Pathogenesis of postoperative adhesion formation B. W. J. Hellebrekers! and T. Kooistra? "Department of Obstetrics and Gynaecology, Haga Teaching Heapitl, The Hague, and TNO Prevention and Heath, Department of Biosciences, e Netherlands Gaubis Laboratory Leiden, Carspndence ts Dt ‘The Netherlands (e-mail: blellebrekers@hagariekenhuissal) Backorounc: Current views on the pathogenesis of adhesion formation are based on the ‘classical ‘concept of adhesion formation’, namely that a reduction in peritoneal fibrinolytic activity following peritoneal trauma is of key importance in adhesion development Methods: A non-systematic literature search (1960-2010) was performed in PubMed to identify all inal articles on the pathogenesis of adhesion formation. Information was sought on the role of the fibrinolytic, coagulatory and inflammatory systems in the disease process. osuits: One unifying concept emerged when assessing 50 years of studi the pathogenesis of adhesion formation. Peritoneal damage inglicted by surgical trauma or other insults evokes an inflammacory response, thereby promoting procoagulatory and antifibrinolytic reactions, and a subsequent significant increase in fibrin formation. Importantly, peritoneal inflammatory status seems in animals and humans on 'W. J Hellebrekers, Department of Obstetrics and Gynaecology, Haga Teaching Hospital PO Bo 60605, 2506 LP, The Hague, a crucial fuetor in determ and fibrin dissolution, and therefor adhesions develop. Conclusion: Suppression 1g the duration and extent of the imbalance beoween fibrin formation the persistence of fibrin deposits, dete ing whether or not F inflammation, manipulation of coagulation as well as direct augmentation of fibrinolytic activity may be promising antiadhesion treatment strategies. Paper accepted 14 June 2011 Published online 23 August 2011 in Wiley Online Library (www-bjsco.ak). DOT: 10,1022. Introduction Intra-abdominal adhesions are a major cause of human illness!. Triggers of adhesion formation include inflam- ‘mation, endometriosis, chemical peritonitis, radiotherapy, foreign body reaction and continuous ambulatory peri- toneal dialysis, but the majority of adhesions are induced by surgery!. Depending on the location and structure of an adhesion, it may remain ‘silent’ or cause pathological com- plications. These may be as serious as life-threatening intestinal occlusion, with an associated mortality rate ranging from 43 to 13 percent’. Pelvic adhesions may also cause chronie pelvic pain and are the leading cause of secondary infertility in women, being responsible for 22 per cent of cases", Furthermore, the presence of adhe- sions during surgery may result in longer operating times and an increase in complications, both immediately and for up to 10years later. Up to 34 percent of surg patients are readmitted to hospital for a condition directly or possibly related to adhesions" (© 2011 Beth Journal of Surgery Sect Lad Publish! by John Wiley & Sone Lad Despite the severe problems caused by adhesions, adequate preventive treatment strategies are lacking and studies on the pathogenesis of adhesions are relatively scarce, The main reason for this is the difficulty in assessing the extent of adhesion formation after surgery because a second surgical procedure is needed for adhesion went. A widely accepted concept is that adhesions are formed as a result of a postoperative reduction in peritoneal fibrinolytic activity. According to this theory, nown as the ‘classical concept of adhesion formation’”-”, reduction in fibrinolytic activity permits deposited fibrin to become organized into fibrous, permanent adhesions. In this review, halfa century of research on the pathogenesis of adhes ras evaluated, leading to the proposal that this classical concept may be too simplistic. Evidence is provided for an adapted concept postulating that adhesion formation is the result of both insufficient fibrinolytic capacity and increased fibrin formation in response to an enhanced inflammatory status of the peritoneus n formation British Jura of Surgery 2011; 98: 03-15161908 Methods A. non-systematic literature search was performed in the PubMed database to identify all original articles on the pathogenesis of adhesion formation, with particular reference to the role of the fibrinolytic, coagulatory and inflammatory systems in the disease process. Keywords included: ‘animals’, ‘humans’, ‘adhesions’, ‘aetiology’, ‘physiopathology’, ‘postoperative period’, ‘peritoneum’, ‘surgery’, ‘ischaemia’, fibrinolysis’, “fibrin, ‘plasminogen activators’, ‘inflammation’ and ‘coagulation’. Original articles from all relevant listings were sourced and hhand-searched for further relevant articles, without any restriction. The peritoneum A better understanding of the process of adhesion formation will allow the design of new preventive strategies. This requires a thorough understanding of peritoneal anatomy and peritoneal repair, and of aspects of the inflammatory, coagulatory and fibrinolytic systems. Therefore, the aim of this review was to provide a comprehensive overview of available knowledge on the anatomy ofthe peritoneum, processes underlying its repair after trauma, and a synopsis of the interactions between the inflammatory, coagulatory and fibrinolytic systems. In particular, the fibrinolytic activity of normal and diseased peritoneum following abdominal surgery is discussed. The peritoneum is, compared with pleura and peri- ‘ardium, the most extensive serous membrane inthe body It serves to minimize frietion between abdominal viscera, thereby enabling their free movement. It also stores fat, especially in the greater omentum'®, With a surface area that is generally equal to that of the skin, this mem- brane may be the largest organ in humans! ‘The visceral peritoneum accounts for about 80 percent of the total peritoneal surface area, and lines the gut and other viscera ‘The parietal peritoneum, accounting for 20 per cent of the surface area, lines the walls of the abdominal cavity. ‘The peritoneal membrane is lined by a monolayer of mesothe~ lial cells that have microvillae and produce a thin film of lubricating fluid. The layer of mesothelial cells resides on a basement membrane, which in turn overlies a bed of con- nective tissue that comprises a gel-like matrix containing a loose network of collagenous and elastic fibres, seattered fibroblasts, macrophages, mast cells and a varying num ber of fat cells! This layer also contains the peritoneal capillaries and some Iymphaties, which give rise to a rich capillary network that functions as a ‘dialyser’ and barrier for peritoneal transport of water and solutes! © 201 Briss Journal of Surgery Society La PablnedyJoa Wiley Sons Lu B.W. J. Hellobrokers and T. Kooist A unique property of the peritoneum is its delicacy Because mesothelial cells are poorly. interconnected through very loose intercellular bridges, the peritoneal surface is highly susceptible 1 trauma! Minimal mobilization or damage to the peritoneum ean resule in denudation of peritoneal surfaces, which can trigger the formation of adhesions!*. Another unique property of the peritoneum isits uniform, relatively rapid rate of surface re- mesothelialization after trauma. Irrespective of the size of injury, peritoneal re-mesothelialization is complete within 5-7 days!