**3. Pathophysiology**

Adhesion formation has three steps;: (A) inhibition of extracellular matrix degradation system and fibrinolytic (B) induction of an inflammatory response involving cytokine production and transforming growth factor-β (TGF-β); and (C) induction of tissue hypoxia, leading to increase in expression of vascular endothelial growth factor (VEGF). As adhesions mature their cell population changes from days one to three, cells are mainly polymorphonuclear cells (PMN) leukocytes, whereas between days five and seven fibroblasts predominate [4]. Factors that have been identified include those important for the regulation of inflammatory and immune responses, tissue remodeling, and angiogenesis.

Cellular insult results in an outpouring of fibrin and subsequent fibrinolysis. The insult causes hypoxia and the release of reactive oxygen species (ROS), which lead to inflammation and activation of the coagulation cascade. This increases the production of thrombin, which is a key activator of fibrin [4, 5]. Fibrin production and fibrinolysis are part of the physiologic process; if the balance between fibrin production and fibrinolysis becomes compromised pathological adhesion formation occurs [4].

Deposition of fibrin monomers (red and white blood cells, macrophages, platelets, and tissue exudates) develops a polymeric matrix within which fibroblasts can adhere and produce components of extracellular matrix (ECM), setting the stage for mature adhesion formation [3–5]. A major determinant of the persistence of the fibrinous mass is the degree of plasminogen activator activity (PAA). PAA, which can be considered to be represented by the ratio of tissue plasminogen activator (tPA) to its inhibitor, plasminogen activator inhibitor 1 (PAI-1), resides in both the mesothelial cells and the underlying fibroblasts [5]. Plasminogen activator inhibitors (PAIs) can prevent PAs from activating plasmin, leading to compromised fibrinolytic activity [6].

Then proliferating fibroblasts invade and keep extracellular matrix material including collagen and also have contributed to the formation of adhesion. And next step is after elicitation of angiogenesis factor, for example vascular endothelial growth factor (VEGF). Imbalances in any of these could potentially contribute to adhesion development [1].

It has been shown that fibroblasts derived from tissue adhesions have a different phenotype (myofibroblasts) when compared to normal fibroblasts found in peritoneal tissue. Transformation of the phenotype has been associated with tissue hypoxia, whereas fibroblast adhesions determine increased mRNA expression of fibronectin, collagen I, metalloproteinase-1, Tissue Growth Factor TGF-beta1, Tissue Inhibitors of Metalloproteinases (TIMP-1), Cyclooxygenase-2 (COX-2), and IL-10. All of these proteins support the formation of adhesion action at different times [3, 7].

An enzyme that regulates the inflammatory process of angiogenesis in the formation of postoperative adhesions is COX-2. In the presence of tissue hypoxia

#### *Adhesiolysis during Hysterectomy DOI: http://dx.doi.org/10.5772/intechopen.112520*

and/or fibroblast adhesion, COX-2 expression is increased. While the formation of dense postoperative adhesions, the fibrinolytic system has an important role in converting plasminogen to plasmin. The conversion is determined by the tissue Plasminogen Activator (tPA) and activator-type urokinase (uPA), both are expressed by the complex of the endothelial and mesothelial cells, macrophages, and fibroblasts. The tPA has been shown to be responsible for the plasminogen activation and fibrin degradation, whereas uPA plays a role during tissue remodeling [1, 3].

The process of adhesion formation might be regarded as an ischemic disease. Under hypoxic conditions, metabolic enzymes are regulated via hypoxic responsive elements by the hypoxia-inducible factor 1 (HIF-1) [8]. Molecular pathways involved in fibrinolysis inhibition, inflammation, and tissue hypoxia crosstalk and potentiate the effect of each. The principal molecular aberrations included the reduction of tissue plasminogen activator (tPA) and up-regulation of TGF-β1 and HIF-1α [1].

## **4. Clinical consequences of adhesion formation**

Small bowel obstruction, infertility, and chronic abdominal pain are generally mentioned as the main clinical consequences formation of adhesion [9]. The most important risk of adhesion formation is infertility, abdominal or pelvic pain, obstruction of the bowel, and injury to intra-abdominal structure on another or next surgeries. Imaging tools such as the visceral slide test have been used to determine the presence of periumbilical adhesions before laparoscopy. However, there is no other method for identifying preoperative adhesions and only direct visualization on surgery that accurately identify and measure postoperative adhesion, though periumbilical adhesions could be detected by ultrasonography [10, 11].

The most common cause of postoperative small-bowel obstruction is adhesions [12]. The incidence of small bowel obstruction is 2–3 percent in the first year after surgery in all patients who undergo abdominal or pelvic surgery [13]. The risk of adhesive small bowel obstruction depends on the anatomical location of surgery, the breadth of surgery, and peritoneal injury [13, 14]. And risk varies in abdominal wall surgery from 0.5 percent; 1.2 percent after upper gastrointestinal surgery to 3.2 percent in lower gastrointestinal surgery and 4.2 percent in pediatric surgery [13].

Infertility and adhesions may affect fertility adversely by distorting adnexal anatomy and interfering with gamete and embryo transport. Among infertile women with unexplained infertility diagnosed with adnexal adhesions by laparoscopy, the pregnancy rates were 32 percent at 12 months after subsequent adhesiolysis by laparotomy and 45 percent at 24 months compared with 11 percent at 12 months and 16 percent at 24 months in untreated women [15].

In another study of 198 patients after lower gastrointestinal tract surgery for adhesive small bowel obstruction, 40 percent of patients developed chronic abdominal pain. In four studies following patients with chronic postoperative pain after previous surgery, adhesions were identified as the most likely cause of pain during diagnostic laparoscopy in 57 percent of patients [13]. The relationship between adhesions and pelvic pain is unclear. Between the extent of adhesions and the severity of pain, there is no relationship. In some cases, adhesions may cause visceral pain with impairing organ immobility. A study of patients with chronic pelvic pain randomized to laparotomy with adhesiolysis or laparotomy only, found adhesiolysis was effective for those who had dense adhesions involving the bowel.
