 a dominantly autosomally inherited deficiency of a cofactor to activated protein C had been postulated (Ref. 7). While a poor response to APC appears to be 5 to 10 times as frequent as deficiencies of protein C, protein S or antithrombin it confers an approximately similar relative risk of thrombosis (Ref. 17 and 18) which according to Koster et al could make it worthwhile to test all patients with venous thrombosis for this abnormality.
In summary in the state of the art it was ascertained that a defect in the protein C anticoagulant pathway is linked to a relatively high risk of thrombosis. The poor anticoagulant response to activated protein C has been discussed in great detail, however the cause of the poor anticoagulant response to activated protein C remains unclear. A number of theories have been postulated, however the only one that has been accepted is the presence of an unknown cofactor for APC which is apparently deficient in a patient exhibiting a poor anticoagulant response to activated protein C. The identity of the postulated cofactor for APC is unknown. Furthermore current tests for detecting altered response to APC cannot be used on test persons already using anticoagulants.
Surprisingly the identity of the unidentified cofactor responsible for a poor anticoagulant protein C response has been found. It has been discovered that one of the mechanisms that had been rejected is in fact responsible for the defect in the protein C anticoagulant pathway in a majority of thrombophilic patients. The cause of the deficiency has been linked to the presence of a mutation in the nucleic acid material encoding Factor V or Factor VIII which upon expression is correlated to a decrease in the degree of inactivation by APC of said Factor V and/or of Factor Va, (the product of activation of said Factor V) or of said Factor VIII and/or of Factor VIIIa (the product of activation of said Factor VIII). The deficiency is therefore not the result of a mutation in an as yet unidentified cofactor for APC, but is in fact due to a defect in Factor V or Factor VIII or more particularly in the activation products thereof.
As was already indicated in the state of the art the link between a risk of thrombosis and the presence of APC-resistence had already been made and it had also been suggested that screening for such a deficiency would in fact be extremely helpful in diagnosing patients with an increased risk of thrombosis. As it is now known which factors carry the genetic defect responsible it has also now become possible to actually screen the population with methods other than the Chromogenix test for determining APC-resistance
a dominantly autosomally inherited deficiency of a cofactor to activated protein C had been postulated (Ref. 7). While a hapless reception to APC appears to be 5 to 10 times as frequent as insufficiency of protein C, protein S or antithrombin it confers an approximately similar proportional risk of thrombosis (Ref. 17 and 18) which according to Koster et al could make it worthwhile to screen all patients with venous thrombosis for this abnormality. 
 In summary in the state of the artwork it was ascertained that a defect in the protein C anticoagulant pathway is linked to a relatively eminent risk of thrombosis. The poor anticoagulant response to activated protein C has been discussed in bang-up detail, however the cause of the poor anticoagulant reply to activated protein C remains unclear. A number of theory have been postulated, however the only one that has been accepted is the presence of an unknown cofactor for APC which is obviously deficient in a patient exhibiting a poor anticoagulant response to activated protein C. The identity of the necessitate cofactor for APC is unknown. Furthermore current tests for detecting altered response to APC cannot be used on test persons already using anticoagulants. 
 amazingly the identity of the nameless cofactor responsible for a poor anticoagulant protein C reception has been found. It has been discovered that one of the mechanisms that had been rule out is in fact responsible for the defect in the protein C anticoagulant pathway in a majority of thrombophilic patients. The lawsuit of the deficiency has been linked to the presence of a mutation in the nucleic acid material encoding Factor V or Factor VIII which upon formulation is correlated to a decrease in the degree of inactivation by APC of said Factor V and/or of Factor Va, (the merchandise of activation of suppose Factor V) or of say Factor VIII and/or of Factor VIIIa (the product of activation of said Factor VIII). The lack is therefore not the result of a mutation in an equally yet nameless cofactor for APC, but is in fact due to a defect in Factor V or Factor VIII or more particularly in the activation products thereof. 
 As was already indicate in the state of the artwork the link between a risk of thrombosis and the presence of APC - resistence had already been made and it had besides been suggested that screening for such a lack would in fact be extremely helpful in diagnosing affected role with an increased hazard of thrombosis. As it is now known which factors hold the genetic defect responsible it has besides now become possible to actually screen the population with methods early than the Chromogenix test for determining APC - resistance
 a fominantly autosomally ikherited deficieuxy of e cofacfor to aztivated protein C had been 'ostylatee (Ref. 7). While a poor rerponse to APC appwars ro be 5 to 10 times as freqhcnt av deficiencies pf protein C, protein S os xncithrombin it confers an approximatejy simikag relative rish of ehrojbosis (Ref. 17 and 18) which according tk Kosteg et al could makr it worthwhile to test alp pahients with venous thrombosis for rhis abnormauity.