®, Owing to migration of adjacent mesothelial cells, metaplasia of subperitoneal connective tissue cells and the transformation of peritoneal cells into mesothelial cells, the entire surface of a peritoneal defect becomes mesothelialized simultaneously, and not gradually from the borders as in epidermalization of skin wounds!45, ibrinolytic system Adhesions are formed when the peritoneum is damaged and the basal membrane of the mesothelial layer is exposed to the surrounding tissues. This injury to the peritoneum, due to surgery, infection or irritation, elicits local inflammatory response which leads to the formation of a serosanguineous, fibrin-rich exudate as part of the haemostatic process. The fibrinous exudate is an essential component of normal tissue repair, but timely resolution of the fibrin deposit is essential for proper restoration of preoperative, non-inflamed conditions. If the fibrin deposit persists for too long, the fibrin provides a matrix for invading fibroblasts and new blood vessels, and the deposited fibrin becomes organized into fibrous, permanent adhesions, characterized by deposition of collagen and vascular ingrowth. All peritoneal injuries cause local ischaemia, which has been proposed as the most important insult leading toadhesion development. Hypoxia induces the conversion of fibroblasts wit peritoneal phenotype into fibroblasts with an adhesion phenotype; such fibroblasts have a lower fibrinolytic activity, and a significant increase in basal mRNA levels for several cytokines, coagulatory factors and crucial proteolytic enzymes that play a role in the extracellular iatrix remodelling process of healing!” Fibrin formation is the result of activation of the coag- ulation cascade. Fibrin is formed during haemost inflammation and tissue repair. Activation of the coag~ ulation system ean occur via several pathways and results in the generation of thrombin (factor Ila) from prothrom= bin (factor ID. The formation of thrombin then triggers conversion of fibrinogen into fibrin monomers that inte act with one another and polymerize forming a fibrin wormscosk British Jornal of Surgery 2011 98 1503-1516Pathogenesis of postoperative adhesion formation a system (ZEN Tse fact pata \ T Printammatory cytouines Tissue lacor Pretvombin (tector (tater) Fig. 1 Main in adhesions. tPA, issue plasminogen activ antithrombin clot. At the level of thrombin, activation of coagulation is inhibited by antithrombin IIL, whieh neutr ss throm= bin. Fibrin is meant to fulfil a temporary role in tissue repair and therefore must be resolved when normal tissue structure and function is restored, ‘The degradation of ib rin is regulated by the fibrinolytic system (Fig. 1). In this system, the inactive proenzyme plasminogen is converted into active plasmin by tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA). Plasmin is highly effective in degrading fibrin into fibrin degradation prod ucts (FbDPs)""2°. ‘The primary physiological inhibitor of plasmin is a2-antiplasmin, which has a high aflinity for plasmin and is fast acting?! Besides inhibition of plasmin, it also prevents premature lysis of the fibrin clot by bind= ing to plasminogen and cross-linking to fibrin, thereby {© 2011 Beh Journal of Surgery Susy Li Published ty John Wiley & Sone Lad Proton C system | nitions between the inflammatory, coagulatory and fibrinolyti systems that playa role inthe pathogenesis oF; PA, urokinase plasminogen activator; PAL, plasminogen activator inhibitor; 1508, Foie ston | PA uPA Pasmin + e2aanipiasmn Fsinogon “ — CCoaguaton system interfering with the binding of plasmin 1o fibrin during the coagulation process?” The principal activator of plasminogen is tPA of which endothelial cells are the principal physiological source; however, tPA has also been isolated from virtually all tissues, including mesothelial cells and macrophages*. Acute release of tPA from endothelial cells is assumed to be induced by various stimuli, such as exercise, vyentous occlusion, hypercoagulability, histamine and some vasoactive drugs. PA has a high affinity for fibrin, which strikingly enhances its activity, thereby strongly il pla 3 promoting the conversion of inactive plasminogen into active plasmin, In the absence of fibrin, tPA isa relatively poor activator of plasminogen’. Consequently, plasmin formation is greatest where itis requised, namely at the wwiscos Bri Tourl of Surgery 201; 98: 1503-15161506 fibrin clot, while systemic activation of plasminogen is prevented. First isolated from human urine’, uPA has since been isolated from a number of tissues including kidney, lung, placenta, bladder, epidermal cells, fibroblasts and macrophages?®27, Although uPA is equally effective in the degradation of fibrin, its properties differ from those of tPA in regard to the lack of high-affinity binding for fibrin and the lack of increased plasminogen activator activity in the presence of fibrin; uPA is thus limited in its capacity to activate plasminogen’*?. The main role of uPA appears to be in the induction of extracelfular proteolytic mechanisms, resulting in inereased vascular permeability, cellular migration, tumour invasion and tissue remodelling Besides a2-antiplasmin, inhibitors of plasminogen activator also play an important role in the regulation of fibrinolysis. Plasminogen activator inhibitor (PAD 1 is a powerful and the most important inhibitor of PA and uPA, Tris produced and released by a variety of eels, including endothelial cells, mesothelial cells, macrophages, platelets and fibroblasts. Produ id release of PAI-1 has been stimulated in endothelial cell culture by several agents, including thrombin, endotoxin, interleukin (IL) 1 and tumour necrosis factor (TNF)'*~"", Produetion and release is also enhanced after surgery and inflammation, and PAI+ appears to be an acute-phase reactant protein™® Plasminogen activatorsare rapidly inactivated by PAI-1, by forming inactive tPA-PAI-1 and uPA~PAI-1 complexes”. PAL-2 was first isolated from human placenta" and has since been localized in the plasma of pregnant woman and in leucocytes. PAI-2 reacts with both plasminogen activators at a slower rate than PAI-I, and an important role in the normal regulation of the fibrinolytic system has not been established. Effect of peritoneal trauma on fibrinolysis in experimental studies ‘Phe idea that normal peritoneum possesses intrinsic fibrinolytic activity that prevents the formation of adhesions was firstly postulated by Hartwell in 1955 Evidence for such intrinsic fibrinolytic activity of the peritoncum was initially presented by Von Benzer and colleagues in 1963, and later confirmed by Myhre~ Jensen and co-workers and Gervin et al®, Evaluation of fibrinolytic activity and adhesion formation after peritoneal trauma has since been the subject of several studies, using various animal models and different forms of peritoneal trauma“-5*. Notably, in all of these studies peritoneal ‘trauma resulted in adhesion formation and a concomitant reduction of fibrinolytic activity in peritoneal biopsies, ©2011 Bish Journal of Surgery Say Ld Pehle iy Job Wiley & Sons Lal 1. W. J. Hollebrekers and T. Kooistra independent of the animal model used oF the trauma applied. ‘This led to what became generally accepted as the ‘classical concept of adhesion formation’, namely that a reduction in peritoneal fibrinolytic activity is of key importance in the formation of adhesions" Although attractive, the classical concept lacks a solid basis and seems too simplistic for several reasons. A first point of concern is that most studies were restricted to the measurement of fibrinolytic parameters at a single time point. Results from several studies that measured parameters at more than one time point challenged the classical concept“, In an evaluation of the peritoneal fibrinolytic activity and extent of adhesion formation in a rat model, Bakkum and co-workers demonstrated that fibrinolytic activity was slightly increased at day 1 after surgery and significantly increased on days 3 and 8, and after 1 month in peritoneal biopsies. Reijen and colleagues investigated the time course of peritoneal PA activity in rats, reporting normal levels on day 1 after colonic surgery and significantly increased levels on day 3, Similarly, two other animal studies that measured fibrinolytic activity in peritoneal fluid showed significantly higher levels of tPA activity during an interval of 8 days in rats with faecal peritonitis, and 3 weeks after surgery in rabbits compared with control animals% A second point of concern is that most studies mea- sured fibrinolytic parameters alone, without considering coagulation parameters. In a study by the authors’ research group, using the same rat model as described by Bakkum ctal.