Ischemic colitis revisited: a prospective study identifying hypercoagulability as a risk factor.

Background: Although causes for ischemic colitis have been identified, many cases are deemed idiopathic. Some reports suggest an association between ischemic colitis and coagulation disorders. Our purpose was to explore the relationship of ischemic colitis and clotting abnormalities.

Methods: Eighteen patients consented to undergo a hypercoagulability evaluation. Tests included protein C, protein S, activated protein C resistance, factor V Leiden, anticardiolipin antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, antithrombin III, anti-smooth muscle antibody, lupus anticoagulant panel, and prothrombin 20210G/A mutation (in women undergoing hormone replacement therapy).

Results: Five of 18 patients tested positive for coagulation abnormalities, including factor V and activated protein C resistance, protein S deficiency, prothrombin 20210G/A mutation, and anticardiolipin antibody.

Conclusion: To our knowledge, this is the largest series of patients with ischemic colitis studied for coagulation defects in the United States. The prevalence of clotting disorders in our study (28%) was higher than that in the general population (8.4%). Coagulation disorders should be considered in some cases of ischemic colitis that are thought to be idiopathic.

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A number of causes of ischemic colitis have been identified, including cardiovascular disease, diabetes mellitus, renal disease, abdominal surgery, cancer, and some medications. (1-6) Nevertheless, many cases are deemed idiopathic. There have been a few case reports of ischemic colitis and hypercoagulation disorders. The literature usually divides thrombosis-induced ischemic colitis into inherited and acquired types. Inherited causes of thrombosis include abnormalities in antithrombin III, protein C, protein S, factor V, activated protein C (APC), and prothrombin 20210G/A. Acquired causes include antiphospholipid syndrome and malignancy (Trousseau syndrome). Mann et al (7) described a patient who acquired resistance to APC while on oral contraceptive pills and subsequently developed ischemic colitis. Lucas and Schroy (8) described a 30-year-old female marathon runner who developed reversible intestinal ischemia. Along with a multitude of factors, a hypercoagulable state secondary to polycythemia was suggested as a causative factor of her ischemic colitis. Ludwig et al (9) described a patient who inherited a heterozygous resistance to APC and subsequently developed simultaneous ischemic colitis, pulmonary embolism, and right atrial thrombosis. A study in 1999 found hypercoagulable states to be present in a subset of patients with ischemic colitis. Clotting factor abnormalities, including elevated antithrombin III and antiphospholipid antibody, were detected in three of nine patients in that study. (3) Koutroubakis et al (10) conducted the largest study to date, in Greece. Their study included 36 patients with ischemic colitis and two control groups: 18 patients with diverticulitis and 52 healthy volunteers. They found a significant association between ischemic colitis and hereditary and acquired hypercoagulability. In the 36 patients studied with ischemic colitis, one or more prothrombotic abnormalities were present in 26 patients (72%). Thus, there seems to be corroborating evidence that hypercoagulable states may contribute to ischemic colitis. The purpose of this study was to further define the clinical spectrum of ischemic colitis and its relationship to coagulation disorders.

Methods

Twenty-eight consecutive patients with the diagnosis of ischemic colitis were identified retrospectively. The cases occurred between January 1999 and February 2001. The patients were diagnosed on the basis of a combination of clinical presentation, radiography, endoscopy, and biopsy. The endoscopic findings of ischemic colitis included patchy areas of erythema, erosions, linear ulcerations, and submucosal edema. Histologic description of ischemic colitis included mucosal and submucosal hemorrhage and edema, varying degrees of crypt distortion, dilated capillaries with thrombosis, and mixed submucosal inflammatory cell infiltrates. In all 28 cases, the diagnosis of ischemic colitis was made on the basis of the endoscopic and biopsy findings.

Eighteen patients consented to a prospective hypercoagulability evaluation that included assays for protein C, protein S, APC resistance, factor V Leiden mutation, anticardiolipin antibodies, antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, antithrombin III, anti-smooth muscle antibody, and lupus anticoagulant panel. Female patients who were being treated with hormone replacement therapy (HRT) were tested for prothrombin 20210G/A mutation. All of the tests were performed a minimum of 1 month after the diagnosis of ischemic colitis was made. The same commercial reference laboratory analyzed all samples and was blinded in our study.

