<p>UVOD: Komplikacije terminalne bubrežne isuficijencije (TBI) kada se jačina glomerularne filtracije (JGF) smanji ispod 10 mL/min moguće je lečiti jedino hroničnom dijalizom ili transplantacijom bubrega tj. nadoknadom potpuno ili delimično izgubljene bubrežne funkcije. Uz blagovremenu edukaciju bolesnika o progresivnom toku hronične bubrežne bolesti, mogućnostima dijaliznog tretmana i transplantacije bubrega, treba na vreme obezbediti stalni funkcionalni vaskularni pristup za hemodijalizu (HD) hirurškom intervencijom kreiranja arteriovenske fistule (AVF), po mogućnosti najmanje 6 meseci pre anticipiranog započinjanja HD, jer je za njenu maturaciju potrebno 4 do 6 nedelja. Primarna AVF je opštepreporučeni najbolji stalni vaskularni pristup za bolesnike kod kojih se planira hemodijaliza. Najčešći razlog za disfunkciju vaskularnog pristupa za hemodijalizu su u 80% slučajeva trombozne komplikacije, koje se u 90% slučajeva javljaju na venskom segmentu AVF i posledica su progresivne venske neointimalne hiperplazije. Pored histoloških karakteristika zida venskog krvnog suda i hemodinamskih uslova, u etiopatogenezi ovog »adaptivnog odgovora« vrlo značajnu ulogu igraju endotel i ostale komponente hemostaznog sistema (trombocitna, koagulaciona i fibrinolizna), imunološki i citološki činioci i genetski faktori. Prevencija nastanka rane tromboze vaskularnog pristupa za hemodijalizu kod bolesnika sa TBI je moguća primenom antitromboznih lekova, tj. antitrombocitne ili antikoagulantne terapije. CILJ: Proceniti efikasnost primenjenih antitromboznih lekova (tiklopidina i nadroparin-kalcijuma) u prevenciji nastanka rane tromboze/afunkcionalnosti AVF za hemodijalizu za vreme njene maturacije unutar 6 nedelja od kreiranja u bolesnika sa TBI. Ispitati nivo biomarkera hemostaznog sistema i markere trombofilije u bolesnika sa TBI pre kreiranja AVF u cilju dopune uzroka nastanka rane tromboze/afunkcionalnosti arteriovenskih fistula za hemodijalizu. Ispitati učestalost trombofilije i njen uticaj na funkcionalnost AVF i uporediti efikasnost primenjenih preventivnih režima između bolesnika sa i bez trombofilije. MATERIJAL I METODE: U ispitivanje su uključene osobe oba pola sa prethodno postavljenom dijagnozom TBI kod kojih nisu postojale kontraindikacije za planirno hirurško kreiranje prvog stalnog vaskularnog pristupa za hemodijalizu u vidu autologne arteriovenske fistule (AAVF). Nakon hirurškog kreiranja radiocefalične arteriovenske fisule u distalnoj trećini podlaktice nedominantne ruke (89/121), intermedijalne (4/121) ili proksimalne (28/121) AAVF u studiju je uključen 121 ispitanik, koji su u cilju procene uticaja različitih antitromboznih lekova na sprečavanje nastanka rane tromboze fistula za hemodijalizu kod bolesnika sa TBI ispitanici su podeljeni u 3 grupe: Grupa I, kontrolna; 40 ispitanika koji nakon kreiranja AVF nisu dobijali antitromboznu terapiju, Grupa II; 42 ispitanika kod kojih je dan nakon kreiranja AVF započeta primena antitrombocitnog leka iz grupe tienopiridina, Ticlodix® (ticlopidin) tbl a 250 mg, 2 x ½ tbl dnevno tokom 6 nedelja i Grupa III; 39 ispitanika kod kojih je dan nakon kreiranja AVF započeta subkutana primena antikoagulantnog leka iz grupe niskomolekularnih heparina, Fraxiparine® (nadroparin-kalcijum) 2850 anti Xa i.j. (0.3 ml) dnevno tokom 6 nedelja. Jednokratno određivanje laboratorijskih parametara pokazatelja bubrežne funkcije, metabolizma glukoze i hroničnog zapaljenja, funkcionalnosti hemostaznog sistema, trombofilnih markera i genskog polimorfizma vršeno je unutar dve nedelje pre hirurškog kreiranja AAVF. Kriterijum za utvrđivanje ishoda uticaja antitrombozne terpije predstavlja maturacija AVF koja je definisana kao uspešna ako je započeto sprovođenje efikasne hemodijalize najranije 6 nedelja nakon njenog hirurškog kreiranja po proceni nadležnog nefrologa. Dijagnoza prisustva tromboze AVF postavljena je od strane nadležnog vaskularnog hirurga/nefrologa fizikalnim pregledom tokom njene maturacije, koji je podrazumevao inspekciju, palpatorno utvrđivanje odsustva karakterističnog trila i auskultatornih karakteristika protočnosti AVF ili ultarsonografskim pregledom