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Immune thrombocytopenic purpura in ulcerative colitis: a case report and systematic review.
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PMID:  24765254     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Over 100 extraintestinal manifestations are reported in ulcerative colitis (UC). A commonly reported hematological manifestation is autoimmune hemolytic anemia. On rare occasions, immune thrombocytopenic purpura (ITP) has been reported with UC. The presence of thrombocytopenia can complicate the clinical scenario as the number of bloody bowel movements is an important indicator of disease activity in UC. A proposed theory for this association is antigenic mimicry between a platelet surface antigen and bacterial glycoprotein. We are reporting a case of UC and associated ITP managed successfully with anti-TNF therapy. We also performed a systemic review of case reports and a case series reporting this association.
Authors:
Subhash Chandra; Sarah Finn; Eugene Obah
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Publication Detail:
Type:  Journal Article     Date:  2014-04-14
Journal Detail:
Title:  Journal of community hospital internal medicine perspectives     Volume:  4     ISSN:  2000-9666     ISO Abbreviation:  J Community Hosp Intern Med Perspect     Publication Date:  2014  
Date Detail:
Created Date:  2014-04-25     Completed Date:  2014-04-25     Revised Date:  2014-04-28    
Medline Journal Info:
Nlm Unique ID:  101601396     Medline TA:  J Community Hosp Intern Med Perspect     Country:  Sweden    
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Languages:  eng     Pagination:  -     Citation Subset:  -    
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Journal ID (nlm-ta): J Community Hosp Intern Med Perspect
Journal ID (iso-abbrev): J Community Hosp Intern Med Perspect
Journal ID (publisher-id): JCHIMP
ISSN: 2000-9666
Publisher: Co-Action Publishing
Article Information
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© 2014 Subhash Chandra et al.
open-access:
Received Day: 19 Month: 11 Year: 2013
Accepted Day: 27 Month: 1 Year: 2014
Electronic publication date: Day: 14 Month: 4 Year: 2014
collection publication date: Year: 2014
Volume: 4 Issue: 2
E-location ID: 10.3402/jchimp.v4.23386
PubMed Id: 24765254
ID: 3992354
Publisher Id: 23386
DOI: 10.3402/jchimp.v4.23386

Immune thrombocytopenic purpura in ulcerative colitis: a case report and systematic review
Subhash Chandra, MD*
Sarah Finn, MD
Eugene Obah, MD
Department of Internal Medicine, Greater Baltimore Medical Center, Baltimore, MD, USA
*Correspondence to: Subhash Chandra, Department of Internal Medicine, Greater Baltimore Medical Center, Baltimore, MD 21204, USA, Email: Subhash.budania@gmail.com

A 26-year-old African American female with a history of genital herpes developed hematochezia 6 weeks prior to hospital admission. She was seen at an urgent care center and was prescribed a 1-week course of oral antibiotics. The patient continued to have hematochezia for which she was scheduled to have a colonoscopy as an outpatient. Her hematochezia worsened over the next 2 weeks and she was admitted to an outside hospital where she was managed with a presumed flare of ulcerative colitis (UC) based on clinical diagnosis. The patient was treated with oral steroids and intravenous antibiotics and discharged on a tapering course of steroids for 1 week. During the hospitalization, her platelet count was 236×103/mm3.

She experienced partial improvement in her symptoms with steroids use, but shortly after stopping steroids her symptoms worsened. She presented to our hospital emergency department with 2 days of 8–9 bloody bowel movements per day, mild left-lower quadrant abdominal pain, no fever or chills but reported a 20 pound weight loss. On admission, her white cell count was 10,370/mm3, hemoglobin of 11.4 g/dL, and platelet count was 76×103/mm3. Intravenous methylprednisolone was administered. Her medications were reviewed for possible thrombocytopenia and there was no reported history of alcohol use. HIV and H. pylori serology and blood cultures were negative. Colonoscopy showed pan colitis with histopathology consistent with UC without any viral inclusions.