The Human Research Review Board approved the study and the informed consent procedure. Patients were contacted by telephone to explain the nature of the study and to inquire about their interest in participating. Testing was provided free of charge, and a small travel stipend was paid to each participant. The individuals who consented to participate were scheduled for a clinic visit. At the visit, the informed consent process was conducted, a complete medical history was obtained, and laboratory tests were conducted. The individuals' medical records were reviewed for demographic data, clinical presentation, diagnostic procedures, laboratory results, treatment, and diagnostic follow-up.

Results

A total of 28 patients were identified for inclusion in the study. Eighteen consented to the additional clotting studies. The remaining 10 individuals either refused (n = 8) or were deceased (n = 2). Seventy-nine percent (n = 22) of the patients were female. The mean age of the sample population was 67.3 years. Eight patients (29%) were younger than 60 years of age, three of whom were 49 years old.

The medical history was obtained from the patients. The medical records of all 28 patients were reviewed, with the focus being on predisposing factors. The records revealed that 25% had a history of coronary artery disease. Other illnesses in this group occurred at the following rates: deep vein thrombosis/pulmonary embolism, three patients; congestive heart failure, two patients; atrial fibrillation, three patients; and cancer six patients. The three patients with deep vein thrombosis/pulmonary embolism were not undergoing anticoagulation therapy at the time of the study. Ten patients were either active smokers or had a history of smoking. Two days before the onset of the ischemic colitis, one patient had a right-sided stroke and one patient underwent angioplasty after having an acute myocardial infarction. Eight (36%) of the 22 female patients were undergoing HRT. None of the patients had a history of a vasculitic syndrome, myeloproliferative disorder, or polycythemia. A family history of coronary artery disease was positive in 16 patients, and 13 had a family history of cancer. The predisposing factors were similar in both groups of patients.

Most of the patients presented with classic signs and symptoms of ischemic colitis. The presenting symptoms were also relatively consistent in all patients studied. Twenty-four of 28 patients reported a chief complaint of abdominal pain. Twenty-one patients complained of diarrhea. Hematochezia was reported in most (22 of 28) patients. Other associated symptoms consisted of nausea (12 patients), vomiting (8 patients), vertigo (4 patients), constipation, diaphoresis, chest pain, and syncope (1 patient each). Two patients presented in shock. One of the patients who presented in shock had experienced a recent right-sided stroke. Surprisingly, two asymptomatic patients were diagnosed with ischemic colitis on the basis of routine colonoscopy.

Laboratory test results at the time of initial presentation were noncontributory. Nineteen of 28 patients presented with a leukocytosis. Seven patients were anemic, three had thrombocytopenia, and one had thrombocytosis.

Several radiographic techniques were used to evaluate the abdominal pain. Computed tomography (CT) of the abdomen was performed in half of the patients. The radiographic readings were consistent with ischemic colitis in 10 cases.

The anatomic locations of the involved colonic segments varied from patient to patient. Eleven patients had a primary injury of the sigmoid and descending colon. Five patients had predominant injury in the splenic flexure and the transverse and descending colon. The entire left side of the colon was affected in four patients, and the entire right side was affected in two patients. Three patients had predominant transverse colonic lesions. Three other patients were diagnosed with pancolitis, affecting patches throughout the entire colon.

Treatment and Outcome Profile

In the overall group of 28 patients, only 1 patient died during the acute event. Her case was complex and included peritonitis and septicemia. The remaining 27 patients were managed medically and had favorable outcomes. All patients had follow-up colonoscopies to document healing.

Eighteen patients had the panel of clotting studies performed. The eight female patients who had been prescribed HRT were tested for prothrombin 20210G/A mutation. Five of 18 patients tested positive for one or more clotting abnormalities. Four of these five were found to have genetic mutations that produce a hypercoagulable state. The clinical spectrum of patients with clotting abnormalities is shown in Table 1. The remaining 13 patients had normal clotting studies.

Two patients were positive for factor V Leiden mutation and APC resistance. One patient demonstrated protein S deficiency. Of the eight patients tested for prothrombin 20210G/A, one was positive. One patient was anticardiolipin immunoglobulin (Ig) M-positive, which is an acquired disorder. Anti-smooth muscle antibody and rheumatoid factors were negative or low titer in all patients. Two additional patients showed increased lupus anticoagulant titers. One patient had elevated total ANCA with increased IgG titers as well as being c-ANCA-positive. One patient had mildly elevated antithrombin III (135%). Seven of the 18 patients had completely normal laboratory findings. There were no patients with protein C deficiency.