od strane radiologa. REZULTATI: Između ispitivanih grupa u odnosu na broj tromboziranih/ afunkcionalnih AVF tokom njene maturacije (12/40 vs. 4/42 vs. 5/39; P=0.033), ustanovljena je značajna statistička razlika kao i poređenjem broja tromboziranih/afunkcionalnih AVF tokom sazrevanja u kontrolnoj grupi u odnosu na grupu ispitanika (objedinjene Grupe II i Grupa III) koja je primala antitromboznu profilaksu (12/40 vs. 9/81; P=0.009). Daljom analizom ispitivanih grupa, utvrđena je statistički značajna razlika u broju tromboziranih/afunkcionih AV fistula između kontrolne Grupe I i Grupe II (P=0.019). Testiranjem razlike u broju tromboziranih/ afunkcionalnih AVF između ispitanika kontrolne Grupe I i Grupe III nije dobijena statistički značajna razlika, kao ni između Grupe II i Grupe III. Zastupljenost broja tromboziranih/afunkcionalnih distalnih AVF za vreme njihove maturacije (12/33 vs 2/31 vs. 3/24; P=0.008) se između ispitivanih grupa značajno statistički razlikovala kao i zastupljenost tromboziranih/afunkcionalnih distalnih AVF tokom sazrevanja u kontrolnoj grupi u odnosu na grupu ispitanika koja je primala antitromboznu profilaksu (12/34 vs. 5/55; P=0.002). Testiranjem statističke razlike u broju tromboziranih/afunkcionalnih distalnih AVF između ispitanika kontrolne Grupe I i Grupe II utvrđena je statistički značajna razlika (P=0.005), dok između Grupe I i Grupe III (P=0.051), kao ni između Grupe II i Grupe III (P=0.439) nije dobijena statistički značajna razlika. Između podgrupa ispitanika kod kojih je došlo do tromboze/afunkcionalnosti AVF 21/121 (17.35%) i podgrupe ispitanika sa funkcionalno maturiranom AVF 90/121 (82.64%), značajna statistička razlika ispitanih hemostaznih parametara je bila prisutna u vrednostima agregabilnosti trombocita uz kolagen kao induktor (59.33±33.1 vs. 75.04±29.6; P=0.033). Značajna statistička razlika je zabeležena i u zastupljenosti sledećih trombofilnih markera: deficita PC (3/21 vs. 3/100; P=0.030), APC-R (4/21 vs. 5/100; P=0.026), prisustva antifosfolipidnih ACL IgM antitela (1/21 vs. 0/100; P=0.028), heterozigotnog polimorfizma FV G1691A (3/21 vs. 3/100; P=0.03) i homozigotne mutacije gena FII G20210A (1/21 vs. 0/100; P=0.028), između podgrupa bolesnika sa tromboziranom afunkcionalnom i funkcionalnom AVF. Takođe je značajna statistička razlika između podgrupa bolesnika kod kojih je došlo tromboze/afunkcionalnosti AVF i podgrupe ispitanika sa funkcionalno maturiranom AVF bila prisutna u odnosu na postojanje ranijih tromboza (23/21 vs 19/100; P=0.000) kao i zastupljenosti izolovanih venskih tromboza (9/21 vs. 2/100; P=0.000). Prediktivni potencijal pojedinačnih parametara za maturaciju AVF ispitan je univarijantnom logističkom regresionom analizom. Prilikom ispitivanja uticaja pojedinačnih parametara na maturaciju fistule, zapazili smo da su ispitanici koji su primali antitromboznu terapiju imali 3 puta veću šansu za funkcionalno maturiranu AVF [OR 3.45 (1.3-9.03)] u odnosu na bolesnike bez terapije. Ispitanici koji su imali prethodne tromboze su imali višestruko povišen rizik [OR 6.92 (2.51-19.06)] za nastanak tromboze/afunkcionalnost AVF tokom maturacije. Prilikom ispitivanja uticaja pojedinačnih parametara na rizik od pojave tromboze/afunkcionalnosti distalne AVF, zapažamo da primena antitrombozne terapije [OR 5.4 (CI 1.7 - 17.35)] petostruko snižava rizik za nastanak tromboze/ afunkcionalnosti distalne AVF, odnosno da primena antitrombozne terapije petostruko povećava šansu za adekvatnu maturaciju distalne AVF. Ispitanici koji su imali aterosklerotske KVB [OR 0.32 (0.1-0.98)] i ranije tromboze [OR 0.14 (0.04-0.44)] su imali za 68% i 86% manju verovatnoću za adekvatnu maturaciju distalne AVF (334). Trombofilija je bila prisutna u 59/121 (48.8%) ispitanika. U odnosu na markere aktivacije koagulacione komponente hemostaznog sistema i inflamatorne pokazatelje, između podgrupa ispitanika sa ili bez trombofilije statistički značajna razlika je bila prisutna u vrednostima koncentracije FVIII (170.35±103.97 vs. 235.26±124.80; P=0.02) i odnosa trombociti/limfociti (181±64.58 vs. 148.11±66.15; P=0.026). U odnosu na lokalizaciju AVF, u