Subscribe to RSS
DOI: 10.1160/TH07-08-0513
Idiopathic thrombocytopenic purpura: Current concepts in pathophysiology and management
Publication History
Received:
22 August 2007
Accepted after major revision:
10 October 2007
Publication Date:
24 November 2017 (online)
Summary
Idiopathic thrombocytopenic purpura (ITP) is characterized by a low platelet count, which is the result of both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP, several abnormalities involving the cellular mechanisms of immune modulation have been identified. Conventional treatments for ITP aim at reducing platelet destruction, either by immunosuppression or splenectomy. Two new thrombopoietic agents, AMG 531 and eltrombopag, have been used in clinical trials to stimulate platelet production in ITP patients not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin, but still bind and activate the thrombopoietin receptor. This review will focus on the pathophysiology and treatment of ITP in adults, highlighting recent advances in both fields.
-
References
- 1 George JN, Woolf SH, Raskob GE. et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 3-40.
- 2 Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood 1999; 94: 909-913.
- 3 Neylon AJ, Saunders PW, Howard MR. et al. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003; 122: 966-974.
- 4 Stasi R, Amadori S, Osborn J. et al. Long-term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia. PLoS Med 2006; 3: e24.
- 5 Cohen YC, Djulbegovic B, Shamai-Lubovitz O. et al. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Int Med 2000; 160: 1630-1638.
- 6 Portielje JE, Westendorp RG, Kluin-Nelemans HC. et al. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97: 2549-2554.
- 7 Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clinic Proc 2004; 79: 504-522.
- 8 Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood 2005; 106: 2244-2251.
- 9 George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost 2006; 4: 1664-1672.
- 10 Bussel J. Treatment of immune thrombocytopenic purpura in adults. Sem Hematol 2006; 43: S3-10 discussion S18-19.
- 11 Beardsley DS. ITP in the 21st century. Hematology / the Education Program of the American Society of Hematology American Society of Hematology. 2006: 402-407.
- 12 Harrington WJ, Minnich V, Hollingsworth JW. et al. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J Lab Clin Med 1951; 38: 1-10.
- 13 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 NY Acad Sci 1965; 124: 499-542.
- 14 van Leeuwen EF, van der Ven JT, Engelfriet CP. et al. Specificity of autoantibodies in autoimmune thrombocytopenia. Blood 1982; 59: 23-26.
- 15 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; 1: 485-491.
- 16 Brighton TA, Evans S, Castaldi PA. et al. Prospective evaluation of the clinical usefulness of an antigen-specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Blood 1996; 88: 194-201.
- 17 Stockelberg D, Hou M, Jacobsson S. et al. 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; 56: 72-77.
- 18 McMillan R, Lopez-Dee J, Bowditch R. Clonal restriction of platelet-associated anti-GPIIb/IIIa autoantibodies in patients with chronic ITP. Thromb Haemost 2001; 85: 821-823.
- 19 Fischer P, Jendreyko N, Hoffmann M. et al. Platelet-reactive IgG antibodies cloned by phage display and panning with IVIG from three patients with autoimmune thrombocytopenia. Br J Haematol 1999; 105: 626-640.
- 20 Roark JH, Bussel JB, Cines DB. et al. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 2002; 100: 1388-1398.
- 21 Semple JW. Immune pathophysiology of autoimmune thrombocytopenic purpura. Blood Rev 2002; 16: 9-12.
- 22 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; 102: 1393-1402.
- 23 Kuwana M, Kaburaki J, Kitasato H. et al. Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura. Blood 2001; 98: 130-139.
- 24 Zhou B, Zhao H, Yang RC. et al. Multi-dysfunctional pathophysiology in ITP. Crit Rev Oncol Hematol 2005; 54: 107-116.
- 25 Semple JW, Milev Y, Cosgrave D. 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; 87: 4245-4254.
- 26 Fogarty PF, Rick ME, Zeng W. et al. T cell receptor VB repertoire diversity in patients with immune thrombocytopenia following splenectomy. Clin Exp Immunol 2003; 133: 461-466.
- 27 Stasi R, Del Poeta G, Stipa E. 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 in press.
- 28 Olsson B, Andersson PO, Jernas M. et al. T-cell-me-diated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nature Med 2003; 9: 1123-1124.
- 29 Gruel Y, Boizard B, Daffos F. et al. Determination of platelet antigens and glycoproteins in the human fetus. Blood 1986; 68: 488-492.
- 30 Filion MC, Proulx C, Bradley AJ. 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; 88: 2144-2150.
- 31 Liu B, Zhao H, Poon MC. et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol 2007; 78: 139-143.
- 32 Olsson B, Andersson PO, Jacobsson S. et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; 93: 139-144.
- 33 Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2002; 2: 580-592.
- 34 Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346: 995-1008.
- 35 Henn V, Slupsky JR, Grafe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
- 36 Hermann A, Rauch BH, Braun M. et al. Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001; 12: 74-82.
- 37 Solanilla A, Pasquet JM, Viallard JF. et al. Platelet-associated CD154 in immune thrombocytopenic purpura. Blood 2005; 105: 215-218.