Discussion

Ischemic colitis occurs in approximately 1 of 2,000 hospital admissions. (6) The true incidence of the disease is probably underestimated, however, because symptoms are often mild or the condition may be misdiagnosed.

On the basis of the literature, we know that patients with hypercoagulable states may present with ischemic colitis. Specifically, patients with coagulation defects have an increased propensity to clot in either the arteries or the venous system or both. The known hereditary causes of thrombophilia include factor V Leiden mutation, APC resistance, protein S deficiency, protein C deficiency, antithrombin III, and prothrombin 20210GA mutation. In 5 to 15% of cases, inherited thrombophilia is caused by deficiencies in protein C, protein S, and antithrombin III. Factor V Leiden and APC resistance explain an additional 15% of cases. (7)

The prevalence of factor V mutation and APC resistance is 3 to 5% in the general population. (7) We found a prevalence of 11% in this study. Factor V mutation, better known as factor V Leiden, is an inherited autosomal dominant disorder. APC resistance is caused by factor V Leiden mutation in 90% of the cases. Because the inactivation of factor V by protein C is inhibited, the thrombogenic effect of factor V activation is prolonged. (11), (12) These defects specifically predispose patients to venous thrombosis.

The prevalence of protein S deficiency in the general population is 0.2 to 0.5% (13) We report 1 (5.5%) of 18 patients with a protein S deficiency. Protein S deficiency is inherited in an autosomal dominant manner. (14) Protein S and protein C are major inhibitors of the coagulation cascade and, when activated, act as anticoagulants. Specifically, protein S inactivates factors Va and VIIIa. (13) With a deficiency in protein S, venous clots may develop. Protein S deficiency typically presents as deep vein thrombosis and pulmonary embolism. However, mesenteric, axillary, and cerebral venous thrombosis have been reported. (12), (14)

The prevalence of prothrombin 20210G/A mutation is 2% in healthy volunteers. (15) In our study, one of the eight female patients tested was positive for the mutation (12.5%). The defect is located in the 3' region of the prothrombin gene and is associated with an elevated plasma prothrombin. Prothrombin plays an integral part in the coagulation cascade as a precursor to thrombin, an essential element in clot stabilization. (15) Because of the elevated level of prothrombin, the mutation is associated with a three-fold increased risk for venous thrombosis. (15) It typically presents as a deep vein thrombosis and pulmonary embolism. There are only a few reported cases in literature of digestive vessel thrombosis with subsequent ischemic colitis associated with prothrombin 20210G/A mutation. (15) Prothrombin 20210G/A mutation has been identified in females on HRT who developed ischemic colitis. Women taking oral contraceptives and HRT have a six-fold relative risk of developing thromboembolisms alone. With the combination of prothrombin 20210G/A mutation and hormone therapy, a 30-fold risk of thromboembolism results. Without other predisposing factors, patients with this mutation alone may not develop thrombosis. (6)

Besides hereditary hypercoagulation defects, the tendency for thrombosis may be acquired. Antiphospholipid antibody syndrome is an example. To be characterized as antiphospholipid antibody syndrome, the patient must be positive for lupus anticoagulant or have elevated levels of IgG or IgM anticardiolipin antibody. (12), (16) One study suggests that the prevalence of antiphospholipid antibody syndrome is 2% in healthy individuals. (17) Antiphospholipid antibodies are associated with certain autoimmune diseases and cancers. Antiphospholipid antibody syndrome may present with both arterial and venous thrombosis. The mechanism that antiphospholipid antibodies play in clotting is unknown. (11), (14) Antiphospholipid antibodies include anticardiolipin antibodies and/or a lupus anticoagulant. The lupus anticoagulant prolongs the activated partial thromboplastin time because of the antibody's effect on the phospholipid-dependent clotting assay. (12) Our patient with anticardiolipin antibody syndrome had a prolonged activated partial thromboplastin time. He also has a history of bladder cancer with metastasis to the lung.

