Factor XI in Haemostasis and Thrombosis

AnniversaryIssueContribution

FactorXIinhaemostasis andthrombosis: Past, present andfuture

1957–2007) Uri Seligsohn

y( The Amalia BironResearchInstitute of Thrombosisand Hemostasis, Chaim ShebaMedicalCenter,Tel-Hashomer and Sackler Faculty of Medicine,Tel Aviv University,Tel Aviv,Israel

he discipline of haemostasis and thrombosis has set an trigger activation of FXII, laterfound to occur in the presenceof Anniversar example, perhapsmore than other disciplines of Medicine, prekallikrein (PK) and high-molecular-weight kininogen (HK). th T in discoveries based on observations of the so called“ex- FXIIa thenactivatesFXI, and FXIa activatesFIX leading 50 periments of nature”.During arelativelyshorttime of 13 years throughadditional reactions to thrombin generation. However, (1947–1960), most coagulation factorswere identifiedinpa- this sequenceofthe so-called intrinsiccoagulation pathway was tients whopresentedwith ableeding tendencyand were worked difficulttoreconcile with the observations thatpatients affected up by rather simple laboratoryassays.This era of discoveries was by severe deficienciesofFXII, PK or HK didnot have ableeding followedbythe characterization of the biochemical reactions in- tendency, whereas FXI-deficient patients did present with an in- volved in blood coagulation, delineation of the sequence of reac- jury-related haemostatic defect. This apparentparadox wasre- tions in the coagulation pathwaysand more recentlybyun- solved in 1991bythe demonstration that thrombin is the physio- raveling the molecular genetic aspectsofthe variouscoagulation logicalactivator of FXI (5, 6) bypassing the initial contact in- components. The objective of this reviewistodescribe some of ducedreactions.These seminal studies leadtothe design of are- the major developments in understandingthe role of factor (F)XI visedschemeofthe coagulation pathway in whichFXII, PK and in haemostasis and thrombosis thathaveoccurred over more HK play no role in physiologic haemostasis, while FXI is impor- than50years of research,and to highlight recent evidencewhich tant for amplifying thrombin generation followingits initial suggests that FXI deficiencycan have an antithrombotic effect. formation by the tissue factor (TF)-FVII pathway (5). The earlyyears BiochemistryofFXI Soonafter the distinction of haemophilia B(FIXdeficiency) FXIisa160 kDa homodimer in whicheach 80 kDamonomer from haemophilia A(FVIII deficiency),Rosenthaletal. de- comprises 607 residues organizedinaheavy chainwith fourtan- scribedin1953 and 1955 athird haemophilia (FXI deficiency) dem repeatsof90–91residues(apple domains),and alight whichwas associatedwith amild to moderate bleeding tenden- chainharboring aserine protease(7). cy (1, 2).Thepresence of the disorder in twosisters and their ma- Apple 1domain contains binding sites for HK forming a ternal unclewas regarded as an indication thatitisinherited as an FXI:HK complex in the circulation and athrombin binding site, autosomal dominant trait (2).However,aseminalstudy by Rapa- apple 3domain bears binding sites for FIX and plateletglycopro- portetal. in 1961clearlyestablished thattransmission of the dis- tein Ibα ,and apple 4harborsthe binding sitefor FXII (8, 9) and orderwas autosomal recessive and distinguishedbetween sub- contains the interfacebetween the monomers as recently defined jects with amajor deficiencyexhibiting FXI levels of less than in the FXI crystal structure(10). FXI is activatedbythrombin 20 U/dl from subjects with aminor deficiency(FXIlevel 30–60 that cleaves an Arg369-Ile370bond yielding a47kDa heavy U/dl) (3). Thisstudy as well as othersindicated that FXI defi- chain bound by adisulfide bondtoa33kDa light chain. FXIa ac-

