H e m a t o lo g y E d u c a t io n - European Hematology Association

against the TPO receptor (cMpl). 61 Predictably, the antibody
present dictates the clinical features: patients with
anti-GPIIb/IIIa antibodies have normal or increased
bone marrow megakaryocyte density and, similar to
patients with immune thrombocytopenic purpura (ITP),
show a good response to conventional immunosuppression.
Those with anti-TPO receptor antibodies demonstrate
megakaryocytic hypoplasia and have a poor
response to steroids and intravenous immunoglobulin. 61
Patients with some lymphoproliferative disorders,
particularly those with chronic lymphocytic leukemia
(CLL) and CD8 T-lymphocyte large granular lymphocytic
leukemia (LGL), appear to have an increased incidence
of immune thrombocytopenia. ITP occurs in
approximately 5% of patients with CLL when stringent
diagnostic criteria are applied. 62 The development of
ITP is significantly associated with unmutated IgVH, a
positive direct antiglobulin test, and the development
of autoimmune hemolytic anemia. Patients with CLL
and IT have poorer survival than other patients with
CLL, and this effect appears to be independent from
common clinical prognostic variables. 62 Severe thrombocytopenia
occurs in about 1% of patients with LGL,
and has been associated with clonal suppression of
megakaryopoiesis. 63,64
Conclusions
The pathophysiology of ITP is much more complex
than once believed; we can depict a simplified view of
our current understanding in this area (Figure 1). While
abnormalities of both the B cell and the T cell compartments
have been identified, the mechanisms of the failure
of the immune tolerance remain poorly understood.
Recent studies have focused on the specificity of the
antiplatelet immune response in patients with ITP and
showed that GPIIIa is the most important target of the
autoantibodies. GPIIIa is known to contain important Band
T-cell determinants, and seven immunodominant
epitopes. Identification of GPIIIa sequences that are recognized
by autoreactive Th cells from most patients
with ITP is the first step towards specific peptide
immunotherapy to re-induce Th tolerance.
There is now greater understanding of the mechanisms
of thrombocytopenia in ITP, which involve both
increased platelet destruction and, in a significant proportion
of cases, impaired platelet production. In fact,
stimulation of platelet production with thrombopoietin
receptor agonists has been a recent successful therapeutic
application deriving from this concept.
Many important issues still need to be adequately
addressed in future research. Major gaps remain the
understanding of the role played by T cell and B cell
subtypes, as well as the role of factors modulating the
clinical phenotype of the disease, including response to
treatment and spontaneous remissions.
References
1. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D,
Arnold DM, et al. Standardization of terminology, definitions
and outcome criteria in immune thrombocytopenic purpura of
adults and children: report from an international working
group. Blood. 2009 Mar 12;113(11):2386-93.
London, United Kingdom, June 9-12, 2011
2. Harrington WJ, Minnich V, Hollingsworth JW, Moore CV.
Demonstration of a thrombocytopenic factor in the blood of
patients with thrombocytopenic purpura. J Lab Clin Med.
1951 Jul;38(1):1-10.
3. Shulman NR, Marder VJ, Weinrach RS. Similarities between
known antiplatelet antibodies and the factor responsible for
thrombocytopenia in idiopathic purpura. Physiologic, serologic
and isotopic studies. Ann N Y Acad Sci. 1965 Jun 30;124(2):
499-542.
4. van Leeuwen EF, van der Ven JT, Engelfriet CP, von dem Borne
AE. Specificity of autoantibodies in autoimmune thrombocytopenia.
Blood. 1982 Jan;59(1):23-6.
5. Sukati H, Watson HG, Urbaniak SJ, Barker RN. Mapping
helper T-cell epitopes on platelet membrane glycoprotein IIIa
in chronic autoimmune thrombocytopenic purpura. Blood.
2007 May 15;109(10):4528-38.
6. McMillan R, Wang L, Tani P. Prospective evaluation of the
immunobead assay for the diagnosis of adult chronic immune
thrombocytopenic purpura (ITP). J Thromb Haemost. 2003
Mar;1(3):485-91.
