, Maria Kotschy. , Paweł Socha, Leszek Masłowski, Justyna Kwapisz, Natalia Żuk, Joanna Dubis, Maciej Karczewski, Wojciech Witkiewicz

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1 Postey Hig d Dosw (online), 2015; 69: e-issn Oiginal Aticle Received: Acceted: Published: Authos Contibution: Study Design Data Collection Statistical Analysis Data Inteetation Manuscit Peaation Liteatue Seach Funds Collection Intoduction: Aim: Patients & methods: Results: Selected endothelial hemostatic makes in atients with eiheal ateial disease afte endovascula evasculaization and estenosis fomation* Wybane śódbłonkowe makey hemostazy u acjentów z miażdżycą tętnic kończyn dolnych o wewnątznaczyniowej ewaskulayzacji i o owstaniu estenoz Daniel Kotschy,,,, Maia Kotschy,,, Paweł Socha, Leszek Masłowski, Justyna Kwaisz, Natalia Żuk, Joanna Dubis, Maciej Kaczewski, Wojciech Witkiewicz Regional Secialized Hosital Reseach and Develoment Cente in Wocław, Poject WoVasc- Integated Cente of Cadiovascula dicine, Poland Summay Sugical and endovascula evasculaization of ischemic legs in atients with eiheal ateial disease (PAD) can damage the ateial wall (endothelial and smooth muscle cells). Hemostatic factos eleased duing endothelial dysfunction can lead to estenosis. 1. Detemination of selected endothelial hemostatic factos in PAD atients and a efeence gou. 2. Posective obsevation of new estenosis aeaance in PAD atients afte endovascula evasculaization. 3. Comaison of selected endothelial hemostatic factos between non-estenotic and estenotic PAD atients. 150 PAD atients afte endovascula evasculaization 90 men and 60 women, aged (mean 65.5) yeas wee examined. Duing one-yea obsevation afte the evasculaization ocedues in 38 PAD atients estenosis occued, when blood samles wee also collected. The efeence gou consisted of 53 healthy esons 44 men and 9 women, aged yeas. Blood was dawn in the moning into 3.2% sodium citate at a atio of 9:1. Tissue facto (TF), tissue facto athway inhibito (TFPI), thombomodulin (TM), von Willeband facto (vwf) and tissue lasminogen activato (t-pa) wee measued in lasma with commecial tests using the enzyme immunoassay. In the lasma of PAD atients afte evasculaization, the concentations of TF and vwf wee significantly highe, TM lowe, TFPI and t-pa simila comaed to the efeence gou. Six months afte evasculaization the level of TF had inceased and vwf had significantly deceased. The endothelial hemostatic factos befoe and afte estenosis did not significantly diffe excet TF, which afte estenosis was highe. *This ublication is at of the oject Wovasc Integated Cadiovascula Cente, co-financed by the Euoean Regional Develoment Fund, within the Innovative Economy Oeational Pogam, , imlemented in the Regional Secialist Hosital, Reseach and Develoment Cente in Woclaw. Postey Hig d Dosw (online), 2015;

2 Postey Hig d Dosw (online), 2015; tom 69: Inceased TF and vwf levels in PAD atients indicate ateial endothelial cell damage, by atheoscleotic and evasculaization ocesses. In PAD atients with estenosis comaed to these atients befoe estenosis the detemined endothelial hemostatic factos, excet TF level, did not significantly diffe. Pehas TF aticiates in estenosis fomation. Keywods: endothelial hemostatic factos endovascula evasculaization estenosis Full-text PDF: Wod count: Tables: Figues: Refeences: htt:// Ades autoki: of. Maia Kotschy, Wojewódzki Szital Secjalistyczny. Ośodek Badawczo-Rozwojowy we Wocławiu, ul. H.M. Kamieńskiego 73a, Wocław; kwaisz@wssk.woc.l Intoduction In atients with eiheal ateial disease (PAD) of the legs, inceased coagulation and thomboembolic comlications occu [2,25,28]. Sugical and endovascula evasculaization ocedues incease this thombogenic state, sometimes leading to estenosis [19,22]. Vascula endothelium is located at the inteface between vascula tissue and blood. It is ivotal fo otecting against