0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Autoimmune Thrombocytopenic Purpura and Helicobacter pylori Infection FREE

Marc Michel, MD; Mehdi Khellaf, MD; Lionel Desforges, MD; Ketty Lee, MD; Annette Schaeffer, MD; Bertrand Godeau, MD; Philippe Bierling, MD, PhD
[+] Author Affiliations

From the Service de Médecine Interne (Drs Michel, Khellaf, Schaeffer, and Godeau), Laboratoire de Bactériologie (Dr Desforges), and Laboratoire d'Immunologie Leuco-plaquettaire, Etablissement Français du Sang (Drs Lee and Bierling), Hôpital Henri-Mondor, Créteil, France.


Arch Intern Med. 2002;162(9):1033-1036. doi:10.1001/archinte.162.9.1033.
Text Size: A A A
Published online

Background  The mechanisms triggering the production of platelet autoantibodies in autoimmune thrombocytopenic purpura (AITP) are poorly understood. Recently, marked improvements in platelet counts have been reported in patients with AITP and concurrent Helicobacter pylori infection after eradication of H pylori by a standard antibiotic regimen. We looked for an association between H pylori infection and AITP in adults.

Methods  Fifty-one adults of white French origin, negative for human immunodeficiency virus (mean ± SD age, 40 ± 19.8 years), with AITP and a platelet count of less than 50 × 103/µL at onset were included. Thirty-five consecutive nonthrombocytopenic patients (mean ± SD age, 43 ± 22 years) of the same origin and with unknown H pylori status served as control subjects. Antibodies against H pylori were detected by means of an agglutination method in both patients and control subjects. Sex ratio, mean age, hemorrhagic manifestations, response to corticosteroid therapy, and final outcome were compared in H pylori–negative and H pylori–positive patients with AITP. To test for a possible molecular mimicry mechanism, we also used an immunoblot assay to look for specific H pylori antibodies in platelet eluates from 3 H pylori–positive patients with AITP.

Results  Seroprevalence of H pylori in patients with AITP (15 [29%]) was not significatively different from that in control subjects (10 [29%]). The H pylori–positive and H pylori–negative patients with AITP did not differ in main characteristics at AITP onset, response rate to corticosteroids, and final outcome. None of the 3 patients investigated had H pylori antibodies in platelet eluates.

Conclusion  Although the role of H pylori in a subgroup of patients with AITP cannot be excluded, we found no evidence of an association between H pylori infection and AITP.

AUTOIMMUNE thrombocytopenic purpura (AITP) is an acquired bleeding disorder in which autoantibodies bind to platelet surface, leading to platelet destruction.1 The mechanisms triggering the production of platelet autoantibodies are poorly understood. In childhood, AITP is usually an acute self-limited problem; in contrast, AITP in adults is most often chronic, and up to 25% of cases of chronic AITP are refractory to standard therapy. Recently, it was suggested that Helicobacter pylori may contribute to AITP pathogenesis, as partial or even complete remission of thrombocytopenia has been reported in a few patients after eradication of H pylori.26 However, although there is evidence implicating H pylori in some autoimmune disorders,79 the link between H pylori infection and AITP remains speculative.

The aim of our study was to compare the prevalence of H pylori infection in a group of patients with AITP with that in a group of nonthrombocytopenic control subjects. We also compared the main characteristics and outcome of AITP between H pylori–positive and H pylori–negative patients and looked for cross-reactivity between platelet and H pylori antibodies.

PATIENTS

Fifty-one unselected adults (older than 18 years) of white French origin with AITP and whose H pylori infection status was not known were included in the study. All patients had a definite diagnosis of AITP according to usual criteria10 and presented with a platelet count of less than 50 × 103/µL at AITP onset. Patients infected with the human immunodeficiency virus were not included.

Initial treatment of AITP is standardized in our center. Briefly, all patients received corticosteroids at a mean dosage of 1 mg/kg per day for 3 weeks as a first-line therapy. Patients with life-threatening hemorrhages also initially received intravenous immune globulin at a dosage of 1 to 2 g/kg per day.11 Treatment was considered effective if the platelet count rose to 50 × 103/µL and increased at least 2-fold. Splenectomy was considered only in patients with a chronic outcome, ie, when the platelet count remained below 50 × 103/µL after at least 6 months of follow-up.

Acute AITP was defined by a treatment-free remission of thrombocytopenia (platelet count >150 × 103/µL) within 6 months of AITP onset.