There are other acquired conditions that cause thrombosis formation. Transient defective clot lysis, rheumatoid arthritis, inflammatory bowel disease, surgery, infection, and malignancy are recognized causes of thrombosis. (12), (14) Armand Trousseau found an association between cancer and hypercoagulability in the mid-19th century. It is postulated that patients with cancer are predisposed to thrombosis because tumor cells and their byproducts activate the coagulation cascade and inhibit the fibrinolytic system. (16) In our group of 18 patients, 5 had a history of cancer. Before the diagnosis of ischemic colitis was made, two of these five patients manifested problems that were a likely consequence of the clotting disorders that we detected. In patients with a history of thrombotic disease who present with ischemic colitis, clinicians should have a high index of suspicion for clotting abnormalities.

To our knowledge, this study represents the largest series of patients with ischemic colitis examined for coagulation defects in the United States. The study by Koutroubakis et al (10) in Greece and our findings in the United States suggest that ischemic colitis associated with acquired or hereditary hypercoagulable states is prevalent. There seems to be a link between ischemic colitis and clotting disorders. Although the number of patients in our study is small, we found a higher prevalence of clotting disorders (28%) than that reported in the general population (8.4%). We conclude that clotting abnormalities are a causative factor in many cases of ischemic colitis that were once labeled idiopathic. Therefore, in patients with idiopathic ischemic colitis, we advocate a battery of tests to evaluate their coagulation status. These tests include factor V Leiden, antithrombin III, protein C, protein S, prothrombin 20210G/A (in females undergoing HRT), anticardiolipin antibody, and lupus anticoagulant.

Key Points

* To our knowledge, this study comprised the largest series of patients with ischemic colitis evaluated for coagulation defects in the United States.

* The prevalence of clotting disorders in our study (28%) was higher than that in the general population (8.4%).

* A thorough hypercoagulability evaluation should be performed in patients with ischemic colitis that is deemed idiopathic.

Table 1. Patients with clotting abnormalities (a)

Patient
no.               Results              Clinical picture

   1     Factor V mutation-positive,      75-year-old man CAD treated
           heterozygous                   with CABG Smoking and
         APC resistance 1:8 ratio         alcohol history
           (normal, [greater than or
           equal to]2.0 negative)

   2     Factor V mutation-positive,      80-year-old man DVT at age
           heterozygous                   72 CVA at age 57
         APC resistance 1:4 (normal,      Hypercholesterolemia,
           [greater than or equal to]2.0    hypertension
           negative)
         ANCA total antibodies 1:40 FIU
           (normal <1:20 FIU)
           c-ANCA-positive

   3     Protein S deficiency, 56%        57-year-old man
           (normal. >60%)                 PMH-negative
                                          Family history of PE
                                            (mother)

   4     Prothrombin 20210G/A             73-year-old woman Hormone
           mutation-positive,             replacement therapy
           heterozygous                   Hypertension

   5     Cardiolipin IgM antibodies 30    75-year-old man CAD,
           mlp (normal, <10 mlp)          hypertension Metastatic
         Lupus anticoagulant 56.2 s       bladder cancer
           (normal, 31-50 s)

(a) APC, activated protein C; CAD, coronary artery disease; CABG,
coronary artery bypass graft; DVT, deep vein thrombosis; CVA,
cardiovascular accident; ANCA, antineutrophil cytoplasmic
antibodies; FIU, fluorescent international unit; PMH, past
medical history; PE, physical examination; IgM,
immunoglobulin M.

Accepted January 31, 2003.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9702-0120

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(15.) Balian A, Veyradier A, Naveau S, et al. Prothrombin 20210G/A mutation in two patients with mesenteric ischemia. Dig Dis Sci 1999;44:1910-1913.

(16.) Alving BM. The hypercoagulable states. Hosp Pract (Off Ed) 1993;28:109-121.

(17.) Grosset AB, Rodgers GM. Acquired coagulation disorders, in Lee GR, Foerster J, Lukens J, et al (eds). Wintrobe's Clinical Hematology. Philadelphia, Lippincott Williams & Wilkins, 1999, vol 2, ed 10, pp 1759-1763.

Robin Midian-Singh, MD, Ann Polen, MED, Catherine Durishin, MD, Ronald D. Crock, MD, Frederick C. Whittier, MD, and Nabil Fahmy, MD

From the Northeastern Ohio Universities College of Medicine, Affiliated Hospitals at Canton, Canton, OH.

This study was funded in part by a grant from the Aultman Health Foundation, Canton, OH.

Reprint requests to Ronald D. Crock, MD, Affiliated Hospitals at Canton, 1320 Mercy Drive NW, Canton, OH 44708. Email: [e-mail]