vascula injuy and maintaining blood fluidity. Injuy of endothelium is accomanied by loss of otective molecules, ocoagulant activities and mitogenic factos, leading to endothelial and smooth muscle cell olifeation and migation and to develoment of atheoscleosis and thombosis in PAD [31]. Endothelium eleases nitic oxide and ostacyclin, otent vasodilatos and inhibitos of latelet activation. Injuy of the ateial wall induces a hemostatic esonse and elease of: tissue facto (TF), tissue facto athway inhibito (TFPI), thombomodulin (TM), von Willeband facto (vwf) and tissue lasminogen activato (t-pa). TF eleased fom the damaged endothelial, smooth muscle cells and monocytes induces olifeation and migation of these cells. TF leads to an inflammatoy ocess and induces blood coagulation, thombin geneation and fibin fomation. This ocess involves contolled inteaction between diffeent hemostatic oteins [28]. TF and TFPI with othe clotting factos wee found in the stuctue of atheoscleotic laques [15,16]. TF is the incile initiato of the extinsic blood coagulation and the majo facto inducing fibin deosition in vivo. The TF/VIIa comlex is assembled on the cell suface with the stongest natual lasma inhibito TFPI [10,27]. TFPI inhibits TF and TF/VIIa comlex and also aticiates in a tenay comlex with facto X and facto VIIa bound to tissue facto [13]. TM seves as a binding site fo thombin, foming a TM/thombin comlex, in which thombin deeciates its ossibility to activate factos V, VIII and XIII, blood latelets and convesion of fibinogen to fibin. The TM/thombin comlex activates oteins C and S and also inhibits fibinolysis, blocking the activation of thombin activatable fibinolysis inhibito (TAFI) [7]. Recombinant human thombomodulin inhibits ateial neointimal hyelasia afte balloon injuy [12]. Endothelium oduces and secets vwf, which mediates latelet adhesion to bind latelets at the site of vascula damage. VWF is also a caie of facto VIII, an imotant isk facto fo venous thombosis [3,26]. Nomal endothelium also secets t-pa, which activates lasminogen to lasmin and beaks fibin to fibin degadation oducts, e.g. D-dimes. This ocess is called fibinolysis [18]. Diffeent sugical and endovascula evasculaization methods exist fo teatment of PAD atients. Cuently, ecutaneous tansluminal angiolasty (PTA) with o without stenting is the best ocedue to imove blood flow in naowed ateies. These ocedues ae minimally invasive, but sometimes again can cause an atey stenosis (estenosis) o occlusion. When a estenosis aeas, this ocedue can be eeated. The effects ae less successful when multile leg ateies ae naowed o occluded and when vey small vessels have to be oened [5,6,23]. Aim 1. Detemination of selected endothelial hemostatic factos in PAD atients and efeence gou, 2. Posective obsevation of new estenosis aeaance in PAD atients afte endovascula evasculaization. 3. Comaison of selected endothelial hemostatic facto levels between non-estenotic and estenotic PAD atients. 906

3 Kotschy D. et al. - Selected endothelial hemostatic makes... Patients and methods The study included 150 PAD atients 90 men and 60 women, aged 44 to 88 (mean 65.5) yeas 1-18 months afte successful eiheal endovascula evasculaization, mainly PTA with stenting and stent imlantation. The time between evasculaization and blood dawing was divided into thee eiods: I) 1-3 months 77 atients, II) >3-6 months 30 atients, III) >6-18 months 43 atients. In all PAD atients, medical inteview, hysical examination, hematological and biochemical tests and vascula examinations wee efomed. Ischemia of legs was diagnosed based on ultasound examination (USG dulex Dole). Befoe evasculaization and afte estenosis fomation, comuted tomogahy and/o ateiogahy wee efomed. Intemittent claudication and ankle bachial essue index (ABPI) wee also measued. Of the atients included in the study, 101 (66%) had vaious