The severity of the hemorrhagic syndrome at AITP onset was assessed by means of a clinical severity scale taking the following items into account: cutaneous purpura (localized, score of 1; extensive and/or progressive, 3; associated with large ecchymoses, 4), hemorrhagic oral bullae and/or spontaneous gingival bleeding (score, 4), epistaxis (unilateral, score of 2; bilateral, 3), macroscopic hematuria (score, 5), gastrointestinal tract hemorrhage (score, 5), major menorrhagia and/or metrorrhagia (score, 5), and bleeding on the fundus oculi in the absence of other causes (score, 5). The age at onset was considered as an independent risk factor of bleeding (age >65 years, score of 1; age >80 years, 3).

CONTROL GROUP

Thirty-five unselected patients older than 18 years, seen consecutively in our department during a 1-month period (March 1 to April 1, 2000) served as control subjects. Since the seroepidemiologic characteristics of H pylori infection differ between countries,12 only individuals of white French origin were included. None of them had a history of thrombocytopenia. Their H pylori infection status and history were not known.

DETECTION OF H PYLORI ANTIBODIES

An agglutination method (Pyloriset kit TMEIA-G; Orion Diagnostica, Helsinki, Finland) was used to detect anti– H pylori antibodies of IgG type in both patients and control subjects. In patients, tests were performed on serum samples collected and frozen when AITP was diagnosed. None of the patients had been previously treated with intravenous immune globulin. All serologic tests in the control group were performed consecutively on fresh samples.

DETECTION OF PLATELET AUTOANTIBODIES

Patients were screened for circulating and surface-bound IgG and IgM antiplatelet antibodies by an indirect13 and a direct suspension immunofluorescence technique on paraformaldehyde-fixed platelets.14 In patients in whom platelet antibodies were detected in serum samples by indirect suspension immunofluorescence technique, the presence of antibodies directed against specific platelet membrane targets was investigated by a direct and indirect monoclonal antibody–specific immobilization of platelet antigens assay with the use of a panel of monoclonal antibodies directed against platelet membrane glycoprotein (Gp) IIb-IIIa, GpIa-IIa, and GpIb-IX as previously described by Kiefel15 with minor modifications.16

PLATELET ELUATES

To determine whether H pylori antibodies could cross-react with platelet-membrane antigens, an immunoblot assay (Mikrogen, Martinsried, Germany) was used to test platelet eluates from 3 H pylori–positive patients with AITP. This immunoassay was used to detect IgG and IgA antibodies directed against specific H pylori antigens (CagA, VacA, UreB, HspA, HsB, FlaA, and UreA). Platelet eluates were obtained by an ether-elution method16 and were also tested for the presence of platelet antibodies by means of the indirect suspension immunofluorescence technique and the indirect monoclonal antibody–specific immobilization of platelet antigens assay.

STATISTICAL ANALYSIS

Patients were compared with controls and H pylori–positive patients with H pylori–negative patients for AITP characteristics and outcome. Results are expressed as mean ± SD. A χ2 test (or Fisher exact test if necessary) was used for comparison of categorial data, and the nonparametric Mann-Whitney test was used for comparison of quantitative data. A P value of less than .05 was considered significant.

PATIENT CHARACTERISTICS

Fifty-one patients, including 13 men (25%) and 38 women (75%), with AITP were included. The mean ages of patients (40 ± 19.8 years) and control subjects (43 ± 22 years) were not significantly different. The mean platelet count in patients at AITP onset was 21 × 103/µL (range, 1-50 × 103/µL). The course of AITP was chronic in 42 patients (82%) and acute in 9 (18%). Splenectomy was required in 14 patients with chronic AITP. All patients were alive after a median follow-up of 10 months (range, 6 months to 10 years) from AITP onset. None of the patients had a history of gastric or duodenal ulcer. After AITP onset, only 2 (4%) of the 51 patients underwent an upper digestive endoscopy, one for dyspepsia related to a peptic esophagitis and the other for occult bleeding associated with a duodenal ulcer; H pylori was present only in the duodenal biopsy specimen of the second patient. At the time of AITP diagnosis, only 1 patient was being treated by a proton pump inhibitor for dyspepsia; none of the patients had received antibiotics during the 4 weeks before AITP onset.

Fifteen (29%) of the 51 patients with AITP and 10 (29%) of the 35 control subjects (P = .93) were seropositive for H pylori.