podgrupi ispitanika sa trombofilijom i tromboziranom/ afunkcionalnom AVF, njih 8/11 su pripadale distalnim AVF, 3/11 proksimalnim AVF, dok je u podgrupi ispitanika bez trombofilije i tromboziranom/afunkcionalnom AVF, njih 9/10 imalo distalnu, a 1/10 proksimalnu AVF. U grupi bolesnika sa trombofilijom nije zabeleženo prisustvo statistički značajne razlike u efikasnosti primenjenih antitromboznih režima merene učestalošću tromboza/afunkcionalnosti AVF u odnosu na bolesnike sa trombofilijom koji nisu primali antitromboznu terapiju (5/19 vs. 2/18 vs. 4/22; P=0.493). U grupi ispitanika bez trombofilije utvrđeno je postojanje statistički značajne razlike u učestalosti tromboza/afunkcionalnosti AVF između grupe sa i bez primene antitromboznih lekova kako u ukupnom broju tromboziranih/afunkcionalnih AVF (7/21 vs. 2/24 vs. 1/17; P=0.030). Iako je zastupljenost tromboza/afunkcionalnosti AVF u bolesnika sa kombinovanom trombofilijom češća u odnosu na ispitanike koji su imali drugu vrstu ili uopšte nisu imali trombofiliju (6/18 vs. 15/103; P=0.052), ona nije dostigla statistički značajnu vrednost. ZAKLJUČAK: Profilaktička primena antitromboznih lekova (tiklopidina i nadroparin-kalcijuma) smanjuje učestalost pojave rane tromboze i pojavu primarne nefunkcionalnosti AVF za hemodijalizu tokom njene maturacije. Primena antitrombozne terapije petostruko snižava rizik za nastanak tromboze/ afunkcionalnosti distalne AVF tokom njene maturacije. Bolesnici koji su imali prethodne tromboze imaju višestruko povišen rizik za nastanak tromboze AVF tokom njene maturacije. Kod bolesnika koji su imali aterosklerotske KVB i ranije tromboze verovatnoća za adekvatnu maturaciju distalne AVF je niža za 68% , odnosno 86%. U našem istraživanju nije utvrđeno postojanje superiornosti antikoagulantne u odnosu na antitrombocitnu profilaksu tj. oba primenjena režima su bila podjednako efikasna. U terminalnoj bubrežnoj insuficijenciji prisutan je značajan poremećaj funkcionalnosti hemostaznog sistema koji se očituje u disfunkciji endotela i poremećenoj (sniženoj) funkcionalnosti trombocita, prisustvu prokoagulantnog stanja koje se manifestuje povišenom trombinskom aktivnošću, povišenom koncentracijom činilaca koagulacije i smanjenom fibrinoliznom aktivnošću. Češća zastupljenost ukupnih ranijih tromboza (arterijskih i venskih), češća zastupljenost izolovanih venskih tromboza i učestalije prisustvo trombofilije prezentovano deficitom PC, prisustvom rezistencije na APC, prisusustvom antifosfolipidnih antikardiolipinskih antitela IgM, heterozigotnog polimorfizma FV G1691A, homozigotne mutacije FII G201210A i niža vrednost agregabilnosti trombocita uz kolagen kao induktor su markeri koji su u našem ispitivanju signifikantno češće zastupljeni kod ispitanika sa trombozom/ afunkcijom AVF za hemodijalizu tokom njenog sazrevanja. Trombofilija je prisutna kod 48.8% bolesnika saTBI, ali našim ispitivanjem nije utvrđen njen uticaj na nastanak rane tromboze/afunkcionalnosti AVF izuzev u grupi bolesnika sa kombinovanom trombofilijom. Mali broj krvarećih komplikacija u našoj studiji ukazuje na bezbednost primenjenog preventivnog režima. Na osnovu dobijenih rezultata može se preporučiti profilaktička primena tiklopidina ili nadroparin-kalcijuma u preventivnim dozama kod bolesnika sa TBI neposredno nakon kreiranja AVF. Primenu profilakse tromboznih komplikacija kod bolesnika sa novokreiranom AVF preporučujemo posebno kod bolesnika koji su imali prethodne tromboze i/ili kliničke manifestacije aterosklerotskih kardiovaskularnih bolesti.