foms of ischemic heat disease, 126 (82%) ateial hyetension, 120 (78.4%) dysliidemia, 90 (58.7%) wee ex-smokes, 41 (26.8%) atients wee cuent smokes, and 19 (12.6%) neve smoked. Tye 2 diabetes was obseved in 91 (60.1%), oveweight and obesity in 115 (75.1%). PAD atients, excet those in whom estenosis occued, wee examined evey 3 months, 5 times duing 1 yea with USG and blood collection. The efeence gou consisted of 53 healthy esons, who wee qualified fo thei fist blood donation at the Blood Donation Cente 44 men and 9 women aged yeas. In the healthy subjects, medical histoy and hysical examination as well as laboatoy tests including blood tye identification, blood cell count and vial tests wee efomed. The efeence gou was younge than the atients with PAD, but some liteatue data suggest that in healthy esons sex and age do not influence TF, TFPI, TM, and t-pa but vwf deends on age. 4.5 ml blood samles fo laboatoy tests wee dawing in the moning afte night fasting fom an antecubital vein to a test tube with 3.2% sodium citate at a atio of 9:1. The lasma was obtained by centifugation of blood samles at 2500 g fo 15 minutes. Subsequently, 0.2 ml of the lasma to be tested was ietted into Eendof tubes and stoed at -80 C until measuements. The lasma concentation of endothelial hemostatic factos was measued with commecial enzyme immunoassay tests fom Ameican Diagnostica Inc. The manufactue has not secified the nomal ange of esults, but ecommends that each laboatoy establish its own efeence values. TF Imubind TF ELISA Kit. This assay detects TF and TF/VIIa comlexes. TFPI Imubind Total TFPI ELISA Kit. This assay detects both full-chain and tuncated TFPI comlexes with eithe TF o facto VIIa. TFPI suesses both facto Xa and TF/VIIIa comlexes. TM Imubind Thombomodulin ELISA Kit. It is a sandwich ELISA emloying a monoclonal antibody, which ecognizes the EGF 1 and EGF 2 domains of TM. A second hoseadish eoxidase (HRP) conjugated with monoclonal antibody secific fo EGF 5 and EGF 6 was used. vwf Imubind vwf ELISA Kit. It is a sandwich ELISA test using goat olyclonal antibody as the catue antibody. t-pa Imubind t-pa ELISA Kit. In this test goat olyclonal antibodies diected against human t-pa wee used. Statistical analysis Results ae esented in tables as mean values (M) and standad deviation (SD) o medians () and intequatile ange (lowe Q1 and ue Q3). Nomality of distibution was assessed using the D Agostino-Peason test. The statistical significance of diffeences between gous was analyzed in the case of non-nomal data with the nonaametic Mann-Whitney test and with Student s t-test in atients with nomal data. The coelations between the measued aametes chaacteized by non-nomal data distibution wee calculated using the Seaman ank coelation coefficient (). The level of statistical significance was adoted as < Statistical analysis was efomed with R fo Windows (the R Foundation fo Statistical Comuting, Vienna, Austia) and dcalc fo Windows (dcalc Softwae, Maiakeke, Belgium). This otocol of the study was aoved by the Bioethical Committee at the Regional Secialist Hosital, no. KB/2/2008. Results Risk factos and comobidities in PAD atients afte endovascula evasculaization with and without estenosis ae esented in table 1. No significant diffeences between the two gous wee obseved. Table 2 esents measued concentations of TF, TFPI, TM, vwf and t-pa in lasma of atients with PAD afte endovascula evasculaization comaed to the efeence gou. As demonstated by ou study, TF and vwf concentations wee significantly highe, TM lowe, but TFPI and t-pa simila comaed to the efeence gou. Table 3 esents coelations between endothelial hemostatic factos: TF, TFPI, TM, vwf, tpa and age of PAD atients. Excet TFPI, all factos deend in a weak but significant manne on PAD atients age. Simila coelations also exist between TF/TFPI, TF/vWF, TM/vWF, and t-pa/vwf. We divided the time of 1-18 months fom endovascula evasculaization to blood collection into thee eiods: 907