CHARACTERISTICS AND OUTCOME OF AITP

The mean age at AITP onset was slightly higher in H pylori–positive patients (47.8 years; range, 19-92 years) than in H pylori–negative patients (35.5 years; range, 18-75 years) (P = .05).

Neither the main features of AITP nor the response to corticosteroids was significantly different between H pylori–positive and H pylori–negative patients (Table 1).

Table Graphic Jump LocationComparison of Patients With Autoimmune Thrombocytopenic Purpura Positive and Negative for Helicobacter pylori
H PYLORI IMMUNOBLOT ON PLATELET ELUATES

Helicobacter pylori–specific antibodies were sought by immunoblotting on platelet eluates in 3 H pylori–positive patients with AITP who had circulating platelet antibodies detected by indirect suspension immunofluorescence technique and in whom platelet eluates were available. None of them had detectable anti–H pylori antibodies in platelet eluates. Conversely, platelet-associated antibodies were detected on platelet eluates in 2 of the 3 patients tested, specifically directed against GpIIb-IIIa and GpIb-IX, as detected by means of monoclonal antibody–specific immobilization of platelet antigens assay in one patient.

Helicobacter pylori is a ubiquitous gram-positive bacterium involved in the pathogenesis of gastric and duodenal ulcers. Recently, the involvement of H pylori has also been suggested in various autoimmune diseases, including megaloblastic anemia17,18 and extraintestinal diseases such as Sjögren syndrome and immune thyroiditis.7,9 Previous in vitro studies suggested that H pylori has the potential to initiate autoreactivity through molecular mimicry, since monoclonal antibodies directed against H pylori may also react with ductal cells of the salivary glands and renal tubular cells.8 Within the past 2 years, a role for H pylori in the pathogenesis of AITP has been suggested because significant and, in some cases, very substantial improvements in platelet count have been reported after H pylori eradication with a standard antibiotic regimen37 from patients with AITP and concurrent H pylori infection. However, 3 of the relevant reports are anecdotal case reports2,4,5 and 2 are uncontrolled brief reports.3,6 Therefore, the implication of H pylori in pathogenesis of AITP is not backed by strong evidence.

We compared the prevalence of antibodies directed toward H pylori in patients with AITP and in ethnically matched controls. Although a positive culture obtained from gastric biopsy samples is considered the gold standard to confirm active H pylori infection or carriage,19 we used a blood antibody detection method for the following reasons: (1) Endoscopic methods of H pylori isolation were not feasible in our patients with a platelet count less than 50 × 103/µL at AITP onset. (2) Nonendoscopic methods of detection, such as urea breath tests or stool antigen testing, did not allow retrospective determination of the patients' H pylori carriage or previous infection status. (3) The reliability (sensitivity of 95.8% and specificity of 95.5%) of the enzyme immunoassay kit has been validated.20

The observed prevalence of anti–H pylori antibodies was similar in patients with AITP and control subjects and consistent with the expected value of 25% to 35%, observed in the French adult population.21

We also compared H pylori–positive and H pylori–negative patients with AITP and found that neither clinical and biological characteristics of AITP nor the response to corticosteroids and final outcome were influenced by the serologic H pylori status.

Finally, a molecular mimicry mechanism has been demonstrated in human immunodeficiency virus–related immune thrombocytopenia,22 and has been suggested by Emilia et al6 as the possible mechanism for H pylori–associated AITP. We therefore performed an H pylori immunoblot assay on platelet eluates obtained in 3 of our H pylori–positive patients, and there was no evidence of cross-reactivity between platelet and H pylori antibodies.

In conclusion, although the implication of H pylori infection in the pathogenesis of AITP in a particular subgroup of patients cannot be expressly ruled out by our case-control study, we found no evidence of an association between these 2 conditions. Moreover, since spontaneous remissions can occur in chronic AITP,23 controlled trials comparing the effect of an H pylori eradication therapy with that of a placebo are warranted to determine whether the subgroup of patients with AITP and active H pylori infection may benefit from eradication of H pylori.

Accepted for publication September 18, 2001.

Corresponding author and reprints: Marc Michel, MD, Service de Médecine Interne, CHU Hôpital Henri-Mondor, 51 Av du Mal de Lattre de Tassigny, 94010 Créteil CEDEX, France (e-mail: Marc.MICHEL8@wanadoo.fr).