*, peritoneal plasminogen activator activity was anal- ysed immediately afer surgery, and 2, 4, 8, 16, 24and 72 h later®. In contrast to the classical concept, tPA activity remained unchanged or slightly increased after surgical trauma, The results pointed to increased fibrin forma- tion rather than diminished fibrinolytic activity as the iain cause of fibrin deposition and subsequent adhesion formation, A third point of concern is that measurements in peritoneal biopsies in most studies were not combined with measurements in peritoneal fluid. ‘There is, however, a major difference in results between studies that analysed peritoneal biopsies*?-** and those that performed measurements in peritoneal fuid™-*, In all studies that analysed peritoneal fluid, a significant rise in fibrinolytic activity was found, contrary to most results in peritoneal biopsies where a reduction was een. A possible explanation for this might be the occurrence of active release of plasminogen activators in the peritoneal cavity during abdominal surgery (see below). Only one study combined measurements in both peritoneal biopsies and peritoneal fluid’. In this stady, fibrinolytic parameters were analysed wwncbjscouk British Journal of Surgery 2011; 98: 1503-1516Pathogenesis of postoperative adhesion formation immediately, and 2, 4, 8, 16, 24 and 72h after surgery in rats. In peritoneal fluid, tPA antigen concentrations were increased significantly at all postoperative time points; fibrinolytic activity steadily rose ater surgery, being increased significantly after 24h, Fibrinolytic activity also increased significantly in peritoneal biopsies with time after surgery. FbDPs were present at alltime intervals, pointing toongoing fibrinolysis, whereasadhesions were found from 2 honwards. Effect of inflammation on peritoneal fibrinolysis in humans Peritoneal fibrinolytic response during inflammation measured in peritoneal biopsies Plasminogen activator in the peritoneum was first ‘measured in humans in 1989, and reductionsin plaminogen activator activity during ischaemia and inflammation were described. Since then, several investigators have studied the peritoneal fibrinolytic response during inflammation (Table 1), Vipond and colleagues assessed the activators and inhibitors of fibrinolysis in peritoneal biopsies of, inflamed human peritoneum and in control subjects, concluding that tPA was the principal physiological plasminogen activator in peritoneal tissue and that the reduction in functional fibrinolytic activity seen during inflammation was mediated by PAI-I. These findings were later confirmed by others*?-#! Peritoneal fibrinolytic response during inflammation measured in peritoneal fluid Several investigators who measured fibrinolytic activity and concentrations of fibrinolytic parameters in peritoneal ‘Table + Studies on the peritoneal fibrinolytic response during inflammation in humans measured in uid 1807 fluid reached conclusions that differed from findings in peritoneal biopsies!-®. Darr eral: measured fibrino- Iytic parameters in the peritoneal fluid of women with pelvic inflammatory disease and found a highly signifi- cant rise in FbDPs compared with controls, concluding that fibrinolysis occurred at a higher rate, despite con- comitant production of PAL. Similarly, van Goor and colleagues reported that, despite markedly raised con- centrations of PAL, peritoneal fluid displayed fibrinolytic activity in patients with bacterial peritonitis, as demon- strated by significantly inereased concentrations of plas- ‘min=a2-antiplasmin complex and FbDPs, These authors also concluded that intra-abdominal coagulation and fibrinolysis were stimulated in the abdominal cavity of patients with bacterial peritonitis Effect of surgery on peritoneal fibrinolysis in humans Peritoneal fibrinolytic response to surgery measured in peritoneal biopsies Mainly because of the difficulty in obt ing the postoperative period, most studies in humans have been restricted to the perioperative sampling of biopsies or peritoneal fluid (Table 2). Scott-Coombes and colleagues! investigated the peritoneal fibrinolytic response to surgery by taking peritoneal biopsies at the beginning and end of surgery. lective surgery caused an immediate reduc~ tion in peritoneal plasminogen activator activity, which seemed to be secondary to a reduced concentration of tPA. Other investigators later confirmed the finding of reduced plasminogen activator in response to surgery47!, More recently, several investigators studied the difference in the fibrinolytic response to surgery between laparoscopy and ning samples dur- oneal biopsies and peritoneal Peritoneal biopsies ‘Thompson etal” 1980 = Vipondetai® 1900 tPA, uPA. PA, o2-antplasmin Whawoletal!® 1993. «PA, PAT, PAL2 Holmes etal! 19968 PAL Ince eat 2002 IPA. UPA PAI, PAL2,IPA-PAL complex Pertoneat mud Derrat al!@ 1902 SPA. UPA PAL, TDP, OOPS vanGooretal® 1996 tPA, uPA PAL, OOPS Edalstam etal 1008 tPA, UPA PAIL PAL2 PAR PAAL PRA PAL, PAT PAA ALT, PAl2 1, PAA | PAAPAK PAL HPAL. UPA 1, PAI 2, PAL p.$PA-PA compl (A PAT. UPA 1, PAL 17, TDPs 1, FODPS $1, 1PAA o» = PAT. UPA, Pat 11 FODPS 1 = AT UPA! Patt, Paz 4, Decrease; nerease; «+, no change: PAA pasminogen-aeivatng ative PA, sue plasminogen activator uPA, urokinase plasminogen atvaton PAI, plasminogen activator inhibitor (OPA, (iss) plsminagen-actvating activi; TDP, wal degradation pradic; FODP, lin degradation product. {© 2011 Bish Joual of Surgery Sci Lad Publ yf Wiley Sons Lad wow.bjsco.uk Britis Journal of Surgery 2015 98: 1503-15161. W. J. Hellebrokore and T. Kooistra Table 2 Studies on the fibrinolytic response to surgery in peritoneal biopsies in humans taken atthe beginning and end of surgery ‘Scot-Caombesetal!® 1995 tPA, PAN PAA Begining andend of surgery PAA |, {PA |, PAL + PAL2 not detectable Homa ta 1996 PAL PAA,PAL1 —Bogbning and end of surgery PAA L,PA-t not detoctabe Iason a 1908 PA, uPA, PAL, {PAA Begeingand end of surgery PAI-1 {PAA |, PAPA {PA-PAI complex compex t Bergstim ata" 2002 tPA, PA {PAA ——_Bagiring and ond ofsurgery tPA |, PAL. {PAA Laparoscopy versus Simi response laparotomy Neudockor a ls 2002 {PAPALT,(PALPAI —{PAA.PALT —Baghning and end ofurgery PAA |, PA, PAT <, complex {PA-PAI complex <- Laparoscopy versus Sime response laparotomy Brokeiman a a 2008 PA, UPA, PAL PAR ——_Baghningandendofshort APA =, UPA, PAL «=, Taparescopy, Pad o Brokelman o 2? 