TY - JOUR
AU - Kooistra, T
AB - Abstract Background 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 original articles on the pathogenesis of adhesion formation. Information was sought on the role of the fibrinolytic, coagulatory and inflammatory systems in the disease process. Results One unifying concept emerged when assessing 50 years of studies in animals and humans on the pathogenesis of adhesion formation. Peritoneal damage inflicted by surgical trauma or other insults evokes an inflammatory response, thereby promoting procoagulatory and antifibrinolytic reactions, and a subsequent significant increase in fibrin formation. Importantly, peritoneal inflammatory status seems a crucial factor in determining the duration and extent of the imbalance between fibrin formation and fibrin dissolution, and therefore in the persistence of fibrin deposits, determining whether or not adhesions develop. Conclusion Suppression of inflammation, manipulation of coagulation as well as direct augmentation of fibrinolytic activity may be promising antiadhesion treatment strategies. Introduction Intra-abdominal adhesions are a major cause of human illness1. Triggers of adhesion formation include inflammation, endometriosis, chemical peritonitis, radiotherapy, foreign body reaction and continuous ambulatory peritoneal dialysis, but the majority of adhesions are induced by surgery1. Depending on the location and structure of an adhesion, it may remain ‘silent’ or cause pathological complications. These may be as serious as life-threatening intestinal occlusion, with an associated mortality rate ranging from 4·3 to 13 per cent2. Pelvic adhesions may also cause chronic pelvic pain and are the leading cause of secondary infertility in women, being responsible for 22 per cent of cases3,4. Furthermore, the presence of adhesions during surgery may result in longer operating times and an increase in complications, both immediately and for up to 10 years later. Up to 34 per cent of surgical patients are readmitted to hospital for a condition directly or possibly related to adhesions5,6. 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 assessment. A widely accepted concept is that adhesions are formed as a result of a postoperative reduction in peritoneal fibrinolytic activity. According to this theory, known as the ‘classical concept of adhesion formation’7–9, reduction in fibrinolytic activity permits deposited fibrin to become organized into fibrous, permanent adhesions. In this review, half a century of research on the pathogenesis of adhesion formation was 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 peritoneum. 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 hand-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 of the 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 pericardium, the most extensive serous membrane in the body. It serves to minimize friction between abdominal viscera, thereby enabling their free movement. It also stores fat, especially in the greater omentum10. With a surface area that is generally equal to that of the skin, this membrane may be the largest organ in humans11. The visceral peritoneum accounts for about 80 per cent 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 mesothelial 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 connective tissue that comprises a gel-like matrix containing a loose network of collagenous and elastic fibres, scattered fibroblasts, macrophages, mast cells and a varying number of fat cells12. This layer also contains the peritoneal capillaries and some lymphatics, which give rise to a rich capillary network that functions as a ‘dialyser’ and barrier for peritoneal transport of water and solutes13. 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 to trauma14. Minimal mobilization or damage to the peritoneum can result in denudation of peritoneal surfaces, which can trigger the formation of adhesions15. Another unique property of the peritoneum is its uniform, relatively rapid rate of surface re-mesothelialization after trauma. Irrespective of the size of injury, peritoneal re-mesothelialization is complete within 5–7 days16. 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 wounds14,15. Fibrinolytic 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 a 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 to adhesion development. Hypoxia induces the conversion of fibroblasts with a normal 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 matrix remodelling process of healing17,18. Fibrin formation is the result of activation of the coagulation cascade. Fibrin is formed during haemostasis, inflammation and tissue repair. Activation of the coagulation system can occur via several pathways and results in the generation of thrombin (factor IIa) from prothrombin (factor II). The formation of thrombin then triggers conversion of fibrinogen into fibrin monomers that interact with one another and polymerize forming a fibrin clot. At the level of thrombin, activation of coagulation is inhibited by antithrombin III, which neutralizes thrombin. 