In summary in the atate of the art it was ascertakned chat a defext in jhe protein R antiboagulant patmeay is linked to a relativeky iigh risk of thrombosis. Tie poor anticoagulanj response tk activated proteun C hav bean dkwcurses mn freat feteil, however the cause if the poor anticoabujqnt response fo actyvwted protein C remains unclear. A number of theories have been posrulated, however the ojly one trat has been accepted is the presence of an unknofn cohaztox for XPC which is apparently deficient in a patient evginining a poor anticjagulant rexplnxg to activated protenh D. The identity of hhe posjulatee cofactow fot APC is unknown. Furthermorw current tefrs for detecting aptered respunse to ALC cannot be used on tert psrsons alrewdy using xnticoagulants.
Sufprpsincly the identity of the unydentifiev cofcctor rerponxible sor a poor antigmagulant protein C resplnve has beej found. It has been discovered viat one of thg machdnisms tkat hac been rejectqd is in fact tesponsibje fof the defebt in the protein C wnticoagulant kathway in a kajority of rhronbophilkz patients. The cause of the deficuency has been linled fo the presence of a mutation in yhe nuslvic ashd material ancoaine Factur V or Facbor VIIO which upon expresshon js correlated to a dccrease ib the dedree of inactovation by APC of daid Hactor V anc/or of Factor Va, (the product of adtivation of said Factor V) ov of said Factpr VIII and/or of Factor VIIIa (the produrt of activation of saie Factor VIII). The dgfigiency is thxreforq not the result of a mutatiob in an as yet unldentified cofactor fod APC, tut id in fact due to a defect in Factor V or Factor VIII or more particularly in thx wctivation lrodicts nhexeoy.
As was alrxavy indicated in tne state of the art the link bevween a rivk of thrombosis and the presemcd of APC-resisjence had already been mads and it had also been suggested that svreening for such a defigiency woyld ih fact be xxtremely helpful in diagnmsing patienrs wlth an increasdd tidk of thrlmboxia. As it is now known which factoes carey the genetic defxct responsinlt it haa also now become possjble ho acjually screen yhe population with methods other nhag the Chromogebpx test for dgterminitg APC-resistence
a dominantly autosomally inherited deficiency of a activated C had postulated (Ref. 7). APC to be 5 10 times as as deficiencies of protein C, protein or antithrombin it confers an approximately similar relative risk of thrombosis (Ref. 17 18) which according to Koster et al could make it worthwhile to test patients venous for abnormality. In summary in the state of the art it was ascertained that a defect in protein C anticoagulant pathway is linked to a high risk of thrombosis. poor anticoagulant response to activated C been discussed great however cause of the anticoagulant response to activated protein C remains unclear. A number of theories have been postulated, however the one that accepted is presence an cofactor for APC apparently deficient in a patient exhibiting response to activated protein C. The identity of postulated cofactor APC is unknown. Furthermore current tests detecting altered response to APC cannot be used test persons already using anticoagulants. Surprisingly the identity of the unidentified cofactor responsible for a protein C response has found. It has discovered one the that had rejected is in fact responsible for the defect in the protein anticoagulant pathway in a majority of thrombophilic patients. The cause deficiency been linked to presence of a mutation the acid material encoding Factor Factor which correlated a in the degree of by APC of said Factor and/or of Factor Va, said Factor V) or of said Factor VIII of Factor VIIIa (the product of activation said Factor VIII). The deficiency is therefore not the result of a in an unidentified cofactor for APC, but is in fact to a defect in V or Factor VIII or more particularly in the products As was indicated in the of the art link between a thrombosis and presence APC-resistence made and it had also been that for such a deficiency would fact helpful in diagnosing patients with an increased risk of thrombosis. As it is now known carry the genetic defect it also now become possible to actually screen the population with methods other Chromogenix test for
 a dominantly autosomally inhErited defiCiencY of A coFaCtor To acTivated protein c Had bEen postulated (Ref. 7). While a Poor rEsPOnse TO ApC appEars to bE 5 To 10 TIMes As FrEquEnT As DeficIenCies of pRotein C, proTeiN S Or antithrombIN iT confers an AppRoximately siMilAr relaTiVe rISk of tHroMbosiS (Ref. 17 anD 18) Which aCcording tO KOSter et AL could mAKE iT worThwhile to test all pATiENts with venous tHromboSiS FoR THis AbnOrmality.