George  JNel-Harake  MARaskob  GE Chronic idiopathic thrombocytopenic purpura. N Engl J Med. 1994;3311207- 1211
Link to Article
Garcia Perez  AValverde de la Osa  JGimenez Samper  MAlonso Garcia  I Resolution of an autoimmune thrombocytopenic purpura after eradicating treatment of Helicobacter pyloriSangre (Barc). 1999;44387- 388
Gasbarrini  AFranceschi  FTartaglione  RLandolfi  RPola  PGasbarrini  G Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori [letter]. Lancet. 1998;352878
Link to Article
Grimaz  SDamiani  DBrosolo  PSkert  CGeromin  Ade Pretis  G Resolution of thrombocytopenia after treatment for Helicobacter pylori: a case report. Haematologica. 1999;84283- 284
Tohda  SOhkusa  T Resolution of refractory idiopathic thrombocytopenic purpura after eradication of Helicobacter pyloriAm J Hematol. 2000;65329- 330
Link to Article
Emilia  GLongo  GLuppi  M  et al.  Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood. 2001;97812- 814
Link to Article
Gasbarrini  AFranceschi  F Autoimmune diseases and Helicobacter pylori infection. Biomed Pharmacother. 1999;53223- 226
Link to Article
Ko  GHPark  HBShin  MK  et al.  Monoclonal antibodies against Helicobacter pylori cross-react with human tissue. Helicobacter. 1997;2210- 215
Link to Article
Figura  NGiordano  NBurroni  D  et al.  Sjögren's syndrome and Helicobacter pylori infection. Eur J Gastroenterol Hepatol. 1994;3321- 322
George  JNRaskob  GE Idiopathic thrombocytopenic purpura: diagnosis and management. Am J Med Sci. 1998;31687- 93
Link to Article
Vantelon  JMGodeau  BAndre  CBierling  P Screening for autoimmune markers is unnecessary during follow-up of adults with autoimmune thrombocytopenic purpura and no autoimmune markers at onset. Thromb Haemost. 2000;8342- 45
Megraud  FBrassens-Rabbe  MPDenis  FBelbouri  AHoa  DQ Seroepidemiology of Campylobacter pylori infection in various populations. J Clin Microbiol. 1989;271870- 1873
von dem Borne  AEVerheugt  FWOosterhof  Fvon Riesz  Ede la Riviere  ABEngelfriet  CP A simple immunofluorescence test for the detection of platelet antibodies. Br J Haematol. 1978;39195- 207
Link to Article
von dem Borne  AEGKHelmerhorst  FMvan Leeuwen  EFPegels  JGvon Reisz  EEngelfriet  CP Autoimmune thrombocytopenia: detection of platelet autoantibodies with the suspension immunofluorescence test. Br J Haematol. 1980;45319- 323
Link to Article
Kiefel  V The MAIPA assay and its applications in immunohaematology. Transfus Med. 1992;2181- 188
Link to Article
Godeau  BPiette  JCFromont  PIntrator  LSchaeffer  ABierling  P Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br J Haematol. 1997;98873- 879
Link to Article
Negrini  RSavio  APoiesi  C  et al.  Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology. 1996;111655- 665
Link to Article
Kaptan  KBeyan  CUral  AU  et al.  Helicobacter pylori: is it a novel causative agent in vitamin B12 deficiency? Arch Intern Med. 2000;1601349- 1353
Link to Article
Peterson  WLFendrick  MCave  DRPeura  DAGarabedian-Ruffalo  SMLaine  L Helicobacter pylori– related disease: guidelines for testing and treatment. Arch Intern Med. 2000;1601285- 1291
Link to Article
Feldman  RADeeks  JJEvans  SJfor the Helicobacter pylori Serology Study Group, Multi-laboratory comparison of eight commercially available Helicobacter pylori serology kits. Eur J Clin Microbiol Infect Dis. 1995;14428- 433
Link to Article
Broutet  N Prévalence actuelle de l'infection à Helicobacter pylori et tendances évolutives en Europe. Lett Infectiol. 2000;1528- 29
Bettaieb  AOksenhendler  EDuedari  NBierling  P Cross-reactive antibodies between HIV-gp120 and platelet gpIIIa (CD61) in HIV-related immune thrombocytopenic purpura. Clin Exp Immunol. 1996;10319- 23
Link to Article
Stasi  RStipa  EMasi  M  et al.  Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med. 1995;98436- 442
Link to Article

Figures

Tables

Table Graphic Jump LocationComparison of Patients With Autoimmune Thrombocytopenic Purpura Positive and Negative for Helicobacter pylori