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 fibrin 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 products (FbDPs)19,20. The primary physiological inhibitor of plasmin is α2-antiplasmin, which has a high affinity for plasmin and is fast acting21. Besides inhibition of plasmin, it also prevents premature lysis of the fibrin clot by binding to plasminogen and cross-linking to fibrin, thereby interfering with the binding of plasmin and plasminogen to fibrin during the coagulation process22,23. Fig. 1 Open in new tabDownload slide Main interactions between the inflammatory, coagulatory and fibrinolytic systems that play a role in the pathogenesis of adhesions. tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; PAI, plasminogen activator inhibitor; AT, antithrombin 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 macrophages8. Acute release of tPA from endothelial cells is assumed to be induced by various stimuli, such as exercise, venous occlusion, hypercoagulability, histamine and some vasoactive drugs. tPA has a high affinity for fibrin, which strikingly enhances its activity, thereby strongly promoting the conversion of inactive plasminogen into active plasmin. In the absence of fibrin, tPA is a relatively poor activator of plasminogen24. Consequently, plasmin formation is greatest where it is required, namely at the fibrin clot, while systemic activation of plasminogen is prevented. First isolated from human urine25, uPA has since been isolated from a number of tissues including kidney, lung, placenta, bladder, epidermal cells, fibroblasts and macrophages26,27. 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 plasminogen28,29. The main role of uPA appears to be in the induction of extracellular proteolytic mechanisms, resulting in increased vascular permeability, cellular migration, tumour invasion and tissue remodelling30,31. Besides α2-antiplasmin, inhibitors of plasminogen activator also play an important role in the regulation of fibrinolysis32. Plasminogen activator inhibitor (PAI) 1 is a powerful and the most important inhibitor of tPA and uPA33,34. It is produced and released by a variety of cells including endothelial cells, mesothelial cells, macrophages, platelets and fibroblasts. Production and 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)35–37. Production and release is also enhanced after surgery and inflammation, and PAI-1 appears to be an acute-phase reactant protein38. Plasminogen activators are rapidly inactivated by PAI-1, by forming inactive tPA–PAI-1 and uPA–PAI-1 complexes39. PAI-2 was first isolated from human placenta40 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-141, and an important role in the normal regulation of the fibrinolytic system has not been established. Effect of peritoneal trauma on peritoneal fibrinolysis in experimental studies The idea that normal peritoneum possesses intrinsic fibrinolytic activity that prevents the formation of adhesions was firstly postulated by Hartwell in 195542. Evidence for such intrinsic fibrinolytic activity of the peritoneum was initially presented by Von Benzer and colleagues43 in 1963, and later confirmed by Myhre-Jensen and co-workers44 and Gervin et al.45. 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 trauma46–52. Notably, in all of these studies peritoneal trauma resulted in adhesion formation and a concomitant reduction of fibrinolytic activity in peritoneal biopsies, independent of the animal model used or 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 adhesions51,53. 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 concept54–58. In an evaluation of the peritoneal fibrinolytic activity and extent of adhesion formation in a rat model, Bakkum and co-workers54 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 colleagues55 investigated the time course of peritoneal tPA 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 animals56,57. A second point of concern is that most studies measured fibrinolytic parameters alone, without considering coagulation parameters. In a study by the authors' research group, using the same rat model as described by Bakkum et al.54, peritoneal plasminogen activator activity was analysed immediately after surgery, and 2, 4, 8, 16, 24 and 72 h later58. In contrast to the classical concept, tPA activity remained unchanged or slightly increased after surgical trauma. The results pointed to increased fibrin formation rather than diminished fibrinolytic activity as the main 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 biopsies42–55 and those that performed measurements in peritoneal fluid56–58. 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 seen. 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 fluid58. In this study, fibrinolytic parameters were analysed immediately, and 2, 4, 8, 16, 24 and 72 h after surgery in rats. In peritoneal fluid, tPA antigen concentrations were increased significantly at all postoperative time points; fibrinolytic activity steadily rose after surgery, being increased significantly after 24 h. Fibrinolytic activity also increased significantly in peritoneal biopsies with time after surgery. FbDPs were present at all time intervals, pointing to ongoing fibrinolysis, whereas adhesions were found from 2 h onwards. 