New Developments in the Pathophysiology and Management of Primary Immune Thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disease that is characterized by a significant reduction in the number of circulating platelets and frequently associated with bleeding. Although the pathogenesis of ITP is still not completely elucidated, it is largely recognized that the low platelet count observed in ITP patients is due to multiple alterations of the immune system leading to increased platelet destruction as well as impaired thrombopoiesis. The clinical manifestations and patients' response to different treatments are very heterogeneous suggesting that ITP is a group of disorders sharing common characteristics, namely, loss of immune tolerance toward platelet (and megakaryocyte) antigens and dysfunctional primary hemostasis. Management of ITP is challenging and requires intensive communication between patients and caregivers. The decision to initiate treatment should be based on the platelet count level, age of the patient, bleeding manifestation, and other factors that influence the bleeding risk in individual patients. In this review, we present recent data on the mechanisms that lead to platelet destruction in ITP with a particular focus on current findings concerning alterations of thrombopoiesis. In addition, we give an insight into the efficacy and safety of current therapies and management of ITP bleeding emergencies.

Keywords

platelet immunology - immune thrombocytopenia - autoantibodies - autoimmune diseases

Publikationsverlauf

Eingereicht: 08. Juli 2020

Angenommen: 15. November 2020

Artikel online veröffentlicht:
21. Dezember 2020

• References

• 1 Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (02) 168-186
• 2 Neunert C, Lim W, Crowther M, Cohen A, Solberg Jr L, Crowther MA. American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117 (16) 4190-4207
• 3 Moulis G, Palmaro A, Montastruc JL, Godeau B, Lapeyre-Mestre M, Sailler L. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 2014; 124 (22) 3308-3315
• 4 Neunert C, Terrell DR, Arnold DM. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv 2019; 3 (23) 3829-3866
• 5 Bennett CM, Neunert C, Grace RF. et al. Predictors of remission in children with newly diagnosed immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group Registry II participants. Pediatr Blood Cancer 2018; 65 (01) DOI: 10.1002/pbc.26736.
• 6 McKenzie CG, Guo L, Freedman J, Semple JW. Cellular immune dysfunction in immune thrombocytopenia (ITP). Br J Haematol 2013; 163 (01) 10-23
• 7 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; 124 (02) 499-542
• 8 Ku FC, Tsai CR, Der Wang J, Wang CH, Chang TK, Hwang WL. Stromal-derived factor-1 gene variations in pediatric patients with primary immune thrombocytopenia. Eur J Haematol 2013; 90 (01) 25-30
• 9 Rank A, Weigert O, Ostermann H. Management of chronic immune thrombocytopenic purpura: targeting insufficient megakaryopoiesis as a novel therapeutic principle. Biologics 2010; 4: 139-145
• 10 Cines DB, Liebman HA. The immune thrombocytopenia syndrome: a disorder of diverse pathogenesis and clinical presentation. Hematol Oncol Clin North Am 2009; 23 (06) 1155-1161
• 11 D'Orazio JA, Neely J, Farhoudi N. ITP in children: pathophysiology and current treatment approaches. J Pediatr Hematol Oncol 2013; 35 (01) 1-13
• 12 Provan D, Arnold DM, Bussel JB. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3 (22) 3780-3817
• 13 Zhao Z, Yang L, Yang G. et al. Contributions of T lymphocyte abnormalities to therapeutic outcomes in newly diagnosed patients with immune thrombocytopenia. PLoS One 2015; 10 (05) e0126601
• 14 Ji X, Zhang L, Peng J, Hou M. T cell immune abnormalities in immune thrombocytopenia. J Hematol Oncol 2014; 7: 72
• 15 Zhang F, Chu X, Wang L. et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76 (05) 427-431
• 16 Zhao C, Li X, Zhang F, Wang L, Peng J, Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 2008; 93 (09) 1428-1430
• 17 Nieswandt B, Bergmeier W, Rackebrandt K, Gessner JE, Zirngibl H. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood 2000; 96 (07) 2520-2527
• 18 Nieswandt B, Bergmeier W, Schulte V, Rackebrandt K, Gessner JE, Zirngibl H. Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. J Biol Chem 2000; 275 (31) 23998-24002
• 19 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 (03) 943-946
• 20 Li J, van der Wal DE, Zhu G. et al. Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun 2015; 6: 7737
• 21 Tao L, Zeng Q, Li J. et al. Platelet desialylation correlates with efficacy of first-line therapies for immune thrombocytopenia. J Hematol Oncol 2017; 10 (01) 46
• 22 Li J, Sullivan JA, Ni H. Pathophysiology of immune thrombocytopenia. Curr Opin Hematol 2018; 25 (05) 373-381
