ࡱ> `b__Tbjbjkk .V;\;\  ~~~~~tL".RpA-C-C-C-C-C-C-$1h4vg-u~g-~~-e%e%e%>~~A-e%A-e%e%:]*,*ܶ!* ---0".*R4y$4**L4~1+e%g-g-U%".4 > D: XXXVth World Congress of the International Society of Hematology. September 4-7, 2014. Beijing, China. Alteration in coagulation profile in naturally overweight and obese dogs Renata Bari Rafaj, Josipa Kulea, Vladimir Mrljak Faculty of Veterinary Medicine, University of Zagreb, Croatia, EU Introduction Overweight and obesity are a major health problem today, both in humans and in dogs. It is estimated that more than 40% of dogs that people keep as pets are overweight. Proliferated adipose tissue may release numerous mediators that induce a chronic inflammatory state, which is closely connected with haemostatic disturbances. Fibrinogen (FIB) is a disulfide-bonded dimer, composed of six polypeptide chains, including two sets of three polypeptide chains termed A, B, and  (1). Gamma chains of fibrinogen (Y FIB) are in focus of current interest, because their key novel discovered roles in fibrin clot formation, platelet aggregation and wound healing. These interactions can also contribute to pathophysiologic processes, including inflammation and thrombosis (2). The identification of new interactions with Y FIB has revealed novel targets for the treatment of inflammation and thrombosis (2) leading to extensive investigations of mechanisms controlling Y FBG expression. Earlier evidence of increased activities of clotting factors in obesity originates from studies of closely related metabolic disorders in humans, while apparently healthy state of obese individuals and coagulation profile in animal obesity are much less represented in literature. In many laboratory and clinical aspects, maintaining haemostatic balance in overweight is poorly understood, so we investigated whether inflammatory and/or prothrombotic states exist in otherwise healthy, naturally overweight and obese dogs. Material and methods Tventy-five overweight and obese dogs and 15 normal-weighted healthy dogs with similar age and gender were included in the study. The body condition score (scale of 1 - 5, 3-normal, 4-overweight, 5-obese) was used to assess weight excess. Exclusion criteria were any known secondary obesity syndromes, any ongoing medical therapy and concomitant chronic or acute illnesses. Blood samples were collected from the cephalic vein. Measurement of Y FIB was performed using a canine-specific ELISA kits (Cusabio, Wuhan, China) according to the manufacturer instructions. Total fibrinogen and factor activities (FVII, FIX, FX) were measured using the ACL 7000 analyser (Instrumentation Laboratory, Bedford, USA) and standard methods, canine calibration curve and original reagents of manufacturer. Differences between overweight and lean dogs were tested by the t test or the Mann-Whitney U test, depending on distribution. Data were represented as mean SD or median and min-max range. Probability values <0.05 were considered statistically significant. Results Proinflammatory state and derangements of blood coagulation are present in canine overweight and obesity. The concentrations of