</p> / <p>INTRODUCTION: Complications in end stage renal disease (ESRD) when the glomerular filtration rate (GFR) decreases below 10mL/min can only be treated by chronic dialysis or kidney transplant ie. total or partial renal replacement therapy. With prompt education of the patient regarding the progressive course of the chronic kidney disease, possibilities of dialysis treatment and kidney transplantation, the patient should timely be granted permanent functional vascular hemodialysis (HD) access through surgical intervention by creating arteriovenous fistula (AVF), preferably at least 6 months prior to the anticipated start of HD, as period for its maturation is between 4 and 6 weeks. Primary AVF is the generally best recommended permanent vascular access for patients planned for dialysis. The most common reason for dysfunction of the vascular access for hemodialysis are thrombotic complications in 80% of the cases, 90% of which appear in the venous segment of AVF as the consequence of progressive venous neointimal hyperplasia. Beside the histological characteristics of the venous blood vessel wall and hemodynamic conditions, in the etiopathogenesis of this “adaptive answer”, endothel and other components of the hemostatic system (platelet, coagulation and fibrinolysis), immunological and cytological components as well as genetic factors play a very important role. Prevention of occurrence of early thrombosis of vascular access for hemodialysis in patients with ESRD is possible by treatment with antithrombotic drugs, ie. antiplatelet or anticoagulant therapy. OBJECTIVE: Estimate the efficiency of applied antithrombotic drugs (ticlopidine and nadroparincalcium) in prevention of occurrence of early thrombosis/dysfunction of AVF for hemodialysis during its time of maturation within the 6 week period. Examine the level of biomarkers of the hemostatic system and thrombophilic markers in patients with ESRD before the creation of AVF with the goal of finding additional causes of occurrence of early thrombosis/dysfunction of arteriovenous fistula for hemodialysis. Determine the incidence of thrombophilia and its impact on the functionality of AVF and compare the efficiency of applied preventive regimen between patients with and without thrombophilia. MATERIAL AND METHODS: The study included persons of both sexes with previously established diagnosis of ESRD in which there were no contraindications for the planned surgical creation of the first permanent vascular access for hemodialysis in the form of autologous arteriovenous fistula (AAVF). After the surgical creation of the radiocephalic arteriovenous fistula in the distal third of the forearm of the non-dominant hand (89/121), intermedial (4/121) or proximal (28/121) AAVF, the total number of 121 patients were included in the study and divided into three groups in order to estimate the influence of different antithrombotic drugs in prevention of early thrombosis for hemodialysis in patients with ESRD: Group I, control; 40 subjects which did not receive antithrombotic therapy after the creation of AVF, Group II; 42 subjects which started receiving an antithrombotic drug from the tienopiridine group, Ticlodix® (ticlopidine) 2 x ½ of 250mg tbl, daily, during the period of 6 weeks, after the creation of AVF, and Group III; 39 subjects which started subcutaneously receiving a drug from the low-molecular weight herapin group, Fraxiparine® (nadroparine-calcium) 2850 anti Xa i.j. (0.3 ml) daily, during the period of 6 weeks. One-time determination of laboratory parameters and renal function, glucose metabolism and chronic inflammation, hemostatic system functionality, thrombophilic markers and gene polymorphism was performed within two weeks prior to surgical creation of AAVF. The criteria for determining the outcome of the impact of antithrombotic therapy is the maturation of AVF, which is defined as successful if the implementation of effective hemodialysis started at least 6 weeks after its creation, where the effectiveness of hemodialysis is estimated by a competent nephrologist. The diagnosis of the presence of AVF thrombosis was set by a competent vascular surgeon/nephrologist through physical examination during its maturation, which included inspection, palpatory determination of absence of the characteristic thrill and auscultatory characteristics of the flow of AVF, or by ultrasonographic examination by the radiologist. RESULTS: Between the groups in terms of number of thrombosed/dysfunctional AVF during its maturation (12/40 vs. 4/42 vs. 5/39, P = 0.033), a significant statistical difference was established, as well as by comparing the number of thrombosed/dysfunctional AVF during maturation in the control group compared to the group of respondents (unified Group II and Group III) which received antithrombotic prophylaxis (12/40 vs. 9/81, P = 0.009). Through further analysis of the examined groups, a statistically significant difference was observed in the number of thrombosed/dysfunctional AV fistula between the control Group I and Group II (P = 0.019). There was no statistically significant difference noticed in the numbers of thrombosed/dysfunctional AVF between the subjects in the control Group I and Group III, as well as between Group II and Group III. Presence of the number of thrombosed/dysfunctional distal AVF during their maturation (12/33 vs 2/31 vs. 3/24, P = 0.008) between the groups statistically significantly varied, as well as the presence of the number of thrombosed/dysfunctional distal AVF during the maturation in the control group as compared to the group of subjects who received antithrombotic prophylaxis (12/34 vs. 5/55; P=0.002). By testing statistical differences in the number of thrombosed/dysfunctional distal AVF between the subjects in the control Group I and Group II a statistically significant difference (P = 0.005) was established, while there was no statistically significant difference between Group I and Group III (P = 0.051), nor between Group II and Group III (P = 0.439). Among the subgroup of patients with thrombosis/dysfunction of AVF 21/121 (17.35%) and the subgroup of subjects with functionally maturated AVF 90/121 (82.64%), a statistically significant difference of the examined hemostasis parameters was present in the values of platelet aggregation with collagen as the inducer (59.33 ± 75.04 vs. 33.1 ± 29.6; P = 0.033). A significant statistical difference was recorded in the presence of the following thrombophilic markers: deficit of PC (3/21 vs. 3/100; P = 0.030), APC-R (4/21 vs. 5/100; P = 0.026), the presence of antiphospholipid ACL IgM antibodies ( 1/21 vs. 0/100; P = 0.028), heterozygous FV G1691A polymorphism (3/21 vs. 3/100; P = 0.03) and homozygous gene mutation FII G20210A (1/21 vs. 0/100; P = 0.028), between the subgroups of patients with thrombosed/dysfunctional and functional AVF. There also was a significant statistical difference between the groups of patients which encountered thrombosis/dysfunction of AVF and subgroups of subjects with functional maturated AVF in relation to the existence of previous thrombosis (23/21 vs. 19/100; P = 0.000) and the presence of isolated venous thrombosis (9/21 vs. 2/100; P = 0.000). Predictive potential of individual parameters for AVF maturation was tested by univariate logistic regression analysis. During the examination of the influence of individual parameters on fistula maturation, we observed that subjects who received antithrombotic therapy were 3 times more likely to develop functionally maturated AVF [OR 3.45 (1.3-9.03)] as compared to subjects who did not receive any treatment. Subjects which previously had thrombosis had a multiple times increased risk [OR 6.92 (2:51 to 19:06)] of developing thrombosis/dysfunctional AVF during its maturation. When examining the influence of individual parameters on the risk of thrombosis/dysfunction of the distal AVF, we noted that the implementation of antithrombotic therapy [OR 5.4 (CI 1.7 - 17:35)] reduced risk of thrombosis/dysfunction of the distal AVF by five times, ie. that the implementation of antithrombotic therapy increases the chance for adequate distal AVF maturation by five times. The subjects that had atherosclerotic cardiovascular diseases (CVD) [OR 0.32 (0.1-0.98)] or previous thrombosis [OR 0.14 (0.04-00.44)] had a 68% or 86% less chance for adequate distal AVF maturation (334). Thrombophilia was present in 59/121 (48.8%) patients. In relation to the markers of activation of coagulation components of the hemostatic system and inflammatory markers, among subgroups of subjects with or without thrombophilia a statistically significant difference was present in the FVIII concentration (170.35 ± 103.97 vs. 235.26 ± 124.80; P = 0.02) and the platelets/lymphocytes ratio (181 ± 64.58 vs. 148.11 ± 66.15; P = 0.026). In relation to the localization of