• 23 Quach ME, Dragovich MA, Chen W. et al. Fc-independent immune thrombocytopenia via mechanomolecular signaling in platelets. Blood 2018; 131 (07) 787-796
• 24 Marini I, Zlamal J, Faul C. et al. Autoantibody-mediated desialylation impairs human thrombopoiesis and platelet life span. Haematologica 2019; ; (epub ahead of print) DOI: 10.3324/haematol.2019.236117.
• 25 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128 (06) 1173-1186
• 26 van der Wal DE, Gitz E, Du VX. et al. Arachidonic acid depletion extends survival of cold-stored platelets by interfering with the [glycoprotein Ibα–14-3-3ζ] association. Haematologica 2012; 97 (10) 1514-1522
• 27 Alvarez Román MT, Fernández Bello I, Arias-Salgado EG. et al. Effects of thrombopoietin receptor agonists on procoagulant state in patients with immune thrombocytopenia. Thromb Haemost 2014; 112 (01) 65-72
• 28 Winkler J, Kroiss S, Rand ML. et al. Platelet apoptosis in paediatric immune thrombocytopenia is ameliorated by intravenous immunoglobulin. Br J Haematol 2012; 156 (04) 508-515
• 29 Goette NP, Glembotsky AC, Lev PR. et al. Platelet apoptosis in adult immune thrombocytopenia: insights into the mechanism of damage triggered by auto-antibodies. PLoS One 2016; 11 (08) e0160563
• 30 McMillan R, Luiken GA, Levy R, Yelenosky R, Longmire RL. Antibody against megakaryocytes in idiopathic thrombocytopenic purpura. JAMA 1978; 239 (23) 2460-2462
• 31 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 (06) 1951-1958
• 32 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 (03) 887-895
• 33 McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103 (04) 1364-1369
• 34 Iraqi M, Perdomo J, Yan F, Choi PY, Chong BH. Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro. Haematologica 2015; 100 (05) 623-632
• 35 Yang L, Wang L, Zhao CH. et al. Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia. Blood 2010; 116 (20) 4307-4316
• 36 Radley JM, Haller CJ. Fate of senescent megakaryocytes in the bone marrow. Br J Haematol 1983; 53 (02) 277-287
• 37 Houwerzijl EJ, Blom NR, van der Want JJ. et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103 (02) 500-506
• 38 Vrbensky JR, Nazy I, Toltl LJ. et al. Megakaryocyte apoptosis in immune thrombocytopenia. Platelets 2018; 29 (07) 729-732
• 39 Cooper N. State of the art - how I manage immune thrombocytopenia. Br J Haematol 2017; 177 (01) 39-54
• 40 Kiefel V, Freitag E, Kroll H, Santoso S, Mueller-Eckhardt C. Platelet autoantibodies (IgG, IgM, IgA) against glycoproteins IIb/IIIa and Ib/IX in patients with thrombocytopenia. Ann Hematol 1996; 72 (04) 280-285
• 41 Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97 (09) 2549-2554
• 42 Page LK, Psaila B, Provan D. et al. The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP. Br J Haematol 2007; 138 (02) 245-248
• 43 Arnold DM, Nazy I, Clare R. et al. Misdiagnosis of primary immune thrombocytopenia and frequency of bleeding: lessons from the McMaster ITP Registry. Blood Adv 2017; 1 (25) 2414-2420
• 44 Godeau B, Chevret S, Varet B. et al; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359 (9300): 23-29
• 45 Mayer B, Salama A. Successful treatment of bleeding with tranexamic acid in a series of 12 patients with immune thrombocytopenia. Vox Sang 2017; 112 (08) 767-772
• 46 Bartholomew JR, Salgia R, Bell WR. Control of bleeding in patients with immune and nonimmune thrombocytopenia with aminocaproic acid. Arch Intern Med 1989; 149 (09) 1959-1961
• 47 Adelborg K, Kristensen NR, Nørgaard M. et al. Cardiovascular and bleeding outcomes in a population-based cohort of patients with chronic immune thrombocytopenia. J Thromb Haemost 2019; 17 (06) 912-924
• 48 Piel-Julian ML, Mahévas M, Germain J. et al; CARMEN Investigators Group. Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. J Thromb Haemost 2018; 16 (09) 1830-1842
• 49 Marini I, Bakchoul T. Pathophysiology of autoimmune thrombocytopenia: current insight with a focus on thrombopoiesis. Hamostaseologie 2019; 39 (03) 227-237
• 50 Mithoowani S, Gregory-Miller K, Goy J. et al. High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol 2016; 3 (10) e489-e496
• 51 Frederiksen H, Ghanima W. Response of first line treatment with corticosteroids in a population-based cohort of adults with primary immune thrombocytopenia. Eur J Intern Med 2017; 37: e23-e25
• 52 Cheng Y, Wong RS, Soo YO. et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349 (09) 831-836
• 53 Beck CE, Nathan PC, Parkin PC, Blanchette VS, Macarthur C. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr 2005; 147 (04) 521-527
• 54 Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994; 121 (04) 259-262
• 55 Ahsan N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIG therapy. J Nephrol 1998; 11 (03) 157-161
• 56 Donga PZ, Bilir SP, Little G, Babinchak T, Munakata J. Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura. J Med Econ 2017; 20 (11) 1200-1206
