One of the oddest treatments to come along in quite some time is the use of a medicine called heparin in the treatment of IBD. The reason this is so odd is that heparin is one of a number of drugs known as anticoagulants. In someone with a disease that causes bleeding it is surprising that ananticoagulant would not make things worse.
Historically, the main drug used in ulcerative colitis was discoveredaccidentally. Sulfasalazine (aka Azulfidine) was initially designed asan antiarthritis drug. It is a molecule of 5-ASA and sulfa antibiotic joinedby a covalent bond. The initial thinking was that the drug would be absorbedand the combination of antibiotic and antiinflammatory would be good forrheumatoid arthritis, a disease that back then was thought to be due toan infection and inflammation. A few patients with UC and arthritis wereseen to do quite well in regards to their colitis. It didn’t work verywell against the arthritis. Turned out that the drug is not well adsorbed,and that in the colon the drug was broken down by bacteria (hooray forbacteria) and locally liberated the antiinflammatory drug 5-ASA.
History seems to have repeated itself with heparin. A patient with UCwas being treated for a blood clot in the leg. Their intrepid physician,knowing that DVT’s could be life threatening, went ahead and used heparin.The patient’s UC improved. Thus the use of heparin in UC had its beginnings.
Further support for the use of heparin in UC is that the microscopicappearance of the tissue is that of multiple tiny blood clots in the vesselsof the injured colon. This was thought to represent coagulation in responseto the inflammation, and perhaps was even protective since clotting mayhave represented the prevention of further bleeding. Well, with the improvementthat was seen, it was only natural to wonder whether the improvement seenin the patients with UC might have been due to better blood flow to theinjured tissue.
A number of patients have now been given heparin during attacks of UC.It seems to work. The abstracts below describe the responses that patientsseem to have. Interestingly, one of the described uses is in patients withextraintestinal complications of IBD, such as erythema nodosum. These complicationscan be very slow to respond to conventional therapy. Bleeding does ometimeshappen, but it does not seem to be uncontrollable. Heparin has no toxicity,and only occasionally has poor outcomes, though as more patients are treatedwe may see injuries occur (massive GI or pulmonary bleeding, strokes).
Below I have reproduced the abstracts from the 1996 DDW meeting thatreferred to heparin in treatment of IBD. They are copyright DDW.
Remember that these are early studies, and a number of treatment forIBD have been found to be worthless over the years. Even if correct, thestudies were small, and did not have controls. There is no data on whatthe optimal dose or duration of treatment is. Even simple things, liketaking advantage of what is known about the histology of UC and checkingwhether the presence of microthrombi predicted whether patients would benefit was not done. Most patients seem to be helped, but a few seem to bleedmore. Can we predict who those will be? These questions will need to beaddressed before heparin moves into the mainstream of treatment of IBD.
TITLE:  HEPARIN THERAPY IN REFRACTORY ULCERATIVE COLITIS – AN UPDATE.
AUTHORS: P.R. Gaffney, A. Gaffney. Dept. of Surgery, Mallow GeneralHospital, Mallow, Co. Cork, Ireland.
BODY: Aims and Methods: At the 1993 meeting of the AGA we reported a beneficial effect associated with heparin therapy in nine of ten cases with refractory UC. As a number of initially promising treatments for IBD have subsequently proved disappointing, we decided to review (a) the outcome of the patients in our pilot study, (b) unpublished case reports of further patients treated with heparin, and (c) recent publications on heparintherapy in refractory UC.
Results: (a) Five of the nine patients who went into remission on heparin had a recurrence off heparin; four of these responded to further heparin treatment. Three patients had colectomies (for cancer; obstruction; pseudopolyps). All three were in clinical remission at the time ofsurgery. (b)Seven further patients with refractory UC were treated at our hospital. Three had fulminant and four moderate disease. All went into remissionon i.v. heparin with sulphasalazine, two having initially failed to respondon s.c. heparin. We received reports of nine cases of UC treated with heparin at other centers here and abroad, seven of whom had a favorable response. (c)an open pilot study of heparin in nine cases of refractory UC reports remission in seven cases, with one relapse. A case study  reportsthe rapid and sustained resolution of pyoderma gangrenosum and refractoryUC on
i.v. heparin. Conclusions: Heparin, used i.v. and with sulphasalazine, appears to be effective in the treatment of refractory UC, and warrants larger controlled trials.