References

George  JNel-Harake  MARaskob  GE Chronic idiopathic thrombocytopenic purpura. N Engl J Med. 1994;3311207- 1211
Link to Article
Garcia Perez  AValverde de la Osa  JGimenez Samper  MAlonso Garcia  I Resolution of an autoimmune thrombocytopenic purpura after eradicating treatment of Helicobacter pyloriSangre (Barc). 1999;44387- 388
Gasbarrini  AFranceschi  FTartaglione  RLandolfi  RPola  PGasbarrini  G Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori [letter]. Lancet. 1998;352878
Link to Article
Grimaz  SDamiani  DBrosolo  PSkert  CGeromin  Ade Pretis  G Resolution of thrombocytopenia after treatment for Helicobacter pylori: a case report. Haematologica. 1999;84283- 284
Tohda  SOhkusa  T Resolution of refractory idiopathic thrombocytopenic purpura after eradication of Helicobacter pyloriAm J Hematol. 2000;65329- 330
Link to Article
Emilia  GLongo  GLuppi  M  et al.  Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood. 2001;97812- 814
Link to Article
Gasbarrini  AFranceschi  F Autoimmune diseases and Helicobacter pylori infection. Biomed Pharmacother. 1999;53223- 226
Link to Article
Ko  GHPark  HBShin  MK  et al.  Monoclonal antibodies against Helicobacter pylori cross-react with human tissue. Helicobacter. 1997;2210- 215
Link to Article
Figura  NGiordano  NBurroni  D  et al.  Sjögren's syndrome and Helicobacter pylori infection. Eur J Gastroenterol Hepatol. 1994;3321- 322
George  JNRaskob  GE Idiopathic thrombocytopenic purpura: diagnosis and management. Am J Med Sci. 1998;31687- 93
Link to Article
Vantelon  JMGodeau  BAndre  CBierling  P Screening for autoimmune markers is unnecessary during follow-up of adults with autoimmune thrombocytopenic purpura and no autoimmune markers at onset. Thromb Haemost. 2000;8342- 45
Megraud  FBrassens-Rabbe  MPDenis  FBelbouri  AHoa  DQ Seroepidemiology of Campylobacter pylori infection in various populations. J Clin Microbiol. 1989;271870- 1873
von dem Borne  AEVerheugt  FWOosterhof  Fvon Riesz  Ede la Riviere  ABEngelfriet  CP A simple immunofluorescence test for the detection of platelet antibodies. Br J Haematol. 1978;39195- 207
Link to Article
von dem Borne  AEGKHelmerhorst  FMvan Leeuwen  EFPegels  JGvon Reisz  EEngelfriet  CP Autoimmune thrombocytopenia: detection of platelet autoantibodies with the suspension immunofluorescence test. Br J Haematol. 1980;45319- 323
Link to Article
Kiefel  V The MAIPA assay and its applications in immunohaematology. Transfus Med. 1992;2181- 188
Link to Article
Godeau  BPiette  JCFromont  PIntrator  LSchaeffer  ABierling  P Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br J Haematol. 1997;98873- 879
Link to Article
Negrini  RSavio  APoiesi  C  et al.  Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology. 1996;111655- 665
Link to Article
Kaptan  KBeyan  CUral  AU  et al.  Helicobacter pylori: is it a novel causative agent in vitamin B12 deficiency? Arch Intern Med. 2000;1601349- 1353
Link to Article
Peterson  WLFendrick  MCave  DRPeura  DAGarabedian-Ruffalo  SMLaine  L Helicobacter pylori– related disease: guidelines for testing and treatment. Arch Intern Med. 2000;1601285- 1291
Link to Article
Feldman  RADeeks  JJEvans  SJfor the Helicobacter pylori Serology Study Group, Multi-laboratory comparison of eight commercially available Helicobacter pylori serology kits. Eur J Clin Microbiol Infect Dis. 1995;14428- 433
Link to Article
Broutet  N Prévalence actuelle de l'infection à Helicobacter pylori et tendances évolutives en Europe. Lett Infectiol. 2000;1528- 29
Bettaieb  AOksenhendler  EDuedari  NBierling  P Cross-reactive antibodies between HIV-gp120 and platelet gpIIIa (CD61) in HIV-related immune thrombocytopenic purpura. Clin Exp Immunol. 1996;10319- 23
Link to Article
Stasi  RStipa  EMasi  M  et al.  Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med. 1995;98436- 442
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 61

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles