombingeneration. However, this model does not explain the predominanceof bleeding in tissues with high levels of local fibrinolyticactivity (the urinary tract, nose, oral cavity, and tonsils)in patients with factor XI deficiency.13,14 The location ofthe bleeding may be explained, however, by the role of secondarythrombin generation in the regulation of fibrinolysis7 throughthe activation of thrombin-activatable fibrinolysis inhibitor.8,9
The role of factor XI in coagulation is twofold: by generatingthrombin, it both contributes to the formation of fibrin andhelps protect fibrin from rapid proteolysis.1 It was thereforeour hypothesis that with high levels of factor XI, the secondarygeneration of thrombin would be enhanced or sustained, leadingto a prolonged down-regulation of fibrinolysis and thereforea risk of thrombosis. The risk of thrombosis associated withhigh levels of factor XI may be explained by the role of factorXI in the down-regulation of fibrinolysis. The Km for the activationof factor XI by thrombin is 50 nM,3 which is within the rangeof the plasma level of factor XI (30 to 60 nM).3 This suggeststhat, at least kinetically, an increase in the factor XI levelshould lead to an increased rate of activation.
The first abnormalities in the clotting system that were foundto be associated with an increased risk of venous thrombosiswere deficiencies of antithrombin, protein C, and protein S.These deficiencies are generally the result of major geneticdisruptions that lead to loss of the protein's natural anticoagulantactivity. Prothrombotic abnormalities that are the result ofmore subtle genetic alterations and a gain of function includefactor V Leiden (a mutated factor V, which is less sensitiveto inactivation)31 and increased levels of three clotting factors(factor VIII,18 prothrombin,24 and fibrinogen32). Until now,the prothrombotic effects of elevated levels of these coagulationproteins were thought to be due to prolonged formation of fibrinas a result of excessive generation of thrombin. At least inthe case of factor VIII and prothrombin, however, an alternativeexplanation may be that the sustained generation of thrombinresults in prolonged down-regulation of fibrinolysis throughthe activation of thrombin-activatable fibrinolysis inhibitor.
In the case of prothrombin, the risk of thrombosis is associatedwith a mutation in the gene (G20210A) that may act through elevatedlevels.24 We are currently investigating whether elevated levelsof factor XI may also be genetically determined.
In conclusion, an elevated factor XI level is a risk factorfor venous thrombosis. We postulate that a high level of factorXI causes thrombosis through sustained generation of thrombin,which leads to the protection of fibrin from proteolysis.
Supported in part by grants from the Netherlands Heart Foundation(89.063 and D96.021).
We are indebted to Drs. F.J.M. van der Meer (AnticoagulationClinic, Leiden), L.P. Colly (Anticoagulation Clinic, Amsterdam),and P.H. Trienekens (Anticoagulation Clinic, Rotterdam) fortheir assistance; to Mrs. A. Schreijer for data management;and to Mr. A. Marquart and Mrs. T. Visser for assistance withthe laboratory studies.
Source Information
From the Thrombosis and Hemostasis Laboratory, Department of Hematology, University Medical Center (J.C.M.M., W.L.H.T., B.N.B.), and the Institute of Biomembranes (J.C.M.M., B.N.B.), Utrecht University, Utrecht; and the Hemostasis and Thrombosis Research Center (R.M.B., F.R.R.) and the Department of Clinical Epidemiology (F.R.R.), Leiden University Medical Center, Leiden — both in the Netherlands.
Address reprint requests to Dr. Meijers at the Department of Vascular Medicine, G1.143, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands, or at j.c.meijers{at}amc.uva.nl.
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Doggen, C. J. M., Rosendaal, F. R., Meijers, J. C. M.
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Mosnier, L. O., Bouma, B. N.
(2006). Regulation of Fibrinolysis by Thrombin Activatable Fibrinolysis Inhibitor, an Unstable Carboxypeptidase B That Unites the Pathways of Coagulation and Fibrinolysis. Arterioscler. Thromb. Vasc. Bio.
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Izbicki, G., Bairey, O., Shitrit, D., Lahav, J., Kramer, M. R.
