4
TepaneBTH'IecKHit apXHB,2008, NfJ 7, C. 88-91 41. Komarova E. JI:, Afanasyeva E. A., Bulatova. M. M. et at. Downstream caspasesare novel targets for the antiapoptotic activity of the molecular chaperone hsp70. Cell&Stress Chap- erones 2004; 9: 265-275. 42. Steel R., Doherty J. P., Buzzard K. et al. Hsp72 inhibits apop- tosis upstream of the mitochondria and not through interac- tions with Apaf-l. J. BioI. Chem. 2004; 279: 51490-51499. 43. Fe"arini M., Heltai S., ZocchiM. R., Rugarli C. Unusual ex- pression and localization of heat-shock proteins in human tu- mor cells. Int. J. Cancer.1992; 51: 613-619. 44. Hantschel M., PfISter K., Jordan A. et al. Hsp70plasma mem- brane expression on primary tumor biopsy material and bone marrowof leukemicpatients.Cell Stress Chaperones 2000;5: 438-442. 37. ,Vabu/as R. M., Ahmad-Nejad P., Ghose S. et al. HSP70 as en- dogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. BioI. Chern. 2002; 277: 1510-1517. 38. Schmitt E., Parce//ier A., Gurbuxani S. et al. Chemosensitiza- tion by a non-apoptogenic heat shock protein 70-binding ap- optosis-inducing factor mutant. Cancer Res. 2003; 63: 8233- 8240. 39. Li C. Y, Lee J. S., Ko Y. G. et al. Heat shock protein 70 in- hibits apoptosis downstream of cytochrome c release and up- stream of caspase-3 activation. J. Bioi. Chern. 2000; 275: 25665-25671. 40. Buzzard K. A., Giaccia A. J., Ki//ender M., Anderson R. L. Heat shock protein 72 modulates pathways of stress-induced apop- tosis. J. Bioi. Chern. 1998; 273: 17147-17153. nOc-rynun3 14.02.08 C KOJIJIEKTHB ABTOPOB, 2008 Y~K 612.115(048.8) M. A. lIanmeAee81, JI. H. KOmO8a2, A. A. TOKape8/, CPo H. AmaY/UlaxanO8/' 2 MEXAHH3MbI PEfYJUI~HH CBEPTbIB4HJJJI KPOBH JIa6opaTOpHH tl>H3H'1eCKO~ 6HOXHMHH CHCTeMbI KpOBH rY [eMaTOJlOrHtleCKOrO Hay'lHOrO ueHTpa PAMH, MOCKBa KJI JO q e B hI e CJI 0 B a: 0630P, C8epmb/8aHUe"PO8U, zeMocma3, mpoM6uH, zeMorjJllAUR Key words: review, blood coagulation, hemostasis, thrombin, hemophilia CBepTbIBaHHe KpOBH npe~CTaBJIHeT c060R CJIO)KHyIOCHCTeMY peaK~HIt, 3anycKalOmHXCH npH nOBpe~eHHH cocy~a H Be~ymHx K JIOKaJIbHOMY nepexo~y nJIa3MbI KpOBH H3 }K~KOrO COCTOHHHH B re- JIe06pa3Hoe [1, 2]. CBepTbIBaHHe HBJlHerCH O~HHM H3 3BeHbeB CHC- TeMbI reMOCTaJa, KOTOpaH OTBe'laer 3a npe~OTBpameHHe KpOBono- TepH npH HapYlIIeHHH ~eJIOCTHOCTH COCY~HcTolt CHCTeMbI. B Ha- CTOHmeeBpeMH CHCTeMa peaKUHR CBepTbIBaHHHH3yqeHa ~OBOJIbHO no~p06HO: 3a nOCJIe~HHe 15 JIeT - O'leHb 60JIbWoR CpOK JJ;JIH co- BpeMeHHolt 6HOXHMHH - B HeR He 6b1J1o OTKpbITO HH O~Horo HO- Boro 6eJIKa HJIH HOBOIt peaKUHH [2, 3]. TeM He MeHee <PYHKUHOHH- pOBaHHe CBePTbIBaHHH KaK e~HHoR CHCTeMbIH pOJIb OT~eJIbHbIXpe- aK~HR B ero peryJIH~HH npe~CTaBJIHIOT c0601t 3ara.nKY, KOTOpaH JIHWb He~aBHO Ha'laJIa nOCTeneHHO paCKPbIBaTbCH 6JIarO~apH CO- BMeCTHbIM YCHJIHHM Bpa'lelt, 6HOXHMHKOB, 6HO<pH3HKOB H MaTeMa- THKOB. 