IL-6, FIB and Y FIB, FX and FVII activities were all significantly increased in the overweight and obese group of dogs compared with lean population. Factor IX activities were also increased, but without significance. Table 1. Concentrations of IL-6, FIB, Y FIB, activities of FVII, FIX and FX in plasma of overweight and obese (O) compared with normalweight control (C) dogs. * p<0.05 IL-6 (ng/l)FIB (g/l)YFIB(ng/ml)FVII (%)FIX (%)FX (%) O264 * 31,13,0 * 1,42,5 * 1,0125 * (68-291)100 (69-238)119 * 17,9 C233 43,12,0 0,41,5 1,3104 (66-141)95 (51-161)104 11,9 Conclusion Our findings indicate the presence of chronic inflammatory state in canine obesity, characterised by increase of proinflammatory citokine IL-6. As a major mediator of acute phase protein synthesis, IL-6 could contribute to upregulation of FIB as well as Y FIB, which lead to prothrombotic state. Rein-Smith et al. (3) showed that IL-6 cause 3.6 fold increase A mRNA and 8.3-fold increase in ' mRNA. Since elevated plasma FIB and especially the Y FIB promotes thrombosis, disruption of IL-6 signaling may be a potential target for minimalizing the influence of inflammatory state to haemostatic disturbances and thrombotic events. Excess of weight in humans may influence the function of coagulation cascade through a transcription factor which regulates the synthesis of FVII and FIX in liver (4). The obtained results in our study confirms the mechanisms of simultaneous activities of plasma coagulation factors, predisposing overweight and obese dogs to hypercoagulability. Canine obesity have a great potential as a study model for human obesity, because there is a vast amount of background literature on the physiology of the dog (5), which is similar to humans in many aspects. Also, the dog genome has been mapped (6). In addition, a wide range of diagnostic tests with species-specific antibodies allows the implementation of comparative research of broad spectrum of pathways of current interest, so our best friend may easily become our model too. (1) Moseson, Fibrinogen c chain functions. Journal of Thrombosis and Haemostasis 2002;1:231238. (2)  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Farrell%20DH%5BAuthor%5D&cauthor=true&cauthor_uid=15257013" Farrell DH. Pathophysiologic roles of the fibrinogen gamma chain.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/15257013" \o "Current opinion in hematology." Current Opinion in Hematology2004;11: 151-155. (3)  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Rein-Smith%20CM%5BAuthor%5D&cauthor=true&cauthor_uid=23036532" Rein-Smith CM,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Anderson%20NW%5BAuthor%5D&cauthor=true&cauthor_uid=23036532"  . 0 4 * 7 R T h i n o C K  ䷲ynf_[TPhG hshh h.hthozB*phh.h B*ph h.h h_Yh<8g h_Yh: h:h:h: h.h<8gheh/t5 h?5 h 5 h55h CJOJQJ^JaJhkhhkh5hkh5B*phDDDhkhhkh5B*phDDDhkhCJOJQJ^JaJhlFCJOJQJ^JaJj ) * 7 (34LM 7$8$H$`gdy 7$8$H$`gd9 7$8$H$gdI 7$8$H$gd"dd[$\$`gd*#dd[$\$`gd 7$8$H$gdEW 7$8$H$gd/t 7$8$H$gdlF  ( * . 0 4 6 @ B P l |   0 n 689:;»wlwaaVh0%h_YB*phh0%h7iB*phh0%h*TB*phh0%hB*phh0%htB*phh0%hlFB*ph h0%ht h0%hc h0%hV. h0%hlH h0%h*n h0%hC {h/.:B*phh0%hC {B*phh0%h*nB*phhsh*nB*ph hsh hsh hsh*n;<=hn  x%'(Q^ȵvpvjvdvdv]VO h_Yh?