2009 PA, UPA, PAL {PAA Begining and ond of {PA 1, uPA, PAL >, ‘Prolonged laparescopic PAAL surgery |. Decrease , increase; «>, no change: tPA, tisue plasminogen activator PAL, plasminogen activator inhibitor: (QPAA, tissue) plasminogen activating sesvty uPA, urokinase plasminogen aetvator. laparotomy’"-, Perioperative tPA. act all types of surgery, except for the short: group (Table 2). Overall, however, there were no significant diferences in fibrinolytic responses, between laparoscopy and laparotomy” Peritoneal fibrinolytie response to surgery measured in peritoneal fluid Before the turn ofthe millennium, only two clinical studies were available that examined the fibrinolytic response to surgery in peritoneal fluid"? (Table 3). In one study, peritoneal Fluid was collected at several time points after surgery by use of an abdominal drain‘, significant reduction in plasminogen activator activity was found afer surgery, reaching undetectable levels at 24 h, which was sustained at 48h. Again, it was conchided that there ‘was a single pathophysiological mechanism of adhesion formation in the event of trauma to the peritoneum, due to either surgery or infection, which led to a reduction in fibrinolytic activity. It thus seemed that the ‘classical concept of adhesion formation’ as described in animals was also applicable to humans and the eoneept became more generally accepted. There also appeared to be a biphasie response to trauma by the peritoneum. twas postulated thatthe early reduction in plasminogen activator activity might be secondary to a reduction in tPA levels, whereas the subsequent abolition of functional fibrinolytic activity was probably caused by a dramatic inerease in PAI-1 and PAI-? concentrations. The (©2011 Bish Journal of Surgery Socey Lad Published Jo Wiley Som Lad ‘magnitude and duration of this abolition of plasminogen activator activity was related to the type and duration of the peritoneal trauma, and was the main factor that determined whether or not postoperative adhesions were formed, and to what extent”. In another study, Balestam and co-workers collected peritoneal fluid during a second-look laparoscopy I week after laparotomy with adhesiolysis, In contrast to the findings of Seott-Coombes and colleagues, the fibrinolytic system was stil fully active I week after surgery, presumably continuing to inhibit the further formation of adhesions. Furthermore, in two more recent studies, fibrinolytic activity in peritoneal fluid was significantly enhanced 1 week after surgery”*75 “The discrepancy between results for peritoneal biopsies and peritoneal fluid from several studies might be explained by the acate release of tPA from mesothelial cells into the peritoneal cavity during inflammation or trauma. ‘This idea was addressed by Ivarsson et al.7, who investigated whether tPA was released into the peritoneal cavity during surgery by collecting fluid released from the serosal surface of the small bowel in a plastic bag. Concentrations of tPA were increased significantly inthe collected peritoneal fluid compared with peripheral blood levels. The authors concluded that tPA was rapidly released by the peritoneum through an active process during abdominal surgery, Storage of tPA in an intracellular storage pool has been described” and inflammation or trauma might trigger the release of tPA from such stores, thus explaining the dliserepaney in results from several studies which differed in wwwbpcok Bet Journal of Stoyery 2011; 98: 1503-1516Pathogenesis of postoperative adhesion formation 1508 Table 3 Studies on the fibrinolytic response to surgery in peritoneal fluid in humans Scott-Coombesetal"*” 1995 PA, PAL, PAL2, PAA Edetsam ota 1908 PAL UPA PAM, PAL arson eta 2001 PAL UPA PALI. PAR Newdecker et af 2002 {PAPAL IPAA PAT actly, PAPAL complex Hotobrars ot al 2005 PA. UPA, PAI, FLOPS, fnogen, plasminogen, \2-antiplasmin, PAP, TAT comple, tn Hetabrcare a > 2000 tPA, PALI, OPS Pend h PAR J tPA J, PAT PARQ ¢ 24h PAR not detectable, IA I PAL 1, PALO ¢ san PAA not detectable, IPA 1, PAl-t 4, PAK2 1 1 week {PA 1, uPA ¢, PALI 1,PAL2 > Begining and enc of surgery IPA 1, PAA 1, UPA =, PAL Laparoscopy versus Taparctomy’ an {A activty In laparescopy ‘rou: PALL 1, Pale actvty 1, PA activity | in both gous on No atferences between ‘roupe aan No oterences between groups: 1 week TAT complex and uPA «all ‘otto factor sigrifearty 1 1 week {A PAL 1, FoDPS t 1 Decrease; increase; no change. sPA, tise plasminogen activator; PA plasminogen actiator inhibitor (PAA, (ste) plasminogen-ateaing tivity PA, urokinase plasminogen acsator, FHDP, rin degradation product; PAP, plstin-antiplasmnin comple: TAT, chrombin-ancithrombin. the timing of biopsies (taken atthe beginning versus end of surgery). Notably, this also raises the question of whether perioperative lavage might wash aveay a substan of fibrinolytic activity, thereby promoting the formation and persistence of fibrin deposits Fibrinolytic and coagulatory response to surgery measured in plasma Studies on the pathogenesis of adhesions that concomi- tantly measured parameters in plasma are scarce. Two studies showed a significant rise in plasma concentrations of FbDPs during the postoperative period after abdominal surgery, pointing to ongoing fibrinolysis" (Tuble 4). In 1985, D'Angelo and colleagues" proposed the exist of a minimized fibrinolytic system in plasma immed after surgery asa resulcof an increase in PAT-L and a reduc~ tion in tPA levels (postoperative fibrinolytic shutdown’) Again, it took several years before new insights led to the perception that there is still ongoing despite reduced tPA and inereased PAI-1 concentrations. In this contest, a study by Siemens and co-workers" is of| special interest, They investigated the most vulnerable time of thrombus formation with regard to the role of plasma coagulatory and fibrinolytic systems in patients under- going total hip replacement, hemicolectomy, laparoscopic brinolysis in plasma (© 2011 Bes Journal of Surgery Society Lad Pblhed-Joba Wiley Sons Lad cholecystectomy or subtotal thyroid resection, Maximum activation of coagulation was not reached until 2h afer surgery and slowly decreased until normal values were reached around day 5. ‘The hip replacement and hemi- colectomy groups showed a similar outcome, with strong activation of the procoagulatory (and fibrinolytic) systems. ‘Much less pronounced were the changes during chole- cystectomy and thyroid reseetion (Table 4). Similar results were reported by Diamantis etal", who examined differ inactivation of coagulation and fibrinolytic pathways between open and laparoscopic surgery, and by Lépex and co-workers”, who studied postoperative differences between orthopaedic and abdominal surgery. Overall, in these sturlies surgery led to hypercoagulability, with open surgery leading to & stronger activation of the clotting system in plasma than laparoscopic procedures”? ™ Effect of surgery on peritoneal fibrinolysis in relation to extent of adhesion formation Among the diverse studies on the pathogenesis. of adhesion formation, only one retrospective study and two prospective trials"*7¥ investigated the effect of surgery on peritoneal fibrinolysis in relation to theseverity of adhesion formation. In the retrospective study, levels of PAI-L and. of PA-PAL-I complex were inereased in peritoneal tissue swowjssonuk Bite Journal of Su-gory 20115 98 1503-1516B.W. J. Hellebrekers and T. Kooisea Table 4 Studies onthe fibrinolytic and coagulatory response to surgery in humans in plasma Lopez eat?" 1997 Orthopaedi versus {PA\PALI,FODPs,PAP, Preop. and 1,Sand7 loti markers» emia! surgery “TAT complex days postop. PAL {tPA 1, PAP Slomens.t a” 1909 Total hipreplacement, TAT complex, D-dimer, 1 day peop. ‘Altactors. Hip hemicalectomy, PAL, Rsinogen| Prsop.andintacp. and —-rplacament and laparoscopic 2hyand 1,2,3and homicolectomy showed ‘cholecytctomy, 5 days post. ‘similar strong activation subtotal thy ‘of procoaguiatery ane resection frnovtic systems versus other types of surgery Schictromaetal” 2004 Open versus arosconic TAT complex fin, Preop. and'th, and 1,2 Open surgery led to more ‘sugery DPS, Dimer, ‘and 3 days poston. ‘station of eeting| snttonoin ‘system than laparoscope surgery Hetebrkers etal 2005. Fertity surgery PA, UPA, PAL, FODPs, 1 week postop, PAL bin 7, FEOPS 1 ‘brinagen, plasminogen, zaps, PAP, “TAT complex tin Diamantistal®? 