3TH pe3YJIbTaTbIy)Ke ceR'Iac npHBOJ1,HT K nOHBJIeHHIO HOBbIX ~eR H MeTO~OBB ~HarHOCTHKe H TepanHH pa3JIH'IHbIX naTOJIOrHIt reMOCTaJa. l(eJIblO ~aHHoro 0630pa HBmleTCH paCCMOTPeHHe cyme- CTBYIOIUHX ~OCTH}KeHHit H np06JIeM B 3TOit 06JIacTH. JIHMepOB, KOTOpbIe MOryr JIarepaJIbHO arperHpOBaTb, 4>OPMHPYH HH- TH 4>H6pHHoBOrOBOJIOKHa. BOJlOKHa p83BeTBJISIJOTCH, 06pa3YH Tpex- MepHYJO CeTb 4>H6pHHoBOrO cryCTKa. KpOMe TOrO, TPOM6HH ytIaCTByeT BO MHO)KeCTBe TaK H83bIBae- MbIX 06paTHbiX CBH3e~ - peryJIHTOpHbIX peaKUH~, B KOTOpbIX OH BJIHHeTHa CBOe C06CTBeHHOenpOH3BOJ!CTBO. OCHOBHbIMH TaKHMH peaK~HHMH HBJUlJOTCH peaKUHH aKTHBa~HH TpOM6HHOM 4>aKTOpOB V, VIII, XI H nporeHHa C. <I>aKTOpbI V H VIII npeJ!CTaBJIHJOT c060~ npeJ!wecTBeHHliKH Ko4>aKTOpoB, Ii nOCJIe aKTliBBUHIi TpoM6liHOM cnoc06HbI Ha HeCKOJIbKO nopjIJIKOB YBeJlH'IliBaTb CKOpOCTb pa60TbI 4>aKTOpOB Xa Ii IXa COOTBeTCTBeHHO [5, 7, 8]. 31"0 J!ocrnraeTCH ny- TeM C60PKii 4>epMeHTarnBHbIX KOMnJIeKCOB npOTpOM6liH83bI (4>aK- TOpbI Xa-Va) Ii BHYTpeHHe~ reHa3bI (4>aKTOpbI IXa-VIIIa) Ha MeM6paHax aKrnBlipOBaHHbIx TpoM60~TOB. <I>aKTop XI HBJUleTCH npeJ!weCTBeHHliKoM cepliHoBo~ nporeliHa3bI, KOTOpbI~ noCJIe aK- TliBa~liH TPOM6liHOM (HJlIi 4>aKTOpOM Xlia li3 KOHTaKTHOrO llYTli aKTHBa~1i1i CBepTbiBaHliH) cnoc06eH aKTHBlipOBaTb 4>aKTOp IX [9, 10]. TpH paCCMOTPeHHbIe neTJIH 06paTHO~ CBjl3H OTHOCjlTCjI K KJIaC- cy nOJlO)KHTeJIbHbIX: B HHX TPOM6HH YCKOpjleT CBOe CO6CTBeHHOe npOH3BOJJ,CTBO. HanpOTHB, nyrb npOTeHHa C jlBJUleTCjI Ba)KHe~llIe~ OTPHuaTeJlbHO~ o6paTHo~ CBjl3blO, B KOTOpO~ TPOM6HH HHrn6HPYeT CBOIO aKTHBauHIO. npOTeHH C npeJJ,CTaBJUIeT co6o~ npeJJ.llIeCTBeH- HHK CepHHoBoit npOTeHHaJbI. no CBoeit MOJIeKYJUIpHoit cTPYKTYPe OH O'ieHb nOXO)K Ha llJaKTOpbI IX, X, VII H npoTPoM6HH. npH aK- THBaUHH TPoM6HHOM noJlyqHBIlI~CjI npOTeHHaJa npoH3BOJJ,HT He- CKOJlbKO npOTeOJIHTH'ieCKHXpaCllIenJIeHHit B llJax:ropax CBepTbIBa- HHj{ Va H VIIIa, 3aCTaBJUUI HX nOJIHOCTbIO TepjlTb CBOH KollJaKTOp- HbIe cBoitCTBa [11]. Ba)KHbIM peryJUITOpOM nYTH npOTeHHa C jlBJUI- eTCH TPOM6oMOJJ,YJIHH, MeM6paHHbIit 6eJIOK, SKcnpeccHpyeMbIit SH- JJ,OTeJlHeM. OH CBjl3bIBaeT TPOM6HH, YBeJIH'iHB~ Ha HeCKOJIbKO no- PJJJJ.KOB CKOpOCTb aKTHBauHH npOTeHHa C TPOM6HHOM Ha