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 reductions in plaminogen activator activity during ischaemia and inflammation were described7. Since then, several investigators have studied the peritoneal fibrinolytic response during inflammation (Table 1). Vipond and colleagues8 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-1. These findings were later confirmed by others59–61. Table 1 Studies on the peritoneal fibrinolytic response during inflammation in humans measured in peritoneal biopsies and peritoneal fluid . . Parameters measured . . Reference . Year . Antigen . Activity . Measured changes . Peritoneal biopsies  Thompson et al.7 1989 — PAA PAA ↓  Vipond et al.8 1990 tPA, uPA, PAI-1, α2-antiplasmin PAA PAA ↓, PAI-1 ↑  Whawell et al.59 1993 tPA, PAI-1, PAI-2 PAA PAI-1 ↑, PAI-2 ↑, PAA ↓  Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 PAA ↓  Ince et al.61 2002 tPA, uPA, PAI-1, PAI-2, tPA–PAI complex — tPA ↓, uPA ↑, PAI-1 ↑, PAI-2 ↑, tPA–PAI complex ↑ Peritoneal fluid  Dörr et al.62 1992 tPA, uPA, PAI-1, TDP, FbDPs tPA tPA ↑, uPA ↑, PAI-1 ↑↑, TDPs ↑↑, FbDPs ↑↑, tPAA ↔  van Goor et al.63 1996 tPA, uPA, PAI-1, FbDPs — tPA ↑, uPA ↑, PAI-1 ↑↑, FbDPs ↑  Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 — tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ . . Parameters measured . . Reference . Year . Antigen . Activity . Measured changes . Peritoneal biopsies  Thompson et al.7 1989 — PAA PAA ↓  Vipond et al.8 1990 tPA, uPA, PAI-1, α2-antiplasmin PAA PAA ↓, PAI-1 ↑  Whawell et al.59 1993 tPA, PAI-1, PAI-2 PAA PAI-1 ↑, PAI-2 ↑, PAA ↓  Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 PAA ↓  Ince et al.61 2002 tPA, uPA, PAI-1, PAI-2, tPA–PAI complex — tPA ↓, uPA ↑, PAI-1 ↑, PAI-2 ↑, tPA–PAI complex ↑ Peritoneal fluid  Dörr et al.62 1992 tPA, uPA, PAI-1, TDP, FbDPs tPA tPA ↑, uPA ↑, PAI-1 ↑↑, TDPs ↑↑, FbDPs ↑↑, tPAA ↔  van Goor et al.63 1996 tPA, uPA, PAI-1, FbDPs — tPA ↑, uPA ↑, PAI-1 ↑↑, FbDPs ↑  Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 — tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ ↓, Decrease; ↑, increase; ↔, no change. PAA, plasminogen-activating activity; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; TDP, total degradation product; FbDP, fibrin degradation product. Open in new tab Table 1 Studies on the peritoneal fibrinolytic response during inflammation in humans measured in peritoneal biopsies and peritoneal fluid . . Parameters measured . . Reference . Year . Antigen . Activity . Measured changes . Peritoneal biopsies  Thompson et al.7 1989 — PAA PAA ↓  Vipond et al.8 1990 tPA, uPA, PAI-1, α2-antiplasmin PAA PAA ↓, PAI-1 ↑  Whawell et al.59 1993 tPA, PAI-1, PAI-2 PAA PAI-1 ↑, PAI-2 ↑, PAA ↓  Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 PAA ↓  Ince et al.61 2002 tPA, uPA, PAI-1, PAI-2, tPA–PAI complex — tPA ↓, uPA ↑, PAI-1 ↑, PAI-2 ↑, tPA–PAI complex ↑ Peritoneal fluid  Dörr et al.62 1992 tPA, uPA, PAI-1, TDP, FbDPs tPA tPA ↑, uPA ↑, PAI-1 ↑↑, TDPs ↑↑, FbDPs ↑↑, tPAA ↔  van Goor et al.63 1996 tPA, uPA, PAI-1, FbDPs — tPA ↑, uPA ↑, PAI-1 ↑↑, FbDPs ↑  Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 — tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ . . Parameters measured . . Reference . Year . Antigen . Activity . Measured changes . Peritoneal biopsies  Thompson et al.7 1989 — PAA PAA ↓  Vipond et al.8 1990 tPA, uPA, PAI-1, α2-antiplasmin PAA PAA ↓, PAI-1 ↑  Whawell et al.59 1993 tPA, PAI-1, PAI-2 PAA PAI-1 ↑, PAI-2 ↑, PAA ↓  Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 PAA ↓  Ince et al.61 2002 tPA, uPA, PAI-1, PAI-2, tPA–PAI complex — tPA ↓, uPA ↑, PAI-1 ↑, PAI-2 ↑, tPA–PAI complex ↑ Peritoneal fluid  Dörr et al.62 1992 tPA, uPA, PAI-1, TDP, FbDPs tPA tPA ↑, uPA ↑, PAI-1 ↑↑, TDPs ↑↑, FbDPs ↑↑, tPAA ↔  van Goor et al.63 1996 tPA, uPA, PAI-1, FbDPs — tPA ↑, uPA ↑, PAI-1 ↑↑, FbDPs ↑  Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 — tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ ↓, Decrease; ↑, increase; ↔, no change. PAA, plasminogen-activating activity; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; TDP, total degradation product; FbDP, fibrin degradation product. Open in new tab Peritoneal fibrinolytic response during inflammation measured in peritoneal fluid Several investigators who measured fibrinolytic activity and concentrations of fibrinolytic parameters in peritoneal fluid reached conclusions that differed from findings in peritoneal biopsies62–64. Dörr et al.62 measured fibrinolytic parameters in the peritoneal fluid of women with pelvic inflammatory disease and found a highly significant rise in FbDPs compared with controls, concluding that fibrinolysis occurred at a higher rate, despite concomitant production of PAI. Similarly, van Goor and colleagues63 reported that, despite markedly raised concentrations of PAI, peritoneal fluid displayed fibrinolytic activity in patients with bacterial peritonitis, as demonstrated by significantly increased concentrations of plasmin–α2-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 obtaining samples during the postoperative period, most studies in humans have been restricted to the perioperative sampling of biopsies or peritoneal fluid (Table 