ciencyisparticularlyprevalent in Jews.This wasindeedproven tivatesFIX in the presence of calcium ions by sequential cleav- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. in 1978bymeintwo largesurveysofAshkenazi (European) ages of Arg146 –Ala147 and Arg180 –Val181bonds yielding Jews indicating thatthe estimated frequency(95% confidence activatedFIXaβ and an activation peptide. interval)ofmajor FXIdeficiencywas 0.1–0.3% and of minor The FXIgene consists of 15 exons and 14 introns (GenBank FXI deficiency5.5 –11% (4). M18295) and is located on chromosome4q34–35 (11, 12). FXI In the classicalsequence of the coagulation reactionsde- is produced in the liverand circulates in blood at aconcentration signedin1964, FXI wasassignedwith arole in the initial contact of 3–7 µg/ml. activation phase.Itwas shown thatnegativelycharged surfaces

Correspondence to: Received April 4, 2007 Uri Seligsohn, MD Accepted May21, 2007 TheAmaliaBiron Research Institute of Thrombosis and Hemostasis Chaim ShebaMedical Center, Te lHashomer 52621, Israel Prepublished onlineJune 12, 2007 Te l.:+972 3530 2104, Fax: +972 3535 1568 doi:10.1160/TH07–04–0246 E-mail: [email protected] ThrombHaemost 2007; 98: 84–89

84 Seligsohn: FactorXIinhaemostasis and thrombosis

Mutations, founder effectsand ethnic from the Netherlands(25). At high TF concentrations, the rate of fibrin formation in plasma wasindependent of FXI, butatde- distribution creasing amountsofTF, there wasagradual increase in the con- In 1989 the firstthreemutations causing FXIdeficiency were tribution of FXI to the rate of fibrin formation. This observation identifiedinsix Jewish patients (13). Twoofthe three mutations, and amore recent study (26) areconsistent with amodel in which Glu117X(typeII) andPhe283Leu (type III) predominate in initialclot formation occursatthe siteofTFexposure indepen-