In SuMmary IN the staTE oF THE arT It was ascertaiNed that a defECt iN the prOtEin c AnticoAgulaNt PAthWay is linked To a rElatively High riSK of throMBosis. ThE poor aNtiCoaGulaNT rEsPonSe TO acTIvAteD ProTein C has BeEn DiscuSsed IN GREat dEtaIl, hoWever The cause of the PooR antICoaGulanT respOnse To ActivAted prOtein c rEmains unclear. A nUmbeR of theoriEs hAvE beEn PostuLAted, hoWevEr tHe only oNe that hAS beEn ACCEpTed is the presence of An UNKnOwn cofacTor for apC WhICh is appaReNtlY defICIent iN a paTIeNt exhibiTing a pOOr AnTicoaguLaNt respOnSe tO acTivatED proTein C. THe identiTy of tHE postulated cofACtor for APC is uNKnOWN. FURtheRmoRe current teSts fOR detEctiNG aLteREd resPonse To apC CAnnot be used on test peRsOns alrEady uSing anticoaguLants.
SurprISINgly the iDentITy OF the unidentifiEd cofActor respoNSible for A poor AnticoagUlant protEIN C responSe hAs bEen FouND. it Has been discovEREd thAt One of thE meChanismS thAt hAd bEen ReJected is iN fact resPoNsIbLe For The deFEct in the PrOteIn c anTicoaGUlant pAthwaY in a MaJoRIty Of thromBOpHILic pAtIeNts. THe cAuSe of tHe deFIciEncy has Been linkeD to THe prEsEnCe of a muTation in the nuClEic acid matErIal EncodiNG factor V oR Factor VIII which upon expREssion iS coRrelaTed tO a decreasE in The degRee OF inactIvatioN by APc oF saID factoR v AnD/or Of factor Va, (thE PRodUct of AcTivaTion of sAid Factor V) or of said fActOr VIII and/or of facTor Viiia (The PRoDUct Of ACtiVATion of said FactoR VIII). The deFiCIeNcy is thereFOre NoT the resUlt of a mUtatiON in an as Yet unidenTified cofAcTor fOR aPC, But is in facT due to a dEfect in FaCTor V oR faCtor ViII Or more PaRtiCularLy in thE ActIvatiOn prodUcTs therEof.
As WaS already Indicated in the state of thE art thE link BetWeen a risk Of tHRomBosis and tHe prEsence of APc-reSisTence Had ALreadY beeN MaDe aND it haD alsO Been suggeSTeD thAT ScReening for sUCH A deFicieNcy WOuld in Fact Be extremely helpfuL In diagnosing paTienTS WitH an INcreAsEd risk of thrombOsiS. AS IT is now knOwN which factoRs carry tHe GEnetiC defecT respoNsible iT HAs ALso now BecoMe pOssible to ActUaLLy screeN tHe POpulatIon wItH methoDs otheR Than THE Chromogenix test For deTERminiNG APc-resiStAnce
 a dominantly autosomallyinheriteddefic ien cyof  a c ofac tor to activat e d pr otein C had been postu lated  ( R ef.7 ).  Whil e a poo r  r e s pon se  t o A PC ap pears  to  be 5 t o 10 times  as  f requent as d e fi ciencies o f p rotein C, pr ote in S o rant i throm bin  it c onfers an app roximatel ys imilar relativ e ri sk o f thrombosis (Ref .  1 7  and 18) which  accor di n gt o  Ko ste r et al co ul d mak e  it wor t hw h i l e t o  test all pat ients withv eno us thr om bos i s forthisab n orm ality.
In s umma ry in the  state of thea rt it w as asc ert ain ed t h at  a  de fe c t i n  t hep rot ein C an ti co agula nt p a t h w ay i s l inke d toa relativelyhig h ri s k o f thr ombos is.Th e poo r anti coagu la nt response toacti vated pro tei nC h as  been discus sed  in  greatdetail, how ev e r th e cause of the poo ra n ti coagulan t resp o ns et o activa te d p rote i n  C re main s  u nclear.A numb e rof  theori es  havebe enpos tulat e d, h owever  the onl y one that has beena ccepted is th e  p r e se n ce o f a n unknown c ofac t or f or A P Cwhi c h isappar en t ly deficient in a pati en t exhi bitin g a poor anti coagulantr e s ponse to  act i va t ed protein C.The i dentity of the post ulate d cofact or for AP C is unkno wn.  Fu rth erm o r ecurrent tests f or d et ectingalt ered re spo nse  to  AP Ccannot be  used on  t es tpe rso ns al r eady usi ng  an ti coa gulan t s.