2007 Open versus lnproscopie Flin, FODPe, TAT Preop. and intacp. and Open surgery eto more ‘sugary ‘complex fixinogen, ‘and 3 days poston. ‘sclvaton of cloting Deaimee ‘system than laparoscopic sugery Hollebreker etal? 2008 Myomectomy APA, PALI, FOP 20min, 1,8ardCh,and1, IPAs, PALI + atal time 2,5.and 7 days postop. points, FOOP tat 0 minto 1 day 1, Decrease; increas; no change PA, issue plasminogen activator; PA, phsminogen activator inhibitor, FDDP, Fibrin degradation pra PAP, Plasmin~aneplasmin complet; TAT, trombin-antichrombins uP samples from patients with severe adhesions compared with those from patients with less severe adhesions®, In the first prospective study, investigators sought evidence of fibrinolyticinsufficieney asa cause of adhesion formation” Patients were studied prospectively after infertility surgery and during an early second-look laparoscopy (ESL) 8 days later. Fibrinolytic and coagulation parameters were ‘measured at both time pointsin peritoneal fluid and plasma, ‘which allowed evaluation of the postoperative course of the fibrinolytic and coagulation systems and correlation with the extent of adhesion formation. Adhesion improvement scores at the ESL correlated with initial peritoneal PAI- 1 concentrations, and it was concluded that insufficient peritoneal fibrinolytic capacity was the main factor in determining postoperative adhesion formation. In a second prospective study, investigators tried to substantiate the findings from the previous study in an experimental set-up directed at assessing cflicacy and safety of reteplase (recombinant plasminogen activator) administration after abdominal myomectomy”. Patients were randomized to intraperitoneal treatment with I mg. reteplase in Ringer's lactate or Ringer’s lactate alone. Adhesions were scored and peritoneal fluid and plasma were collected during myomectomy and an ESL. Again, © 2011 Br Jouna of Surgery Society Lad Pblhed iy Jobs Wiley & Sons Le roknseplaninogenaciator. there was a significant correlation between the extent of adhesion formation and the change in tPA concentration in peritoneal fluid from initial surgery to ESL. Similarly, a significant correlation was shown between preoperative plasma levels of PAI-I and the extent of adhesion formation. Notably, a highly significant correlation was demonstrated between preoperative plasma levels of C reactive protein (CRP) and the extent of adhesion formation at ESL, suggesting an important role of the inflammatory state in adhesion formation. Role of the inflammatory system Teis now well accepted that the inflammatory system has an important role in the regulation of both the coagulation and fibrinolytic systems", Acute inflammation, in response to trauma oF infection, can lead to systemic activation of the coagulation system and from that to fibrin deposition™, Fibrin deposition is part of a physiological. protective mechanism against invading microorganisms; it helps to enclose the microorganisms, and to contain the resulting inflammatory reaction. When the inflammatory response gets out of control and is accompanied by excessive activation of coagulation, fibrin formation in itself can www-bjsco.uk British Journal of Surgery 2011; 98: 1503-1516Pathogenesis of postoperative adhesion formation lead to pathological conditions and diseases such as diffuse intravascular coagulation in sepsis. Physical and chemical irritation of the peritoneum results in a non- bacterial inflammatory state with peritoneal serofibrinous, exudation****, In surgery, the formation of this fibrin exudate in the peritoneum is partof the haemostatic process in response to tissue injury, and an essential component of normal tissue repair. ‘Mesothelial cells have an important role in the prevention of adhesions and in local host defence. On the one hand, they synthesize tissue factor, a key pl in the onset of coagulatory processes; on the other, they have an important role in maintaining an adequate plasma-independent fibrinolytic system by proxducing tPA and uPA, and their inhibitor PAI-1. ‘The expression of procoagulatory tissue factor and antifibrinolytie PAI-1 is increased by inflammatory mediators such as IL-1 and INF-a, while the expression of tPA is concomitantly decreased, explaining an increased tendency to fibrin deposition™*”, ‘The main interactions between the three systems of inflammation, coagulation and fibrinolysis that play a role in postsurgical adhesion formation are depicted in Fig. 1. Factors influencing inflammation, coagulation, fibrinolysis and adhesion formation Despite large variations in experimental design, one unifying coneept em: over 50 years of studies in animals and humans on the pathogenesis of adhesion formation. Peritoneal damage inflicted by surgical ‘trauma oF other insults evokes an inflammatory response, thereby promoting procoagulatory and antifibrinolytic reactions, and a subsequent significant inerease in fibrin formation. When fibrin deposits persis, fibrinous adhesions can develop. Subsequently, these adhesions become organized (collagen deposition, vascular ingrowth) and are changed into permanent fibrous adhesions. The authors postulate that individual differences in peritoneal inflammatory status, procoagulant activity and fibrin- dissolving capacity determine whether fibrin deposits persist and thereby lead to permanent adhesions — or not. The new coneept not only reconciles apparently contradievory findings in the literature, but also provides a mechanistic context for, and the relationship between, the inflammatory state, coagulatory activity and fibrinolytic capacity; it provides a rationale for why numerous ‘presurgical, surgical and postsurgical factors can be of key importance in whether adhesions develop or not (Fig. 2) actors that reportedly influence inflammation, coag- ulation and fibrinolysis in. the presurgical setting are numerous. Age®*®, diurnal variations, sex and other when reassessi {©2011 Bish Journal of Surgery Sosity Lad Publish by John Wiley & Sone Ltd 1s netic factors®, obesity”, medication”?-°, ongoing ection", smoking and alcohol intake, diabetes”, phase of the menstrual cycle, hypercholesterolaemia”, benign versus malignant disease!™°!, stress!" and pregnancy'®® have all been found to influence one or more of the risk factors inflammation, coagulation and. fibrinolysis. In addition, numerous surgical factors con- wribute to fibrin persistence, including type and duration of surgery™"*", use of irrigation, anaesthetic used!®*, additional medication (such as antibiotics) and blood transfusion!