Doggen, Carine J.M.

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the recent identification of TET2 mutations insome JAK2 V617F–negative myeloid precur-sors of JAK2 V617F–positive patients indi-cates that the acquisition of TET2 mutationsmay predate the acquisition of JAK2 V617F ina subset of CMPN patients, and, therefore,could be the initiating mutation.7 Thus, it willbe interesting to study the relationship be-tween TET2 and polyclonal JAK2 V617F–positive ET. The prediction is that these pa-tients will have either no or different TET2mutations. Moreover, CMPNs display a fa-milial predisposition, suggesting that a heri-table factor can predispose to the acquisition ofJAK2 V617F. Consistent with this, 3 groupsindependently identified a specific JAK2 hap-lotype as a major risk factor for the develop-ment of MPN and showed that the JAK2V617F mutation preferentially arises on theallele bearing this susceptibility haplotype.8-10Lambert et al propose that polyclonal ETshould not be considered a malignancy. Infact, their previous work has shown that ETpatients with polyclonal hematopoiesis have adecreased risk of thrombosis, suggesting thatpolyclonality may be a marker of a more be-nign disease course.3 We think it is importantto point out that polyclonality on its own is notsynonymous with nonmalignancy. Thus, theindependent acquisition of identical oncogenicmutations in the same gene has been observedin highly malignant multifocal solid tumors,such as lung and pancreatic cancers.11,12 InET, the fact that JAK2 V617F may arise inde-pendently in multiple progenitor cells sug-gests that this progenitor cell pool may still besusceptible to acquiring additional mutations,such as TET2, which could lead to leukemictransformation.13That a single type of point mutation ispresent in the majority of CMPN patients hasbeen puzzling to the field ever since its discov-ery.14 Clearly, there must be a selective advan-tage to the acquisition of JAK2 V617F, and theobservation that this particular mutation canoccur at multiple independent times in the sameindividual makes this argument even more com-pelling. The big question is now what this selec-tive advantage may be. The race is on.Conflict-of-interest disclosure: The authorsdeclare no competing financial interests. ■REFERENCES1. Lambert JR, Everington T, Linch DC, Gale RE. In es-sential thrombocythemia, multiple JAK2-V617F clones arepresent in most mutant-positive patients: a new diseaseparadigm. Blood. 2009;114(14):3018-3023.2. Campbell PJ, Green AR. The myeloproliferative disor-ders. N Engl J Med. 2006;355(23):2452-266.3. Harrison CN, Gale RE, Machin SJ, Linch DC. A largeproportion of patients with a diagnosis of essential thrombo-cythemia do not have a clonal disorder and may be at lower riskof thrombotic complications. Blood. 1999;93(2):417-424.4. Campbell PJ, Baxter EJ, Beer PA, et al. Mutation ofJAK2 in the myeloproliferative disorders: timing, clonalitystudies, cytogenetic associations, and role in leukemic trans-formation. Blood. 2006;108(10):3548-3555.5. Theocharides A, Boissinot M, Girodon F, et al. Leuke-mic blasts in transformed JAK2-V617F-positive myelopro-liferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007;110(1):375-379.6. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycy-themia vera is not initiated by JAK2V617F mutation. ExpHematol. 2007;35(1):32-38.7. Delhommeau F, Dupont S, Della Valle V, et al. Muta-tion in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289-2301.8. Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is amajor risk factor for the development of myeloproliferativeneoplasms. Nat Genet. 2009;41(4):446-449.9. Olcaydu D, Harutyunyan A, Jäger R, et al. A commonJAK2 haplotype confers susceptibility to myeloproliferativeneoplasms. Nat Genet. 2009;41(4):450-454.10. Kilpivaara O, Mukherjee S, Schram AM, et al. A germ-line JAK2 SNP is associated with predisposition to the de-velopment of JAK2(V617F)-positive myeloproliferativeneoplasms. Nat Genet. 2009;41(4):455-459.11. Moskaluk CA, Hruban RH, Kern SE. p16 and K-rasgene mutations in the intraductal precursors of human pan-creatic adenocarcinoma. Cancer Res. 1997;57(11):2140-2143.12. Sozzi G, Miozzo M, Pastorino U, et al. Genetic evi-dence for an independent origin of multiple preneoplasticand neoplastic lung lesions. Cancer Res. 1995;55(1):135-140.13. Lambert JR, Gale RE, Linch DC. The production ofJAK2 wild-type platelets is not downregulated in patientswith JAK2 V617F mutant-positive essential thrombocy-thaemia. Br J Haematol. 2009;145(1):128-130.14. James C, Ugo V, Le Couédic JP, et al. A unique clonalJAK2 mutation leading to constitutive signalling causespolycythaemia vera. Nature. 2005;434(7037):1144-1148.