• 57 Padmore RF. Hemolysis upon intravenous immunoglobulin transfusion. Transfus Apheresis Sci 2012; 46 (01) 93-96
• 58 Miltiadous O, Hou M, Bussel JB. Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood 2020; 135 (07) 472-490
• 59 Ammann EM, Haskins CB, Fillman KM. et al. Intravenous immune globulin and thromboembolic adverse events: a systematic review and meta-analysis of RCTs. Am J Hematol 2016; 91 (06) 594-605
• 60 Ammann EM, Jones MP, Link BK. et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood 2016; 127 (02) 200-207
• 61 Daniel GW, Menis M, Sridhar G. et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion 2012; 52 (10) 2113-2121
• 62 Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 1991; 77 (09) 1884-1893
• 63 Meyer O, Kiesewetter H, Hermsen M. et al. Replacement of intravenous administration of anti-D by subcutaneous administration in patients with autoimmune thrombocytopenia. Pediatr Blood Cancer 2006; 47 (5, Suppl): 721-722
• 64 Scaradavou A, Woo B, Woloski BM. et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997; 89 (08) 2689-2700
• 65 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 (05) 1532-1537
• 66 Tarantino MD, Bussel JB, Cines DB. et al. A closer look at intravascular hemolysis (IVH) following intravenous anti-D for immune thrombocytopenic purpura (ITP). Blood 2007; 109 (12) 5527 , author reply 5528
• 67 Neunert CE. Thrombopoietin receptor agonist use for immune thrombocytopaenia. Hamostaseologie 2019; 39 (03) 272-278
• 68 Kuter DJ, Bussel JB, Lyons RM. et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371 (9610): 395-403
• 69 Cheng G, Saleh MN, Marcher C. et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet 2011; 377 (9763): 393-402
• 70 Khellaf M, Viallard JF, Hamidou M. et al. A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia. Haematologica 2013; 98 (06) 881-887
• 71 González-Porras JR, Mingot-Castellano ME, Andrade MM. et al. Use of eltrombopag after romiplostim in primary immune thrombocytopenia. Br J Haematol 2015; 169 (01) 111-116
• 72 González-López TJ, Pascual C, Álvarez-Román MT. et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol 2015; 90 (03) E40-E43
• 73 Newland A, Godeau B, Priego V. et al. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol 2016; 172 (02) 262-273
• 74 Rodeghiero F. Is ITP a thrombophilic disorder?. Am J Hematol 2016; 91 (01) 39-45
• 75 Wong RSM, Saleh MN, Khelif A. et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood 2017; 130 (23) 2527-2536
• 76 Kuter DJ, Bussel JB, Newland A. et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol 2013; 161 (03) 411-423
• 77 Jurczak W, Chojnowski K, Mayer J. et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol 2018; 183 (03) 479-490
• 78 Chugh S, Darvish-Kazem S, Lim W. et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol 2015; 2 (02) e75-e81
• 79 Patel VL, Mahévas M, Lee SY. et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012; 119 (25) 5989-5995
• 80 Ghanima W, Khelif A, Waage A. et al; RITP Study Group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015; 385 (9978): 1653-1661
• 81 Khellaf M, Charles-Nelson A, Fain O. et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014; 124 (22) 3228-3236
• 82 Puavilai T, Thadanipon K, Rattanasiri S. et al. Treatment efficacy for adult persistent immune thrombocytopenia: a systematic review and network meta-analysis. Br J Haematol 2020; 188 (03) 450-459
• 83 Bussel J, Arnold DM, Grossbard E. et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 2018; 93 (07) 921-930
• 84 Mohammadpour F, Kargar M, Hadjibabaie M. The role of hydroxychloroquine as a steroid-sparing agent in the treatment of immune thrombocytopenia: a review of the literature. J Res Pharm Pract 2018; 7 (01) 4-12
• 85 Kojouri K, Vesely SK, Terrell DR, George JN. 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 (09) 2623-2634
• 86 Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood 2018; 131 (11) 1172-1182
• 87 Matzdorff A, Meyer O, Ostermann H. et al. Immune thrombocytopenia - current diagnostics and therapy: recommendations of a joint working group of DGHO, ÖGHO, SGH, GPOH, and DGTI. Oncol Res Treat 2018; 41 (Suppl. 05) 1-30
• 88 Qu Y, Xu J, Jiao C, Cheng Z, Ren S. Long-term outcomes of laparoscopic splenectomy versus open splenectomy for idiopathic thrombocytopenic purpura. Int Surg 2014; 99 (03) 286-290
• 89 Nørgaard M, Cetin K, Maegbaek ML. et al. Risk of arterial thrombotic and venous thromboembolic events in patients with primary chronic immune thrombocytopenia: a Scandinavian population-based cohort study. Br J Haematol 2016; 174 (04) 639-642
• 90 Boyle S, White RH, Brunson A, Wun T. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 2013; 121 (23) 4782-4790