nOBepx- HOCTHSHJJ,OTeJIHH [12]. J].JIJI peryJUIUHH npouecca cBepTbIBaHHjI B KpOBH npHcyrcTByJOT HHfH6HTOpbI cepHHoBblX npOTeHHaJ. OCHOBHbIMH HHfH6HTopaMH cBepTbIBaHHH HBJUlIOTCH aHTHTpoM6HH III, HHfH6HPYlOLUHit nO'irn Bce llJaKTOpbICBepTbIBaHHjI KpOMe llJaKTopa VIla, H HHrn6HTop nyrH T<I> (tissue factor pathway inhibitor HJlH TFPI), HHfH6HPYlOLUHit BHeWHlO1O TeHaJY [13-15]. nOMHMO nyrH T<I> CBepTblBaHHe MO)KeTaKTHBHpOBaTbCH no TaK HaJblBaeMOMY KOHTaKTHOMY nyrH. OCHOBHoit 6eJIOK STOfO nyrH, llJaKTop XII, aKTHBHpYeTCH npH KOHTaKTe nJla3MbI C npaKTH'ieCKH Jl1O6o~ 'iy)KepoJJ,Ho~ nOBepXHOCTbIO, a 3aTeM aKTHBHpYeTllJaKTop XI [16]. nOCKOJIbKYC'iHTaeTCH, 'iTO OH He HrpaeT pOJIH B HOpMaJlbHOM CBePTbIBaHHH, OH He nOKa3aH Ha pHC. 1. TeM He MeHee eCTbJJ,aHHbIe, 'ITO OH MO)KeT HrpaTb Ba)KHbIe pOJIH B JJ,pyrHX cHcTeMax opfaHH3Ma, a TaK)Ke B naTOJIOfH'IeCKOMCBepTbIBaHHH [Ib]. BHOXHMHJI CBepTblBaHHJI KpOBH KJTeTKH npaKTM'leCKH BCeX TKaHe~ OpraHM3Ma, 3a MCKJIIO'leHM- HM 3!{JlOTeJlMH M KJIeTOK KpOBM, 3KCnpeCCMpylOT TPaHCMeM6paHHbli% 6eJIOK - TKaHeBbI~ q,aKTOp (T<I». TaKMM 06PaJOM, JIIO60e nOBpe- )K.!1eHMe 3!{JlOTeJIMH npMBO~MT K TOMY, 'lTO nJIa3Ma KpOBM BCTYnaeT B KOHTaKT C KJIeTKaMM, HeCY\UMMM T<I>. B nJIaJMe nOCTOHHHO npM- CYTCTByeT q,aKTOp VIla (OCHOBHble 6eJ1KH CMCTeMbI CBePTbIBaHMH HaJblBalOTCH q,aKTOpaMM CBePTblBaHMH Ii, npOHYMepOBaHbI B noPM- Ke OTKpblTHH; CMMBOJI "a" 0603Ha'laeT aKTMBMpOBaHHYIO q,OPMY 6eJI- Ka), cepMHOBaJI npOTeHHaJa, KOTOpaJI caMa no ce6e no'lTM He 06- JIa,naeT q,epMeHTaTHBHO~ aKTMBHOCTbIO. Kor~a q,aKTop VIla CBH3b1- BaeTCH C T<I>, nOJIyqMB\UM~CH KOMnJIeKC, Ha3b1BaeMbIi% BHeIUHe~ Te- HaJO~ [4], npM06peTaeT cnoC06HOCTb aKTHBMpOBaTb q,aKTOpbl IX M X. KaK M nO'lTM Bce q,ax:rOpbl CBepTblBaHMH, OHM CMHTe3MpylOTCH H ~MPKYJIMpylOT B KpOBOTOKe B HeaKTMBHoi% q,opMe. I1x aKTHBa~MH npe~CTaBmreT c060i% pa3pe3aHMe MOJIeKYJIbI 6eJ1Ka B O~HOM MJIH He- CKOJIbKHX MecTax, KOTopoe OTKpblBaeT era aKTHBHbI~ Cai%T M M3Me- HHeT KOHq,OpMal!MIO TaK, '!TO 6eJIOK CTaHOBMTCH aKTMBHblM q,ep- MeHTOM, cnoc06HbIM caMOCTOHTeJIbHO npoM3BO~MTb paJpe3b1 B ~PY- rMX 6eJIKax. OnMcaHHaH CMCTeMa pea~Mi%, OTBe'lalO\UHX 3a 3anycK cBepTblBaHMH, HaJblBaeTCH BHelUHHM nyreM CBepTblBaHMH, MJIM ny- TeMT<I> [4). <l>aKTop Xa cnoc06eH KaTaJIH3MpOBaTb npeBpa\UeHMe npOTPOM- 6MHa B aKTHBHyIO cepMHOByIO npOTeMHaJY TPoM6MH, KOTOpbl~ HB- JIHeTCH rJIaBHblM q,epMeHTOM CBepTbIBaHMH [5]. I1MeHHo TPoM6MH ocy\UeCTBJIHeT npeBpa\UeHMe 6eJIKa q,M6pMHoreHa B q,M6pMH [6]. MoJIeKYJIbI q,M6pMHa ~aJIee cnoc06HbI 06pa30BblBaTb ~enO'lKH no- 88 -