(2006). Increased thromboembolic events after lung transplantation.. Chest
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Monroe, D. M., Hoffman, M.
(2006). What Does It Take to Make the Perfect Clot?. Arterioscler. Thromb. Vasc. Bio.
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Uitte de Willige, S., de Visser, M. C. H., Houwing-Duistermaat, J. J., Rosendaal, F. R., Vos, H. L., Bertina, R. M.
(2005). Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen {gamma}' levels. Blood
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Cheng, Q., Zhao, Y., Lawson, W. E., Polosukhin, V. V., Johnson, J. E., Blackwell, T. S., Gailani, D.
(2005). The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice. Blood
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Kaftan, O., Balcik, O. S., Cipil, H., Ozet, G., Bavbek, N., Kosar, A., Dagdas, S.
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(2005). Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events. JAMA
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Lisman, T., de Groot, P. G., Meijers, J. C.M., Rosendaal, F. R.
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Rosendaal, F. R.
(2005). Venous Thrombosis: The Role of Genes, Environment, and Behavior. ASH Education Book
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Tripodi, A., Chantarangkul, V., Martinelli, I., Bucciarelli, P., Mannucci, P. M.
(2004). A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood
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Goldenberg, N. A., Knapp-Clevenger, R., Manco-Johnson, M. J., the Mountain States Regional Thrombophilia Group,
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Caprini, J. A., Glase, C. J., Anderson, C. B., Hathaway, K.
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Shi, T., Iverson, G. M., Qi, J. C., Cockerill, K. A., Linnik, M. D., Konecny, P., Krilis, S. A.
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Colucci, M., Binetti, B. M., Tripodi, A., Chantarangkul, V., Semeraro, N.
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Weitz, J. I., Middeldorp, S., Geerts, W., Heit, J. A.
(2004). Thrombophilia and New Anticoagulant Drugs. ASH Education Book
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Toorians, A. W. F. T., Thomassen, M. C. L. G. D., Zweegman, S., Magdeleyns, E. J. P., Tans, G., Gooren, L. J. G., Rosing, J.
(2003). Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People. J. Clin. Endocrinol. Metab.
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Gruber, A., Hanson, S. R.
(2003). Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates. Blood
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Anderson, F. A. Jr., Spencer, F. A.
(2003). Risk Factors for Venous Thromboembolism. Circulation
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Dahm, A., van Hylckama Vlieg, A., Bendz, B., Rosendaal, F., Bertina, R. M., Sandset, P. M.
(2003). Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood
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Wolberg, A. S., Monroe, D. M., Roberts, H. R., Hoffman, M.
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Ameri, A., Kurachi, S., Sueishi, K., Kuwahara, M., Kurachi, K.
(2003). Myocardial fibrosis in mice with overexpression of human blood coagulation factor IX. Blood
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Crowther, M. A., Kelton, J. G.
(2003). Congenital Thrombophilic States Associated with Venous Thrombosis: A Qualitative Overview and Proposed Classification System. ANN INTERN MED
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Dalen, J. E.
(2002). Pulmonary Embolism: What Have We Learned Since Virchow?: Natural History, Pathophysiology, and Diagnosis. Chest
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Tarumi, T., Kravtsov, D. V., Zhao, M., Williams, S. M., Gailani, D.
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Renne, T., Gailani, D., Meijers, J. C. M., Muller-Esterl, W.
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Bauer, K. A., Rosendaal, F. R., Heit, J. A.
(2002). Hypercoagulability: Too Many Tests, Too Much Conflicting Data. ASH Education Book
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Bauer, K. A.
(2001). The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications. ANN INTERN MED
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(2001). Laboratory Investigation of Thrombophilia. Clin. Chem.
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Kamphuisen, P. W., Eikenboom, J. C. J., Bertina, R. M.
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Federman, D. G., Kirsner, R. S.
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Seligsohn, U., Lubetsky, A.
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(2000). High levels of factor IX increase the risk of venous thrombosis. Blood
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[Abstract][Full Text]
18.5 µmol per liter), factor VIII:C (>150 IU per deciliter or 
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