Jews; theywerefound to be harboredby98% of 295 unrelatedpa- tentlyofFXI, while at the propagation phase,when the clot in- 1957–2007) tients with severe FXIdeficiency (14). The third mutation, type I, creases in size,the process becomes dependent on FXI. Another is located at thelastsplice site of the FXI gene and has so farbeen novelfindingwas thatthrombin-inducedactivation of FXI leads y( identified in sevenunrelatedpatients (14). Polymerase chain to inhibition of tissue plasminogenactivator (tPA)-induced fibri- reaction and restriction analysis fordetectionofthe twocommon nolysis of the clot (25).This effect wasmediated by FXI-depend- mutations in Jews (15) as well as aseries of polymorphisms (16) ent generation of substantialamounts of thrombin after clot enabled us to obtain the following information: i) Homozygotes formation, whichinturnactivatesthe thrombin-activatablefibri- for the Glu117Xmutation have amean FXIlevel of 0.012 U/ml, nolysis inhibitor (TAFI) thatremoves carboxy-terminallysine Anniversar homozygotesfor the Phe283Leu have amean FXIlevel of 0.097 residues from fibrin, the sites of plasminogen binding to fibrin th U/ml andcompound heterozygotesfor Glu117X andPhe283Leu (27).Inthe presenceofamonoclonalantibody to TAFI,this ef- 50 have amean FXIlevel of 0.033 U/ml;ii) the allele frequencyof fect wasabolished as in the presenceofamonoclonalantibody to the Glu117Xmutation in Ashkenazi andIraqi Jews was0.0217 FXI implicating TAFI as amediator of the antifibrinolytic activ- and0.0167, respectively (16), while among other Jewish ethnic ity of FXI.Further supportfor the role of FXI in inhibiting fibri- groups andPalestinianArabs it wassignificantlylower,i.e. nolysis comesfrom observations in patients with severe FXI 0.0026 and0.0065, respectively (17); iii)the Phe283Leu mu- deficiencywho areparticularlypronetobleed followinginjury tation wasonlypresent in Ashkenazi Jews in whom the allele fre- at sites where there is augmentedlocalfibrinolysis likethe oral quencywas 0.0254 (16, 17); iv)distinct founder effects forthe cavity,nose, tonsils and urinary tract (15, 28,29). Furthermore, Glu117X andPhe283Leu mutationweredefined by haplotype tooth extractions in suchpatients can be carried outuneventfully analysis (17); v) mutation ageestimatesrevealed that the by using tranexamic acid insteadofreplacement therapy(30). Glu117Xmutation occurred approximately2,500 yearsago when all Jews residedinthe Middle Eastbefore theywereexiled Clinicalfeatures by the Romansin70A.D., whereas thePhe283Leu occurred more recently(18).Theseage estimates fitwith the current distribution The commonpresentation of severe FXIdeficiencyisinjury-re- of Glu117X in various Jewish ethnic groups,and with the con- lated bleeding,e.g. tooth extractions,tonsillectomy, nasalsur- finement of Phe283Leu to Ashkenazi Jews whoseparated from gery, or prostatectomy. Alternatively,aprolonged activatedpar- other Jewish ethnic groups approximately1,900 yearsago. tialthromboplastin timefound in aroutine examination leads to Twoadditional clustersofFXI-deficient patients were re- the diagnosis. Bleeding occurs less frequently followingsurgery cently ascertainedbyus. One wasidentified in French Basques, performed at sites where there is no local fibrinolytic activity, aCys38Argmutation, and the second,aCys128X mutation, was e.g.orthopedic surgery, appendicectomy, circumcision or her- identifiedinBritons,with allele frequencies of 0.005and 0.009, niorrhaphy(15, 29). In contrast, surgeryatsiteswith local fibri- respectively (19,20). Foreach mutation, haplotype analysis was nolysis (vide supra)isassociatedwith excessive bleeding in consistent with afounder effect, butanage estimate wasnot pos- 49–67% of cases (29).Regarding post-partum haemorrhage, a sible to performbecauseofinsufficient data. retrospective analysis of 62 womenwith severe FXIdeficiency As of February2007, 120 mutations causing FXI deficiency revealed that43(70%) had 93 uneventful deliveries (85 vaginal have beendescribed in peer-reviewed journals. All are listedina and 8caesarian) withoutblood componenttherapy(31). Conse- database of rare clotting factor deficiencies(www.med.unc.edu/ quently, an on demand policyofblood componenttherapywas isth/welcome). Characterization of these mutations hasshed proposed forsuch patients.

light on understanding the structure-function relationships of Whether or not heterozygotes with partial FXI deficiency This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. FXI and has defined several dysfunctionalmutations such as display ableeding tendencyiscontroversial. Ableeding risk as- Gly555Glu and Pro520Leu (21, 22). Interestingly, fourmu- sessmentinalargecohortofpatients with FXI deficiency tations were showntoexert adominant negative effect which yielded an odds ratio (OR) of 13 (95% CI 3.8–45) in patients stems from impaired secretion of heterodimers consisting of a with FXI levels less than0.2 U/ml and an OR of 2.6 (95% CI normal and amutant monomer (23, 24). Such heterozygotes may 0.8–9) in patients with FXI levels of 0.2–0.69 U/ml (32). Hence, present with bleeding episodescaused by FXIlevelsthat arecon- major FXI deficiencyconfers amarkedlyhigherrisk of bleeding siderablylower thanobservedinusualheterozygotes in whom thanminor deficiency. Patients with aminor deficiencywho dimerization of anormal monomer and amutated monomer does have ableeding historyshould be tested for an additional hemos- not impair the secretion of FXI dimer from producing cells. tatic disorder.Guidelines for therapyinFXI-deficient patients can be foundelsewhere (14, 33). Discoveryofanew functionofFXI Development of inhibitorstoFXI in patients withsevere FXI deficiencyhas been described.Inour recent study of 118 unre- The procoagulant activityofFXI wasfurther refined in 1995 by latedpatients with severe FXIdeficiency, sevenwere foundwith an elegant in-vitrostudy performedbythe group of B. Bouma an inhibitor (34).Theseven patients were among 21 patients who