TepaneBTH'IecKHit apXHB, 2008, NfJ 7, C. 88-91rus)_2008.pdf · HeHHe TaKHX nOJI.XOJI.OB 6YJI.eT JIHJI.HpyIOIltHM HanpaBJIeHHeM B 611H-- - 91

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TepaneBTH'IecKHit apXHB, 2008, NfJ 7, C. 88-91

41. Komarova E. JI:, Afanasyeva E. A., Bulatova. M. M. et at.Downstream caspases are novel targets for the antiapoptoticactivity of the molecular chaperone hsp70. Cell&Stress Chap-erones 2004; 9: 265-275.

42. Steel R., Doherty J. P., Buzzard K. et al. Hsp72 inhibits apop-tosis upstream of the mitochondria and not through interac-tions with Apaf-l. J. BioI. Chem. 2004; 279: 51490-51499.

43. Fe"arini M., Heltai S., Zocchi M. R., Rugarli C. Unusual ex-pression and localization of heat-shock proteins in human tu-mor cells. Int. J. Cancer. 1992; 51: 613-619.

44. Hantschel M., PfISter K., Jordan A. et al. Hsp70 plasma mem-brane expression on primary tumor biopsy material and bonemarrow of leukemic patients. Cell Stress Chaperones 2000; 5:438-442.

37. ,Vabu/as R. M., Ahmad-Nejad P., Ghose S. et al. HSP70 as en-dogenous stimulus of the Toll/interleukin-1 receptor signalpathway. J. BioI. Chern. 2002; 277: 1510-1517.

38. Schmitt E., Parce//ier A., Gurbuxani S. et al. Chemosensitiza-tion by a non-apoptogenic heat shock protein 70-binding ap-optosis-inducing factor mutant. Cancer Res. 2003; 63: 8233-8240.

39. Li C. Y, Lee J. S., Ko Y. G. et al. Heat shock protein 70 in-hibits apoptosis downstream of cytochrome c release and up-stream of caspase-3 activation. J. Bioi. Chern. 2000; 275:25665-25671.

