Download PDF
Transfusionsmedizin 2019; 9(02): 96-108
DOI: 10.1055/a-0626-6467
Übersicht
Georg Thieme Verlag KG Stuttgart · New York

Diagnose der Thrombozytenfunktionsstörungen – eine Herausforderung im Labor

The Diagnosis of Platelet Function Disorders – A Challenge in the Laboratory
Karina Althaus
1   Zentrum für Klinische Transfusionsmedizin gemeinnützige GmbH, Tübingen
,
Miriam Wagner
2   Transfusionsmedizin, Medizinische Fakultät der Eberhard-Karls-Universität, Tübingen
,
Tamam Bakchoul
1   Zentrum für Klinische Transfusionsmedizin gemeinnützige GmbH, Tübingen
2   Transfusionsmedizin, Medizinische Fakultät der Eberhard-Karls-Universität, Tübingen
› Author Affiliations
Further Information

Publication History

Publication Date:
16 May 2019 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die Ursache von Thrombozytenfunktionsstörungen kann erblich bedingt sein, aber auch infolge von Begleiterkrankungen und Arzneimittelwirkungen auftreten. Die Thrombozytenfunktionsuntersuchung ist jedoch komplex und kaum standardisiert. Die Bestimmung der Thrombozytenzahl und die morphologische Untersuchung der Blutplättchen sind auch für eine erste Beurteilung der Thrombozytenfunktion extrem hilfreich. Bei Patienten mit Verdacht auf eine Thrombozytenfunktionsstörung sollte nach Bestimmung der Thrombozytenzahl und der ersten morphologischen Untersuchung die Lichttransmissionsaggregometrie (LTA) und wenn möglich die Sekretionsanalyse z.B. in der Durchflusszytometrie bzw. die Immunfluoreszenzmikroskopie durchgeführt werden. Bei auffälligen Befunden können weitere spezialisierte Verfahren wie z.B. die Elektronenmikroskopie und genetische Untersuchungen zielführend sein. Hierbei ist eine Vereinheitlichung von Thrombozytenfunktionsanalysen und Antikörperuntersuchungen zwischen den verschiedenen Laboren extrem wichtig, um die Diagnostik auf diesem Gebiet zu optimieren. Wir möchten uns in diesem Artikel auf die angeborene Thrombozytenfunktionsstörung und die derzeit aktuellen Labormethoden fokussieren, um die zugrunde liegenden molekularen und genetischen Defekte genauer bestimmen zu können. Ziel ist es, eine optimale Anwendung des diagnostischen und therapeutischen Ansatzes für die Behandlung von Patienten mit erblichen Thrombozytenfunktionsstörungen zu ermöglichen.

Abstract

Inherited platelet disorders as well as comorbidities or drugs can cause platelet dysfunctions. Platelet function testing is complex and poorly standardized. Evaluation of platelet count, review of peripheral blood cell morphology and bleeding assessment tools can aid the initial differential diagnosis. For patients requiring further laboratory testing, light transmission aggregometry, secretion assays, and immunofluorescence are the most useful next steps and will direct further specialized testing including flow cytometry, electron microscopy, and genetic diagnostics. Standardization of platelet function analysis and antibody testing is essential and can provide a template for clinical laboratories that will optimize diagnosis and assure high quality results. In this article we will focus on platelet function disorders and on current laboratory methods to identify the underlying molecular and genetic defect. Information provided in this article will allow applying the best possible diagnostic and therapeutic approach to patients with inherited as well as acquired platelet disorders. The aim of this review is to provide information on applying the best possible diagnostic and therapeutic approach to patients with inherited as well as acquired platelet function disorders.