- 38 Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 1991; 78: 2619-2625.
- 39 McMillan R, Longmire RL, Yelenosky R. et al. Immunoglobulin synthesis in vitro by splenic tissue in idiopathic thrombocytopenic purpura. N Engl J Med 1972; 286: 681-684.
- 40 Kuwana M, Okazaki Y, Kaburaki J. et al. Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J Immunol 2002; 168: 3675-3682.
- 41 Siegel RS, Rae JL, Barth S. et al. Platelet survival and turnover: important factors in predicting response to splenectomy in immune thrombocytopenic purpura. Am J Hematol 1989; 30: 206-212.
- 42 Louwes H, Zeinali Lathori OA, Vellenga E. et al. Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura. Am J Med 1999; 106: 430-434.
- 43 Nimmerjahn F, Ravetch JV. Fcgamma receptors: old friends and new family members. Immunity 2006; 24: 19-28.
- 44 Ericson SG, Coleman KD, Wardwell K. et al. Monoclonal antibody 197 (anti-Fc gamma RI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down-modulation of Fc gamma RI on circulating monocytes. Br J Haematol 1996; 92: 718-724.
- 45 Crow AR, Lazarus AH. Role of Fcgamma receptors in the pathogenesis and treatment of idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol 2003; 25 (Suppl. 01) S14-18.
- 46 Crow AR, Song S, Siragam V. et al. Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia. Ped Blood Cancer 2006; 47: 710-713.
- 47 Webster ML, Sayeh E, Crow M. et al. Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbalpha antibodies. Blood 2006; 108: 943-946.
- 48 Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response to intravenous immunoglobulin G in the treatment of patients with immune thrombocytopenia. Haematologica 2007; 92: 283-284.
- 49 Heyns AD, Lotter MG, Badenhorst PN. et al. Kinetics and sites of destruction of 111Indium-oxine-labeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am J Hematol 1982; 12: 167-177.
- 50 Ballem PJ, Segal GM, Stratton JR. et al. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987; 80: 33-40.
- 51 Hoffman R, Zaknoen S, Yang HH. et al. An antibody cytotoxic to megakaryocyte progenitor cells in a patient with immune thrombocytopenic purpura. N Engl J Med 1985; 312: 1170-1174.
- 52 Chang M, Nakagawa PA, Williams SA. et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood 2003; 102: 887-895.
- 53 Takahashi R, Sekine N, Nakatake T. Influence of monoclonal antiplatelet glycoprotein antibodies on in vitro human megakaryocyte colony formation and proplatelet formation. Blood 1999; 93: 1951-1958.
- 54 Handin RI, Stossel TP. Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelets by human leukocytes. Blood 1978; 51: 771-779.
- 55 Fujisawa K, Tani P, Piro L. et al. The effect of therapy on platelet-associated autoantibody in chronic immune thrombocytopenic purpura. Blood 1993; 81: 2872-2877.
- 56 Kitchens CS, Pendergast JF. Human thrombocytopenia is associated with structural abnormalities of the endothelium that are ameliorated by glucocorticosteroid administration. Blood 1986; 67: 203-206.
- 57 Cheng Y, Wong RS, Soo YO. et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349: 831-836.
- 58 Mazzucconi MG, Fazi P, Bernasconi S. et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 2007; 109: 1401-1407.
- 59 Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci 2003; 28: 249-255.
- 60 Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science NY 2001; 291: 484-486.
- 61 Ott VL, Fong DC, Cambier JC. Fc gamma RIIB as a potential molecular target for intravenous gamma globulin therapy. J Allergy Clin Immunol 2001; 108: S95-98.
- 62 Crow AR, Song S, Freedman J. et al. IVIg-mediated amelioration of murine ITP via FcgammaRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 2003; 102: 558-560.
- 63 Bussel JB, Pham LC. Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature. Vox Sang 1987; 52: 206-211.
- 64 Godeau B, Lesage S, Divine M. et al. Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin. Blood 1993; 82: 1415-1421.
- 65 Scaradavou A, Woo B, Woloski BM. et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997; 89: 2689-2700.
- 66 Newman GC, Novoa MV, Fodero EM. et al. A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol 2001; 112: 1076-1078.
- 67 Meyer O, Kiesewetter H, Hermsen M. et al. Replacement of intravenous administration of anti-D by subcutaneous administration in patients with autoimmune thrombocytopenia. Ped Blood Cancer 2006; 47: 721-722.
- 68 Bussel JB, Pham LC, Aledort L. et al. Maintenance treatment of adults with chronic refractory immune thrombocytopenic purpura using repeated intravenous infusions of gammaglobulin. Blood 1988; 72: 121-127.
- 69 Cooper N, Woloski BM, Fodero EM. et al. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?. Blood 2002; 99: 1922-1927.
- 70 George JN, Raskob GE, Vesely SK. et al. Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care. Am´J Hematol 2003; 74: 161-169.
- 71 Kattamis AC, Shankar S, Cohen AR. Neurologic complications of treatment of childhood acute immune thrombocytopenic purpura with intravenously administered immunoglobulin G. J Pediatr 1997; 130: 281-283.