2). Scott-Coombes and colleagues65 investigated the peritoneal fibrinolytic response to surgery by taking peritoneal biopsies at the beginning and end of surgery. Elective surgery caused an immediate reduction 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 surgery60,66,71. More recently, several investigators studied the difference in the fibrinolytic response to surgery between laparoscopy and laparotomy67–70. Perioperative tPA activity decreased in all types of surgery, except for the short-time laparoscopy group (Table 2). Overall, however, there were no significant differences in fibrinolytic responses between laparoscopy and laparotomy67,68. Table 2 Studies on the fibrinolytic response to surgery in peritoneal biopsies in humans taken at the beginning and end of surgery . . Parameters measured . . . . . . Timing of samples/type . Measured periop. and . . Reference . Year . Antigen . Activity . of surgery . postop. changes . Scott-Coombes et al.65 1995 tPA, PAI-1, PAI-2 PAA Beginning and end of surgery PAA ↓, tPA ↓, PAI-1 + PAI-2 not detectable Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 Beginning and end of surgery PAA ↓, PAI-1 not detectable Ivarsson et al.66 1998 tPA, uPA, PAI-1, tPA–PAI complex tPAA Beginning and end of surgery PAI-1 ↑, tPAA ↓, tPA–PAI complex ↑ Bergström et al.67 2002 tPA, PAI-1 tPAA Beginning and end of surgery tPA ↓, PAI-1 ↑, tPAA ↓ Laparoscopy versus laparotomy Similar response Neudecker et al.68 2002 tPA, PAI-1, tPA–PAI complex tPAA, PAI-1 Beginning and end of surgery tPAA ↓, tPA ↔, PAI-1 ↔, tPA–PAI complex ↔ Laparoscopy versus laparotomy Similar response Brokelman et al.69 2006 tPA, uPA, PAI-1 tPAA Beginning and end of short laparoscopy tPA ↔, uPA ↔, PAI-1 ↔, tPAA ↔ Brokelman et al.70 2009 tPA, uPA, PAI-1 tPAA Beginning and end of prolonged laparoscopic surgery tPA ↓, uPA ↔, PAI-1 ↔,  tPAA ↓ . . Parameters measured . . . . . . Timing of samples/type . Measured periop. and . . Reference . Year . Antigen . Activity . of surgery . postop. changes . Scott-Coombes et al.65 1995 tPA, PAI-1, PAI-2 PAA Beginning and end of surgery PAA ↓, tPA ↓, PAI-1 + PAI-2 not detectable Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 Beginning and end of surgery PAA ↓, PAI-1 not detectable Ivarsson et al.66 1998 tPA, uPA, PAI-1, tPA–PAI complex tPAA Beginning and end of surgery PAI-1 ↑, tPAA ↓, tPA–PAI complex ↑ Bergström et al.67 2002 tPA, PAI-1 tPAA Beginning and end of surgery tPA ↓, PAI-1 ↑, tPAA ↓ Laparoscopy versus laparotomy Similar response Neudecker et al.68 2002 tPA, PAI-1, tPA–PAI complex tPAA, PAI-1 Beginning and end of surgery tPAA ↓, tPA ↔, PAI-1 ↔, tPA–PAI complex ↔ Laparoscopy versus laparotomy Similar response Brokelman et al.69 2006 tPA, uPA, PAI-1 tPAA Beginning and end of short laparoscopy tPA ↔, uPA ↔, PAI-1 ↔, tPAA ↔ Brokelman et al.70 2009 tPA, uPA, PAI-1 tPAA Beginning and end of prolonged laparoscopic surgery tPA ↓, uPA ↔, PAI-1 ↔,  tPAA ↓ ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; uPA, urokinase plasminogen activator. Open in new tab Table 2 Studies on the fibrinolytic response to surgery in peritoneal biopsies in humans taken at the beginning and end of surgery . . Parameters measured . . . . . . Timing of samples/type . Measured periop. and . . Reference . Year . Antigen . Activity . of surgery . postop. changes . Scott-Coombes et al.65 1995 tPA, PAI-1, PAI-2 PAA Beginning and end of surgery PAA ↓, tPA ↓, PAI-1 + PAI-2 not detectable Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 Beginning and end of surgery PAA ↓, PAI-1 not detectable Ivarsson et al.66 1998 tPA, uPA, PAI-1, tPA–PAI complex tPAA Beginning and end of surgery PAI-1 ↑, tPAA ↓, tPA–PAI complex ↑ Bergström et al.67 2002 tPA, PAI-1 tPAA Beginning and end of surgery tPA ↓, PAI-1 ↑, tPAA ↓ Laparoscopy versus laparotomy Similar response Neudecker et al.68 2002 tPA, PAI-1, tPA–PAI complex tPAA, PAI-1 Beginning and end of surgery tPAA ↓, tPA ↔, PAI-1 ↔, tPA–PAI complex ↔ Laparoscopy versus laparotomy Similar response Brokelman et al.69 2006 tPA, uPA, PAI-1 tPAA Beginning and end of short laparoscopy tPA ↔, uPA ↔, PAI-1 ↔, tPAA ↔ Brokelman et al.70 2009 tPA, uPA, PAI-1 tPAA Beginning and end of prolonged laparoscopic surgery tPA ↓, uPA ↔, PAI-1 ↔,  tPAA ↓ . . Parameters measured . . . . . . Timing of samples/type . Measured periop. and . . Reference . Year . Antigen . Activity . of surgery . postop. changes . Scott-Coombes et al.65 1995 tPA, PAI-1, PAI-2 PAA Beginning and end of surgery PAA ↓, tPA ↓, PAI-1 + PAI-2 not detectable Holmdahl et al.60 1996 PAI-1 PAA, PAI-1 Beginning and end of surgery PAA ↓, PAI-1 not detectable Ivarsson et al.66 1998 tPA, uPA, PAI-1, tPA–PAI complex tPAA Beginning and end of surgery PAI-1 ↑, tPAA ↓, tPA–PAI complex ↑ Bergström et al.67 2002 tPA, PAI-1 tPAA Beginning and end of surgery tPA ↓, PAI-1 ↑, tPAA ↓ Laparoscopy versus laparotomy Similar response Neudecker et al.68 2002 tPA, PAI-1, tPA–PAI complex tPAA, PAI-1 Beginning and end of surgery tPAA ↓, tPA ↔, PAI-1 ↔, tPA–PAI complex ↔ Laparoscopy versus laparotomy Similar response Brokelman et al.69 2006 tPA, uPA, PAI-1 tPAA Beginning and end of short laparoscopy tPA ↔, uPA ↔, PAI-1 ↔, tPAA ↔ Brokelman et al.70 