7. McMillan R, Lopez-Dee J, Bowditch R. Clonal restriction of
platelet-associated anti-GPIIb/IIIa autoantibodies in patients
with chronic ITP. Thromb Haemost. 2001 May;85(5):821-3.
8. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of
autoantibodies in idiopathic thrombocytopenic purpura
reveals evidence of clonal expansion and somatic mutation.
Blood. 2002 Aug 15;100(4):1388-98.
9. Brighton TA, Evans S, Castaldi PA, Chesterman CN, Chong
BH. Prospective evaluation of the clinical usefulness of an antigen-specific
assay (MAIPA) in idiopathic thrombocytopenic
purpura and other immune thrombocytopenias. Blood. 1996
Jul 1;88(1):194-201.
10. Stockelberg D, Hou M, Jacobsson S, Kutti J, Wadenvik H.
Detection of platelet antibodies in chronic idiopathic thrombocytopenic
purpura (ITP). A comparative study using flow
cytometry, a whole platelet ELISA, and an antigen capture
ELISA. Eur J Haematol. 1996 Jan-Feb;56(1-2):72-7.
11. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to
platelet GPIIb-IIIa in immune thrombocytopenic purpura.
Role in production of anti-platelet autoantibody. J Clin Invest.
1998 Oct 1;102(7):1393-402.
12. Kuwana M, Kaburaki J, Kitasato H, Kato M, Kawai S, Kawakami
Y, et al. Immunodominant epitopes on glycoprotein IIb-IIIa recognized
by autoreactive T cells in patients with immune thrombocytopenic
purpura. Blood. 2001 Jul 1;98(1):130-9.
13. Zhou B, Zhao H, Yang RC, Han ZC. Multi-dysfunctional
pathophysiology in ITP. Crit Rev Oncol Hematol. 2005 May;
54(2):107-16.
14. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A,
Blanchette V, et al. Differences in serum cytokine levels in
acute and chronic autoimmune thrombocytopenic purpura:
relationship to platelet phenotype and antiplatelet T-cell reactivity.
Blood. 1996 May 15;87(10):4245-54.
15. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska MM,
Cooper N, et al. Response to B-cell depleting therapy with rituximab
reverts the abnormalities of T-cell subsets in patients
with idiopathic thrombocytopenic purpura. Blood. 2007 Oct
15;110(8):2924-30.
16. Sood R, Wong W, Gotlib J, Jeng M, Zehnder JL. Gene expression
and pathway analysis of immune thrombocytopenic purpura.
Br J Haematol. 2008 Jan;140(1):99-103.
17. Fogarty PF, Rick ME, Zeng W, Risitano AM, Dunbar CE,
Bussel JB. T cell receptor VB repertoire diversity in patients
with immune thrombocytopenia following splenectomy. Clin
Exp Immunol. 2003 Sep;133(3):461-6.
18. Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B,
Carlsson LM, et al. T-cell-mediated cytotoxicity toward platelets
in chronic idiopathic thrombocytopenic purpura. Nat Med.
2003 Sep;9(9):1123-4.
19. Zhang F, Chu X, Wang L, Zhu Y, Li L, Ma D, et al. Cell-mediated
lysis of autologous platelets in chronic idiopathic thrombocytopenic
purpura. Eur J Haematol. 2006 May;76(5):427-31.
20. Filion MC, Proulx C, Bradley AJ, Devine DV, Sekaly RP,
Decary F, et al. Presence in peripheral blood of healthy individuals
of autoreactive T cells to a membrane antigen present on
bone marrow-derived cells. Blood. 1996 Sep 15;88(6):2144-50.
21. Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu M, et al.
Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic
thrombocytopenic purpura. Eur J Haematol. 2007 Feb;78(2):
139-43.
22. Olsson B, Andersson PO, Jacobsson S, Carlsson L, Wadenvik
H. Disturbed apoptosis of T-cells in patients with active idiopathic
thrombocytopenic purpura. Thromb Haemost. 2005 Jan;
93(1):139-44.
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