40. Buzzard K. A., Giaccia A. J., Ki//ender M., Anderson R. L. Heatshock protein 72 modulates pathways of stress-induced apop-tosis. J. Bioi. Chern. 1998; 273: 17147-17153. nOc-rynun3 14.02.08

C KOJIJIEKTHB ABTOPOB, 2008

Y~K 612.115(048.8)

M. A. lIanmeAee81, JI. H. KOmO8a2, A. A. TOKape8/, CPo H. AmaY/UlaxanO8/' 2

MEXAHH3MbI PEfYJUI~HH CBEPTbIB4HJJJI KPOBH

JIa6opaTOpHH tl>H3H'1eCKO~ 6HOXHMHH CHCTeMbI KpOBH rY [eMaTOJlOrHtleCKOrO Hay'lHOrO ueHTpa PAMH, MOCKBa

KJI JO q e B hI e C JI 0 B a: 0630P, C8epmb/8aHUe "PO8U, zeMocma3, mpoM6uH, zeMorjJllAUR

Key words: review, blood coagulation, hemostasis, thrombin, hemophilia

CBepTbIBaHHe KpOBH npe~CTaBJIHeT c060R CJIO)KHyIO CHCTeMYpeaK~HIt, 3anycKalOmHXCH npH nOBpe~eHHH cocy~a H Be~ymHx KJIOKaJIbHOMY nepexo~y nJIa3MbI KpOBH H3 }K~KOrO COCTOHHHH B re-JIe06pa3Hoe [1, 2]. CBepTbIBaHHe HBJlHerCH O~HHM H3 3BeHbeB CHC-TeMbI reMOCTaJa, KOTOpaH OTBe'laer 3a npe~OTBpameHHe KpOBono-TepH npH HapYlIIeHHH ~eJIOCTHOCTH COCY~HcTolt CHCTeMbI. B Ha-CTOHmee BpeMH CHCTeMa peaKUHR CBepTbIBaHHH H3yqeHa ~OBOJIbHOno~p06HO: 3a nOCJIe~HHe 15 JIeT - O'leHb 60JIbWoR CpOK JJ;JIH co-BpeMeHHolt 6HOXHMHH - B HeR He 6b1J1o OTKpbITO HH O~Horo HO-Boro 6eJIKa HJIH HOBOIt peaKUHH [2, 3]. TeM He MeHee <PYHKUHOHH-pOBaHHe CBePTbIBaHHH KaK e~HHoR CHCTeMbI H pOJIb OT~eJIbHbIX pe-aK~HR B ero peryJIH~HH npe~CTaBJIHIOT c0601t 3ara.nKY, KOTOpaHJIHWb He~aBHO Ha'laJIa nOCTeneHHO paCKPbIBaTbCH 6JIarO~apH CO-BMeCTHbIM YCHJIHHM Bpa'lelt, 6HOXHMHKOB, 6HO<pH3HKOB H MaTeMa-THKOB. 3TH pe3YJIbTaTbI y)Ke ceR'Iac npHBOJ1,HT K nOHBJIeHHIO HOBbIX~eR H MeTO~OB B ~HarHOCTHKe H TepanHH pa3JIH'IHbIX naTOJIOrHItreMOCTaJa. l(eJIblO ~aHHoro 0630pa HBmleTCH paCCMOTPeHHe cyme-CTBYIOIUHX ~OCTH}KeHHit H np06JIeM B 3TOit 06JIacTH.

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10].TpH paCCMOTPeHHbIe neTJIH 06paTHO~ CBjl3H OTHOCjlTCjI K KJIaC-