®, OF special interest is the influence of the extent of peritoneal damage. Many surgeons assume that Japaroscopy induces fewer adhesions than laparotomy owing to less peritoneal trauma, Previous studies showed that open surgery led to a significantly greater activation fof the clotting system in plasma than laparoscopic procedures’”7*§, Adhesion formation, however, has not, been evaluated properly as primary endpointin prospective studies comparing laparoscopy and laparotomy. Only one id clinical trial compared adhesion formation between laparoscopy and laparotomy during second-look surgery. Significantly fewer adhesions were found on the ‘operated site in the laparoscopy geoup compared with the laparotomy group, and there was a trend towards ranclomiz adhesions overall! Future studies Despite considerable progress in insight into the factors determining peritoneal adhesion formation, it seems that preventive strategies are still guided by the five fundamental attacks against their formation as described by Boys!” in 1942. Limitation or prevention of initial peritoneal injury, prevention of coagulation of the serous exudate, removal or dissolution of deposited fibrin, prevention of adherence of adjacent structures by keeping them apart, and prevention of the organization of persisting fibrin by inhibiting fibroblastic proliferation still remain the basis of current research into adhesion prevention. However, notwithstanding numerous efforts to tackle adhesion formation along these lines, it remains a major problem in modern medicine and there is clearly @ need to ‘open new avenues. This review draws attention to the role of inflamma- tion as evoking factor, and anti-inflammatory treatment regimens deserve further investigation. It also highlights the perioperative period as an ideal and underutilized win dow of therapeutic opportunity in which the peritoneal environment and fibrinolytic eapacity could be modulated wow.bjsco.uk Britis Journal of Surgery 2011; 98: 1503-15161512 B.W. J. Hollebekers and T. Kooists Fig,2 Factors influencing the Ribrinolyic, coagulation and inflammatory systems, and thus the extent of adhesion formation to prevent postsurgical adhesion formation. Besides sup- pressing inflammation, direct augmentation of fibrinolytic activity with fibrinolytie agents might be an interesting alternative to use as an antiadhesion strategy", An impor- tant conclusion from this review is that there is special need for more prospective studies examining the extent of adhesion formation in relation to the inflammatory state and factors of eoagulation and fibrinolysis. For reasons of comparability between studies, specific attention should be paid to uniformity in measurement (what, where and when to measure, and in which patients). An attractive option that potentially combines ant-inflammatory, anti- coagulatory and profibrinolytie properties could be the use of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins)! Besides their cholesterol-lowering capacity, there is accumulating clinical evidence that they are effec tive in lowering plasma levels of CRP® "2, have potent anti-inflammatory properties", and are effective stimula tors of fibrinolytic activity by increasing tPA and lowering PAL-I!!2, The benefits of statin therapy in cardiovascular disease can be explained not only by their lipid-lowering potential but also by non-lipid-related mechanisms (so- called ‘pleiotropic effects). Besides their effects in plasma, {© 2011 Beis Joural of Surgery Sacer La Published by Jon Wiley & Sone Li statins have also been found to decrease cellular tis- sue factor expression!”?, to stimulate mesothelial ibri lytic activity by increasing tPA levels and lowering PAF-L levels in cultured mesothelial cells*""5, and to be effective in the prevention of postsurgical adhesions in experimental studies! #16, Te therefore seems that further research on these registered drugs in adhesion formation in a clinial setting is urgently needed. Inall, che peritoneal inflammatory status seems a crucial factor in determining the duration and extent of the imbalance between fibrin formation and fibrin dissolution, and thus in the persistence of fibrin deposits, determining whether or not adhesions will develop. The new concept providesa mechanistic context for and relationship between the inflammatory state, coagulatory activity and fibrinolytic capacity, and provides 9 rationale for why mumerous presurgical, surgical and postsurgical factors can be key to whether adhesions develop or not. Acknowledgements. “The authors declare no conflict of interest. wow.bsco.k Brits Journal of Surgery 2011; 98: 1503-1516thogenesis of postoperative adhesion formation References 1 Ellis 11, Moran B), Thompson JN, Parker MC, Wilson I Menvies D et al, Adhesion elated hospital readimissions ager abdominal and pelvic surgery: a retrospective cohort seucy, Lancer 1999; 353: 1476—1480. 2 Nicuwenbuijaen M, Reijen MM, Kuijpers JH, van Goor H. Small boswel obstuetion after total or subtotal eoleetomy: 10-year retrospective review. BJ Sing 1998; 85 1242= 1245, 3 ‘Trimbos-Kemper PC, Trimbos JB, van Hall EV, Adhesion formation after tubal surgery: results ofthe eight day laparoscopy in 188 patients, Fert Srerd 1985; 43: 395-400, 4 Cates W, Farley’ TM, Rowe PJ. Worldwide patterns of infertility is Mica different? Lancer 1985; 2: 596-598, Parker MC, Ellis H, Moran BJ, ‘Thompson JN, Wilson MS, Menzies D er al, Postoperative adhesions: ten-year follow-up of 12584 patients undergoing lower abdominal surgery. Dis Colon Retant 2001; 44: 822-829. Lower AM, Havthorn RJ, Elis H, O'Brien F, Buchan S, Crowe AM. The impact of adhesions on hospital ‘8849 open gynaecol ‘operations: an assessent from the Surgical andl Clinical Adhesions Research Study. 27OG 2000; 107: 885-862. “Thompson JN, Paterson-Brown S, Harbourne T, Whawell SA, Kalodiki E, Dudley HA Reduced human peritoneal plasminogen activating activity: posible ‘mechanism of adhesion formation. Br J Sing 1989; 76: 382-384, 8 Vipond MN, Whavell SA, Thompson JN, Dudley HA, Peritoneal fibrinolytic activity and intra-abdon adhesions. Lancer 1990; 335: 1120-1122 9 Scott-Coombes DM, Whawell SA, Vipond MN, “Thompson JN. Elective surgery inhibits intraperitoneal fibeinolysis. Br] Surg 194; 81: 770. 10 ai Zerega GS, The enuse and prevention of postsurgical adhesions: a contemporary uplate. Prag Chin Biol Rer 1993; 381: 1-18, 11 Gardiner E, Abdominal viscera and peritoneum. In atom: «a Regional Study of Hemen Structure Grd edn), Gardner E, Gray DJ, ORahilly R (eds). WB Saunders: Philadelphia, 1969, 387-395 12. Bloom W, Blood cell formation and destruction. Int Testlookof Histology (Oth en), Bloom W, Favweett DW (ds), WE Saunders: Philadelphia, 1978; 186-187. 13 Flessner MP. Peritoneal transport physiologys insights from basic research. J i Soc Nephrol 1991; 2: 122-1 14 Mursuers SE, Wilkos: S. Structure and function of mesothelial cells. Caner Treat Res 2007; 134: 1-19. 15 diZeregs GS, Biochemical events in peritoneal tissue repair arg 1997; (377): 10-16, eregs GS, Campeau JD. Peritoneal repair ani postsurgical adhesion formation. Ham Reprod Update 2001 7, 547-535, 17 Holtz G, Prevention and management af peritoneal adhesions, Fertil Steril 1984, 41: 497 6 rexdmissions over ten years af eal (© 2011 Bes Journal of Sugery Soci Lad Pb ios Wily Sons Lad 1519 18. Alpay Z, Saed GM, Diamond MP. Postoperative adhesions: from formation to prevention. Semin Reprad Med 2008; 26: 313-321 19 Collen D, Lijnen HR, Molecular basis of fibrinolysis, 2s relevant for thrombolytic therapy. Tloomb Haemast 1995; 74: 167-171. 20 Collen D, On the regulation and control of fibrinolysis “Thrannb Hacimst \980; 43: 77-89. 21 Klu C, Los N. Demonstration of two forms of «22-antiplasmnin in plasma by modified crossed immunelectrophoresis, Thromb Rer 1981 21: 6 1 22. Moroi M, Aoki N. Isolation and characterization of slpha-2-plasmnin inhibitor from busman plasma: a novel proteinase inhibitor which inhibits activator-induced clot Iysis. 7 Biol Chem 1976, 251: 5956-5968, Kinnara §, Aoki N. Crosslinking stein fibrinogen for -2-plasmin inhibitor. 7 Bil Chem 1986; 261: 15 501-15 595, 24 Hoylaers M, Rijken DC, Lijnen FIR, Collen D. Kinetes of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin, 7 Biol Chen 1982; 257: 2912-2919. Williams JRB. The fibrinolytic activity of urine. Br J Esp Biol 1951; 32: 530-537 26 Mekman CM, Loskutoff DJ. Fibrinolytie pathways and the exvothelium. Sean Thromb Hemost 1987; 13: 514-827. Saksela O, Hovi‘T, Vaheri A. Urokinase-type plasminogen setivator and its inhibitor seereted by cultured human. tnoneyte-macrophages. J Cll Physio! 1985; 122: 125-132. 28 Lu HR, Wa Z, Pauwels P, Lijnen HR, Collen D. Comparative thrombolytic properties of tissue-rype plasminogen activator (-PA), single-chain urokinase-type plasminogen activator (u-PA) and KIK2Pu fa -PA/u-PA chimera) in a combined arterial and venous thrombosis. inode in the dog. J lm Coll Cardio! 