On day 5 of hospitalization, her platelet count decreased to 5×103/mm3, her frequency of bloody bowel movement increased, and she became febrile and tachycardic. The patient was started on intravenous ciprofloxacin plus metronidazole and intravenous steroids were continued. The peripheral smear showed few large size platelets and the patient did not have splenomegaly. These results suggested the possibility of immune mediated peripheral destruction of platelets. Intravenous immunoglobulin (IVIGg) was administered and one unit of platelets transfused. On days 6 and 7, platelet counts improved to 24×103/mm3 and 36×103/mm3, respectively, but the patient continued having bloody bowel movements. Positive platelet-associated antibodies confirmed diagnosis of immune thrombocytopenic purpura (ITP). Because of the lack of response to steroids, Infliximab infusion 5 mg/kg was administered on day 7. On days 8 and 9, frequency of bloody stool decreased significantly and platelet count continued to improve, 94×103/mm3 on day 9. At that point, the patient was discharged on a tapering dose of steroids and scheduled Infliximab infusion. On outpatient follow-up 10 days after discharge, her platelet count was normal at 151×103/mm3 and she was free of hematochezia.


Systematic review
Search and data compilation

A comprehensive search of two major databases of biomedical publications was performed during the last week of August 2013. No age or language restrictions were applied. A summary of our search strategy is described in the Appendix. Titles and abstracts were reviewed to identify cases. The references of eligible articles were hand searched to elicit additional cases. All of the adult and pediatric cases reports and series reporting UC associated with ITP were included. Data points were extracted based on the best information reported.


Results

Cases of ITP associated with UC were first reported in 1963 (1). Since then, a total of 40 cases (including the above-mentioned case) were identified, seven of them being of pediatric age group. Table 1 summarizes patient demographics and management of UC and associated ITP. Fifty six percent of cases were male and the median age of presentation was 27 years (interquartile range 14–42 years). Median age of presentation was higher in females (41 vs. 22 years) but the difference was not statistically significant (p =0.0718). As shown in Table 1, 52% of patients were white, 45% were Asian (mostly of Japanese origin). The current report documents the first case in an African American patient.

In the majority of cases, ITP resolved with treatment of UC flare. IVIGg or anti-D antibodies were used in 15 cases; response was adequate and lasting in 11 of them. Amongst the remaining four patients, one responded dramatically to 5-ASA; in two cases, ITP was resistant to both IVIGg and splenectomy and required a colectomy; and in one case, colectomy and splenectomy were performed together, which improved the ITP. Ten patients underwent a colectomy; one of them had a colectomy some years prior to the development of ITP (2). Of the remaining nine cases, eight responded well but one patient continued to have recurrent ITP despite colectomy (3). In one case, ITP resolved with H. pylori eradication (4).


Discussion

The development of ITP adds complexity in the clinical course of UC flare as the number of bloody bowel movements is one of the important criteria to assess disease severity. Since 1965, a total of 40 cases reported association of ITP with UC. Rarity of occurrence limits methodologically sound studies to establish causal relationship between the two disorders. In disease epidemiology, Sir Austin Bradford Hill proposed criteria for causation, also knows has Hill's criteria for causation (5). Results of this systematic review elicit multiple interesting observations to generate a hypothesis of causal relationships between UC and ITP. 1) In most cases, UC preceded ITP, which demonstrates a temporal relationship between UC (exposure) and ITP (effect). Only three cases have been reported where ITP preceded UC (6, 7). In two of the cases, ITP preceded UC by just 18 months. This could be a result of delay in diagnosis or subclinical disease, which is not uncommon in UC. In another case, ITP preceded UC by 18 years, which appears to be a result of random concurrence of the two disorders. 2) Platelet count was lowest during the flare of UC, demonstrating a biological gradient. 3) In most cases, treatment of UC resolved ITP, analogous to the removal of exposure leading to reversal of effect. Biological plausibility in ITP development in patients with UC is hypothesized to be due to antigenic mimicry between platelet surface antigen and luminal antigens, including bacterial surface antigen. Increased exposure to luminal antigens is thought to be the result of mucosal injury. This is also postulated for the association of ITP with Crohn's disease (8).

