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Abstract

We have shown that the contact (kallikrein-kinin) system is involved in the pathogenesis of experimental enterocolitis. We now investigate activation of the contact and coagulation pathways, platelets, and neutrophils in active and inactive ulcerative colitis patients as compared to normal controls. In active ulcerative colitis patients, a significant decrease of plasma prekallikrein, high molecular weight kininogen, and C1 inhibitor levels was observed as compared with controls, as well as prekallikrein activation on western blots. Significant elevation of prothrombin fragment (F1 + 2), which indicates thrombin generation, and elastase-alpha 1-antitrypsin complexes, reflecting neutrophil activation, were found in patients with active disease. Plasma beta-thromboglobulin, a marker of platelet activation, was elevated in both active and inactive disease and appears to be a feature of ulcerative colitis. Activation of contact and coagulation pathways, as well as neutrophils, may mediate inflammation in the active phase of ulcerative colitis.

Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody

“…However, the system has been shown to be activated in vitro and in preclinical disease models by numerous agents that include mast cell heparin (3), misfolded or aggregated proteins (4), sub-endothelial matrix proteins such as collagens and laminin (5–7), extracellular RNA (8), polyphosphate from platelets or bacteria (9, 10), fibrin (11), bacterial infection (12), ventricular assist devices (13), and following exposure of plasma to polyanionic substances such as kaolin, dextran sulfate, phospholipids, or surfaces such as glass (1). Furthermore, there are reports that the contact system is activated in plasma obtained from patients with diseases such as rheumatoid, psoriatic, or osteoarthritis (14), ulcerative colitis (15), systemic lupus erythematosus (16), psoriasis (16), diabetic retinopathy, and macular edema (17, 18), sepsis (19), systemic amyloidosis (4), sickle cell disease (20), Alzheimer disease (21), anaphylaxis (3), brain ischemia and edema (22), cirrhosis (23), and hereditary angioedema with C1-inhibitor deficiency (HAE-C1INH) (24–26). …”

Venous and arterial thromboembolism in patients with inflammatory bowel diseases

“…Activation of coagulation results in thrombin generation, and in turn may generate fibrin formation as well as platelet activation via the cleavage of and binding to thrombin receptors (Figure 1 )[ 22 ]. Several authors have indicated systemic evidence for impairment of fibrinolysis and intravascular thrombin generation in patients with IBD to measure prothrombin fragments (formed during the conversion of prothrombin to thrombin, F1+2) and thrombin–antithrombin complexes[ 23 , 24 ]. The plasma level of protein C, a natural coagulation inhibitor, has been shown to be unchanged or decreased in IBD[ 25 , 26 ], while its decreased cofactor, the protein S plasma level, was demonstrated in most studies[ 27 ].…”

“…Activated by thrombin, TAFI removes lysine residues from fibrin, which is essential for plasmin formation in the fibrin network, and in turn inhibits fibrinolysis, which contributes to the prothrombotic state. Elevated D-dimer levels were found mainly in active IBD patients, which provides evidence of fibrin formation and reactive fibrinolysis (Figure 1 )[ 24 , 25 ].…”

Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

“…In support of these observations, there are similar findings in irritable bowel disease. Patients with ulcerative colitis (UC) showed decreased plasma levels of PKa and HK, which indicated proteolysis of these precursors and therefore contact system activation ( 102 ). Both kinin receptors are expressed in UC patients in intestinal epithelial cells.…”