Ischemic Colitis in Young Healthy Adults Not Associated with Inherited Hypercoagulable Conditions

 

N. Peter Zauber, MD

Sudha Sinha, MD

 

Department of Medicine

Saint Barnabas Medical Center

Livingston, NJ 07039

Funding was provided by the Harvey E. Nussbaum, MD, Research Institute at Saint Barnabas.

 

 KEY WORDS: hypercoagulability, protein C, protein S, anti-thrombin III, Factor V Leiden, prothrombin mutation, DVT.

 

Abstract

Five healthy young patients were diagnosed with ischemic colitis by biopsy at our medical center. We examined these patients for the presence of hypercoagulable conditions: deficiencies of protein C, protein S, and antithrombin III; activated protein C resistance; and factor V Leiden and prothrombin 20210 mutations. We found no association between ischemic colitis and these hypercoagulable disorders in this group of healthy young adults. However, epidemiologic evidence suggests the presence of several possible contributing factors for each patient.

Introduction

Ischemic colitis has traditionally been associated with elderly patients who have comorbid conditions such as surgery, vascular disease, low flow states, colon cancer, intestinal stricture or diverticulosis, and atherosclerosis.1-3 However, this condition has also been reported in young healthy adults without any obvious predisposing factors.4-6 We conducted a retrospective study looking for an association between ischemic colitis in young healthy adults and the inherited hypercoagulable disorders of protein C, protein S, and antithrombin III deficiencies or the presence of activated protein C (APC) resistance, factor V Leiden or prothrombin G20210A mutations.

Materials and Methods

A retrospective review of pathology reports at two community-based medical centers between the years 1996 and 1999 revealed 22 patients younger than 65 years of age at the time of clinical diagnosis whose colonic mucosal biopsy samples revealed ischemic colitis. After reviewing their clinical records and discussing the cases with the gastroenterologists involved in their care, we excluded 11 patients from the study for the following reasons: 3 were in the intensive care unit in low flow states, 2 were diagnosed with Crohn's disease, 3 had colon cancer, 1 had peripheral vascular disease, 1 had end-stage renal disease, and 1 was undergoing chemotherapy for breast cancer. The final study population consisted of 11 patients; 10 women and 1 man. Ages ranged from 44 to 62 years. Of these 11 patients, 5 agreed to participate in the study, 4 were lost to follow-up, and 2 refused. Approximately 15 cc of blood was collected from each of the 5 participating patients. They were interviewed over the telephone in a standardized manner regarding possible history of hypertension, diabetes mellitus, coronary artery disease, stroke, migraine headaches, abdominal surgery, trauma, smoking, use of oral contraceptives, hormone replacement and other medications, and family history of deep vein thrombosis, pulmonary embolism, or "clots." Re-examination of their biopsies by one pathologist confirmed the diagnosis of ischemic colitis in all cases.

Protein C and antithrombin III activity were measured by functional assays of the chromogenic type; protein S activity was measured using a clotting type of assay. Activated protein C resistance was measured with an aPTT (activated partial thromboplastin time) based screening test using factor V-deficient plasma. Factor V Leiden and prothrombin 20210 were assayed by PCR analysis on DNA isolated from leukocytes present in whole blood, using allele-specific primers.

Results

Table 1 presents the clinical data. All 5 patients were women in good health. Patients ranged in age from 51 to 64 years. All experienced sudden onset of severe abdominal pain and cramps followed by bloody diarrhea. None were febrile or hypotensive, and the symptoms resolved with supportive care in all patients. Three women smoked cigarettes. One patient had a 10-year history of migraine headaches initially treated with aspirin and ibuprofen. Rizatriptan was given, but only since her episode of ischemia. Four of the patients were on hormone replacement therapy at the time of the ischemic episode. No patients had diabetes mellitus. Two of the 5 patients reported symptom recurrence identical to the documented episode of colonic ischemia. Patient number 2 had two episodes 6 weeks apart and was subsequently asymptomatic for 3 years. Patient number 4 also had two episodes 4 months apart and has been asymptomatic for 2 years. All patients had normal levels of protein C, S, and antithrombin III. Activated protein C resistance was normal in all 5 patients. None had factor V Leiden or prothrombin G20210A mutations (Table 2).

Conclusion

We found no evidence of the six specific hypercoagulable disorders we tested for in our study population. Their episodes of ischemic colitis could possibly be explained by the following: (1) Four of the women were on hormone replacement therapy, which has been associated with an increased risk of developing ischemic colitis.7,8 (2) Three patients used cigarettes, and the other 2 had a history of hypertension, either of which may have also increased their individual risk for ischemia. (3) Four patients had a family history of myocardial infarction or pulmonary embolism, which suggests the additional possibility of an underlying familial hypercoagulable condition.