2009 tPA, uPA, PAI-1 tPAA Beginning and end of prolonged laparoscopic surgery tPA ↓, uPA ↔, PAI-1 ↔,  tPAA ↓ ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; uPA, urokinase plasminogen activator. Open in new tab Peritoneal fibrinolytic response to surgery measured in peritoneal fluid Before the turn of the millennium, only two clinical studies were available that examined the fibrinolytic response to surgery in peritoneal fluid64,65,72 (Table 3). In one study, peritoneal fluid was collected at several time points after surgery by use of an abdominal drain65. A significant reduction in plasminogen activator activity was found after surgery, reaching undetectable levels at 24 h, which was sustained at 48 h. Again, it was concluded 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 concept became more generally accepted. There also appeared to be a biphasic response to trauma by the peritoneum. Table 3 Studies on the fibrinolytic response to surgery in peritoneal fluid in humans Reference . Year . Parameters measured . Timing of samples after peritoneal trauma/type of surgery . Measured postop. changes . Scott-Coombes et al.65,72 1995 tPA, PAI-1, PAI-2, PAA 2 and 6 h PAA ↓, tPA ↓, PAI-1 ↑, PAI-2 ↑ 24 h PAA not detectable, tPA ↓, PAI-1 ↑, PAI-2 ↑ 48 h PAA not detectable, tPA ↑, PAI-1 ↑, PAI-2 ↑↑ Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 1 week tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ Ivarsson et al.73 2001 tPA, uPA, PAI-1, tPAA Beginning and end of surgery tPA ↑, tPAA ↑, uPA ↔,  PAI-1 ↔ Neudecker et al.68 2002 tPA, PAI-1, tPAA, PAI-1 activity, tPA–PAI complex Laparoscopy versus laparotomy 2 h tPA activity ↓ in laparoscopy group; PAI-1 ↑, PAI-1 activity ↑, tPA activity ↓ in both groups 6 h No differences between groups 24 h No differences between groups Hellebrekers et al.74 2005 tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week TAT complex and uPA ↔, all other factors significantly ↑ Hellebrekers et al.75 2009 tPA, PAI-1, FbDPs 1 week tPA ↑, PAI-1 ↑, FbDPs ↑ Reference . Year . Parameters measured . Timing of samples after peritoneal trauma/type of surgery . Measured postop. changes . Scott-Coombes et al.65,72 1995 tPA, PAI-1, PAI-2, PAA 2 and 6 h PAA ↓, tPA ↓, PAI-1 ↑, PAI-2 ↑ 24 h PAA not detectable, tPA ↓, PAI-1 ↑, PAI-2 ↑ 48 h PAA not detectable, tPA ↑, PAI-1 ↑, PAI-2 ↑↑ Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 1 week tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ Ivarsson et al.73 2001 tPA, uPA, PAI-1, tPAA Beginning and end of surgery tPA ↑, tPAA ↑, uPA ↔,  PAI-1 ↔ Neudecker et al.68 2002 tPA, PAI-1, tPAA, PAI-1 activity, tPA–PAI complex Laparoscopy versus laparotomy 2 h tPA activity ↓ in laparoscopy group; PAI-1 ↑, PAI-1 activity ↑, tPA activity ↓ in both groups 6 h No differences between groups 24 h No differences between groups Hellebrekers et al.74 2005 tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week TAT complex and uPA ↔, all other factors significantly ↑ Hellebrekers et al.75 2009 tPA, PAI-1, FbDPs 1 week tPA ↑, PAI-1 ↑, FbDPs ↑ ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; uPA, urokinase plasminogen activator; FbDP, fibrin degradation product; PAP, plasmin–antiplasmin complex; TAT, thrombin–antithrombin. Open in new tab Table 3 Studies on the fibrinolytic response to surgery in peritoneal fluid in humans Reference . Year . Parameters measured . Timing of samples after peritoneal trauma/type of surgery . Measured postop. changes . Scott-Coombes et al.65,72 1995 tPA, PAI-1, PAI-2, PAA 2 and 6 h PAA ↓, tPA ↓, PAI-1 ↑, PAI-2 ↑ 24 h PAA not detectable, tPA ↓, PAI-1 ↑, PAI-2 ↑ 48 h PAA not detectable, tPA ↑, PAI-1 ↑, PAI-2 ↑↑ Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 1 week tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ Ivarsson et al.73 2001 tPA, uPA, PAI-1, tPAA Beginning and end of surgery tPA ↑, tPAA ↑, uPA ↔,  PAI-1 ↔ Neudecker et al.68 2002 tPA, PAI-1, tPAA, PAI-1 activity, tPA–PAI complex Laparoscopy versus laparotomy 2 h tPA activity ↓ in laparoscopy group; PAI-1 ↑, PAI-1 activity ↑, tPA activity ↓ in both groups 6 h No differences between groups 24 h No differences between groups Hellebrekers et al.74 2005 tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week TAT complex and uPA ↔, all other factors significantly ↑ Hellebrekers et al.75 2009 tPA, PAI-1, FbDPs 1 week tPA ↑, PAI-1 ↑, FbDPs ↑ Reference . Year . Parameters measured . Timing of samples after peritoneal trauma/type of surgery . Measured postop. changes . Scott-Coombes et al.65,72 1995 tPA, PAI-1, PAI-2, PAA 2 and 6 h PAA ↓, tPA ↓, PAI-1 ↑, PAI-2 ↑ 24 h PAA not detectable, tPA ↓, PAI-1 ↑, PAI-2 ↑ 48 h PAA not detectable, tPA ↑, PAI-1 ↑, PAI-2 ↑↑ Edelstam et al.64 1998 tPA, uPA, PAI-1, PAI-2 1 week tPA ↑, uPA ↑, PAI-1 ↑, PAI-2 ↑ Ivarsson et al.73 2001 tPA, uPA, PAI-1, tPAA Beginning and end of surgery tPA ↑, tPAA ↑, uPA ↔,  PAI-1 ↔ Neudecker et al.68 2002 tPA, PAI-1, tPAA, PAI-1 activity, tPA–PAI complex Laparoscopy versus laparotomy 2 h tPA activity ↓ in laparoscopy group; PAI-1 ↑, PAI-1 activity ↑, tPA activity ↓ in both groups 6 h No differences between groups 24 h No differences between groups Hellebrekers et al.74 2005 tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week TAT complex and uPA ↔, all other factors significantly ↑ Hellebrekers et al.75 2009 tPA, PAI-1, FbDPs 1 week tPA ↑, PAI-1 ↑, FbDPs ↑ ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; (t)PAA, (tissue) plasminogen-activating activity; uPA, urokinase plasminogen activator; FbDP, fibrin degradation product; PAP, plasmin–antiplasmin complex; TAT, thrombin–antithrombin. Open in new tab It was postulated that the 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 increase in PAI-1 and PAI-2 concentrations. The 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 extent72. In another study, Edelstam and co-workers64 collected peritoneal fluid during a second-look laparoscopy 1 week after laparotomy with adhesiolysis. In contrast to the findings of Scott-Coombes and colleagues, the fibrinolytic system was still fully active 1 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 surgery74,75. The discrepancy between results for peritoneal biopsies and peritoneal fluid from several studies might be explained by the acute release of tPA from mesothelial cells into the peritoneal cavity during inflammation or trauma. This idea was addressed by Ivarsson et al.73, 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 in the 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 described76 and inflammation or trauma might trigger the release of tPA from such stores, thus explaining the discrepancy in results from several studies which differed in the timing of biopsies (taken at the beginning versus end of surgery). Notably, this also raises the question of whether perioperative lavage might wash away a substantial amount 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 concomitantly 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 fibrinolysis73,74 (Table 4). In 1985, D'Angelo and colleagues81 proposed the existence of a minimized fibrinolytic system in plasma immediately after surgery as a result of an increase in PAI-1 and a reduction in tPA levels (‘postoperative fibrinolytic shutdown’). Again, it took several years before new insights led to the perception that there is still ongoing fibrinolysis in plasma despite reduced tPA and increased PAI-1 concentrations. In this context, a study by Siemens and co-workers78 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 undergoing total hip replacement, hemicolectomy, laparoscopic cholecystectomy or subtotal thyroid resection. Maximum activation of coagulation was not reached until 2 h after surgery and slowly decreased until normal values were reached around day 5. The hip replacement and hemicolectomy groups showed a similar outcome, with strong activation of the procoagulatory (and fibrinolytic) systems. Much less pronounced were the changes during cholecystectomy and thyroid resection (Table 4). Similar results were reported by Diamantis et al.80, who examined differences in activation of coagulation and fibrinolytic pathways between open and laparoscopic surgery, and by López and co-workers77, who studied postoperative differences between orthopaedic and abdominal surgery. Overall, in these studies surgery led to hypercoagulability, with open surgery leading to a stronger activation of the clotting system in plasma than laparoscopic procedures77,79,80. Table 4 Studies on the fibrinolytic and coagulatory response to surgery in humans in plasma Reference . Year . Type of surgery . Parameters measured . Timing of samples . Measured postop. changes or conclusion . López et al.77 1997 Orthopaedic versus abdominal surgery tPA, PAI-1, FbDPs, PAP, TAT complex Preop., and 1, 3 and 7 days postop. Clotting markers ↑,  PAI-1 ↑, tPA ↓, PAP ↓ Siemens et al.78 1999 Total hip replacement, TAT complex, D-dimer, 1 day preop. All factors ↑. Hip  hemicolectomy, laparoscopic cholecytectomy, subtotal thyroid resection  PAI-1, fibrinogen Preop. and intraop., and  replacement and hemicolectomy showed similar strong activation of procoagulatory and fibrinolytic systems versus other types of surgery  2 h, and 1, 2, 3 and  5 days postop. Schietroma et al.79 2004 Open versus laproscopic surgery TAT complex, fibrin, FbDPs, D-dimer, antithrombin Preop., and 1 h, and 1, 2 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.74 2005 Fertility surgery tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week postop. PAI-1↑, fibrin ↑, FbDPs ↑ Diamantis et al.80 2007 Open versus laproscopic surgery Fibrin, FbDPs, TAT complex, fibrinogen, D-dimer Preop. and intraop., and 1 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.75 2009 Myomectomy tPA, PAI-1, FbDPs 30 min, 1, 3 and 6 h, and 1, 2, 5 and 7 days postop. tPA ↔, PAI-1 ↔ at all time points, FbDP ↑ at  30 min to 1 day Reference . Year . Type of surgery . Parameters measured . Timing of samples . Measured postop. changes or conclusion . López et al.77 1997 Orthopaedic versus abdominal surgery tPA, PAI-1, FbDPs, PAP, TAT complex Preop., and 1, 3 and 7 days postop. Clotting markers ↑,  PAI-1 ↑, tPA ↓, PAP ↓ Siemens et al.78 1999 Total hip replacement, TAT complex, D-dimer, 1 day preop. All factors ↑. Hip  hemicolectomy, laparoscopic cholecytectomy, subtotal thyroid resection  PAI-1, fibrinogen Preop. and