85 Seligsohn: FactorXIinhaemostasis and thrombosis

had received replacement therapyand were homozygotesfor the observations in suchpatients and because thrombosis is multi- Glu117X mutation that is associated with extremelylow FXI causal,interpretation of these anecdotalcases is difficult. One levels. Sincenone of the 43 patients with other genotypesassoci- matterhas been clarified; patients with profounddefectsinhae- ated with higher FXIlevelsranging between 0.02–0.15U/ml de- mostasis, e.g.haemophilia A, haemophilia B, severe type 3von velopedaninhibitor despite replacement therapy, it wascon- Willebrand diseaseand Glanzmann thrombasthenia arenot pro- cludedthat development of an inhibitor to FXI can be expected tected against atherosclerosis (41–43).Nevertheless, longitudi-

1957–2007) in one third of patients with an extremelylow FXIlevel follow- nalstudiesinthe Netherlands showedthat haemophiliaAand he- ing treatment with blood components. Interestingly, patients mophilia Bare associated with adecreased incidenceofmyo- y( with an inhibitor usuallydonot bleed spontaneouslybut do pres- cardialinfarction (44, 45), whichsuggests that the lowcoagula- ent achallenge when surgery is needed.RecombinantFVIIa is bility does prevent thromboticocclusion. Whether or notsevere helpful under such circumstances. FXIdeficiencyalso providesprotection against thrombosis has beenrecently addressedbyobservations in animalmodels and The prothrombotic effectofelevated levels of FXI patients. Anniversar th The procoagulant and antifibrinolyticeffectsofFXI couldhypo- Animal studies 50 theticallyimplythat increased FXI levels confer an increased Severalanimal models have been employedfor addressing the risk of venous and or arterial thrombosis.Indeed, in the Leiden question whether FXI deficiency confers afibrinolytic and or an thrombophilia studyof474 patients with venous thromboembol- antithrombotic effect. An initial study revealed that ajugularvein ism and 473 controls, the adjusted OR for patients whose FXI thrombus in rabbits treated locallyorsystemicallybyaFXI anti- wasabove the 90th percentilewas 2.2(95% CI 1.5–3.2) com- body underwentthrombolysis two-foldfaster than acontrol pared to patients with FXI levels below90 th percentile(35). In thrombus (46). Asimilar effect waselicitedbyananti-TAFI anti- anotherstudy,recurrence of venous thrombosis wassignifi- body,suggesting that thrombolysis induced by FXI deficiency cantly morefrequent in patients in whom both FXI activity and wasmediated by diminishedTAFI activation.Inamurine model of TAFI antigenlevel were increased (36). FXIdeficiency,FeCl 3 -inducedinjuryofthe carotidarteryresulted Regarding arterial thrombosis, arecent study of 200 women in significantlybetter blood flow than observedinwild typemice withacutemyocardialinfarction before the age of 49 years and (47, 48). Full protection wasalsoobservedinFIX-deficient mice, 626controls indicatedthat elevatedFXI levels were notassoci- butwhiletail bleedingtime wasnormalinFXI-deficient mice, ated with an increased risk (37). Anotherstudy of 174 menand FIX-deficientmice had amarkedlyprolonged tail bleedingtime 26 womenwith myocardialinfarction at an age range of 32–72 (48).This suggestsaselectiveantithrombotic effect imparted by years also did not reveal an increased relativerisk for subjects in FXI deficiency without ademonstrable anti-haemostatic effect. In the upper quartile of FXI levels (adjustedOR0.8; 95% CI 0.2 – anotherthrombosis modelinbaboons,the growth of athrombus 2.7) (38).However,another study of 560 men with an acute myo- initiated by knitteddacron or TF presenting teflon grafts deployed cardialinfarction before the age of 70 and 646 controls showed in arteriovenous shunts wasmarkedlyreduced by infusion of a thatthe adjusted OR in those subjects whose FXI levelwas in the goatanti-human FXI antibody (49). This antithromboticeffect highestquintile was1.8 (95% CI 1.2–2.7) comparedtothose wascomparabletoheparin infusion. Similar protective effects by with the lowest quintile (39).Interestingly, the highestrisk was FXI deficiency were obtained in an iliac arteryballoon injury observedinasubgroup of patients with both high FXI leveland model in rabbits (50),and in FeCl3 -inducedthrombosis of the in- lowFXII level(adjustedOR6.4, 95% CI 2.2–18.0).The discrep- ferior vena cava in mice (51).Inanotherstudyinmice,the anti- ancyamong these studiesand the question whether an increased thrombotic effects of FXIorFXIIdeficiency wasexaminedby FXIlevel confers arisk of myocardialinfarction in men butnot four thrombosismodels,i.e.pulmonary embolism induced by in- in womenwill awaitfurther studies. fusion of collagen andepinephrine,FeCl 3 -inducedinjuryofmes- An increased relative risk of ischemic strokeinpatients aged enteric arterioles, mechanical injury of the aortaand carotidartery less than55years wasalso recently reported to be associated injury accomplished by ligation with asurgical filament. Striking th withincreased FXI levels (40). FXIabove the 95 percentilewas antithrombotic effects were discernedinFXII-deficient micethat This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. observed in 17 (22%) of 78 patients with stroke(n=65) or tran- were examinedbyall four models of thrombosis (52).Arecent sient ischemic attack(n=13) versustwo of 40 controls (5%), OR study by the sameinvestigators demonstratedthatboth FXII-and 5.3 (95% CI 1.2–24.1). FXI-deficientmice were similarlyprotected from transient middle cerebralarteryocclusion(53). Collectively,these data suggest that, at least in animals,FXIIand FXI playarole in inducing Is severe FXI deficiency protectiveagainst thrombosis, butare dispensable for haemostasis. thrombosis? Human studies Severe inheritedbleeding disorders have for many years served The rather lowprevalenceofuprovokedvenous thromboembol- as paradigmsfor understating the pathogenesis of thrombosis, ism at differentage groups (1:300 –1:1,000) makesithard to as- and fordevelopment of antithrombotic therapy. Reportsof sess whether patients with severe FXIdeficiencyare protected thrombosis in patients with severe hemostatic defects have intro- againstvenous thrombosis. Five anecdotal cases of venous duced some skepticism about the value of mimicking these ex- thromboembolism were includedinarecent review (54)of periments of nature. However, because of the limited number of whom twooccurred followinginfusion of aFXI concentrate