● ● ● CLINICAL TRIALSComment on Cushman et al, page 2878High coagulant factors & venous thrombosis----------------------------------------------------------------------------------------------------------------Carine J. M. Doggen UNIVERSITY OF TWENTEIn this issue of Blood, results from the Longitudinal Investigation of Thromboem-bolism (LITE)1 show that, of the coagulant factors IX through XIII, only elevatedlevels of procoagulant factor XI were associated with a first venous thrombosis.LITE is the first prospective cohort study reporting on all these factors. Factor IXinitially appeared to be associated with thrombosis but, after adjustment for pri-marily body mass index, the association disappeared.The annual incidence of venous thrombosisis 1 per 1000 persons and mortality amongpatients with pulmonary emboli is high. Pa-tients may develop a postthrombotic syn-drome and recurrent events occur frequently.2Major risk factors for venous thrombosis con-sist of acquired and genetic factors. Hypofi-brinolysis appears to be a risk factor, but therole of individual fibrinolytic proteins is stillunclear.3 Hypercoagulability caused by animbalance between anticoagulant and proco-agulant systems increases the risk of venousthrombosis.4 Deficiencies of antithrombin,protein C, and protein S are strong but rarerisk factors for venous thrombosis. Factor VLeiden and the prothrombin 20210A mutationare more prevalent with a moderate increase inrisk. High levels of factor VIII clearly increasethe risk of venous thrombosis, but the resultsof studies investigating the effects of pro-thrombin, factor V, factor VII, and fibrinogenare inconsistent.5 In studies in which associa-tions between these latter factors and venousthrombosis were found, the effects were muchless than those of elevated factor VIII.4So far, the effects of coagulant factors IXthrough XIII have been investigated in only afew case-control studies, including the LeidenThrombophilia Study (LETS)5 and, morerecently, the Multiple Environmental andGenetic Assessment of risk factors for venousthrombosis (MEGA) study.6,7 Prospectivecohort studies have been lacking so far.5In this issue of Blood, an efficient nestedcase-control design has been used withinLITE, a prospective cohort study in individualsaged 45 to 100 years, with a median follow-upperiod of more than 9 years.1 Included in theanalyses were 462 validated cases of venousthrombosis and 1047 controls. Coagulationmeasurements took place in blood samplescollected mostly at baseline. Levels weretherefore measured long before the event, asopposed to case-control studies, in which2854 1 O C T O B E R 2 0 0 9 I V O L U M E 1 1 4 , N U M B E R 1 4 blood For personal use only. at UNIVERSITEIT TWENTE on October 5, 2009. www.bloodjournal.orgFrom levels are measured after the event, thus rulingout the possibility of reverse causation. A dis-advantage is that levels may not reflect thesituation immediately before the event, which,from an etiological point of view, would be theideal situation. However, this is difficult if notimpossible to achieve in any study design.Although one might be inclined to expectdifferences in results between case-controlstudies and this cohort study simply becausedifferent populations were included or differ-ent assays used, the results were quite similar.Levels of factor X, factor XII, and factor XIIIwere not associated with risk of venous throm-bosis.1,5,8 Elevated factor XI was associatedwith a nearly 2-fold increased risk for the topquintile or percentile, which is quite close tothe risk of factor VIII.1,5,7 High levels of factorIX were associated with an increased risk ofvenous thrombosis in all studies,1,5,6,9 but afteradjustment for body mass index (BMI), therisk in LITE attenuated to the null.1 No ad-justments for BMI were performed in thecase-control studies.5,6,9For some coagulation factors, the associ-ated risk is stronger for deep vein thrombosisin the leg than for a pulmonary embolism. Theopposite may be true for elevated factor XI inLITE, as the risk of pulmonary embolismcombined with deep vein thrombosis appearsto be larger than for deep vein thrombosisalone. However, the case classification in thisstudy may not be reliable, preventing strongconclusions.If these overall results are confirmed byother studies, further study into possiblemechanisms for the increased risk of elevatedlevels of factor XI is warranted, which includeincreased fibrin formation and decreased fibri-nolysis.10 Furthermore, this study raises thequestion whether elevated factor XI is also arisk factor for a recurrent venous thromboticevent, and if so, whether treatment preventsrecurrent events. Until these results becomeavailable, measurement in clinical practice isnot yet indicated.Conflict-of-interest disclosure: The authordeclares no competing financial interests. ■REFERENCES1. Cushman M, O’Meara ES, Folsom AR, Heckbert SR.Coagulation factors IX through XIII and the risk of futurevenous thrombosis: the Longitudinal Investigation ofThromboembolism Etiology. Blood. 2009;114(14):2878-2883.2. Cushman M. Epidemiology and risk factors for venousthrombosis. Semin Hematol. 