intraop., and  replacement and hemicolectomy showed similar strong activation of procoagulatory and fibrinolytic systems versus other types of surgery  2 h, and 1, 2, 3 and  5 days postop. Schietroma et al.79 2004 Open versus laproscopic surgery TAT complex, fibrin, FbDPs, D-dimer, antithrombin Preop., and 1 h, and 1, 2 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.74 2005 Fertility surgery tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week postop. PAI-1↑, fibrin ↑, FbDPs ↑ Diamantis et al.80 2007 Open versus laproscopic surgery Fibrin, FbDPs, TAT complex, fibrinogen, D-dimer Preop. and intraop., and 1 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.75 2009 Myomectomy tPA, PAI-1, FbDPs 30 min, 1, 3 and 6 h, and 1, 2, 5 and 7 days postop. tPA ↔, PAI-1 ↔ at all time points, FbDP ↑ at  30 min to 1 day ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; FbDP, fibrin degradation product; PAP, plasmin–antiplasmin complex; TAT, thrombin–antithrombin; uPA, urokinase plasminogen activator. Open in new tab Table 4 Studies on the fibrinolytic and coagulatory response to surgery in humans in plasma Reference . Year . Type of surgery . Parameters measured . Timing of samples . Measured postop. changes or conclusion . López et al.77 1997 Orthopaedic versus abdominal surgery tPA, PAI-1, FbDPs, PAP, TAT complex Preop., and 1, 3 and 7 days postop. Clotting markers ↑,  PAI-1 ↑, tPA ↓, PAP ↓ Siemens et al.78 1999 Total hip replacement, TAT complex, D-dimer, 1 day preop. All factors ↑. Hip  hemicolectomy, laparoscopic cholecytectomy, subtotal thyroid resection  PAI-1, fibrinogen Preop. and intraop., and  replacement and hemicolectomy showed similar strong activation of procoagulatory and fibrinolytic systems versus other types of surgery  2 h, and 1, 2, 3 and  5 days postop. Schietroma et al.79 2004 Open versus laproscopic surgery TAT complex, fibrin, FbDPs, D-dimer, antithrombin Preop., and 1 h, and 1, 2 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.74 2005 Fertility surgery tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week postop. PAI-1↑, fibrin ↑, FbDPs ↑ Diamantis et al.80 2007 Open versus laproscopic surgery Fibrin, FbDPs, TAT complex, fibrinogen, D-dimer Preop. and intraop., and 1 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.75 2009 Myomectomy tPA, PAI-1, FbDPs 30 min, 1, 3 and 6 h, and 1, 2, 5 and 7 days postop. tPA ↔, PAI-1 ↔ at all time points, FbDP ↑ at  30 min to 1 day Reference . Year . Type of surgery . Parameters measured . Timing of samples . Measured postop. changes or conclusion . López et al.77 1997 Orthopaedic versus abdominal surgery tPA, PAI-1, FbDPs, PAP, TAT complex Preop., and 1, 3 and 7 days postop. Clotting markers ↑,  PAI-1 ↑, tPA ↓, PAP ↓ Siemens et al.78 1999 Total hip replacement, TAT complex, D-dimer, 1 day preop. All factors ↑. Hip  hemicolectomy, laparoscopic cholecytectomy, subtotal thyroid resection  PAI-1, fibrinogen Preop. and intraop., and  replacement and hemicolectomy showed similar strong activation of procoagulatory and fibrinolytic systems versus other types of surgery  2 h, and 1, 2, 3 and  5 days postop. Schietroma et al.79 2004 Open versus laproscopic surgery TAT complex, fibrin, FbDPs, D-dimer, antithrombin Preop., and 1 h, and 1, 2 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.74 2005 Fertility surgery tPA, uPA, PAI-1, FbDPs, fibrinogen, plasminogen, α2-antiplasmin, PAP, TAT complex, fibrin 1 week postop. PAI-1↑, fibrin ↑, FbDPs ↑ Diamantis et al.80 2007 Open versus laproscopic surgery Fibrin, FbDPs, TAT complex, fibrinogen, D-dimer Preop. and intraop., and 1 and 3 days postop. Open surgery led to more activation of clotting system than laparoscopic surgery Hellebrekers et al.75 2009 Myomectomy tPA, PAI-1, FbDPs 30 min, 1, 3 and 6 h, and 1, 2, 5 and 7 days postop. tPA ↔, PAI-1 ↔ at all time points, FbDP ↑ at  30 min to 1 day ↓, Decrease; ↑, increase; ↔, no change. tPA, tissue plasminogen activator; PAI, plasminogen activator inhibitor; FbDP, fibrin degradation product; PAP, plasmin–antiplasmin complex; TAT, thrombin–antithrombin; uPA, urokinase plasminogen activator. Open in new tab 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 study66 and two prospective trials74,75 investigated the effect of surgery on peritoneal fibrinolysis in relation to the severity of adhesion formation. In the retrospective study, levels of PAI-1 and of tPA–PAI-1 complex were increased in peritoneal tissue samples from patients with severe adhesions compared with those from patients with less severe adhesions66. In the first prospective study, investigators sought evidence of fibrinolytic insufficiency as a cause of adhesion formation74. 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 points in 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 efficacy and safety of reteplase (recombinant plasminogen activator) administration after abdominal myomectomy75. Patients were randomized to intraperitoneal treatment with 1 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, 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-1 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 It is now well accepted that the inflammatory system has an important role in the regulation of both the coagulation and fibrinolytic systems82,83. Acute inflammation, in response to trauma or infection, can lead to systemic activation of the coagulation system and from that to fibrin deposition82. 