Of course, our patients may also have inherited thombophilic disorders not evaluated in this study. Several cases of young healthy women who had spontaneous ischemic colitis while on oral contraceptives have been reported; these women were also found to have factor V Leiden mutation,9 inherited APC resistance,10 or acquired APC resistance.11 Recently, Koutroubakis et al12 reported that 22 of 36 patients (61%) with ischemic colitis had an abnormality in one of the six tests that we performed in our patients. Probably, however, their patient group was not well screened for obvious underlying disorders. Also, the incidence of genetic mutations in their control groups exceeded the incidence reported for most asymptomatic populations.

The epidemiologic evidence in our patient population strongly suggests that young healthy patients developing ischemic colitis frequently have two or more possible etiologic contributing factors, none of which would be sufficient to cause disease alone. These factors may be acquired or genetic. Our study cohort was small; larger studies may be needed to demonstrate a definite causal relationship between hypercoagulable states and ischemic colitis in young healthy adults. However, ischemic colitis should be considered in the differential diagnosis of abdominal pain or bloody diarrhea even in young healthy adults, especially if they have risk factors such as hormone replacement, cigarette smoking, hypertension, or a significant family history.

Acknowledgements

The authors wish to thank the Harvey E. Nussbaum, MD, Research Institute at Saint Barnabas for funding this study and Dr. Robert R. Rickert, MD, for the review of pathologic slides.

References

1. Gandhi SK, Hanson MM, Vernava AM, et al: Ischemic colitis. Dis Colon Rectum 39:88-100, 1996.

2. American Gastroenterological Association Medical position statement: Guidelines on intestinal ischemia. Gastroenterology 118:951-953, 2000.

3. AGA technical review on intestinal ischemia. Gastroenterology 118:954-968, 2000.

4. Barcewicz PA, Welch JP: Ischemic colitis in young adult patients. Dis Colon Rectum 23:109-114, 1980.

5. Habu Y, Tahashi Y, Kiyota K, et al: Reevaluation of clinical features of ischemic colitis. Scand J Gastroenterol 31:881-886, 1996.

6. Newe11 AM, Deckert JJ: Transient ischemic colitis in young adults. Am Fam Phys 56(4):1103-1108, 1997.

7. Gurbuz AK, Gurbuz B, Sala L, et al: Premarin induced ischemic colitis. J Clin Gastroenterol 19:108-11, 1994.

8. Deana DG, Dean PJ: Reversible ischemic colitis in young women. Am J Surg Pathol 19(4):454-62, 1995.

9. Yee NS, Guerry D, Lichtenstein GR: Ischemic colitis associated with factor V Leiden mutation. Ann Intern Med 132(7):595-596, 2000.

10. Ludwig D, Stahl M, David-Walek T, et al: Ischemic colitis, pulmonary embolism, and right Atrial thrombosis in a patient with inherited resistance to activated protein C. Dig Dis Sci 43(6);1362-1367, 1998.

11. Mann DE, Kessel ER, Mullins DL: Ischemic colitis and acquired resistance to activated protein C in a young woman using oral contraceptives. Am J Gastroenterol 93:1960-1962, 1998.

12. Koutroubakis IE, Sfiridaki A, Theodoropoulou A, Kouroumalis EA: Role of acquired and hereditary thrombotic risk factors in colon ischemia of ambulatory patients. Gastroenterology 121:561-565, 2001.

 

 

 

 

   Table 1. Patient Characteristics

 

 

      1                   F                          56                         Yes                          No                  15 pk-yr                          MI                       Yes

      2                   F                          51                         Yes                         Yes                          No                          MI                          No

      3                   F                          54                         Yes                          No                    2 pk-yr                          MI                          No

      4                   F                          64                          No                         Yes                          No                          No                          No

 

      HRT=hormone replacement therapy; HTN=hypertension; MI=myocardial infarction; PE=pulmonary embolism.
pk-yr= packs per day X years of cigarette use.

 

 

Table 2. Laboratory Results

 

                                                                                                                             

                                                                                        APC Resistance

   Patient Protein C*                Protein S*  Anti-thrombin III*                         >2.3            Prothrombin                 Factor V

 

      1                  131                         80.6                         92.3                           2.6                    Absent                  Absent

      2                  162                         62.6                         92.4                           2.6                    Absent                  Absent

      3                  141                         85.5                         56.9                           2.9                    Absent                  Absent

      4                  140                         75.9                       104.9                           2.5                    Absent                  Absent

 

   * Values are in percentages.