Intestinal blood flow can be altered profoundly by chronic gut inflammation. However, the nature and magnitude of the change in intestinal blood flow appear to be dependent on the stage of progression of the inflammatory response. During the early “exudative” phase of colonic inflammation in patients with either ulcerative colitis (UC) or Crohn’s disease (CD), colonic blood flow (particularly in the mucosal and submucosal layers) is increased significantly (two- to sixfold) [5]. However, in the late “fibrosing” stage of the disease, colonic blood flow is reduced below normal. A reduction in blood flow also has been reported in colonic arterioles of mice with experimental colitis induced by either dextran sodium sulfate (DSS) or T-cell transfer into immunodeficient mice [6, 7]. However, despite the arteriolar constriction and lower blood flow rates in the individual vessels, overall blood flow rates to the ileum and colon in both models were only marginally reduced as a result of an approximate twofold increase in vascular density [6–10]. A subset of mice in the T-cell transfer model does exhibit a significantly reduced overall blood flow, and this is accompanied by mucosal hypoxia and only mild signs of inflammation [11]. There is also evidence that leukocytes recruited into the inflamed bowel may also influence vasoactivity [12]. In a T-cell transfer model of chronic colitis, vasodilation of first-order colonic arterioles and venules was found to correlate with the number of circulating leukocytes [13]. However, it should be noted that the dilation was not accompanied by an increase in blood flow, possibly due to the constriction of smaller arterioles mentioned earlier [6].

Studies on colonic arterioles derived from patients with IBD and from animal models of experimental colitis have revealed an impaired ability of the resistance vessels to respond to endothelium-dependent vasodilators [2, 7, 14]. The arteriolar dysfunction detected in vessels derived from IBD patients is severe, with acetylcholine-induced dilation reduced to only about 10 % of the response detected in normal arterioles. The impaired vasodilatory response appears to result from a diminished capacity of arteriolar endothelial cells (EC) to produce nitric oxide (NO), rather than prostacyclin. The NO deficiency results from an excessive production of superoxide, which rapidly reacts with and inactivates NO, thereby inhibiting smooth muscle relaxation [2, 7, 14]. The deficient dilation appears to be a consequence of endothelial dysfunction, inasmuch as vascular smooth muscle function appears to remain unchanged [15]. Recent work has also implicated circulating microparticles, which are elevated in plasma of CD patients, in the impaired flow (and NO)-dependent dilation that accompanies IBD [16].

The changes in colonic blood flow during IBD may also reflect an altered production of endogenous vasoconstrictors [10, 17]. Several reports describe increased levels of thromboxane synthase and/or thromboxane B₂ in the colon of IBD patients, with a correlation noted between thromboxane synthase and disease activity. It remains unclear whether thromboxane-induced vasoconstriction contributes to disease progression because thromboxane synthase inhibitors showed little effectiveness in promoting remission of IBD. Angiotensin II and endothelin-1 , other endogenous vasoconstrictors generated by the gut, are also elevated in the colonic mucosa of CD patients [17]. Endothelin-1 has been implicated in the tissue hypoxia that accompanies the ischemic phase of IBD progression [18].

The adhesion of leukocytes to vascular endothelium is a hallmark of the inflammatory response. This adhesive interaction between blood cells and the vessel wall largely occurs in postcapillary venules and is critical for the recruitment of inflammatory cells to sites of infection and/or tissue injury. An important determinant of whether leukocytes adhere to vascular endothelium is the pro-adhesive force that is generated by adhesion molecules expressed on the surface of activated leukocytes and endothelial cells (EC). Table 6.1 summarizes some of the EC adhesion glycoproteins that have been implicated in the recruitment of leukocytes in inflamed colonic venules, their ligands (counter-receptors) on leukocytes, and the type of adhesive interaction mediated by the glycoprotein pairs. Studies in animal models of IBD have demonstrated a time-dependent increase in the expression of P- and E-selectins, ICAM-1, VCAM-1, and MAdCAM-1 in the vasculature of the inflamed colon [1, 19, 20]. Similar findings have been reported for mucosal biopsy samples derived patients with active (but not quiescent) ulcerative or Crohn’s colitis. This upregulation of EC adhesion molecules is accompanied by the recruitment of large numbers of rolling, firmly adherent and emigrated (extravasated) leukocytes within (and surrounding) inflamed colonic venules. The critical importance of adhesion molecules in the genesis of experimental IBD is evidenced by a number of studies demonstrating attenuated inflammatory and tissue injury responses in mice that are genetically deficient in specific leukocyte or endothelial cell adhesion molecules, and in animals treated with blocking antibodies directed against these adhesion glycoproteins [1, 19, 20].