1. Evans RC, Rhodes JM.Treatment of corticosteroid resistant ulcerative colitis with heparin -a report of nine cases (abstract). Gut 1995;37(supp1 2);A49.
2. Dwarakanath AD, Yu LG, Brookes C, Rhodes JM. ‘Sticky’ neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis. Gut 1995;37:585-588.
TITLE:  TREATMENT OF ULCERATIVE COLITIS WITH HEPARIN
AUTHORS: F. Brazier1, T. Yzet1, A. Boruchowicz , J.F. Colombel , J.C.Duchmann1, J.L. Dupas1. Department of Gastroenterology, University Hospital,Amiens1, Lille , France
BODY: Activation of procoagulant factors and high incidence of
thromboembolic events observed in ulcerative colitis (UC) suggest thata disorder of coagulation may contribute to the pathogenesis of thisdisease. Preliminary studies have shown that clinical remission may be obtainedby heparin treatment in UC.
The aim of this study was to evaluate on a small group of patients,the efficacy of heparin in active UC.
Methods: 6 patients (2 F, 4 M; age 20-43 yr) with active UC were included in this open label study. Disease activity was established at entryby clinical and colonoscopic criteria. Disease extent was left-sided in 3 patients and extensive to the entire colon in the 3 other patients. UC was moderately active in 4 patients and severe in 2 patients ;3 patients failed to respond to corticosteroids given for at least 2 weeks. Patients were administered heparin, either intravenously (IV) 3000u/4hrs for 1 weekand subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for the 3 following weeks (n=3), or SC 0.1ml/10kg b.i.d. for 4 weeks (n=3). Concomitant treatment with other drugs was not allowed during the study.
Patients were clinically evaluated daily.
Results: 4 patients reported significant clinical improvement: rectal bleeding stopped within the first 3 days and a remarkable decreasein bowel movements was observed in less than 10 days. One patient did not improve and proceeded to colectomy after 1 week. In the last patient heparin treatment was discontinued after 5 days because of a skin allergic reaction. Colonoscopy performed after 4 weeks in the 4 responders showed a complete healing of mucosal damages in 3 patients but persistent superficial erosions in one. Three of these 4 patients were still in clinical remission 4 weeks after the end of heparin treatment.
Conclusion: These preliminary results indicate that heparin treatmentmay be effective in acute UC.
TITLE:  EFFECT OF HEPARIN TREATMENT ON EXTRAINTESTINAL MANIFESTATIONSASSOCIATED WITH INFLAMMATORY BOWEL DISEASES.
AUTHORS: F. Brazier, T. Yzet, J.C. Duchmann, F. Iglicki, J.L. Dupas.Department of Gastroenterology, University Hospital, Amiens, France
BODY: Extra-intestinal manifestations occurring in patients with Crohn’s disease (CD) or ulcerative colitis (UC) are related to the activityof the bowel disease. Microvascular inflammation and hypercoagulable statemaycontribute to the pathogenesis of active inflammatory bowel disease(IBD).Preliminary studies have suggested that heparin, acting by anti-inflammatoryand anticoagulant properties, may be effective in the treatment of activeUC. The aim of this study was to evaluate the efficacy of heparin treatmenton extra-intestinal manifestations associated with active IBD. Methods:Thestudy was undertaken in 7 patients (5 F, 2 M, age 25-35 yr) with activeIBD(6 CD, 1 UC) and one (n=5) or more (n=2) extra-intestinal manifestations(erythema nodosum n=4, pyoderma gangrenosum n=1, peripheral arthritis n=3, apthous stomatitis n=1). These manifestations were associated with flare ofbowel disease in 6/7 patients. Three patients had chronic active CD treatedby prednisolone (20-35 mg/d) for at least 3 months; prednisolone doses werenot altered in the 3-weeks period before and were to be maintained at thesestable doses throughout the 4-weeks study period. Patients wereadministered heparin, either intravenously (IV) 3000u/4hrs for 1 week and subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for thefollowing 3 weeks (n=2), or SC 0.1ml/10kg b.i.d. for 4 weeks (n=4).Concomitant treatment with other drugs was not allowed during the study.Clinical evaluation was performed every week during the treatment,andevery 2 weeks for 3 months after the end of heparin treatment. Results:Extra-intestinal manifestations vanished completely in 5/7 patients withinthe first 2 weeks. In 1 patient erythema nodosum improved but did notvanish completely; for one patient with pyoderma gangrenosum, heparin treatment had to be discontinued after 5 days because of a skin allergic reaction. In 2 responders, erythema nodosum recurrence was observed within2 weeks after the end of heparin treatment. In the 5 responders, the meanC-reactive protein level remarkably decreased from 108 mg/l beforetreatment to 31 mg/l after 1-week treatment. Conclusions: These resultsindicate that heparin may be a potential therapeutic drug forextra-intestinal manifestations in the treatment of active IBD.
