Pathophysiologie und Diagnostik der Immunthrombozytopenie

Zusammenfassung

Die Immunthrombozytopenie (ITP) entsteht durch Autoantikörper-Bildung gegen Oberflächenantigene der Blutplättchen. Die Erkrankung tritt als primäre ITP ohne eindeutigen Auslöser oder als sekundäre ITP (Medikamente, andere Krankheitsbilder) auf. Die Autoantikörper-Bildung führt zu einem Verlust von Thrombozyten in Milz oder Leber und reduziert daneben auch die Bildung von Thrombozyten. Die Synthese von Thrombopoetin ist bei ITP-Patienten – im Gegensatz anderen Bildungsstörungen der Thrombozyten – reduziert. Die ITP ist eine Ausschlussdiagnose, beweisende Laboruntersuchung liegen nicht vor. Nur in 50% der Fälle lassen sich Glykoprotein-spezifische Antikörper nachweisen. Von besonderer Bedeutung ist der Ausschluss der EDTA-induzierten Pseudothrombozytopenie. Andere Ursachen der Thrombozytopenie sollten durch (Medikamenten-)Anamnese, körperliche Untersuchung und gegebenenfalls Knochenmarkpunktion ausgeschlossen werden.

Abstract

Immune thrombocytopenia (ITP) is due to autoantibodies against platelet surface antigens. ITP is considered as either primary, with no clear etiology, or as secondary ITP (drug-induced; underlying diseases). Autoantibodies lead both to loss of platelets in the spleen and/or liver but simultaneously reduce their production. Contrary to other disorders with thrombocytopenia, ITP has reduced levels of thrombopoetin. ITP remains a diagnosis of exclusion. A single defining laboratory test does not exist. Glycoprotein-specific antibodies can be detected in only about 50% of cases. Ruling out EDTA-induced pseudo thrombocytopenia is of particular relevance. Secondary causes of thrombocytopenia should be excluded through medical history (especially medication history), physical examination and possibly bone-marrow puncture.

Kernaussagen

• Die Immunthrombozytopenie ist eine Autoimmun-Erkrankung, die mit einem erhöhten Abbau von Thrombozyten und gleichzeitig verminderter Produktion von Thrombozyten einhergeht.

• Der Ausschluss einer Pseudothrombozytopenie sollte bei Fehlen eindeutiger Blutungszeichen initial immer erfolgen.

• Die Letalität der ITP steigt in höherem Lebensalter stark an.

• Ein beweisender Test, der die Diagnose ITP absichert, existiert nicht.

Schlüsselwörter

Immunthrombozytopenie - Thrombopoetin - Desialylierung - Pathophysiologie - Diagnose

