Heparin in IBD

One of the oddest treatments to come along in quite some time isthe use of a medicine called heparin in the treatment of IBD. The reasonthis 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 sometimeshappen, 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 benefitwas 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.

I participated in a double blind, placebo controlled study which hasbeen completed.  Those results showthe drug was effective.

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria

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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 caseswith
refractory UC. As a number of initially promising treatments for IBDhave
subsequently proved disappointing, we decided to review (a) the outcomeof
the patients in our pilot study, (b) unpublished case reports of further
patients treated with heparin, and (c) recent publications on heparin
therapy 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 withheparin
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[1]. A case study [2] 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. 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.


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 in3
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 patientsfailed
to respond to corticosteroids given for at least 2 weeks. Patientswere
administered heparin, either intravenously (IV) 3000u/4hrs for 1 weekand
subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for the3
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 showeda
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.


AUTHORS: F. Brazier, T. Yzet, J.C. Duchmann, F. Iglicki, J.L. Dupas.Department of Gastroenterology, University Hospital, Amiens, France

BODY: Extraintestinal manifestations occuring in patients with Crohn's
disease (CD) or ulcerative colitis (UC) are related to the activityof the
bowel disease. Microvascular inflammation and hypercoagulable statemay
contribute to the pathogenesis of active inflammatory bowel disease(IBD).
Preliminary studies have suggested that heparin, acting by antiinflammatory
and anticoagulant properties, may be effective in the treatment ofactive
UC. The aim of this study was to evaluate the efficacy of heparin treatment
on extraintestinal manifestations associated with active IBD. Methods:The
study 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) extraintestinal manifestations
(erythema nodosum n=4, pyoderma gangrenosum n=1, peripheral arthritisn=3,
aphtous stomatitis n=1). These manifestations were associated withflare of
bowel disease in 6/7 patients. Three patients had chronic active CDtreated
by prednisolone (20-35 mg/d) for at least 3 months; prednisolone doseswere
not altered in the 3-weeks period before and were to be maintened atthese
stable doses throughout the 4-weeks study period. Patients were
administered heparin, either intravenously (IV) 3000u/4hrs for 1 weekand
subcutaneously (SC) (calcium heparinate) 0.1ml/10kg b.i.d. for the
following 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,and
every 2 weeks for 3 months after the end of heparin treatment. Results:
Extraintestinal manifestations vanished completely in 5/7 patientswithin
the first 2 weeks. In 1 patient erythema nodosum improved but did not
vanish 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 observedwithin
2 weeks after the end of heparin treatment. In the 5 responders, themean
C-reactive protein level remarkably decreased from 108 mg/l before
treatment to 31 mg/l after 1-week treatment. Conclusions: These results
indicate that heparin may be a potential therapeutic drug for
extraintestinal manifestations in the treatment of active IBD.


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 antiinflammatory
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(9
F, 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 ileumin the
10 other patients. Eight patients had chronic active CD treated by
azathioprine and/or prednisolone for at least 3 months; drug doseswere not
altered in the 3 weeks period before and were continued at the doseused 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 ofheparin
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 patientsfailed
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 observedin 2
patients leading to discontinuation of treatment in one of them. Among
responders, 6 patients were still in remission 3 months after the endof
treatment and 1 patient had a relapse at week 6. Conclusions: Theseresults
suggest that heparin treatment may be effective in patients with activeCD.


AUTHORS: F. Brazier1, T. Yzet1, C. Dessaint , J.C. Duchmann1, L. Prin, J.L. Dupas1. Departments of Gastroenterology1, Immunology , UniversityHospital, Amiens, France.

BODY: It has been suggested that proinflammatory cytokines interleukin-6
(IL-6) and tumor necrosis factor - alpha (TNF-alpha) may be involvedin the
pathogenesis of inflammatory bowel diseases (IBD). In a preliminarystudy
conducted to evaluate the effectiveness of heparin treatment in IBD,we
obtained a clinical remission (CDAI<150) in 7/13 (54 %) patientsand 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) serumlevels
were measured before and after 1-week heparin treatment in 12 patientswith
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 comparisonof
CRP, IL-6 and TNF-alpha serum levels for the 12 patients:

              normal       before               after              value       treatment            1 weekCRP mg/l       < 5           79                 36         p<0.02(95 % CI)                 (38-120)           (15-36)IL-6 pg/ml     3-8.5         74.3               42.0       p<0.02(95 % CI)                 (41.7-107)        (26.6-57.35)TNF-alpha pg/ml 3-20       40.8                 27.9       p<0.15(95 % CI)                 (22.8-58.9)        (21.9-33.9)
Conclusion: High values of IL-6, and TNF-alpha serum levels are observedin
acute IBD. IL-6 but not TNF-alpha decreases significantly after 1-week
heparin treatment.


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 clinicaly helpful in 10
patients with steroid-resistant ulcerative colitis (UC). It is notknown
whether this beneficial effect is mediated by anticoagulatory or
antiinflammatory properties of UH. Therefore, we started an open
uncontrolled trial to investigate the clinical and antiinflammatoryeffects
of UH in patients with highly active IBD. Patients and methods: Sofar 6 UC
patients and 1 patient with Crohn`s disease (CD) (2 women, 5 men; meanage:
31+-3 y; mean duration of the disease: 10+-4 y) were studied. At entryUC
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 activityindex
(CDAI, according to Best at al.) of 425 points. The mean follow-upperiod
was 5 weeks. The protocol includes PTT-effective i. v. applicationof UH
(>60 sec.) for 2 wk followed by s. c. UH (12.500 I. E. BID) for another6
wk. In addition, sulfasalazine (1 g/TID) was given orally. Prednisolonein
the 6 UC-patients could be tapered from 38+-7 mg/day at study entryto 26+-10
mg 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 stoppedin all
patients within 4 wk.

The laboratory values at study-entry, after 2 and 4 wk resp. were asfollows:

     baseline           2wk                 4wkESR:    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 becauseof
sudden worsening of the rectal bleeding (PTT at this time <60 sec.)
necessitating blood transfusions. Because the patient noticed a decreasein
bowel movements i. v. UH was restarted after 2 days, resulting in
continuing improvement with no further bleeding. No other unwantedeffects
were seen, apart from a minor reversible increase in ALT-activity in3
patients. Conclusions: These preliminary data confirm that UH couldbe
useful in highly active IBD. This effect may in part be due to
antiinflammatory properties of UH. However, controlled trials haveto be
awaited before routine use of UH can be recommended.

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