Schlüsselwörter

Thrombozyten - Thrombozytenfunktionsstörung - Blutung - Thrombozytopenie

Key words

platelet - platelet function defect - bleeding - thrombocytopenia
 

  • Literatur

  • 1 Orsini S, Noris P, Bury L. et al. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica 2017; 102: 1192-1203
    CrossrefPubMedGoogle Scholar
  • 2 Nurden AT, Pillois X, Wilcox DA. Glanzmann thrombasthenia: state of the art and future directions. Semin Thromb Hemost 2013; 39: 642-655
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Nurden AT, Pillois X. ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia. Platelets 2018; 29: 98-101
    CrossrefPubMedGoogle Scholar
  • 4 Poon MC, Di Minno G, dʼOiron R. et al. New Insights into the Treatment of Glanzmann Thrombasthenia. Transfus Med Rev 2016; 30: 92-99
    CrossrefPubMedGoogle Scholar
  • 5 Nurden AT, Pillois X, Fiore M. et al. Expanding the Mutation Spectrum Affecting αIIbbeta3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort. Hum Mutat 2015; 36: 548-561
    CrossrefPubMedGoogle Scholar
  • 6 Kanaji T, Ware J, Okamura T. et al. GPIbalpha regulates platelet size by controlling the subcellular localization of filamin. Blood 2012; 119: 2906-2913
    CrossrefPubMedGoogle Scholar
  • 7 Savoia A, Kunishima S, De Rocco D. et al. Spectrum of the mutations in Bernard-Soulier syndrome. Hum Mutat 2014; 35: 1033-1045
    CrossrefPubMedGoogle Scholar
  • 8 Nava T, Rivard GE, Bonnefoy A. Challenges on the diagnostic approach of inherited platelet function disorders: Is a paradigm change necessary?. Platelets 2018; 29: 148-155
    CrossrefPubMedGoogle Scholar
  • 9 Afrasiabi A, Artoni A, Karimi M. et al. Glanzmann thrombasthenia and Bernard-Soulier syndrome in south Iran. Clin Lab Haematol 2005; 27: 324-327
    CrossrefPubMedGoogle Scholar
  • 10 Bury L, Malara A, Momi S. et al. Mechanisms of thrombocytopenia in platelet-type Von Willebrand Disease. Haematologica 2019; DOI: 10.3324/haematol.2018.200378.
    CrossrefPubMedGoogle Scholar
  • 11 Giannini S, Cecchetti L, Mezzasoma AM. et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica 2010; 95: 1021-1024
    CrossrefPubMedGoogle Scholar
  • 12 Arthur JF, Dunkley S, Andrews RK. Platelet glycoprotein VI-related clinical defects. Br J Haematol 2007; 139: 363-372
    CrossrefPubMedGoogle Scholar
  • 13 Sharda A, Flaumenhaft R. The life cycle of platelet granules. F1000Res 2018; 7: 236
    CrossrefPubMedGoogle Scholar
  • 14 Gremmel T, Frelinger AL3rd Michelson AD. Platelet Physiology. Semin Thromb Hemost 2016; 42: 191-204
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Albers CA, Cvejic A, Favier R. et al. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet 2011; 43: 735-737
    CrossrefPubMedGoogle Scholar
  • 16 Nurden AT, Nurden P. The gray platelet syndrome: clinical spectrum of the disease. Blood Rev 2007; 21: 21-36
    CrossrefPubMedGoogle Scholar
  • 17 Stevenson WS, Morel-Kopp MC, Chen Q. et al. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost 2013; 11: 2039-2047
    CrossrefPubMedGoogle Scholar
  • 18 Schulze H, Schlagenhauf A, Manukjan G. et al. Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p 37. Haematologica 2017; 102: e375-e378
    CrossrefPubMedGoogle Scholar
  • 19 Stevenson WS, Rabbolini DJ, Beutler L. et al. Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1. Blood 2015; 126: 2027-2030
    CrossrefPubMedGoogle Scholar
  • 20 Nurden AT, Nurden P. Should any genetic defect affecting alpha-granules in platelets be classified as gray platelet syndrome?. Am J Hematol 2016; 91: 714-718
    CrossrefPubMedGoogle Scholar
  • 21 Salles II, Feys HB, Iserbyt BF. et al. Inherited traits affecting platelet function. Blood Rev 2008; 22: 155-172
    CrossrefPubMedGoogle Scholar
  • 22 Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders. Haemophilia 2012; 18 (Suppl. 04) 154-160
    CrossrefPubMedGoogle Scholar
  • 23 Fletcher SJ, Johnson B, Lowe GC. et al. SLFN14 mutations underlie thrombocytopenia with excessive bleeding and platelet secretion defects. J Clin Invest 2015; 125: 3600-3605
    CrossrefPubMedGoogle Scholar
  • 24 Gresele P, Falcinelli E, Bury L. Laboratory diagnosis of clinically relevant platelet function disorders. Int J Lab Hematol 2018; 40 (Suppl. 01) 34-45
    PubMedGoogle Scholar
  • 25 Lordier L, Bluteau D, Jalil A. et al. RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization. Nat Commun 2012; 3: 717
    CrossrefPubMedGoogle Scholar
  • 26 Daly ME. Transcription factor defects causing platelet disorders. Blood Rev 2017; 31: 1-10
    PubMedGoogle Scholar
  • 27 Nichols KE, Crispino JD, Poncz M. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 2000; 24: 266-270
    CrossrefPubMedGoogle Scholar
  • 28 Vo KK, Jarocha DJ, Lyde RB. et al. FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology. Blood 2017; 129: 3486-3494
    CrossrefPubMedGoogle Scholar