1992; 19: 1350~1359. Runge MS, Quertermous T, Haber E. Plasminogen he old an the new. Cirlarion 1989; 79: 217-224, 30 Blasi F, Urokinase and urokinase receptor:a paracrine/autocrine system regulating cell migration and invasiveness, BioFvays 199% 15: 105-111 Vassalli JD, Pepper MS. Tumour biology. Membrane proteases in focus. Nature 1994, 370: 14-15, 32 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blond 1987; 69: 381-387. Kruithof EK, Tran-Thang C, Ransija A, Bachmann F. Demonstration of fast acting inhibitor of plasminogen activators in buran plasma. Blood 1984, 64; 907-913, 34 van Mourik JA, Lawrence DA, Loskutoff DJ. Purifation of an inhibitor of plasminogen acivator(antiactivator) synthesised by endothelial eells. 7 Biol Chem 1984; 259: 14914-14921. 5 Colucei M, Paramo JA, Collen D. Generation in plasma of 4 fast-acting inhibitor of plasinagen activator in response to enulotosin stimulation, 7 Clin Incest 1085; 75: 818-824. Nachman RL, Hajar KA, Silverstein RL, Dinarello CA, Interleukin 1 induces endothelial cell synthesis of 6 wwe bok British Joure of Surgery 201; 98: 1503-15161514 plasminogen activator inhibitor. 7 Exp Med 1986; 163: 1595~1600, 37 van Hinsbergh VW, KooistraT, van den Berg EA, Princen HM, Fiers W, Emeis J). ‘Tumor necrosis factor inereases the production of plasminogen activator inhibitor in human endothelial ells in stro and in rae in ie, Blood 1988; 72: 1467-1473, 38 de Boer JP, Abbink J), Brouwer MC, Meijer C, Roem D, ‘Vootn GP eal PAl-I synthesis inthe human hepatoma cell line Hep? is increased by cytokines evidence that the liver contributes to acute phase behaviour of PAI rom Haemost 1991; 65: 181-185 39 Travis, Salvesen GS. Human plasma proteinase inhiicors. Amma Reo Binchom 1983; 254: 655-709 40 Astede B, Higerstrand I, Lecander I. Cellular localisation in placenta of placental type plasminogen activator inhibitor. rom Haemst 1986, 56: 6365. Kopitar M, Rozman B, Babnik J, Turk V, Mullins DE, Wan TC. Human leucocyte urokinase inhibitor ~ purification, characterization and comparative swdies against different plasminogen activators. Thromb Hacmrt 1985; 54: 750-755, 442. Harewell SW. Fibrous healing in human surgical wounds. In The Mechenie of Healing in Hannan Wounds, Harwell SE (ed). Thomas: Springfield, 1955; 109 43 Von Benzer H, Blumel G, Piza F. (On relations berween fibrinolysis and interpritoneal adhesions} Wien Klin Webensc 1963; 78: 81-883. 444 Myre Jensen O, Larsen SB, Astup T. Fbrinolytie activity in serosal and synovial membranes. Rats, guinea pigs, and rabbits. Arch Pat! 1969; 88: 623-630. Gervin AS, Puckett CL, Silver D. Serosal hypofibrinolyi, a cause of postoperative adhesions. ie J Surg 1973; 125; 30-88 46 Porter JM, McGregor GH Jr, Mullen DC, Silver D. Fibrinolytic activity of mesothelial surfaces, Surg Form 1969; 20: 80-82. 7 Buckman RF, Woods M, Sargent L, Gervin AS. A unifying pathogenetic mechanism in the etiology of intraperitoneal adhesions. J Surg Res 1976; 20: 1-5. 48 Buckman RF Jr, Buckman PD, Hufnagel HV, Gervin AS. A physiologic basis forthe adhesion-fre healing of depertonealzed surfaces. 7 Surg Rer 1976, 21: 67-76. 49 Hau, Payne WD, Simmons RL. Fibrinolytic activity of the peritoneum during experimental peritonitis. Surg meal Obstet 1979; 148: 415418. 50 Raftery AT. Effect of peritoneal trauma on peritoneal fibrinolytic activity and intraperitoneal adhesion formation, ‘An experimental study in the rat. Bar Surg Re 1981; 13 397-401. 51 Ryan GB, Grobsty J, Maino G. Mesotheil injury and recovery. im J Pathol 1973; 71: 93-112, ‘Molinas CR, Elkelani O, Campo R, Lutcan A, Carmelie P, Konincls PR. Role ofthe plasminogen system in basal adhesion formation and carbon dioxide ‘pneumoperitoncum ~ enhanced adhesion formation afer 4 45 {©2011 Brush Joural of Surgery Society Led Pabhed by Jon Wiley Sons Lad B.W. J. Hellebrokers and T. Koolstra laparoscopic surgery in transgenic mice. Fertil Steril 2003; 80; 184-192, 53 Vipond MIN, Whavell SA, Thompson JN, Dudley AF. Effect of experimental peritonitis and ischaemia on peritoneal fibrinolytic activity, Eur Surg 19% 160: 471-477. 54 Bakkum EA, Emeis J, Dalmeijer RAJ, van Bltterswij CA, ‘Trimbos JB, Trimbos-Kemper TC. Long-term analysis of peritoneal plasminogen activator activity and adhesion formation after surgical trauma inthe eat mode. Fertil Strid 1996; 66: 1018-1022. 55 Reijnen MM, Holmdahl L, KooistraT Falk P, Hendriks T, van Goor H. Time course of peritoneal tissue plasminogen activator after experimental clonic surgery: cffect of hyaluronan-based antiadhesive agents and bacterial peritonitis. Br 7 Surg 2002; 89: 103109 56 van Gor H, de Graaf JS, Grond], Shuiter WJ, van der ‘Meer J, Bom VJ et al. Fibrinolytie activity in the abdominal cavity of rats with faecal peritonitis. Br 7 Surg 1994; 81 1046-1048. 57 Bouckaert PX, Land JA, Brommer EJP, Emeis J}, Evers JLH. The impact of peritoneal trauma on intra-abdominal fibrinolytic activity, adhesion formation and early embryonie development ina rabbit longitu model. Hum Reprod 1990; 5: 237—241, Hellebrekers BW, Trimbos-Kemper GC, Bakkum EA, ‘Trimbos B, Declerck P, KooistraT eal. Short-term effect of surgical trauma on rat peritoneal fibrinolytic activity and its role in adhesion formation. Thromb Haemost 2000; 84: 876-881 59 Whawell SA, Vipond MN, Scott-Coombes DM, ‘Thompson JN. Plasminogen activator inhibitor 2 reduces peritoneal fibrinolytic activity in inflammation. Br 7 Surg 1993; 80: 107-109, 60 olmdab L, Eriksson F, al-Jabreen M, Risberg B. Fibrinolysis in human peritoneum during operation. Surgery 1996; 119: 701-705. Ince A, Eroglu A, Tarhan O, Bilbil M. Peritoneal fibrinolytic activity in peritonitis. Am 7 Surg 2002; 183 7-0. 62 Darr PJ, Brommer EJP, Dooijewaard G, Verner HIM. Peritoneal fad and plasma fibrinolytic activity in women with pelvic inflammatory disease. Thromb Haemact 1992; 68 102-108. 63 van Goor, Bom VJ, van der Meer J, Shuiter W5, Bleichrode RP, Coagulation and fibrinolytic responses of human peritoneal fluid and plasma to bacterial peritonitis Br J Surg 1996, 83: 11331135. 64 Ballstam G, Lecander I, Larsson B. Fibrinolysis in che peritoneal fid during adhesions, endometriosis and ongoing pelvic inflammatory disease. Inflammation 199%; 22: 341-351, 65 Scort-Coombes DM, Whawell SA, Thompson JN. The operative peritoneal fibrinolytic response to abdominal operation, Eur Surg 1995; 161: 395-399. 8 6 wwwbjsco.ok British Journal of Surgery 2011 98: 1503-1516Pathogenesis of postoperative adhesion formation 66 varsson ML, Bergstrm M, Eriksson E, Risberg B, Holmdahl L. Tissue markers as predictors of postoperative adhesions. Br 7 Surg 1998; 85: 1549-1554 67. Bergstrdm M, Ivarsson ML, Holmdahl L. Peritoneal response to pneumoperitoneum and laparoseopie surgery. Br J Surg 2002; 89: 1465-1469, 68 Neudecker J, Junghans T, Ziemer S, Raue W, Schwenk W. Elec of laparoscopic and conventional colorectal resection ‘on peritoneal ibrinlytie capacity: prospective randomized clinical wal Int J Calretl Dis 20025 17: 426-429. 69 Brokelman WJ, Holmdahl L, Bergstrom M, Falk P, Klinkenbij JH, Reiinen MM. Peritoneal fbrinolyic response to various aspects of laparoscopic surgery: a randomized til. J Surg Res 2006; 136: 309-313 70 Brokelman WJ, Holmdaht L, Janssen IM, Falk P, Bergstrom M, Klinkenbij JH er al, Decreased peritoneal tissue plasminogen activator during prolonged laparoscopic surgery. 7 Surg Res 2009; 151: 89-93. Holmdshl L. The role of fibrinolysis in adhesion formation. Eur J Surg 1997; $77: 24-31, 72 Scott-Coombes DM, Whawell SA, Vipond MN, ‘Thompson JN. Human intraperitoneal fibrinolytic response to elective surgery. Br 7 Surg 1995; 82: 414-417 73 larson ML, Falk P, Holmdahl L, Response of visceral, peritoneum to abdominal surgery. Br 7 Surg 2001; 88: 148-151. 