4 Postey Hig d Dosw (online), 2015; tom 69: Table 1. Distibution of isk factos and comobilities in PAD atients Risk factos PAD atients without estenosis n=112 PAD atients with estenosis n=38 n % n % -value n % 19 50% Women % 19 50% 0.18 an age / yeas Body Mass Index (BMI) > % % 0.43 Dysliidemia % % 0.96 Hyetension % % 0.83 Diabetes % % 0.26 Coonay heat disease % % 0.7 Stoke % 2 5.3% 0.28 Cuent smokes % % 0.51 Fome smokes % % 0.94 ASA mg % % 0.72 Ticloidine % % 0.28 Cloidogel % % Acenocoumaol 3 2.7% 1 2.6% 0.58 Table 2. Some endothelial hemostatic factos in PAD atients afte successful endovascula evasculaization and in efeence gou Detemined aametes PAD atients n=150 Q1 Q3 Refeence gou n=53 Q1 Q3 -value TF g/ml ± ± TFPI ng/ml 58.0 ± ± TM ng/ml 3.0 ± ± vwf U/ml ± ± t-pa ng/ml 8.8 ± ± n numbe, M mean, median, PAD - eiheal ateial disease, -value - significance level of statistical test, Q quatiles, SD - standad deviation, TF - tissue facto, TFPI - tissue facto athway inhibito, TM thombomodulin, t-pa - tissue lasminogen activato, vwf - von Willeband facto 908

5 Kotschy D. et al. - Selected endothelial hemostatic makes... Table 3. Coelations between age of PAD atients and detemined endothelial hemostatic factos Detemined aamets Age TFPI TM vwf TF TFPI TM vwf t-pa x x x x x x PAD - eiheal ateial disease, -value - significance level of statistical test TF- tissue facto, - Seaman ank coelation coefficient, TFPI - tissue facto athway inhibito, TM thombomodulin, t-pa - tissue lasminogen activato, vwf - von Willeband facto, x - significant coelation x x x I) 1-3 months, II) > 3-6 months, III) >6-18 months. This is esented in table 4. TF had the lowest value (167±106 g/ml) in eiod 1 and afte 6 months of evasculaization significantly inceased to 220±117 g/ml (<0.018). TFPI and t-pa levels wee simila, not significant, in the thee hases. VWF concentation was vey high (2.213±0.763 U/ml) and afte 6 months had deceased by about 20%. TM level afte 3 months also deceased, but emained in the nomal ange fo this facto. Table 5 shows the comaison of endothelial hemostatic factos in 38 PAD atients afte endovascula evasculaization with new estenosis comaed with the same gou of 38 atients but without estenosis (< 3 months ealie) and with the whole gou of 112 PAD atients without estenosis. Only TF level was significant highe in PAD atients with new estenosis (<0.013). Othe endothelial factos did not significantly diffe between PAD atients with and without estenosis. Discussion Atheoscleosis, sugical and endovascula evasculaization damage ateial wall (endothelium and smooth muscle cells) in PAD atients. Can eleased fom the tissue to blood endothelial hemostatic factos induce fomation of new estenosis? In the esent study we detemined the concentation of TF, TFPI, TM, vwf and t-pa in the lasma of 150 PAD atients, 1 to 18 months afte endovascula evasculaization. The levels of TF (<0.013) and vwf (<0.0001) wee significantly highe and TM significantly lowe (<0.0001) comaed to the efeence gou. PTA with stenting had no influence in PAD atients on elease of TFPI (=0.78) and t-pa (=0.18). Ou esults of TF concentation agee with the obsevation of Steffel et al. (2006) on inceased TF level in cadiovascula diseases [27]. It seems that TF is eleased duing PAD and also afte a evasculaization ocedue. Moe than six months afte evasculaization TF inceased fom 167±106 g/ml to 220±117 g/ml (Table 4). A weak coelation exists between the age of PAD atients and TF level (=0.175 <0.035) and between TF and TFPI (=0.167 <0.045). TF concentation is significantly highe afte estenosis (223 ± 127 g/ml) comaed to atients befoe estenosis (192 ± 120 g/ml), and the diffeence was statistically significant (<0.013). Pehas TF can take lace in the athogenesis of estenosis. Mizuno