A variety of factors contribute to the modulation of leukocyte–endothelial cell adhesion during gut inflammation either by affecting the intensity of adhesion molecule expression and/or the ability of these glycoproteins to sustain strong adhesive interactions between the blood cell and vascular endothelium. Nitric oxide, adenosine, and prostacyclin produced by EC tend to prevent leukocyte–EC adhesion while reactive oxygen species (superoxide, hydrogen peroxide) produced by activated leukocytes and EC appear to promote leukocyte adhesion [14, 15]. These endogenous regulators of leukocyte adhesion exert either a direct (transcription-dependent) or indirect (i.e., altering the production of inflammatory cytokines) effect on the production/expression of EC adhesion molecules. Vasoactive agents (e.g., nitric oxide) can also influence the quality of the adhesive interaction between glycoproteins expressed on leukocytes and EC by altering shear forces generated by the movement of blood through the microvasculature. The number of leukocytes recruited in inflamed venules is inversely related to wall shear rate, suggesting that it is easier for leukocytes to create strong adhesive bonds with ECs at low shear rates and that high shear rates are likely to prevent the creation of such bonds. This dependency of leukocyte adhesion on shear rate suggests that the changes in blood flow associated with the early and late stages (discussed above) of inflammation may significantly influence the intensity of leukocyte recruitment during IBD [19–21].

Platelets also accumulate in the microvasculature of the inflamed colon. The adhesion of platelets to the walls of colonic venules appears to reflect platelet binding to activated ECs rather than adhesion to the collagen-rich subendothelial surface of damaged blood vessels [22, 23]. Intravital microscopic evaluation of platelet binding in inflamed colonic venules has revealed that a relatively small proportion (<10 %) of the platelets bind directly to ECs, while most attach to leukocytes that are already bound to the vessel wall. P-selectin blockade effectively inhibits both the leukocyte-dependent and -independent components of platelet adhesion in colonic venules of colitic mice, suggesting that P-selectin (whether expressed on the platelet or EC) contributes to both recruitment processes [23]. While platelet binding to EC is not altered by ICAM-1 or CD18 immunoblockade, the accumulation of leukocyte-bound platelets is dramatically reduced. The findings are consistent with a model wherein leukocytes require P-selectin to roll on venular endothelium and subsequently establish firm adhesion via CD18-ICAM-1 interactions. The adherent leukocytes, which constitutively express PSGL-1, then create a platform onto which platelets can bind using P-selectin. Similar P-selectin (platelet-associated)-PSGL-1 (leukocyte-associated) interactions also likely account for the platelet-leukocyte aggregates that are detected in blood of IBD patients. Platelet recruitment into inflamed microvessels may be important because, upon activation, platelets produce/release a variety of pro-inflammatory mediators. Furthermore, platelets attachment to neutrophils enhances superoxide production by the latter cells [24].

Additional consequences of the altered platelet function that occurs during IBD include hyper-reactivity, hyper-aggregability, and an increased propensity for thrombus formation in large and microscopic blood vessels [3, 20–23]. Intravascular platelet aggregates are detected in mucosal biopsies from patients with ulcerative colitis, and the number of platelet aggregates in mesenteric venous blood is increased in IBD. The enhanced reactivity and aggregability of platelets in IBD are accompanied by evidence of significant systemic activation of the coagulation system. The anticoagulant role of ECs is diminished during inflammation, which is reflected in an increased expression of tissue factor, downregulation of anticoagulant protein C pathway, and the inactivation of nitric oxide by superoxide. Collectively, the hemostatic alterations that accompany inflammation tip the balance between procoagulant and anticoagulant mechanisms in favor of thrombus formation. This combination of a hypercoagulable state and platelet hyper-reactivity/aggregability in IBD likely accounts for the fact that vascular beds distant from the inflamed bowel are vulnerable to thrombosis [3, 25–29].

Systemic thromboembolic events (TE ) are a significant cause of morbidity and mortality in IBD patients. Clinical studies have revealed that the incidence of TE events in IBD patients is ~6.2 %, with a 3.6-fold increase in risk for TE complications compared to the general population [3, 30, 31]. A much higher incidence of systemic TE (41 %) is predicted from postmortem studies. Both the arterial and venous circulations appear to be involved in IBD-associated TE , although venous complications occur more frequently. TE is most commonly manifested as deep vein thrombosis (DVT) or pulmonary embolism (PE) , although thromboses have been detected in other regional circulations, including brain, retina, and liver [3].

Many of the hemostatic alterations reported in patients with IBD have been recapitulated in animal models [3]. These include increases in blood levels of fibrinogen and TAT complexes, thrombocytosis , and a reduced capacity for protein C activation [32, 33]. Mice with experimental colitis also exhibit an increased vulnerability to microvascular thrombus formation in extra-intestinal tissues, a response that is largely confined to arterioles [3, 32]. Tissue factor activation , an impaired protein C pathway, and thrombin have all been implicated in the enhanced extra-intestinal thrombosis in experimental IBD models. While the chemical and/or cellular signals produced by the inflamed gut that initiates this distant organ thrombogenic response remain undefined, there is evidence implicating the cytokines, interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 (IL-6) [3, 34]. Immunoblockade of these cytokines, particularly IL-6, appears to largely prevent the enhanced extra-intestinal thrombosis associated with DSS-induced murine colitis [34]. The DSS model has also been useful in demonstrating a role for procoagulants (tissue factor) and anticoagulants (activated protein C) in modulating the initiation and perpetuation of gut inflammation, findings consistent with the view that inflammation and coagulation are interdependent processes that can initiate a vicious cycle wherein each process propagates and intensifies the other [35].