Keywords

immune thrombocytopenia - pathophysiology - diagnostics

Publication History

Received: 05 November 2023

Accepted after revision: 30 April 2024

Article published online:
01 July 2024

• Literatur

• 1 Werlhof P. De Variolis et Anthracibus. Hannover: Avla Hannoverana Regivs; 1735.
• 2 Rodeghiero F, Stasi R, Gernsheimer T. 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; 113: 2386-2393
• 3 Cooper N, Ghanima W. Immune Thrombocytopenia. N Engl J Med 2019; 381: 945-955
• 4 Bussel J, Cooper N, Boccia R. et al. Immune thrombocytopenia. Exp Rev Hematol 2021; 14: 1013-1025
• 5 McMillan R, Tani P, Millard F. et al. Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP. Blood 1987; 70: 1040-1045
• 6 Kiefel V, Santoso S, Kaufmann E. et al. Autoantibodies against platelet glycoprotein Ib/IX: a frequent finding in autoimmune thrombocytopenic purpura. Br J Heamatol 1991; 79: 256-262
• 7 Audia S, Mahévas M, Nivet M. et al. Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments. HemaSphere 2021; 5: e574
• 8 He R, Reid DM, Jones CE. et al. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 1994; 83: 1024-1032
• 9 McMillan R, Wang L, Tomer A. et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103: 1364-1369
• 10 Stoll D, Cines DB, Aster RH. et al. Platelet kinetics in patients with idiopathic thrombocytopenic purpura and moderate thrombocytopenia. Blood 1985; 65: 584-588
• 11 Heyns Adu P, Badenhorst PN, Lötter MG. et al. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ. Blood 1986; 67: 86-92
• 12 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
• 13 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
• 14 Iraqi M, Perdomo J, Yan F. et al. Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro. Haematologica 2015; 100: 623
• 15 Nugent D, McMillan R, Nichol JL. et al. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production. Br J Haematol 2009; 146: 585-596
• 16 Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016; 535: 75-84
• 17 Liu C, Cheng L, Ji L. et al. Intestinal microbiota dysbiosis play a role in pathogenesis of patients with primary immune thrombocytopenia. Thromb Res 2020; 190: 11-19
• 18 Wang Q, Li J, Yu TS. et al. Disrupted balance of CD4(+) T-cell subsets in bone marrow of patients with primary immune thrombocytopenia. Int J Biol Sci 2019; 15: 2798-2814
• 19 Kuwana M, Iki S, Urabe A. The role of autoantibody-producing plasma cells in immune thrombocytopenic purpura refractory to rituximab. Am J Hematol 2007; 82: 846-848
• 20 Li X, Zhong H, Bao W. et al. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood 2012; 120: 3318-3325
• 21 Consolini R, Legitimo A, Caparello MC. The Centenary of Immune Thrombocytopenia – Part 1: Revising Nomenclature and Pathogenesis. Front Pediatr 2016; 4: 102
• 22 Lee-Sundlov MM, Rivadeneyra L, Falet H. et al. Sialic acid and platelet count regulation: Implications in immune thrombocytopenia. Res Pract Thromb Haemost 2022; 6
• 23 Amini SN, Nelson VS, Porcelijn L. et al. The interplay between GPIb/IX antibodies, platelet hepatic sequestration, and TPO levels in patients with chronic ITP. Blood advances 2023; 7: 1066-1069
• 24 Peng J, Ma SH, Liu J. et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost 2014; 12: 497-504
• 25 Li J, van der Wal DE, Zhu G. et al. Platelet desialylation: a novel mechanism of Fc-independent platelet clearance and a potential diagnostic biomarker and therapeutic target in immune thrombocytopenia. In: American Society of Hematology Washington, DC. 2014
• 26 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
• 27 Zheng SS, Ahmadi Z, Leung HHL. et al. Antiplatelet antibody predicts platelet desialylation and apoptosis in immune thrombocytopenia. Haematologica 2022; 107: 2195-2205
• 28 Shao L, Wu Y, Zhou H. et al. Successful treatment with oseltamivir phosphate in a patient with chronic immune thrombocytopenia positive for anti-GPIb/IX autoantibody. Platelets 2015; 26: 495-497
• 29 Leede C. Hautblutungen durch Stauung hervorgerufen als diagnostisches Hilfsmittel beim Scharlach. München med Wchnschr 1911; 58: 293-295
• 30 Rumpel T. Photographien von Scharlachkranken mit multiplen Hautblutungen. Dtsch Med Wochenschr 1909; 35: 2297
• 31 Cooper N, Morrison MA, Vladescu C. et al. Identification of occult cerebral microbleeds in adults with immune thrombocytopenia. Blood 2020; 136: 2875-2880
• 32 Moulis G, Palmaro A, Montastruc JL. et al. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood 2014; 124: 3308-3315
• 33 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
• 34 Severinsen MT, Engebjerg MC, Farkas DK. et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol 2011; 152: 360-362
• 35 Hill QA, Newland AC. Fatigue in immune thrombocytopenia. Br J Haematol 2015; 170: 141-149
• 36 Hawkins J, Aster RH, Curtis BR. Post-Transfusion Purpura: Current Perspectives. J Blood Med 2019; 10: 405-415
• 37 Reese JA, Peck JD, Deschamps DR. et al. Platelet Counts during Pregnancy. N Engl J Med 2018; 379: 32-43
• 38 Kelton JG, Vrbensky JR, Arnold DM. How do we diagnose immune thrombocytopenia in 2018?. Hematology 2018; 2018: 561-567
• 39 Markewitz R, Sharifzadeh SR, Junker R. et al. EDTA-associated pseudothrombocytopenia: definition and real-world occurrence. Lab Med 2023; 47: 105-114
• 40 Althaus K, Greinacher A. MYH9-related platelet disorders. Semin Thromb Hemost 2009; 35: 189-203
• 41 Vrbensky JR, Moore JE, Arnold DM. et al. The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. J Thromb Haemost 2019; 17: 787-794
• 42 Al-Samkari H, Rosovsky RP, Karp Leaf RS. et al. A modern reassessment of glycoprotein-specific direct platelet autoantibody testing in immune thrombocytopenia. Blood advances 2020; 4: 9-18