86 Seligsohn: FactorXIinhaemostasis and thrombosis

(known to sometimes induce thrombosis)and one had systemic ciency(55). Of 96 unrelated patients (55 womenand 41 men) lupus erythematosis. whowere morethan 35 years old, 16 had ahistoryofacutemyo- The incidenceofacutemyocardialinfarction wasrecently as- cardialinfarction, of whom six underwent coronaryarteryby- sessedsystematicallyinIsraelipatients with severe FXIdefi- pass grafting and four had recurrent events. One or more athero- 1957–2007) y( Anniversar th 50

Figure1:Revisited schemesofthe coagulation cascadehighlighting thepotential differences betweenhaemostasisand thrombosis. Theschemes (A andB)are basedonrecentexperimentsinanimal models of thrombosis which underscore theimport- anceofthe contact phase of coagulation for This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. propagationofthrombi, and on theclinical observations that patientswithaseveredeficien- cy of FXII,PKorHKdonot have ableeding tendency whichrenders thecontact phase of coagulation unimportant forhaemostasis. Alternativesites fortriggering FXII activation areactivatedplatelets and clot surface (see text). Coagulation factors aredepicted in Romannumbers, activated factors areshown in red, and cofactors areingreen.PLindicates phospholipids mainlyprovided by activated platelets,HK–high-molecular-weight kininogen, PK –prekallikrein, KAL –kallikrein, TAFI – thrombinactivatable serine protease inhibitor, u-PA –urokinase plasminogenactivator, t-PA– B) tissue plasminogenactivator.

