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 an
anticoagulant would not make things worse.
Historically, the main drug used in ulcerative colitis was discovered accidentally. Sulfasalazine (aka Azulfidine) was initially designed as an antiarthritis drug. It is a molecule of 5-ASA and sulfa antibiotic joined by a covalent bond. The initial thinking was that the drug would be absorbed and the combination of antibiotic and antiinflammatory would be good for rheumatoid arthritis, a disease that back then was thought to be due to an infection and inflammation. A few patients with UC and arthritis were seen to do quite well in regards to their colitis. It didn't work very well 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 for bacteria) and locally liberated the antiinflammatory drug 5-ASA.
History seems to have repeated itself with heparin. A patient with UC was 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 microscopic appearance of the tissue is that of multiple tiny blood clots in the vessels of the injured colon. This was thought to represent coagulation in response to the inflammation, and perhaps was even protective since clotting may have represented the prevention of further bleeding. Well, with the improvement that was seen, it was only natural to wonder whether the improvement seen in the patients with UC might have been due to better blood flow to the injured 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 patients seem to have. Interestingly, one of the described uses is in patients with extraintestinal complications of IBD, such as erythema nodosum. These complications can be very slow to respond to conventional therapy. Bleeding does sometimes happen, but it does not seem to be uncontrollable. Heparin has no toxicity, and only occasionally has poor outcomes, though as more patients are treated we may see injuries occur (massive GI or pulmonary bleeding, strokes).
Below I have reproduced the abstracts from the 1996 DDW meeting that referred to heparin in treatment of IBD. They are copyright DDW.
Remember that these are early studies, and a number of treatment for IBD have been found to be worthless over the years. Even if correct, the studies were small, and did not have controls. There is no data on what the optimal dose or duration of treatment is. Even simple things, like taking advantage of what is known about the histology of UC and checking whether the presence of microthrombi predicted whether patients would benefit was not done. Most patients seem to be helped, but a few seem to bleed more. Can we predict who those will be? These questions will need to be addressed before heparin moves into the mainstream of treatment of IBD.
I participated in a double blind, placebo controlled study which has
been completed. Those results show
the drug was effective.
Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria
TITLE: [65] HEPARIN THERAPY IN REFRACTORY ULCERATIVE COLITIS - AN UPDATE.
AUTHORS: P.R. Gaffney, A. Gaffney. Dept. of Surgery, Mallow General Hospital, 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 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 of
surgery.
(b)Seven further patients with refractory UC were treated at our hospital.
Three had fulminant and four moderate disease. All went into remission
on
i.v. heparin with sulphasalazine, two having initially failed to respond
on
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[1]. A case study [2] reports
the
rapid and sustained resolution of pyoderma gangrenosum and refractory
UC 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.
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 that
a
disorder of coagulation may contribute to the pathogenesis of this
disease.
Preliminary studies have shown that clinical remission may be obtained
by
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 entry
by
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 week
and
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 decrease
in 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 treatment
may
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 activity
of the
bowel disease. Microvascular inflammation and hypercoagulable state
may
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 of
active
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 active
IBD
(6 CD, 1 UC) and one (n=5) or more (n=2) extraintestinal manifestations
(erythema nodosum n=4, pyoderma gangrenosum n=1, peripheral arthritis
n=3,
aphtous stomatitis n=1). These manifestations were associated with
flare of
bowel disease in 6/7 patients. Three patients had chronic active CD
treated
by prednisolone (20-35 mg/d) for at least 3 months; prednisolone doses
were
not altered in the 3-weeks period before and were to be maintened at
these
stable doses throughout the 4-weeks study period. Patients were
administered heparin, either intravenously (IV) 3000u/4hrs for 1 week
and
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 patients
within
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 observed
within
2 weeks after the end of heparin treatment. In the 5 responders, the
mean
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 ileum
in the
10 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 2
patients 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.
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 proinflammatory 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 treatment
on
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 value treatment 1 week CRP 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 observed in
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 not
known
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 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 Gomes
et
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-up
period
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 another
6
wk. 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+-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 stopped
in all
patients within 4 wk.
The laboratory values at study-entry, after 2 and 4 wk resp. were as follows:
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
antiinflammatory properties of UH. However, controlled trials have
to be
awaited before routine use of UH can be recommended.