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 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 exudation84,85. In surgery, the formation of this fibrin-rich exudate in the peritoneum is part of 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 player in the onset of coagulatory processes; on the other, they have an important role in maintaining an adequate plasma-independent fibrinolytic system by producing tPA and uPA, and their inhibitor PAI-1. The expression of procoagulatory tissue factor and antifibrinolytic PAI-1 is increased by inflammatory mediators such as IL-1 and TNF-α, while the expression of tPA is concomitantly decreased, explaining an increased tendency to fibrin deposition86,87. 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 concept emerges when reassessing over 50 years of studies in animals and humans on the pathogenesis of adhesion formation. Peritoneal damage inflicted by surgical trauma or other insults evokes an inflammatory response, thereby promoting procoagulatory and antifibrinolytic reactions, and a subsequent significant increase in fibrin formation. When fibrin deposits persist, 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 concept not only reconciles apparently contradictory 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). Fig. 2 Open in new tabDownload slide Factors influencing the fibrinolytic, coagulation and inflammatory systems, and thus the extent of adhesion formation Factors that reportedly influence inflammation, coagulation and fibrinolysis in the presurgical setting are numerous. Age80,88, diurnal variations89, sex and other genetic factors90, obesity91, medication92–95, ongoing infection82,94, smoking and alcohol intake96, diabetes97, phase of the menstrual cycle98, hypercholesterolaemia99, benign versus malignant disease100,101, stress90,102 and pregnancy103 have all been found to influence one or more of the risk factors inflammation, coagulation and fibrinolysis. In addition, numerous surgical factors contribute to fibrin persistence, including type and duration of surgery77,78,80, use of irrigation, anaesthetic used104, additional medication (such as antibiotics) and blood transfusion105. Of special interest is the influence of the extent of peritoneal damage. Many surgeons assume that laparoscopy induces fewer adhesions than laparotomy owing to less peritoneal trauma. Previous studies showed that open surgery led to a significantly greater activation of the clotting system in plasma than laparoscopic procedures77,78,80. Adhesion formation, however, has not been evaluated properly as primary endpoint in prospective studies comparing laparoscopy and laparotomy. Only one randomized 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 group compared with the laparotomy group, and there was a trend towards fewer adhesions overall106. 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 Boys107 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 a need to open new avenues. This review draws attention to the role of inflammation as evoking factor, and anti-inflammatory treatment regimens deserve further investigation. It also highlights the perioperative period as an ideal and underutilized window of therapeutic opportunity in which the peritoneal environment and fibrinolytic capacity could be modulated to prevent postsurgical adhesion formation. Besides suppressing inflammation, direct augmentation of fibrinolytic activity with fibrinolytic agents might be an interesting alternative to use as an antiadhesion strategy108. An important 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 coagulation 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 anti-inflammatory, anticoagulatory and profibrinolytic properties could be the use of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins)109. Besides their cholesterol-lowering capacity, there is accumulating clinical evidence that they are effective in lowering plasma levels of CRP89,110, have potent anti-inflammatory properties111, and are effective stimulators of fibrinolytic activity by increasing tPA and lowering PAI-1112. 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, statins have also been found to decrease cellular tissue factor expression112, to stimulate mesothelial fibrinolytic activity by increasing tPA levels and lowering PAI-1 levels in cultured mesothelial cells86,113, and to be effective in the prevention of postsurgical adhesions in experimental studies114–116. It therefore seems that further research on these registered drugs in adhesion formation in a clinical setting is urgently needed. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
TI - Pathogenesis of postoperative adhesion formation
JF - British Journal of Surgery
DO - 10.1002/bjs.7657
DA - 2011-10-03
UR - https://www.deepdyve.com/lp/oxford-university-press/pathogenesis-of-postoperative-adhesion-formation-gIPcdNvS3J
SP - 1503
EP - 1516
VL - 98
IS - 11
DP - DeepDyve
ER -