Helicobacter pylori and ITP: where do we stand

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Helicobacter pylori and ITP where do we stand?
EHA Scientific Working Group Thrombocytopenias V
ienna, 7 June 2007

• Dr. Roberto Stasi
• S.C. di Oncologia ed Ematologia
• Ospedale Regina Apostolorum
• Albano Laziale

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Helicobacter pylori
Micro-aerophilic, Gram-negative, slow-growing,
spiral-shaped, flagellated bacterium
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Prevalence of H.Pylori infection
100
90
Developing World
80
Developed World
infected
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80

• Age (years)

Marshall et al. Med Clin N Am 200589313344
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How To Diagnose H. pylori

• Invasive tests (biopsy through endoscope)
• Rapid Urease Test (RUT)
• Culture
• Histology
• Polymerase Chain Reaction (PCR)
• Non-Invasive tests
• Urea Breath Tests (UBT)
• Serological tests
• 13C bicarbonate assay
• Salivary assay
• Urine
• Stool antigen tests

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H. pylori associated diseases

• 14th leading cause of death in the world
• 8th leading cause by 2010
• Gastritis
• Duodenal and gastric ulcers
• Gastric adenocarcinomas
• MALTomas
• Autoimmune diseases?

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H. pylori infection and ITP
Gasbarrini et al. Lancet 1998352878
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Systematic review Literature search

• Computer-assisted search of the literature
  published in English since 1998.
• The review was conducted independently by two of
  the authors in May 2007 using the electronic
  database of PubMed/MEDLINE
• The MeSH subheading search was idiopathic
  thrombocytopenic purpura.
• Key words searched were thrombocytopenia,
  thrombocytopenic purpura, idiopathic
  thrombocytopenic purpura, immune thrombocytopenic
  purpura, idiopathic thrombocytopenia, and immune
  thrombocytopenia. These terms were combined with
  the terms Helicobacter pylori or H. pylori and
  with the words eradication or treatment.
• The bibliographies of all retrieved articles were
  searched for additional relevant citations.

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Systematic review Article selection

• We excluded articles reporting fewer than 10
  patients.
• Articles reporting 10 or more total patients were
  reviewed to determine whether they described any
  patient with chronic ITP according to the
  American Society of Hematology guidelines.
• If no reference to such guidelines was made,
  articles were selected only if the ITP duration
  was reported and secondary causes of
  thrombocytopenia had been clearly ruled out
• Initially, titles and abstracts of all articles
  were evaluated independently by the 2 reviewers.
  Full-text articles were retrieved when they were
  judged by either reviewer to possibly contain
  relevant original data. Final article selection
  was done independently by both reviewers, and
  disagreements were resolved by consensus in all
  cases.
• Where duplicate or redundant publications were
  uncovered, the latest and most informative
  version was retained.

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Systematic review Data extraction

• Our research strategy was to obtain
  individual-level patient data from case series.
• If patient-level data were not reported, we used
  the group-level data.
• The following data were collected in duplicate
  study design and use of controls methods of H.
  pylori detection demographics associated with H.
  pylori infection previous ITP treatments
  concomitant ITP treatments duration of ITP
  before eradication treatment baseline platelet
  count eradication regimen administered
  toxicities associated with the eradication
  regimen proportion of H. pylori eradication
  definition of platelet count responses
  proportion of patients with platelet count
  responses time of assessment of platelet count
  responses time to platelet count responses and
  duration of platelet count responses.

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Systematic review Final selection

• 25 studies included (42 excluded)
• 23 adult studies
• 20 prospective phase 2, 1 prospective randomized,
  2 retrospective
• Evaluable for efficacy 22
• Evaluable for HP prevalence 21
• Evaluable for HP eradication 23
• Evaluable for demographics of HP-positive 15
• Only a few studies with group-patient data
  reported Mean SD values
• Inconsistent platelet response criteria

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Results

• Evaluable for HP infection 1440
• N of infected 942
• of infected 65.4
• Evaluable for HP eradication 780
• N of eradicated 660
• of eradicated 84.6
• Evaluable for response 652
• N of responders 368 (0/41 in non eradicated)
• of responders 57.7
• N of responders with severe ITP (Plts lt30 x
  109/l) 11

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Demographics Age
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Demographics Male gender
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Demographics ITP duration
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Demographics baseline platelet count
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Response rate Japan vs other countries


Plt 0.0001
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Higher response rates in studies with higher
infection rates
R0.5098, P0.018
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Predictor of response ITP duration
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Pathogenesis of H. pylori-associated ITP

• Molecular mimicry (antibody production in
  response to antigens that cross-react against
  various platelet glycoprotein antigens)
• PAIgG cross-react with the CagA protein1
• CagA antibodies cross-react with a peptide
  specifically expressed by platelets of patients
  with ITP2
• Most Japanese H. pylori strains are positive for
  CagA3
• LPS-induced phagocytosis of IgG-opsonized
  platelets4

1Takahashi et al Br J Haematol.
200412491-96 2Franceschi et al. Ann Intern Med.
2004140766-767 3Maeda et al. Gut.
199944336-341 4Semple et al. Blood 2007
20071094803-4805
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LPS enhances Fc receptormediated phagocytosis of
IgG-opsonized platelets
Platelets were incubated with either (A)
autoantibody-negative sera samples 1 to 4 or (B)
autoantibody-positive sera samples 5 to 8 and
either no LPS ( ) or 0.1 ( ) µg LPS and
incubated with THP-1 cells


Semple et al. Blood 2007 20071094803-4805
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Conclusions

• H. pylori infection is a common finding in ITP,
  particularly in older patients and in countries
  other than USA
• Response rates are variable. The chances of
  response are higher in Japanese patients with a
  short disease history and a mild ITP
• The role of difefrent H. pylori strains in the
  pathogenesis of ITP are yet to be defined