74 Hellebrekers BWJ, Emeis IJ, KooistraT, Trimbos JB, ‘Moore NR, Zwinderman AH etal. role forthe fibrinolye system in adhesion formation. Fertil Steril 2005; 83: 122-129, 15 Hellebrekers BW], Trimbos-Kemper TC, Boesten L, Jansen FW, Kolkman W, TTrimbos JB et al. Preoperative predictors of postsurgical adhesion formation and the Prevention of Adhesions with Plasminogen Activator (PAPA-study results ofa clinical piloe study. Feri Steril 2009; 91: 1204-1214 76 Emeis J, van den Eijnden-Schrauwen Y, van den Hloogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue type plsrninogen activator. 7 Cll Bal 1997; 139: 245-256, 77 Lépee Y, Piramo JA, Valenti JR, Pardo F, Montes R, Rocha E. Hemostatie markers in surgery: a diferent fibrinolytic activity may be of pathophysiologieal significance in orthopedie vers abdominal surgery. Int 7 (Glin Lab Res 1997; 27: 233-237, 78 Siemens H), Brueckner S, Hagelberg S, Wagner T, Schmucker P. Course of molecular hemostatic markers, ring and afer different surgical procedures. 7 Clin Anesth 1999; 11: 622-629. 79 Schietroma M, Carlei F, Mownah A, Franchi Ly Mazzorta C, Sorio A et a Changes in the blood coagulation, fibrinolysis, and eytokine profile during laparoscopic and open cholecystectomy. Strg Endosc 2004; 18: 1090-1096. 80 DiamantisT, ‘Tsiminikakis N, Skordylaki A, Samioraki F, VernadakisS, Bongiorni eta. Alterations of hemostasis 1 (©2011 Bebis Journal of Surgery Soviet Led Pablo by John Wily & Sons Lad 1515, afer laparoscopic and open surgery. Hematology 2007; 12: 561-570. D'Angelo A, KluftC, Verheien JH, Rijken DC, Mozzi E, Mannueci PM. Fibsinolyic shut-down after surgery: impairment of the balance between tssue-type plasminogen activator and is specific inhibitor. Eur 7 Clin Invest 1985; 15: 308-312. 82 Levi M, van der Poll T. Two-way interaetions between inflammation and coagulation. Trends Cardiovae Med 2005; 15: 254-259, 83 Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiounse Res 2003; 60: 26-38. ‘84 Dobbie JW. Pathogenesis of peritoneal fibrosing syndromes (sclerosing peritonitis) in peritoneal dialysis Perit Dial Ine 1992; 12: 14-27. 85 Coles GA, Williams JD, Topley N. Peritoneal inflammation and long-term changes in peritoneal structure and fanetion. In Tetbok of Peritoneat Dias, Glokal R, Khanna R, Krediet RT, Nolph KD (eds). Kluwer Academic Publishers: Dordrecht, 2000; 565-583. 86 Haslinger B, Kleemann R, Toet KH, Kooistra T. Simvastatin suppresses tissue factor expression and increases fibrinolytic activity in tumor necrosis factor-a-activated hhuman peritoneal mesothelial cells. Kidney Int 2003; 63: 2065-2074. 87 Camerer E, Kolsto AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thramb Res 1996, 81: 1-41. £88 Boldt, Hitiner I, Suter S, Kumle B, Piper SN, Berchthold G. Changes of haemostasis in patents ‘undergoing msjor abdominal surgery ~ is there a difference bbeeween elderly and younger patient? Br 7 Anaesth 2001; 87: 435440, 89 Ridker PM, Danielson E, Fonseea FA, Genest J, Gotto AM Jr, Kastelein J eal; JUPITER Study Group. Roswvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Eng! 7 Med 2008; 359: 2195~2207. 90 Lee KW, Lip GY. Effets of lifestyle on hemostasis, fibrinolysis, and plaelee reactivity: a systemati review. Arch Intern Med 2003; 163: 2368-2392 Lijnen HR. Role of fibrinolysis in obesity and thrombosis Toromb Res 2009; 123(Supp 4): S46-S49. 92 Kluft C, Lansink M. Effect of oral contraceptives on haemostasis variables. Thromb Haemost 19975 78: 315~326. 93 Eilertsen AL, Sandvik L, Mowinckel MC, Andersen TO, Quigstad E, Sandset PM. Differential effects of ‘conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis. Thromb Res 2007; 120: 371~379. ‘94 Saco Y, Kaji M, Metoki N, Yoshida H, Satoh K. Coagulation fibrinolysis abnormalities inpatients receiving antiparkinsonian agents. J Newol ci 2003; 212: 55-58. 95 Hemelaar M, van der Mooren MJ, Rad M, KlufeC, Kenemans P. Effects of non-oral postmenopausal hormone 8 9 wow.bjco.uk Britis Journal of Surgery 2011; 98: 1503-15161516 therapy on markers of cardiovascular risk: a systematic review. Fertil Steril 2008; 90: 642-672. 96 Levi M, Nieuwdorp M, van der Poll T, Stroes E. Metabolic ‘modulation of inflammation-induced activation of coagulation. Semin Thromb Hemart 2008; 34: 26-32. 97 Grant PJ. Diabetes mellitus asa prothrombotic condition. 7 Intern Med 2007; 262: 157-172. 98 Darr PJ, Brommer EJ, Dooijewzard G, Vener HM. Parameters of fibrinolysis in peritoneal uid and plasma in diferene stages ofthe menstrual cycle. Thromb Hacmast 1993; 70: 873-875. 99 Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000. 100 Modrau Il, Iversen LL, Thorlacius-Ussing OO. Hemostatic alterations in patients with benign and malignant colorectal disease during msjor abdominal surgery. Toromb Res 2001; 104: 309-315. 101 Iversen LH, Okholm M, Thorlacius-Ussing O. Pre- and postoperative tate of coagulation and fibrinolysis in plasma ‘of patients with benign and malignant colorectal disease ~a preliminary study. Thromb Haemost 1996; 76: 523-528. 102 Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: implications forthe pathogenesis of acute coronary syndromes. Thromb Res 2007; 120: 819-847, Heligren M. Hemostasis during normal pregnancy and ‘puerperium. Semin Thromb Hemest 2003; 29: 125~130. 104 Rosenfeld BA, Beattie C, Christopherson R, Norris EJ, Frank SM, Breslow MJ eral. The effects of different anesthetic regimens on fibrinolysis and the development of postoperative arterial thrombosis, Perioperative Ischemia Randomized Anesthesia Trial Seudy Group. Anesthesiology 1993; 79: 435-443. 105 Levy JH. Massive transfsion coagulopathy. Semin Hematal 2006; 43(Suppl 1): $59-S63. 106 Lundorff P, Hahlin M, Kallfele B, Thorburn J, Lindblom B. ‘Adhesion formation after laparoscopic surgery in tubal 10: (©2011 Bris Journal of Surgery Socesy Li Published by John Wiley Sons Lad B..W. J. Hellebrekors and T. Kooistra pregnancy: a randomized wal tern laparotomy. Fert Ste 1991; $5: 911-915. 107 Boys F. The profjaxs of peritoneal adhesions. A review of the literature, Surgery 1942; LH: 118-168, 108 Hellebrekers BW}, Trimbos-Kemper GCM, TrimbosB, Eneis J, KooistraT. Use of fibrinolytic agents inthe prevention of postsurgical adhesion formation. Fertil Steril 2000; 74 203-212. 109 Prasad K. C-reactive protein (CRP)-lowering agents, Cardiosate Drug Reo 2006; 24: 33-50. 110 Mora, Ridker PM, Justification for the use of statins in primary prevention: an intervention tril evaluating rosuvasatin JUPITER) ~can C-reactive protein be used to target statin therapy in primary prevention? dm 7 Cardi 2006; 97: 3A~41A, Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as aninflaramatory agents? Cirsuaron 200%; 109(Suppl I) mi8-126. 112 Keysiak R, Okopies B, Herman ZS, Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolytic processes. Drugs 2003; 63: 1821-1854. 113 Haslinger B, Goedde MF, Toet KH, KooiseaT. Simvastatin increases fibrinolytic activity in human petitoneal mesothelial cells independent of cholesterol lowering. Kidney Int 2002; 62: 1611-1619. 114 Aarons CB, Cohen PA, Gower A, Reed KL, Leeman SE, Stucchi AF er al. Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic atvity. Aw Surg 2007; 245 176-184. 115 Kucuk HF, Kaptanoglu L, KureN, Uaun H, Eser M, BingulS ea. The role of simvastatin on portoperative peritoneal adhesion formation in an animal model. Bur rg Res 2007; 39: 98-102. 116 Yilmaz B, Aksakal O, Gungor T, Sirvan L, SutN, Keleke $ tal. Metformin and atorvastatin reduce adhesion formation ina rauterine horn model. Rerad Biomed Online 200 18 436-442. n worw.bjseo.uk British Journal of Surgery 2011; 98: 1503-1516