TREATMENT OF CROHN'S DISEASE WITH LOW MOLECULAR WEIGHT HEPARIN IN PATIENTS WHOSE DISEASE HAS NOT
RESPONDED TO CONVENTIONAL THERAPY.
Philip Edlin MD, Charles J Glueck MD. Cholesterol Center, Jewish Hospital, 3200 Burnet Avenue, Cincinnati Ohio,
45229.
Phone: 513-924-8250 Fax: 513-924-8273
E-mail: glueckch@healthall.com or cglueck@fuse.net
web: /cholesterol/index.html
Publication:
10. Glueck CJ, Edlin P, Safdi M, et al. Thrombophilia and hypofibrinolysis: Pathoetiologies of Crohn's Disease? Journal
of Investigative Medicine 1996;44:296A
Background:
We have evidence that some/many of the problems of Crohn's disease may be caused by increased likelihood of blood
clotting (thrombophilia) in tiny veins or arteries of the small or large intestine, leading to reduced oxygenation of tissue and tissue damage (10).
Evidence:
Crohn's disease occurs with great frequency in all parts of the world. It attacks young people predominantly and often
causes severe and prolonged morbidity and sometimes death. There is no certainty as to its pathophysiology or etiology. Treatment therefore is empiric,
symptomatic and often not successful. There is new evidence that prothrombotic diseases can cause inflammatory bowel disease, perhaps by thrombosing
arterioles and/or venules in the small and/or large intestine, leading to ischemia and ulceration (1-5).
We have previously shown that thrombophilic and hypofibrinolytic disorders can cause osteonecrosis by occluding venous
return in bones, thus producing ischemic infarction of bones (6-9). This is reversible (9), provided the coagulation disorders can be reversed with
medical treatment and provided that irreversible segmental collapse of the bone has not occurred.
Our hypothesis is that it may also be possible to reverse inflammatory bowel disease by first diagnosing and then
treating coagulation defects.
There is evidence that treatment with heparin, a standard anticoagulant, more specifically low molecular weight heparin
which you can self-inject at home, may help relieve the symptoms of Crohn's disease10 which has not responded optimally to conventional
therapy.
After consultation with your Gastroenterologist, we can determine whether you might be helped by the low molecular weight
heparin therapy. The research protocol does not cover X rays, colonoscopy, sigmoidoscopy, hospitalization, or emergency room visits.
References:
Duration of the program, eligibility:
The program will last for 42 days (6 weeks).
Inclusion Criteria:
a. Age range:
21-75
b. Failure on conventional therapy:
Patients entering the study will have failed to respond with a
reduction of their Oxford score (1 to 10 scale) to <5 (Scand J Gastroenterol 1984;19:1-27). These conventional therapies typically include
sulfasalizine, prednisone, and immunosupressive agents.
c. The degree of symptomatic IBD required to enter the trial:
If Oxford score is > 5 despite
conventional therapy, then the patients are eligible to enter the trial.
d. Laboratory evidence of thrombophilia and hypofibrinolysis required for study enrollment:
Thrombophilia: High serum homocysteine and/or homozygosity for the MTHFR polymorphism, high
anticardiolipin antibodies, resistance to activated protein C and/or hetero- or homozygosity for the mutant Factor V Leiden gene, high prothrombin
and/or heterozygosity for the mutant prothrombin gene, presence of the lupus anticoagulant.
Hypofibrinolysis: High Lp(a), high plasminogen activator inhibitor activity and or homozygosity for the
4G polymorphism of the promoter region of the PAI-1 gene, low stimulated tissue plasminogen activator activity.
Exclusion criteria:
- Rectal bleeding prior to study enrollment would not disqualify patient enrollment in the study unless it required transfusion of > 2 units of whole blood > once/month for 2 subsequent months prior to study initiation.]
- Hepatic and renal disorders: Liver failure with ascites would be an exclusion from study entry. Renal failure
requiring dialysis would be an exclusion from study entry.
- Infectious diseases: AIDS or HIV positive patients would be excluded.
- Pregnant patients: Pregnant patients, as shown by a positive serum pregnancy test would be excluded.
- Other patients: Patients with any disorder known to be associated with increased risk of bleeding such as
bleeding varices, bleeding ulcers. Patients with concomitant aspirin therapy would not be excluded, as this should not interact adversely with the low
molecular weight heparin. Patients involved in contact team sports.
Protocol: Use of heparin in Inflammatory Bowel Disease:
In those individuals with ulcerative colitis or Crohn's disease found to have a coagulation disorder, and who have failed
to respond satisfactorily to conventional treatment programs (as concluded by their Gastroenterologists), 30 mg low molecular weight heparin will be
given subcutaneously twice each day in an attempt to reduce the symptoms of the disease, to reduce disease progression, and, if possible, to reverse the
disease process. Each patient or family member will be taught how to inject the heparin himself or herself. Current doses of a commonly used drug in
inflammatory bowel disease, Sulfasalazine, will be maintained (10); prednisone (corticosteroid therapy) will be tapered and stopped.
Self-injection of low molecular weight heparin:
Twice per day, in the morning and in the evening after your evening meal, you will self-inject, subcutaneously, 40 mg of
Enoxaparin, a low molecular weight heparin. This is injected just like insulin, just under the skin. We will arrange to have one of our staff instruct
you in the proper injection technique.
Monitoring: Complete blood counts and platelet counts will be measured after 3 and 7 days heparin therapy, and
thereafter once per week for 4 weeks and then once every 4 weeks up to a total of 6 weeks (42 days). These measurements can be done in the Jewish
Hospital Cholesterol Center or in the physicians' offices. With low molecular weight heparin it is not necessary to measure coagulation times. It has
been shown that on 40 mg Enoxaparin/day, satisfactory anticoagulation is achieved in almost all patients.
Assessment of efficacy: We will ask each patient to keep a written diary for stool frequency (average number per
day for the past week). We will ask each patient to keep a record of rectal bleeding graded as follows: 0= absent, 1= streaks of blood in the stool
some of the time, 2= obvious blood in the stool most of the time, 3= blood alone passed, all stools bloody. We will use a written form which we have
debugged in the first year of the study.
Monitoring Safety and Efficacy:
Safety:
Because the low molecular weight heparin is a standard anticoagulant (blood thinner), and because one of the hallmarks
of Crohn's disease is bleeding, it is very important for patients to carefully monitor daily for stool blood. If prior to starting heparin there
was no obvious blood in the stool, and if the stool becomes 1) streaked with blood, 2) obvious [gross] blood most of the time, or 3) blood alone or
all stools bloody, stop the Enoxaparin and call your Gastroenterologist and the Cholesterol Center (513-924-8250) day or night.
If at any time during the treatment period, you experience major blood loss in the stools, feel faint or dizzy,
suggestive of enough blood loss to lower your blood pressure, then call your Gastroenterologist's office, the Cholesterol Center (513-924-8250), and
come immediately to the emergency room.
Efficacy:
We anticipate that there should be major symptomatic improvement by day 42, and we speculate that this symptomatic
improvement might last for months or years.
E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-924-8273