` h?h?` hsh+q hsPJ hPJ hcPJhshyPJhshTPJh0%hTPJha h0%hG h0%hs h0%hyh0%hyB*phh0%h:B*phh/.:B*phh0%hB*phh0%hGB*phh0%h {B*phh0%h B*phh0%hV.B*ph^_hq234qy~#ջxtptxtxtaUhyfHq hnhhY%fHq h_hj hnhhj hjhj hM8hTh< hM8h hehEW5 h*n5heh*n5h"CJOJQJ^JaJ h?hV.h?h/tB*phh0B*phh?h B*ph h?h*#hc h?h?` h_Yh?` h_Yh:!  %&/=gipz  LM»~ocIocI2hnhhY%0Jeh@fHq r@hY%fHq hnhhY%fHq h fHq h$nnH tH h9h9nH tH hGnH tH h_ChGnH tH h_Ch9nH tH  h_ChlH h_Chy h_Ch$n h_Ch_C h_ChY%hY%hy hnhhY%hlHnH tH hY%hY%nH tH    NPQRZ[uνzvnjc_XcXcQMIQIh4^h< h*nhgV h*nhIh*T h*nh"h1heh"5h hM8hY% hsPJh_YhsPJh_YhsPJh_YhlHPJh_Yh:PJh_YhY%PJhnhhY%PJ hnhhY%5fHq hlHfHq hnhhY%fHq ,hY%0Jeh@fHq r@MQRZ[_`amw $7$8$H$Ifgd*T 7$8$H$gd:. 7$8$H$`gd*n 7$8$H$gdI 7$8$H$`gdy  Rpq%)DPY^_`a|ý{ric[h*Th7\ hPJh_Yh7PJhXDCJ\aJh*ThXDCJ\aJh*Thi3p\h*Thw\hRhitCJ\aJhRhXDCJ\aJh*ThXD\ hXDPJ h<PJhnhh)PJ hXD\ h)\ hgV\h*nhgV\h)>h4^ h*nhA= h*nh" h*nhgV#% $7$8$H$Ifgd*Tkd$$Ifl֞ lX < t0644 la $7$8$H$Ifgd $7$8$H$Ifgd$m $7$8$H$Ifgd*T   Ӿ˝ۢ˝vph˝vphh*Thj;\ hj;PJh_Yhj;PJh*Thw\h_YhPJ h7\h*Th$m\ hXD\h*Th\h$mhXD\h*Th$mCJ\aJ h$m\h*Thi3p\h*ThXD\h*Th7\ hPJh_Yh7PJhXDCJ\aJh*ThXDCJ\aJ(% $7$8$H$Ifgd*Tkd$$Ifl֞ lX < t0644 la  "+/5 $7$8$H$Ifgd*T  !"*+./045678CDOPZ#,236BGITjlpſۯ{s{s{ninis{sah5shA\ hD@\ hA\h*nh:.\h*nh+q\h*nh\hP@hc|,\hP@h\ h><\heh:.5\ h)\h*nhXD\h*Th:h\ h:hPJh_Yh:hPJh*Th-\ h-\h*ThXD\h*Thj;\ hj;PJh_Yhj;PJ hXD\&5678% 7$8$H$gd:.kdX$$Ifl֞ lX < t0644 la8CDnoRSTUV!!`NaN#O 7$8$H$gd0%gdhd\-DM gdy 7$8$H$gde 7$8$H$gdd 7$8$H$`gdd 7$8$H$gdK-DM `gd5s-DM `gdAs 7$8$H$gd:.pv~RT&DZrz#-HK^_`avļؼ||xhWQP h5shKhKhTh5s h5sh:. h5shc|,hc|, h*nh:. h*nh+qh*nh:.\ h><\h*nhI\ hA5hAhA\ hAhA hA\h5sh*T\ hWQP\ h/.:\h5shA\h5sh5s\.,-kmno~  ?FSTefiwRSTоqchdCJOJ QJ ^J aJheCJOJ QJ ^J aJhdhdB*phhc|,B*phh5shc|,B*phh5shdB*ph h5shdhv(hWQP h5shZ^ h5shAs hdhdh)> hdhAshhKCJOJ QJ ^J aJh+qhD@hK h*nhKhA&TUVZab. / 9 : r s !ב~בב~k~k~k^ננhhy0JCJaJ$hh80J>*B*CJaJph$hhy0J>*B*CJaJphjhhyCJUaJhh8CJaJhhZUCJaJhh CJaJhheCJaJhhGCJaJhhyCJaJhhMK(CJaJhGhyCJaJhCJaJ#!!!!!!{!|!!!!!!!LLLLLLMMMMMM8N9N?NCNGNLNMNRNSNTNXNYN_N`NaNbNcNeNNNNOиzhhyCJaJhhVCJaJhh8CJaJjhhGCJUaJhhGCJKH$\aJhhGCJaJUhhhCJaJjhhhCJUaJhhWQPCJaJhhMK(CJaJhh0%CJaJ/Anderson NW,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Farrell%20DH%5BAuthor%5D&cauthor=true&cauthor_uid=23036532" Farrell DH, Differential regulation of fibrinogen  chain splice isoforms by interleukin-6.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/23036532" \l "#" \o "Thrombosis research." Thrombosis Research 2013; 131: 89-93. (4) Inoue Y, Peters LL, Yim SH, Inoue J, et al. Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. Journal of Molecular Medicine 2006; 84: 334344. (5) John Speakman, Catherine Hambly, Sharon Mitchell, et al. The contribution of animal models to the study of obesity (6) Lindblad-TOOOOOO$O%O&O(OXOaOOOOOOOTTTTTѻsh\hhCJ \aJ hGhdCJaJ *hPhVCJaJU *hPhdCJaJ *hPhWQPCJaJ *hPhMK(CJaJhhdCJaJhhVCJaJhhAsCJaJhhWQPCJaJhhMK(CJaJhh8CJaJhh0%CJaJhh0%6CJ]aJ#O$OOOTT L@&gdAs 7$8$H$gdd 7$8$H$gdAsoh K, Wade CM, Mikkelsen TS, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 80319. ,1h. A!"