TITLE:  TREATMENT OF ACTIVE CROHN’S DISEASE WITH HEPARIN
AUTHORS: J.L. Dupas, F. Brazier, T. Yzet, B. Roussel, J.C. Duchmann,F. Iglicki, Department of Gastroenterology, University Hospital, Amiens,France
BODY: It has been suggested that microvascular thrombosis related to vasculitis and procoagulant factors activation may contribute to the pathogenesis of Crohn’s disease (CD). Anticoagulant and anti-inflammatory properties of heparin may be useful in the treatment of active inflammatory bowel diseases. The aim of this study was to investigate the potential efficacy of heparin in the treatment of active CD. Methods: 13 patients(9F, 4 M; age 16-31 yr) with active CD (Crohn’s disease activity index,CDAI> 200) were included in the open-label study. Disease activity was clinically and endoscopically assessed before treatment. Disease extended only to the colon in 3 patients and to the colon and terminal ileum in the10 other patients. Eight patients had chronic active CD treated by azathioprine and/or prednisolone for at least 3 months; drug doses were not altered in the 3 weeks period before and were continued at the dose used at entry, throughout the 4-weeks study period. Patients were administered heparin, either intravenously (IV) 3000u/4hrs for 1 week and subcutaneously(SC) (calcium heparinate) 0.1 ml/10kg b.i.d. for the following 3 weeks(n=7), or SC 0.1 ml/10kg b.i.d. for 4 weeks (n=6). Concomitant treatment with other drugs was not allowed during the study. All patients were clinically and biologically evaluated every week for the 4-weeks treatment period and followed up every 2 weeks for 2 months after the end of heparin treatment. Results: After 4-weeks treatment, 7/13 patients (54 %) fulfill the remission criteria (CDAI < 150) and 3 other patients reported significant clinical improvement ([Delta-bar] CDAI>100); 3 patients failed to respond. The mean CDAI decreased from 315 (95%CI:260-369) before treatment to 165 (95%CI:107-222) at the end of heparin treatment (p<0.004).The mean C-reactive protein decreased from 80.5 mg/l (95%CI:45-115) before treatment to 35 mg/l (95%CI:18-52) (p<0.007) after 1-week treatment.Slight increase of rectal bleeding due to overdosage of heparin was observed in 2patients leading to discontinuation of treatment in one of them. Among responders, 6 patients were still in remission 3 months after the end of treatment and 1 patient had a relapse at week 6. Conclusions: These results suggest that heparin treatment may be effective in patients with active CD.
TITLE:  EFFECT OF HEPARIN ON INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-alpha SERUM LEVELS IN INFLAMMATORY BOWEL DISEASES.
AUTHORS: F. Brazier1, T. Yzet1, C. Dessaint , J.C. Duchmann1, L. Prin, J.L. Dupas1. Departments of Gastroenterology1, Immunology, University Hospital, Amiens, France.
BODY: It has been suggested that pro-inflammatory cytokines interleukin-6(IL-6) and tumor necrosis factor – alpha (TNF-alpha) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). In a preliminary study conducted to evaluate the effectiveness of heparin treatment in IBD,we obtained a clinical remission (CDAI<150) in 7/13 (54 %) patients and a significant improvement ([open square]CDAI>100) in 3/13 (23 %) patients with Crohn’s disease (CD) as well as a clinical remission in 4/6 patients with acute ulcerative colitis (UC).
The aim of this study was to evaluate the effect of heparin treatmenton IL-6 and TNF-alpha serum levels in IBD.