The results of our systematic review suggest that peak age for this association is in the third decade of life with a trend towards earlier occurrence in males. Cases have been reported in both pediatrics and adults above 60 years of age. About half of the cases were reported in the Japanese population. We report the first case in the African American population. In the management of this coexistence, treatment of UC is the corner stone. In severe cases of thrombocytopenia, IVIGs or Anti-D antibodies in combination with 5-ASA and/or steroids are effective in most cases. These patients should also be screened for H. pylori. The infection needs to be eradicated if presented. Refractory cases respond to colectomy and splenectomy but are rarely necessary (4). We are reporting a second case where a colectomy was avoided by using anti-tumor necrosis factor therapy (9).

In conclusion, ITP appears to be an extraintestinal manifestation of UC. The proposed pathogenesis is antigenic mimicry between luminal antigen and platelet surface antigen. Treatment of underlying UC flare is the cornerstone in managing the condition and in severe cases of ITP, IVIGs is effective. Though colectomy has been proposed as a definitive treatment option, the use of biological agents is an acceptable alternative in a steroid-resistant case of UC associated with ITP.


Conflict of interest and funding

The authors have not received any funding or benefits from industry or elsewhere to conduct this study.


References
1. Edwards FC,Truelove SC. The course and prognosis of ulcerative colitis. III. ComplicationsGutYear: 1964512214127503
2. Yong S,Persad R,Dower N,Lees G,El-Matary W. Idiopathic thrombocytopenic purpura after colectomy for pediatric ulcerative colitisInflamm Bowel DisYear: 20081413131518344179
3. Higuchi LM,Joffe S,Neufeld EJ,Weisdorf S,Rosh J,Murch S,et al. Inflammatory bowel disease associated with immune thrombocytopenic purpura in childrenJ Pediatr Gastroenterol NutrYear: 200133582711740233
4. Etou T,Iizuka M,Ohshima A,Yagisawa H,Yamano HO,Ishii T,et al. Ulcerative colitis accompanied by idiopathic thrombocytopenic purpura and Helicobacter pylori infectionIntern MedYear: 201352547923448762
5. Hill AB. The environment and disease: Association or causation?Proc R Soc MedYear: 19655829530014283879
6. Chetri K,Aggarwal R,Sharma B,Nityanand S,Naik SR. Ulcerative colitis and immune thrombocytopenia: A report of two casesIndian J GastroenterolYear: 19991817410531721
7. Kawakubo M,Tokunaga T,Kobari S,Nakamura Y,Aono S,Hayashi T,et al. [A case of ulcerative colitis with preexisting idiopathic thrombocytopenic purpura]Nihon Shokakibyo Gakkai ZasshiYear: 200810510556018603851
8. Lazaraki G,Metallidis S,Giannoulis K,Tarpagos A,Germanidis G. Infliximab: An alternative treatment for refractory immune thrombocytopenic purpura related to Crohn's disease?Inflamm Bowel DisYear: 2007131452317576115
9. Mares WG,Gerver J,Masclee AA,Pierik M. Anti-TNF treatment of ulcerative colitis associated with idiopathic thrombocytopenic purpuraInflamm Bowel DisYear: 201117864520848499
Appendix

Database: Embase <1988 to 2013 Week 34>, Ovid MEDLINE(R) <1946 to August Week 2 2013>

Search Strategy:

1. Ulcerative colitis.ab. or Ulcerative colitis.ti. or Ulcerative colitis.kw. or Ulcerative colitis.kf. (54,832)

2. Autoimmune thrombocytopenic purpura.ab. or autoimmune thrombocytopenic purpura.ti. or autoimmune thrombocytopenic purpura.kw. or autoimmune thrombocytopenic purpura.kf. (810)

3. Idiopathic thrombocytopenic purpura.ab. or idiopathic thrombocytopenic purpura.ti. or idiopathic thrombocytopenic purpura.kw. or idiopathic thrombocytopenic purpura.kf. (7,469)

4. ITP.ab. or ITP.ti. or ITP.kw. or ITP.kf. (10,614)

5. 2 or 3 or 4 (15,035)

6. 1 and 5 (61)