et al. (2001) obseved afte ecutaneous tansluminal coonay angiolasty (PTCA) significantly highe levels of TF and TAT comlexes in coonay sinus blood with late estenosis than in atients without estenosis. TF level can be a ognostic facto fo late estenosis afte PTCA [17]. We did not obseve any diffeences between TFPI level in PAD atients and the efeence gou (=0.78). In contast, Radziwon et al. (2001) descibed a vey high level of TFPI in non-oeated PAD atients only with intemittent claudication [21]. Leas et al. also obseved an inceased level of TFPI and TM in eldely non-oeated subjects with cadiovascula diseases and tye 2 diabetes [11]. In ou PAD atients comaed to the efeence gou we obseved significantly lowe TM concentation (<0.0001), but in the nomal ange of this facto. Tschöl et al. (1999) obseved inceased concentation of TM and vwf in 71 PAD atients befoe PTA and a tend fo highe TM at 6 months in 30 atients, those in whom estenosis develoed [22]. We do not know how to exlain the lowe level of TM in ou PAD atients afte endovascula evasculaization. It is known that endothelial and smooth muscle cell olifeation is the majo athohysiologic facto afte injuy, which can induce neointimal hyelasia and ecuent stenosis. Li et al. demonstated in abbits that ecombinant human thombomodulin (TM) inhibits thombin-induced ateial smooth muscle cell olifeation in vito and in vivo [12]. Pehas the deceased TM level in ou PAD atients afte evascula- 909

6 Postey Hig d Dosw (online), 2015; tom 69: Table 4. Endothelial hemostatic factos in PAD atients in diffeent time between endovascula evasculaization and blood dawing. Detemined aametes Time of evasculaization to collections of blood -value Months Numbe of PAD atients I 1-3 mo II > 3-6 m III > 6-18 mo n = 77 n = 30 n = 43 [KW test] Q1 Q3 Q1 Q3 Q1 Q3 I/II I/III II/III TF g/ml 167 ± ± ± [0.008] TFPI ng/ml 57.6 ± ± ± [0.32] TM ng/ml 3.3 ± ,7 ± 1, ± [0.009] vwf U/ml ± ± ± [0,03] 0, t-pa ng/m 8.0 ± ± ± [0,091] mo months, n numbe, median, M mean, PAD - eiheal ateial disease, -value - significance level of statistical test, [KW test] - Kuskall-Wallis test o in case of significant diffeence ost-hoc aiwise comaison between subgous, Q quatiles, SD - standad deviation, TF - tissue facto, TFPI - tissue facto athway inhibito, TM thombomodulin, t-pa - tissue lasminogen activato, vwf - von Willeband facto ization can be caused by its consumtion duing inhibition of neointimal cell olifeation afte ateial damage. TM can also be suessed by TNF (tumo necosis facto), IL-1 and endotoxin. To confim this thesis futhe exeiments must be efomed. Ou PAD atients comaed to the efeence gou had a significantly inceased vwf level: 2.080±0.791 U/ml) vesus 0.907±0.332 U/ml (<0.0001). Ou esults ae difficult to comae with the liteatue, whee the level of vwf is exessed as a ecentage, while we calculate this facto in units. The concentation of vwf coelated with the age of PAD atients ( s =0.285, <0.006), with TF ( s =0.283, <0.0006), TM ( s =0.247, <0.005) and t-pa ( s =0.180, <0.029). Moe than six months afte evasculaization of PAD atients vwf had deceased by ove 20%. We did not obseve any diffeence in vwf concentation in PAD atients befoe and afte the newly ceated estenosis. It was always high. Ou obsevation of an inceased vwf level in PAD atients agees with the liteatue [3,20,24,30,32]. Smith et al. obseved that the mean levels of fibinogen and vwf wee highe in atients develoing PAD. Howeve, vwf was not associated with ogession of PAD [24]. Tsakiis et al. obseved a tend to a highe level of vwf in atients who late develoed estenosis [30]. Blann et al. demonstated that also successful coonay intevention, e.g. stent imlantation, is associated with endothelial damaged and concuent vwf elease [3]. Stenting with dug-eluting devices is associated with educed inflammation and diminished vwf level in the coonay