Methods: IL-6, TNF-alpha (ELISA) and C-reactive protein (CRP) serum levels were measured before and after 1-week heparin treatment in 12 patients with active IBD (8CD, 4 UC). Patients received heparin, either intravenously 3000u/4hrs or subcutaneously (calcium heparinate) 0.1 ml/10kg b.i.d.
Results: table shows mean values and the results of paired comparison of CRP, IL-6 and TNF-alpha serum levels for the 12 patients:
normal before after p-value treatment 1 week CRP mg/l < 5 79 36 <0.02 IL-6 pg/ml 3-8.5 74.3 42.0 <0.02 TNFα pg/ml 3-20 40.8 27.9 <0.15
Conclusion: High values of IL-6, and TNF-alpha serum levels are observed in acute IBD. IL-6 but not TNF-alpha decreases significantly after 1-week heparin treatment.
TITLE:  HEPARIN IN THE TREATMENT OF HIGHLY ACTIVE INFLAMMATORYBOWEL DISEASE (IBD).
AUTHORS: C. Folwaczny, M. Spannagl, W. Wiebecke*, M. Jochum#, W. Heldwein,K. Loeschke. Medizinische Klinik, Klinikum Innenstadt, Pathologisches Institut*,Abteilung für klinische Biochemie#, Ludwig-Maximilians University,Munich, Germany
BODY: Recently (Gaffney et al., Am. J. Gastroenterol. 1995, 90: 220) unfractioned heparin (UH) was reported to be clinically helpful in 10patients with steroid-resistant ulcerative colitis (UC). It is not known whether this beneficial effect is mediated by anti-coagulatory or anti-inflammatory properties of UH. Therefore, we started an openun controlled trial to investigate the clinical and antiinflammatory effects of UH in patients with highly active IBD. Patients and methods: So far 6 UC patients and 1 patient with Crohn’s disease (CD) (2 women, 5 men; mean age:31+-3 y; mean duration of the disease: 10+-4 y) were studied. At entry UC patients had a mean clinical activity index (CAI, according to Gomeset al.) of 17+-3 points and the CD patient had a Crohn’s disease activity index(CDAI, according to Best at al.) of 425 points. The mean follow-upper iod was 5 weeks. The protocol includes PTT-effective i. v. application of UH(>60 sec.) for 2 wk followed by s. c. UH (12.500 I. E. BID) for another6wk. In addition, sulfasalazine (1 g/TID) was given orally. Prednisolone in the 6 UC-patients could be tapered from 38+-7 mg/day at study entry to 26+-10mg after 4 wk. Erythrocyte-sedimentation rate (ESR), C-reactive protein(CRP), white-blood cell (WBC) and platelet count (PC), \alpha_1 and\alpha_2-globulin and fibrinogen were monitored weekly. Results: All patients showed marked clinical improvement. After 2 and 4 wk the CAI decreased to a mean of 5+-1 points and 5+-1 points (p<0,01), resp. and the CDAI decreased to 229 and 250 points, resp. Rectal bleeding stopped in all patients within 4 wk.
The laboratory values at study-entry, after 2 and 4 wk resp. were asfollows:
baseline 2wk 4wk ESR: 77+-8 43+-6 (p<0,01) 47+-9 mm/2h (p<0,01) CRP: 12+-4 2+-1 (p<0,01) 2+-0,5 mg/dl (p<0,01) WBC: 14.0+-2.0 10.0+-1.2 (p<0,01) 9.0+-1.3/ l (p<0,01) PC: 448+-34 387+-47 (p<0,01) 330+-44/ l (p<0,01) \alpha_1-globulin: 5,3+-0,9 3,8+-0,6 (p<0,01) 5,0+-0,6% fibrinogen: 379+-12 290+-37 (p<0,01) 317+-32 mg/dl
The CD patient refused corticosteroids and arthritis resolved after 6 wk. In 1 UC-patient UH treatment was stopped at day 11 because of sudden worsening of the rectal bleeding (PTT at this time <60 sec.) necessitating blood transfusions. Because the patient noticed a decrease in bowel movements i. v. UH was restarted after 2 days, resulting in continuing improvement with no further bleeding. No other unwanted effects were seen, apart from a minor reversible increase in ALT-activity in 3 patients. Conclusions: These preliminary data confirm that UH could be useful in highly active IBD. This effect may in part be due to anti-inflammatory properties of UH. However, controlled trials have to be awaited before routine use of UH can be recommended.