Delivery of Thrombin to the Gastrointestinal Tract

               I continue to be amazed by what I have missed over the years.  In the course of analysis of the development of therapeutic products derived from fibrinogen, I came across a wealth of early studies on the oral administration of thrombin for gastrointestinal bleeding.  Daly and coworkers (1) reported that bovine topical thrombin in phosphate buffer introduced into the stomach either by mouth or intubation was useful in stopping gastrointestinal bleeding.  These investigators emphasized that this technique was not of universal value and surgery was a necessary option in many cases.   In a latter study, Schmutzler and Walter presented a study in 1954 (2) on the oral administration of bovine thrombin for the treatment of gastrointestinal bleeding.  This approach had modest success in provided a hemostatic effect on small bleeding sites but not likely useful for major bleeding.   These investigators emphasized the importance of technique in the use of the thrombin for gastrointestinal bleeding.   Edmunds in 1953 (3) reported a lack of success with oral thrombin.   Otterjan and colleagues reported on the necessity of including an antacid  substance such as magnesium carbonate to neutralize the stomach acid to prevent the acid denaturation of thrombin.  Otterjann and colleagues (5) also noted the apparent absorption of thrombin from the digestive tract into the circulatory system after duodenal or rectal administration as evaluated by the heparin tolerance assay; the absorption of thrombin into the circulation would result in a decrease in antithrombin as measured by this assay.  The absorption of other pharmacologically active enzymes such as glandular kallikrein from the digestive tract has been reported (6-8).  The combination of powdered Gelfoam®  and bovine thrombin has been studied for the management of gastrointestinal bleeding  in a canine model (9) observing that Gelfoam® with thrombin was superior to either Gelfoam® alone or thrombin alone.   This study was followed by a number of clinical studies using Gelfoam® and thrombin (10-13).  The sum of the various observations would suggest that oral thrombin could be useful in the treatment of minor  hemorrhage in the gastrointestinal tract but is most effective in combination with carrier such as powdered gelatin.  There is a recent study using a high viscosity gelatin gel with collagen and thrombin to treat upper gastrointestinal bleeding (14).   Thrombin is also used in the management of bleeding with esophageal varices (15).

 

References
1.  Daly, B.M., Johnston,  C.G., and Penberthy, G.C., The management of patients with bleeding from the upper gastro-intestinal tract with buffer and thrombin solution, Annals.Surg. 129. 832-839, 1949.
2.  Schmutzler, R. and Walter, O., Thrombin per os beim blutenden Magen.  Eine klinische und experimetalle Studie, Die Medizinische October 30, 1470-1472, 1954
3.  Edmunds, V., Oral thrombin in the treatment of haematemesis, Brit.Med.J. June 20, 1371-1372, 1953.
4.   Otterjann, R., Toatis, H., and Steger, W., Zur Wirksamkeit von Schluckthrombin, Medizinische Klinik 62, 1751-1752, 1967.
5.  Gormsen, J., A technique for the heparin-tolerance test, Brit.J.Haematol. 5, 257-267, 1959.
6.  Naito, S.I. and Tanaka, S., Increases in plasma kallikrein-like and pancreas kallikrein-like substances after administration of pancreas or plasma kallikrein, Arzneimittal-Forschung 33, 952-957, 1983.
7.  Fink, E., Feng, X.C., and Richter, E., Studies on the intestinal absorption of tissue kallikrein, Adv.Exptl.Med.Biol. 247B, 663-668, 1989.
8.  Miska, W. and Schill, W.B., Absorption study with porcine pancreatic kallikrein in man, Arzneimittal-Forschung 41, 1061-1064, 1991.
9.  Cantor, M.O. and Reynolds, R.P., Gelfoam® and thrombin in gastrointestinal bleeding, J.Lab.Clin.Med. 35, 890-893, 1950.
10.   Collins, D.C., Enemata of Gelfoam® and milk suspension combined with thrombin-solution to control massive hemorrhage following anorectal surgery, Am.J.Protol.2, 60-63, 1951.
11.  Collins, D.C., Clark, W.F., and Dimitroff, S.P., Hemostatic effects of powdered Gelfoam® thrombin solution and blood transfusions in an instance of recurring massive hemorrhage from a large chronic gastric ulcer: report of a case, Ann.West.Med.Surg. 5, 767-769, 1951.
12.  Cantor, M.O., Kennedy, C.S., and Reynolds, R.P.,Gelfoam® and thrombin in treatment of massive upper gastrointestinal hemorrhage, Am.J.Surg.82, 230-235, 1951.
13. McClure, J.N., Massive gastroduodenal hemorrhage: treatment with powdered Gelfoam® and buffered thrombin solution: a preliminary report, Surgery 32, 630-637, 1952.
14. Farinella, E., Ronca, P., and La Mura, F., Upper gastrointestinal massive bleeding successively treated intra-operatively with a collagen and thrombin-based high viscosity gel for hemostasis-case report, Il Giornale di Chirurgie 31, 186-190, 2010.
15.  Ramesh, J., Limdi, J.K., Sharma, V., et al., The use of thrombin injections in the management of bleeding gastric varices: a single-center experience, Gastrointest.Endocs. 68, 877-882, 2008.