7. Remove duplicates from 6 (37)


Tables
[TableWrap ID: T0001] Table 1 

Summary demographics and treatment in reported cases


Author Year Age Gender Race Medical treatment UC Additional medical treatment for ITP Surgical treatment Comments
Edwards 1964 Adult 3-cases
Kocoshis 1979 Pediatric
Hautefeuille 1985 20 M White Steroid IVIGg Splenectomy, colectomy Good response to surgical intervention
Dooley 1986 63 M White Sulfa, steroid Splenectomy Partial response to steroids, complete resolution of ITP with splenectomy
Gupta 1986 42 M White Sulfa, steroid Splenectomy No response to steroid
Mori 1987 50 F Asian Steroid Platelet count maintained on 1 mg daily betamethasone
Jimbo 1992 24 M Asian Sulfa, steroid No recurrence with subsequent flare
Adachi 1994 49 F Asian Sulfa, steroid Splenectomy
Fernandez-Miranda 1994 22 F White 5-ASA, steroid Splenectomy Partial response to steroids, complete resolution of ITP with splenectomy
Obata 1994 13 F Asian Steroid
Kim 1995 41 M White 5-ASA, steroid IVIGg Splenectomy Good response to medical treatment but underwent splenectomy
McCulley 1996 21 F White 5-ASA, steroid, metronidazole
Yoshida 1996 27 M White 5-ASA, steroid IVIGg Chronic thrombocytopenia despite multiple courses of steroids
Yoshida 1996 65 F White 5-ASA, steroid IVIGg
Yoshida 1996 42 F White 5-ASA, steroid Splenectomy
Nagata 1997 19 M Asian Steroid
Zlatanic 1997 18 M White 5-ASA, steroid, 6-MP 6-MP and IVIGg
Bauer 1999 24 F White 5-ASA IVIGg Splenectomy, Colectomy Resistant to IVIGg and splenectomy but responded to colectomy
Kodaira 1999 23 M Asian Sulfa, steroid Splenectomy Responded to steroids but reoccurred for which splenectomy was performed
Chetri 1999 42 M Asian 5-ASA, steroid azathioprine
1999 52 F Asian 5-ASA, steroid, azathioprine Splenectomy ITP preceded UC by 18 years
Higuchi 2001 9 M Sulfa Anti-D antibodies
2001 17 M Steroid IVIGg
2001 5 F 5-ASA, steroid Anti-D antibodies, IVIGg Responded will after starting 5-ASA
2001 14 M 5-ASA, steroid, 6-MP IVIGg Colectomy Recurrent ITP despite colectomy
Kathula 2001 28 F Steroid IVIGg Colectomy, splenectomy Transient response to IVIGg and splenectomy, complete resolution of ITP with colectomy
Miner 2001 63 F 5-ASA, steroid, metronidazole Splenectomy Splenectomy for recurrence of ITP with steroid tapper
Mizuta 2003 19 M Asian 5-ASA, steroid Colectomy
2003 51 F Asian 5-ASA, steroid Patient expired from intracranial hemorrhage
Puebla-Maestu 2003 41 F White 5-ASA, steroid Cyclosporine, azathioprine Colectomy Splenectomy Not responded well to medical treatment
Varderili 2003 20 M White Steroid Colectomy Partial response to steroids, complete resolution of ITP with colectomy
Hisada 2006 36 M Asian Steroid IVIGg Colectomy Good response to IVIGg and complete response following colectomy
Kawakubo 2008 53 M Asian Steroid ITP preceded UC
Yong 2008 14 M White IVIGg ITP after colectomy
Shao 2009 19 M Asian 5-ASA, steroid
Mares 2011 32 M White Steroid, Infliximab IVIGg
Etou 2013 41 F Asian No exacerbation of UC ITP resolved on eradication of H. pylori
Chandra 2013 26 F Black Steroid, Infliximab IVIGg Patient did not tolerate 5-ASA

ITP: immune thrombocytopenic purpura; IVIGg: intravenous immunoglobulin G; Sulfa: sulfasalazine; UC: ulcerative colitis.



Article Categories:
  • Case Report

Keywords: immune thrombocytopenic purpura, ulcerative colitis, anti-tumor necrosis factor antibodies, intravenous immunoglobulins, extraintestinal manifestation.

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