87 Seligsohn: FactorXIinhaemostasis and thrombosis

sclerotic risk factorswere observed in 13/16(81%) of patients leased fromdamaged cells at injurysites(57) were recently whohad amyocardialinfarction comparedto44/47 (56%)inpa- shown to augment contact activation. Whether or notthis third tients whohad no myocardialinfarction (p<0.001). The calcu- conceptualchange is relevant for thrombosis in humans remains lated annualrateofacutemyocardialinfarction in male patients to be established. Supportiveevidenceisthat elevatedFXI levels wassimilartothe expected rate in the generalIsraelipopulation, confer arisk of venous thromboembolism (35),myocardialin- whereas in femalepatients it wasalmost two-foldhigherbut did farction in men(39) and stroke(40). Evidencewhich does not

1957–2007) not reachstatistical significance. Thesedataindicate that severe supportthe concept includes: i) Lack of protection conferredby FXIdeficiencyconfers no protection against acute myocardial severe FXIdeficiencyagainst myocardialinfarction (55);ii) y( infarction.Whether or notsevere FXIdeficiencyprotects against ElevatedFXI levels in womenare notassociatedwith an in- ischemic strokeisatthe timeofthis writing under investigation. creased risk of myocardialinfarction (37);iii) Decreased rather thanincreased levels of FXIIare associated with arisk of myo- Quovadis cardialinfarction in men (39).iv) Patients with severe FXII defi- ciencyare notprotected against thrombosis (58,59). Thus, more Anniversar Morethan 50 years of research on FXIand FXI deficiencyhave observations on arterial and venous thrombosis,particularlyin th witnessed oscillations in understandingthe role of FXI in hae- patients with severe FXIorFXII deficiencywould be helpful be- 50 mostasis and thrombosis. Thefirst conceptual change emanated foreaccepting the revised scheme. If indeed FXIdeficiencywill fromthe discovery thatFXI can be activatedbythrombin rather be found to be protectiveagainst one or moretypes of thrombo- than by FXIIa. This finding and the observations thatFXI-defi- sis, development of humanized monoclonal antibodiesagainst cient patients have ableeding tendency, while patients deficient FXI or otheragents that interferewith FXI function could serve in FXII, HK or PK do not, ledtoarevision of the clotting cascade as excellent antithrombotic drugs thatwould have no or minimal assigning no role forthe initial contact reactions in haemostasis haemorrhagic potential. (Fig. 1A),and making them relevant onlyfor in-vitro coagu- Also foreseen areimprovementsinthe treatment of patients lation until provenotherwise.Thesecondconceptual change was with severe FXIdeficiencywho undergo surgery. Amore parsi- thatFXI is not onlyaprocoagulant butalso an antifibrinolytic monious use or no use of plasma or FXI concentrate for certain factor.The third conceptualchange emanatedfrom the observa- typesofsurgeryand labor will decrease the frequencyoftrans- tions in animalmodels of arterial and venous thrombosis in mission of infectious agents and development of aFXI inhibitor. whichboth FXII or FXI deficiencyexhibited an antithrombotic Also, useoftranexamic acidwithoutreplacement therapyduring effect.These findings areconsistent with a“thrombosis scheme” surgeryatsiteswith increased fibrinolytic activity seems justi- of the coagulation pathways(Fig. 1B) that swings back the pen- fied to evaluate giventhe experiencegained with tooth extrac- dulumtothe originallydescribed cascade. Recent evidenceindi- tions.Finally, development of rFXI is anticipated. cates that apart from negatively charged surfaces at injurysites of the vesselwall, activatedplatelets or clot surface can serveas Acknowledgments templatesfor triggering FXII activation and propagation of the Iamindebted to Ariella Zivelin, PhD and OphiraSalomon, MD foruseful growing thrombus (52). Moreover, polyphosphatesreleased comments and Tami Livnat, PhD forperforming the artwork(Fig. 1). fromdensegranulesofactivatedplatelets (56), and RNAre-

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