AVF, in the subgroup of subjects with thrombophilia and thrombosed/dysfunctional AVF, 8/11 of them belonged to distal AVF, 3/11 proximal AVF, while in the subgroup of subjects without thrombophilia and thrombosed/dysfunctional AVF, had 9/10 distal and 1/10 proximal AVF. In the group of subjects with thrombophilia there was no record of the presence of statistically significant differences in the efficiency of antithrombotic regimen which was measured by the frequency of thrombosis/dysfunction of AVF as compared to subjects with thrombophilia which did not receive antithrombotic therapy (5/19 vs. 2/18 vs. 4/22, P = 0.493). In the group of subjects without thrombophilia statistically significant differences were found in the frequency of thrombosis/dysfunctions of AVF among groups with and without the use of antithrombotic drugs in the total number of thrombosed/dysfunctional AVF (7/21 vs. 2/24 vs. 1/17, P = 0.030). Although the presence of thrombosis/dysfunction of AVF in patients with combined thrombophilia was more frequent compared to those who had other types of, or did not have thrombophilia (6/18 vs. 15/103; P = 0.052), it did not reach a statistically significant value. CONCLUSION: Prophylactic use of antithrombotic drugs (ticlopidine and nadroparin-calcium) reduces the incidence of early thrombosis and the occurrence of primary AVF dysfunction for hemodialysis during its maturation. Implementation of antithrombotic therapy reduced risk of thrombosis/ dysfunction of the distal AVF during its maturation by five times. Patients who have had previous thrombosis have multiple times greater risk of AVF thrombosis during its maturation. In patients who had atherosclerotic CVD or previous thrombosis, the probability for adequate maturation of distal AVF is lower by 68% or 86%. In our study there was no evidence of superiority of anticoagulant compared to antiplatelet prophylaxis ie. both regimens were equally effective. In ESRD there is significant disarrangement of hemostatic system functionality, which is reflected in endothelial dysfunction and disturbed (reduced) platelet functionality, the presence of procoagulant condition that is manifested by elevated thrombin activity, increased levels of clotting factors and reduced fibrinolytic activity. More frequent presence of total previous thrombosis (arterial and venous), higher frequency of isolated venous thrombosis and frequent presence of thrombophilia presented by the deficit of PC, the presence of resistance to APC, presence of anticardiolipin antiphospholipid antibodies IgM, heterozygous FV G1691A polymorphism, homozygous mutation FII G201210A and lower value of collagen induced platelet aggregation are the markers in our study which are significantly more frequent in patients with thrombosis/dysfunction of AVF for hemodialysis during its maturation. Thrombophilia is present in 48.8% of patients with ESRD, however our study does not determine its impact on early thrombosis/dysfunction of AVF except in the group of patients with combined thrombophilia. A small number of bleeding complications in our study points to the safety of the applied preventive regimen. Based on the obtained results, prophylactic use of ticlopidine or nadroparin-calcium in preventive doses can be recommended for patients with ESRD immediately after AVF creation. Prophylactic treatment of thrombotic complications in patients with newly created AVF is recommended especially in patients who have had previous thrombosis and/or clinical manifestations of atherosclerotic cardiovascular diseases.</p>
| Identifer | oai:union.ndltd.org:uns.ac.rs/oai:CRISUNS:(BISIS)104107 |
| Date | 21 April 2017 |
| Creators | Filipov Predrag |
| Contributors | Mitić Gorana, Božić Dušan, Đurđević-Mirković Tatjana, Vučković (Radulović) Biljana, Petrović Dejan, Pasternak Janko |
| Publisher | Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, University of Novi Sad, Faculty of Medicine at Novi Sad |
| Source Sets | University of Novi Sad |
| Language | Serbian |
| Detected Language | Unknown |
| Type | PhD thesis |
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