- 72 Katz U, Achiron A, Sherer Y. et al. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmunity Rev 2007; 6: 257-259.
- 73 Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0)(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood 2005; 106: 1532-1537.
- 74 British Committee for Standards in Haematology General Haematology Task Force.. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120: 574-596.
- 75 Carr JM, Kruskall MS, Kaye JA. et al. Efficacy of platelet transfusions in immune thrombocytopenia. Am J Med 1986; 80: 1051-1054.
- 76 Culic S. Recombinant factor VIIa for refractive haemorrhage in autoimmune idiopathic thrombocytopenic purpura. Br J Haematol 2003; 120: 909-910.
- 77 Barnes C, Blanchette V, Canning P. et al. Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia unresponsive to platelet-enhancing treatment. Transfus Med 2005; 15: 145-150.
- 78 Busani S, Marietta M, Pasetto A. et al. Use of recombinant factor VIIa in a thrombocytopenic patient with spontaneous intracerebral haemorrhage. Thromb Haemost 2005; 93: 381-382.
- 79 Savani BN, Dunbar CE, Rick ME. Combination therapy with rFVIIa and platelets for hemorrhage in patients with severe thrombocytopenia and alloimmunization. Am J Hematol 2006; 81: 218-219.
- 80 Wrobel G, Dobaczewski G, Patkowski D. et al. Experiences with recombinant activated factor VII in the treatment of severe refractory thrombocytopenia. Ped Blood Cancer 2006; 47: 729-730.
- 81 Kojouri K, Vesely SK, Terrell DR. et al. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004; 104: 2623-2634.
- 82 Najean Y, Rain JD, Billotey C. The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 patients with 268 splenectomies. Br J Haematol 1997; 97: 547-550.
- 83 Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122: 187-188.
- 84 Davies JM, Barnes R, Milligan D. Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. Clin Med 2002; 2: 440-443.
- 85 Stasi R, Stipa E, Masi M. et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995; 98: 436-442.
- 86 Stasi R, Pagano A, Stipa E. et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952-957.
- 87 Cooper N, Stasi R, Cunningham-Rundles S. et al. The efficacy and safety of B-cell depletion with anti- CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004; 125: 232-239.
- 88 Arnold DM, Dentali F, Crowther MA. et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146: 25-33.
- 89 Godeau B, Fain O, Porcher R. et al. Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study. Blood. 2006 108. Abstract 478.
- 90 Arnal C, Piette JC, Leone J. et al. Treatment of severe immune thrombocytopenia associated with systemic lupus erythematosus: 59 cases. J Rheumatol 2002; 29: 75-83.
- 91 Galli M, Finazzi G, Barbui T. Thrombocytopenia in the antiphospholipid syndrome. Br J Haematol 1996; 93: 1-5.
- 92 Finazzi G. The Italian Registry of Antiphospholipid Antibodies. Haematologica 1997; 82: 101-105.
- 93 Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun 2005; 25: 57-62.
- 94 Michel M, Chanet V, Galicier L. et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine (Baltimore) 2004; 83: 254-263.
- 95 Chang M, Qian JX, Lee SM. et al. Tissue uptake of circulating thrombopoietin is increased in immune-mediated compared with irradiated thrombocytopenic mice. Blood 1999; 93: 2515-2524.
- 96 Kosugi S, Kurata Y, Tomiyama Y. et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol 1996; 93: 704-706.
- 97 Porcelijn L, Folman CC, Bossers B. et al. The diagnostic value of thrombopoietin level measurements in thrombocytopenia. Thromb Haemost 1998; 79: 1101-1105.
- 98 Kuter DJ. New thrombopoietic growth factors. Blood 2007; 109: 4607-4616.
- 99 Li J, Yang C, Xia Y. et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001; 98: 3241-3248.
- 100 Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharm Therapeut 2004; 76: 628-638.
- 101 Bussel JB, Kuter DJ, George JN. et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; 355: 1672-1681.
- 102 Newland A, Caulier MT, Kappers-Klunne M. et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol 2006; 135: 547-553.
- 103 Kuter D, Bussel JB, George J. et al. Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 48-week update. Blood. 2006 108. Abstract 476.
- 104 Erickson-Miller CL, DeLorme E, Tian SS. et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol 2005; 33: 85-93.
- 105 Bussel JB, Cheng G, Saleh M. et al. Analysis of bleeding in patients with immune thrombocytopenic purpura (ITP): a randomized, double-blind, placebocontrolled trial of eltrombopag, an oral platelet growth factor. Blood. 2006 108. Abstract 475.
- 106 Bussel J, Provan A, Shamsi T. et al. Eltrombopag raises platelet count and reduces bleeding compared with placebo during short-term treatment in chronic idiopathic thrombocytopenic purpura: a phase III study. Haematologica 2007; 92 (Suppl. 01) Abstract 1814.
- 107 Desjardins RE, Tempel DL, Lucek R. et al. Single and multiple oral doses of AKR-501 (TM477) increase the platelet count in healthy volunteers. Blood 2006; 108 Abstract 477.