#$% $$If!vh#v<#v#v#v#v:V l t065<5555$$If!vh#v<#v#v#v#v:V l t065<5555$$If!vh#v<#v#v#v#v:V l t065<5555s2&6FVfv2(&6FVfv&6FVfv&6FVfv&6FVfv&6FVfv&6FVfv8XV~ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@_HmHnHsHtH@`@ NormalCJ_HaJmHsHtHRR D Heading 1dd@&[$\$5CJ0KH$\aJ0N2N D Heading 3dd@&[$\$5CJ\aJFBF D Heading 4dd@&[$\$5\DA`D Default Paragraph FontRi@R  Table Normal4 l4a (k (No List 4U`4 D Hyperlink >*phBOB Dapple-converted-spaceLL Dui-ncbitoggler-master-textB^"B D Normal (Web)dd[$\$.X`1. Y%Emphasis6]ZYBZ 'd Document Map-D M CJOJ QJ ^J aJjSj XD Table Grid7:V0PK![Content_Types].xmlN0EH-J@%ǎǢ|ș$زULTB l,3;rØJB+$G]7O٭VvnB`2ǃ,!"E3p#9GQd; H xuv 0F[,F᚜K sO'3w #vfSVbsؠyX p5veuw 1z@ l,i!b I jZ2|9L$Z15xl.(zm${d:\@'23œln$^-@^i?D&|#td!6lġB"&63yy@t!HjpU*yeXry3~{s:FXI O5Y[Y!}S˪.7bd|n]671. tn/w/+[t6}PsںsL. J;̊iN $AI)t2 Lmx:(}\-i*xQCJuWl'QyI@ھ m2DBAR4 w¢naQ`ԲɁ W=0#xBdT/.3-F>bYL%׭˓KK 6HhfPQ=h)GBms]_Ԡ'CZѨys v@c])h7Jهic?FS.NP$ e&\Ӏ+I "'%QÕ@c![paAV.9Hd<ӮHVX*%A{Yr Aբ pxSL9":3U5U NC(p%u@;[d`4)]t#9M4W=P5*f̰lk<_X-C wT%Ժ}B% Y,] A̠&oʰŨ; \lc`|,bUvPK! ѐ'theme/theme/_rels/themeManager.xml.relsM 0wooӺ&݈Э5 6?$Q ,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{P8g/]QAsم(#L[PK-![Content_Types].xmlPK-!֧6 0_rels/.relsPK-!kytheme/theme/themeManager.xmlPK-!R%theme/theme/theme1.xmlPK-! ѐ' theme/theme/_rels/themeManager.xml.relsPK] V ;^ pT!OT"#$%(M58#OT !)h{&47)4XXXXXX8@0(  B S  ?-4578BDMY`kuvxy)*RTdinpCE !67mn689< xy%(hi24% & g i L M N R Z [   R S p r % & Y Z ^ a k m u w    !#*+./48CDPQ2367GIjlvw~dehivw  _abePQqr"#WXbcij *-RSaeh|'4*47   EGHJik(*67'(24K M P R Y [ ^ a l m v w    !"*+./48BDcd|  DFkr a    !"./8dkg6EQVRxH H^H` CJo( ^`hH. pLp^p`LhH. @ @ ^@ `hH. ^`hH. L^`LhH. ^`hH. ^`hH. PLP^P`LhH.}H H^H` CJo( ^`hH. pLp^p`LhH. @ @ ^@ `hH. ^`hH. L^`LhH. ^`hH. ^`hH. PLP^P`LhH.g6QVf;|G0[gm(P|0m( d4sIlP|0yx$ 8w7 A= ><,lH]05)>GZU?a"3;#P#MK()c|,V.?b.0kX7/.:j;M@hBDlF 7NWQP6SNVgV_Y-\?`'d<8g:hkh$m*ni3pAs/titozC { {?} vr8D@d4d4^<v(_C.Tht9+Ds-1y-XDe:.xC:Cc*#+qVw7 jAP@Y P0%:M8GR7iIOY% cK9*T_5sEWZ^=n$ng@FFFFpT@ @8@L@@Unknown G.Cx Times New Roman5Symbol3. *Cx Arial_ Times-RomanTimes New Roman=GulliverRM_MinionPro-RegularMS Mincho] HelveticaNeue-MediumArialWTimesNewRomanMS Mincho]TimesNewRomanPSMTPMingLiUO HelveticaNeue-Light5. .[`)TahomaA$BCambria Math"qCGCG . .!r43qIX ?D2! xx Curr Opin HematolRRBRenata Bari Rafaj  Oh+'0p   , 8 DPX`hCurr Opin HematolRRB Normal.dotmRenata Bari Rafaj2Microsoft Office Word@F#@ٶ@ٶ՜.+,D՜.+,< hp|  VEF.  Curr Opin Hematol TitleX 8@ _PID_HLINKSA$7,http://www.ncbi.nlm.nih.gov/pubmed/23036532#4Z chttp://www.ncbi.nlm.nih.gov/pubmed?term=Farrell%20DH%5BAuthor%5D&cauthor=true&cauthor_uid=230365320 dhttp://www.ncbi.nlm.nih.gov/pubmed?term=Anderson%20NW%5BAuthor%5D&cauthor=true&cauthor_uid=230365328Rfhttp://www.ncbi.nlm.nih.gov/pubmed?term=Rein-Smith%20CM%5BAuthor%5D&cauthor=true&cauthor_uid=23036532&5,http://www.ncbi.nlm.nih.gov/pubmed/152570136^chttp://www.ncbi.nlm.nih.gov/pubmed?term=Farrell%20DH%5BAuthor%5D&cauthor=true&cauthor_uid=15257013  !"#$%&'()*+-./012356789:;<=>?@ABCDEFGHIJKLMNPQRSTUVXYZ[\]^aRoot Entry FuܶcData ,1Table44WordDocument.VSummaryInformation(ODocumentSummaryInformation8WCompObjr  F Microsoft Word 97-2003 Document MSWordDocWord.Document.89q