2007;44(2):62-69.3. Meltzer ME, Doggen CJM, de Groot PG,Rosendaal FR, Lisman T. Fibrinolysis and the risk of ve-nous and arterial thrombosis. Curr Opin Hematol.2007;14(3):242-248.4. Bertina RM. The role of procoagulants and anticoagu-lants in the development of venous thromboembolism.Thromb Res. 2009;123(suppl 4):S41-S45.5. Nossent AY, Eikenboom JCJ, Bertina RM. Plasma co-agulation factor levels in venous thrombosis. Semin Hema-tol. 2007;44(2):77-84.6. Bezemer ID, Arellano AR, Tong C, et al. F9 Malmö,factor IX and deep vein thrombosis. Haematologica.2009;94(5):693-699.7. Bezemer ID, Bare LA, Doggen CJM, et al. Gene vari-ants associated with deep vein thrombosis. JAMA.2008;299(11):1306-1314.8. Van Kanel R, Wuillemin WA, Furlan M, Lammle B.Factor XII clotting activity and antigen levels in patientswith thromboembolic disease. Blood Coagul Fibrinolysis.1992;3(5):555-561.9. Lowe G, Woodward M, Vessey M, Rumley A,Gough P, Daly E. Thrombotic variables and risk of idio-pathic venous thromboembolism in women aged 45-64years: relationships to hormone replacement therapy.Thromb Haemost. 2000;83(4):530-535.10. von dem Borne PA, Cox LM, Bouma BM. Factor XIenhances fibrin generation and inhibits fibrinolysis in a co-agulation model initiated by surface-coated tissue factor.Blood Coagul Fibrinolysis. 2006;17(4):251-257.● ● ● GENE THERAPYComments on Burns et al, page 2888The hidden (and lazy) TCR----------------------------------------------------------------------------------------------------------------Chiara Bonini and Vincenzo Russo SAN RAFFAELE SCIENTIF IC INSTITUTEIn this issue of Blood, Burns and colleagues analyzed samples from 18 patients withmelanoma, treated with T lymphocytes gene-modified to express a tumor-specificTCR. Results show persistence of transduced cells, but early shutdown of TCRgene expression. Transgene down-regulation was not caused by epigenetic silenc-ing and could be reversed by T-cell activation.The adoptive transfer of tumor specificcytotoxic T lymphocytes (CTLs) to pa-tients affected by melanoma have producedsignificant clinical results. However, thestrategy is limited by the difficulty of isolat-ing and expanding the rare, high-aviditytumor-specific cells, often deleted inpatients due via central tolerance to self-antigens. To overcome these difficulties,high-affinity T-cell receptors (TCRs) iso-lated from tumor-specific CTLs have beengenetically transferred into human T lym-phocytes to redirect their specificity towardautologous tumor cells.1 In a pivotal clinicaltrial, Morgan and colleagues showed thatthe infusion of TCR gene-modified lympho-cytes caused melanoma regression in a small(13%) fraction of treated patients.2 Althoughessential in proving the feasibility of this ap-proach, clinical results of this initial work weresuboptimal, especially if compared with the highrates (50%) of clinical responses reported by thesame group with non–gene-modified tumor-specific lymphocytes.3 In this issue of Blood,Burns and colleagues analyzed samples from 18patients treated with TCR-transduced cells andobserved that, after an early contraction, gene-modified cells persist but lose TCR expression.4Transgene down-regulation was not causedby epigenetic silencing. Until now, promoter-silencing in adoptively transferred human lym-phocytes was only indirectly excluded by clinicaltrials using gene-modified lymphocytes.5,6 In theBurns study, transgene down-regulation wasapparently related to the nature of the TCRgene, as suggested by the fact that the number ofTCR transgene transcripts in circulating lym-phocytes was similar to that of endogenousTCR- and CD3 transcripts, and always lowerthan that measured in infused cells. Most impor-tantly, Burns and colleagues showed that TCRexpression could be rescued by T-cell activation.The close relationship between the activationstatus of gene-modified cells and the activity ofthe proviral LTR as well as viral promoters waspreviously known and identified as a major issuefor TCR-gene transfer applications, but mainlyin preclinical studies.7Thus, this work is important for the fol-lowing reasons: (1) it rules out DNA methyl-ation as a putative limitation of T cell– basedgene therapy by a thorough and comprehen-sive analysis of treated patients; (2) it under-scores the need to combine adoptive with ac-tive immunotherapy to sustain the function ofgene-modified T cells, and possibly optimizeclinical results; and (3) it highlights the need tomove the focus from persistence of adoptivelygene-transferred cells, a mission accomplishedby gene therapists, to transgene expressionblood 1 O C T O B E R 2 0 0 9 I V O L U M E 1 1 4 , N U M B E R 1 4 2855 For personal use only. at UNIVERSITEIT TWENTE on October 5, 2009. www.bloodjournal.orgFrom 

High coagulant factors & venous thrombosis

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High coagulant factors &amp; venous thrombosis

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High coagulant factors & venous thrombosis