cy nOJlO)KHTeJIbHbIX: B HHX TPOM6HH YCKOpjleT CBOe CO6CTBeHHOenpOH3BOJJ,CTBO. HanpOTHB, nyrb npOTeHHa C jlBJUleTCjI Ba)KHe~llIe~OTPHuaTeJlbHO~ o6paTHo~ CBjl3blO, B KOTOpO~ TPOM6HH HHrn6HPYeTCBOIO aKTHBauHIO. npOTeHH C npeJJ,CTaBJUIeT co6o~ npeJJ.llIeCTBeH-HHK CepHHoBoit npOTeHHaJbI. no CBoeit MOJIeKYJUIpHoit cTPYKTYPeOH O'ieHb nOXO)K Ha llJaKTOpbI IX, X, VII H npoTPoM6HH. npH aK-THBaUHH TPoM6HHOM noJlyqHBIlI~CjI npOTeHHaJa npoH3BOJJ,HT He-CKOJlbKO npOTeOJIHTH'ieCKHX paCllIenJIeHHit B llJax:ropax CBepTbIBa-HHj{ Va H VIIIa, 3aCTaBJUUI HX nOJIHOCTbIO TepjlTb CBOH KollJaKTOp-HbIe cBoitCTBa [11]. Ba)KHbIM peryJUITOpOM nYTH npOTeHHa C jlBJUI-eTCH TPOM6oMOJJ,YJIHH, MeM6paHHbIit 6eJIOK, SKcnpeccHpyeMbIit SH-JJ,OTeJlHeM. OH CBjl3bIBaeT TPOM6HH, YBeJIH'iHB~ Ha HeCKOJIbKO no-PJJJJ.KOB CKOpOCTb aKTHBauHH npOTeHHa C TPOM6HHOM Ha nOBepx-HOCTH SHJJ,OTeJIHH [12].

J].JIJI peryJUIUHH npouecca cBepTbIBaHHjI B KpOBH npHcyrcTByJOTHHfH6HTOpbI cepHHoBblX npOTeHHaJ. OCHOBHbIMH HHfH6HTopaMHcBepTbIBaHHH HBJUlIOTCH aHTHTpoM6HH III, HHfH6HPYlOLUHit nO'irnBce llJaKTOpbI CBepTbIBaHHjI KpOMe llJaKTopa VIla, H HHrn6HTop nyrHT<I> (tissue factor pathway inhibitor HJlH TFPI), HHfH6HPYlOLUHitBHeWHlO1O TeHaJY [13-15].

nOMHMO nyrH T<I> CBepTblBaHHe MO)KeT aKTHBHpOBaTbCH no TaKHaJblBaeMOMY KOHTaKTHOMY nyrH. OCHOBHoit 6eJIOK STOfO nyrH,llJaKTop XII, aKTHBHpYeTCH npH KOHTaKTe nJla3MbI C npaKTH'ieCKHJl1O6o~ 'iy)KepoJJ,Ho~ nOBepXHOCTbIO, a 3aTeM aKTHBHpYeT llJaKTop XI[16]. nOCKOJIbKY C'iHTaeTCH, 'iTO OH He HrpaeT pOJIH B HOpMaJlbHOMCBePTbIBaHHH, OH He nOKa3aH Ha pHC. 1. TeM He MeHee eCTb JJ,aHHbIe,'ITO OH MO)KeT HrpaTb Ba)KHbIe pOJIH B JJ,pyrHX cHcTeMax opfaHH3Ma,a TaK)Ke B naTOJIOfH'IeCKOM CBepTbIBaHHH [Ib].

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Ka), cepMHOBaJI npOTeHHaJa, KOTOpaJI caMa no ce6e no'lTM He 06-

JIa,naeT q,epMeHTaTHBHO~ aKTMBHOCTbIO. Kor~a q,aKTop VIla CBH3b1-BaeTCH C T<I>, nOJIyqMB\UM~CH KOMnJIeKC, Ha3b1BaeMbIi% BHeIUHe~ Te-

HaJO~ [4], npM06peTaeT cnoC06HOCTb aKTHBMpOBaTb q,aKTOpbl IX MX. KaK M nO'lTM Bce q,ax:rOpbl CBepTblBaHMH, OHM CMHTe3MpylOTCH H

~MPKYJIMpylOT B KpOBOTOKe B HeaKTMBHoi% q,opMe. I1x aKTHBa~MH

npe~CTaBmreT c060i% pa3pe3aHMe MOJIeKYJIbI 6eJ1Ka B O~HOM MJIH He-CKOJIbKHX MecTax, KOTopoe OTKpblBaeT era aKTHBHbI~ Cai%T M M3Me-

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89

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