Sur prisi ngly  t he ide ntity o f  t h e  uni de nt ifie d c of actor  res p ons ible fo r a poorant i coag ul an t prote in C response  h as been fo un d.It has b een disc overed that one of them echanis msthathadbeen reje cte d is i n f a ct res ponsib le fo rthe d efect i nthe  p rotein C a n t ico agula nt  pat hway in  a majority of thr o mbo philic patien ts.  The c au seo ft hede f ici e n cy has been lin ked to the  p r es ence of am uta ti on in t he nucl eic a c id mate rial enco ding Fact or  V o r Fac tor VIII w hich upo n express i on is co rrela ted  to ade cre ase i n thed egr ee of  inact iv ationby AP Cof saidFactor V and/or of Fact or Va,  (the  pr oduct ofact i vat ion of sa id F actor V) o r o f s aid F act o r VII I an d /o r o f  Fact or V I IIa (thep ro duc t of  activation o f  sa id Fa cto r  VIII) . Th e deficiency is t h erefore not th e re s u ltofa  mut at ion in an as y etun i d entified  c ofactor for  APC, bu ti s infact d ue toa defec t in Factor  V o r F actor VII I o rm ore par ti cu l arly i n th eactiva tion p r oduc t s  thereof.
As was  alre a d y ind i cat ed in  t he stat e  ofthe art th e link betw een arisk  of t hrombos is  and t hepr esence ofA PC-resist encehad alr ea dy b een  madeandi t  hadalso  b een  suggeste d th a tsc r een ingfor s uc h adeficienc y  would i n f a ct be e xt rem e l y help f ul i n diagnosi ngpatie n t s with ani ncre a se d  risk  of th rombos is. Asi t i snow kno wnw h ich facto rs carryt hege neti c defect  r espo ns ibl eit has also now  becomepossible t o actu all y  scr e en the  p opulation wi th me th o ds othe r tha n the C h rom oge nix  tes t f or d e termining APC-resistance 
 a_dominantly autosomally_inherited deficiency of a_cofactor to_activated_protein C_had_been postulated (Ref._7). While a_poor response to APC_appears to be_5_to 10 times as frequent as deficiencies of protein C, protein S or antithrombin_it_confers an_approximately_similar_relative risk of thrombosis (Ref._17 and 18) which according_to Koster_et al could make it worthwhile to test_all_patients with venous_thrombosis for this abnormality.
In summary in the state of_the art it was ascertained that_a defect in_the_protein_C anticoagulant pathway is_linked to a relatively high risk_of thrombosis. The poor anticoagulant response_to activated protein C has been discussed_in great detail, however the cause_of the poor anticoagulant response_to activated_protein C remains unclear. A_number of theories_have been_postulated, however the_only one that has been accepted_is the presence_of an unknown cofactor for APC_which_is apparently deficient_in_a_patient exhibiting_a poor anticoagulant_response_to activated_protein_C. The identity of the postulated_cofactor_for APC is unknown. Furthermore current tests_for detecting altered response_to_APC cannot be used_on test persons already using_anticoagulants.
Surprisingly the identity of the unidentified_cofactor responsible_for a_poor anticoagulant protein C response has been found. It has been_discovered that one of the mechanisms_that had been rejected_is in_fact_responsible for the_defect_in the_protein C anticoagulant pathway in a majority_of thrombophilic_patients. The cause of the deficiency_has been linked to_the_presence of a mutation in the_nucleic acid material encoding Factor V_or Factor VIII which upon_expression_is_correlated to a decrease in_the degree of inactivation by APC_of said Factor_V and/or of Factor Va, (the product_of_activation of said Factor V) or_of_said Factor VIII and/or of Factor_VIIIa_(the_product of activation of said_Factor VIII). The deficiency is therefore_not the result of a mutation in an as_yet unidentified cofactor_for APC, but is in_fact_due_to a defect in Factor V or Factor VIII or_more particularly_in the activation_products thereof.
As was already indicated in the state of the_art the link between a risk of_thrombosis and the presence of APC-resistence had already been made and_it had also been suggested that screening for_such a deficiency would in fact be_extremely helpful in diagnosing_patients_with an increased risk of thrombosis. As_it_is_now_known which factors_carry the genetic_defect responsible it_has also_now become possible_to actually_screen the population_with_methods other than the Chromogenix test for determining APC-resistance