ciculation. Tambuino et al. descibed ealy stenosis afte dug-eluting stent imlantation [29]. Bongei et al. eoted a highe vwf level in atients with stoke but did not obseve any diffeence in vwf level in atients with and without estenosis [4]. t-pa level in PAD atients afte endovascula evasculaization was a little highe than in the efeence gou, but the diffeence was not statistically significant. t-pa weakly coelates with the age of atients ( s =0.200, <0.016) and with vwf ( s =0.180, <0.029). t-pa level does not statistically change fom 1 to 18 months afte evasculaization. Also a simila level of t-pa was obseved in PAD atients with a newly ceated estenosis and in these same subjects without estenosis. Moe than six months afte evasculaization of PAD atients the TF concentation significantly inceased. It does not agee with the suggestion of Aiyoshi et al. that eptfe gafts lose thei thombogenicity (TAT, D-dimes, CRP) 6 months afte stent imlantation [1]. 910

7 Kotschy D. et al. - Selected endothelial hemostatic makes... Table 5. Endothelial hemostatic factos in PAD atients without and with estenosis (<3 months befoe estenosis and afte estenosis) Detemined aametes TF g/ml TFPI ng/ml TM ng/ml vwf U/ml t-pa ng/ml Without estenosis (n=112) A Q1 - Q3 B befoe Q1 - Q3 With estenosis (n=38) C afte Q1 - Q3 -value 192 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± A/B A/C B/C n- numbe, M mean, median, PAD - eiheal ateial disease, -value - significance level of statistical test, SD - standad deviation, TF - tissue facto, TFPI - tissue facto athway inhibito, TM thombomodulin, t-pa - tissue lasminogen activato, vwf - von Willeband facto Hoshiba et al. (2006) obseved co-localization of vwf with latelet thombi, TF with fibin and consistent esence of inflammatoy cells in coonay thombi obtained by an asiation device fom atients with acute myocadial infaction [8]. Pobably such a ictue aeas in thombi and estenosis in legs of PAD atients. Accoding to Juni et al. (2013), oxidative stess geatly influences the athogenesis of vaious cadiovascula disodes. Coonay inteventions, including balloon angiolasty and coonay stent imlantation, ae associated with inceased vascula levels of eactive oxygen secies in conjunction with alteed endothelial and smooth muscle cell function. These alteations otentially lead to estenosis [9]. Conclusions Inceased TF and vwf level in advanced PAD atients afte endovascula evasculaization comaed to the efeence gou indicates endothelial damage due to atheoscleotic and evasculaization ocesses. Moe than 6 months afte evasculaization of PAD atients a significant incease of TF concentation aeaed. Excet fo TF level, no significant diffeences of othe endothelial hemostatic factos TFPI, TM, vwf and t-pa between PAD atients with and without estenosis wee obseved. Pehas TF takes at in estenosis fomation. Refeences [1] Aiyoshi H., Okuyama M., Okahaa K., Kawasaki T., Kambayashi J., Sakon M., Monden M.: Exanded olytetafluooethylene (eptfe) vascula gaft loses its thombogenicity six months afte imlantation. Thomb. Res., 1997; 88: [2] Blann A.D.: Plasma von Willeband facto, thombosis, and the endothelium: the fist 30 yeas. Thomb. Haemost., 2006; 95: [3] Blann A.D., Naqvi T., Waite M., McCollum C.N.: von Willeband facto and endothelial damage in essential hyetension. J. Hum. Hyetens., 1993; 7: [4] Bonges T.N., de Maat M.P., van Goo M.L., Bhagwanbali V., van Vliet H.H., Gómez Gacía E.B., Diel D.W., Leebeek F.W.: High von Willeband facto levels incease the isk of fist ischemic stoke: influence of ADAMTS13, inflammation, and genetic vaiability. Stoke, 2006; 37: [5] Gabusiewicz A., Słowiński P., Kosny T., Staszkiewicz W.: The esent state of the at of the athohysiology, diagnosis and teatment of the sueficial femoal atey occlusion based on own esults. Postęy N. d., 2012; 25:

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