  • 29 Saultier P, Vidal L, Canault M. et al. Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features. Haematologica 2017; 102: 1006-1016
    CrossrefPubMedGoogle Scholar
  • 30 Melazzini F, Palombo F, Balduini A. et al. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica 2016; 101: 1333-1342
    CrossrefPubMedGoogle Scholar
  • 31 Kamato D, Thach L, Bernard R. et al. Structure, Function, Pharmacology, and Therapeutic Potential of the G Protein, Galpha/q,11. Front Cardiovasc Med 2015; 2: 14
    PubMedGoogle Scholar
  • 32 Scharf RE. Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2. Hamostaseologie 2018; 38: 211-222
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Rao AK, Jalagadugula G, Sun L. Inherited defects in platelet signaling mechanisms. Semin Thromb Hemost 2004; 30: 525-535
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Dragani A, Brancati F, Pascale S. et al. Clinical and laboratory phenotype associated with the aspirin-like defect. Br J Haematol 2010; 148: 661-663 author reply 663–664
    CrossrefPubMedGoogle Scholar
  • 35 Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci 2013; 1285: 26-43
    CrossrefPubMedGoogle Scholar
  • 36 de Witt SM, Swieringa F, Cavill R. et al. Identification of platelet function defects by multi-parameter assessment of thrombus formation. Nat Commun 2014; 5: 4257
    CrossrefPubMedGoogle Scholar
  • 37 Nurden AT, Nurden P. Inherited disorders of platelet function: selected updates. J Thromb Haemost 2015; 13 (Suppl. 01) S2-S9
    CrossrefPubMedGoogle Scholar
  • 38 Lhermusier T, Chap H, Payrastre B. Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 2011; 9: 1883-1891
    CrossrefPubMedGoogle Scholar
  • 39 Misceo D, Holmgren A, Louch WE. et al. A dominant STIM1 mutation causes Stormorken syndrome. Hum Mutat 2014; 35: 556-564
    CrossrefPubMedGoogle Scholar
  • 40 Bidlingmaier C, Grote V, Budde U. et al. Prospective evaluation of a pediatric bleeding questionnaire and the ISTH bleeding assessment tool in children and parents in routine clinical practice. J Thromb Haemost 2012; 10: 1335-1341
    CrossrefPubMedGoogle Scholar
  • 41 Lowe GC, Lordkipanidze M, Watson SP. UK GAPP study group. Utility of the ISTH bleeding assessment tool in predicting platelet defects in participants with suspected inherited platelet function disorders. J Thromb Haemost 2013; 11: 1663-1668
    CrossrefPubMedGoogle Scholar
  • 42 Hvas AM, Favaloro EJ. Platelet Function Analyzed by Light Transmission Aggregometry. Methods Mol Biol 2017; 1646: 321-331
    PubMedGoogle Scholar
  • 43 Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost 2012; 38: 865-883
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Nagler M, Keller P, Siegrist D. et al. A case of EDTA-dependent pseudothrombocytopenia: simple recognition of an underdiagnosed and misleading phenomenon. BMC Clin Pathol 2014; 14: 19
    CrossrefPubMedGoogle Scholar
  • 45 Hvas AM, Grove EL. Platelet Function Tests: Preanalytical Variables, Clinical Utility, Advantages, and Disadvantages. Methods Mol Biol 2017; 1646: 305-320
    CrossrefPubMedGoogle Scholar
  • 46 Noris P, Biino G, Pecci A. et al. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. Blood 2014; 124: e4-e10
    CrossrefPubMedGoogle Scholar
  • 47 Fixter K, Rabbolini DJ, Valecha B. et al. Mean platelet diameter measurements to classify inherited thrombocytopenias. Int J Lab Hematol 2018; 40: 187-195
    CrossrefPubMedGoogle Scholar
  • 48 Greinacher A, Pecci A, Kunishima S. et al. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. J Thromb Haemost 2017; 15: 1511-1521
    CrossrefPubMedGoogle Scholar
  • 49 Knofler R, Streif W. Strategies in Clinical and Laboratory Diagnosis of Inherited Platelet Function Disorders in Children. Transfus Med Hemother 2010; 37: 231-235
    PubMedGoogle Scholar
  • 50 Cattaneo M, Cerletti C, Harrison P. et al. Recommendations for the Standardization of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost 2013; DOI: 10.1111/jth.12231.
    CrossrefPubMedGoogle Scholar
  • 51 Paniccia R, Priora R, Liotta AA. et al. Platelet function tests: a comparative review. Vasc Health Risk Manag 2015; 11: 133-148
    PubMedGoogle Scholar
  • 52 Podda GM, Bucciarelli P, Lussana F. et al. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time. J Thromb Haemost 2007; 5: 2393-2398
    CrossrefPubMedGoogle Scholar
  • 53 Badin MS, Graf L, Iyer JK. et al. Variability in platelet dense granule adenosine triphosphate release findings amongst patients tested multiple times as part of an assessment for a bleeding disorder. Int J Lab Hematol 2016; 38: 648-657
    CrossrefPubMedGoogle Scholar
  • 54 Lundin A, Richardsson A, Thore A. Continous monitoring of ATP-converting reactions by purified firefly luciferase. Anal Biochem 1976; 75: 611-620
    CrossrefPubMedGoogle Scholar
  • 55 Gresele P, Bury L, Mezzasoma AM. et al. Platelet function assays in diagnosis: an update. Expert Rev Hematol 2019; 12: 29-46
    CrossrefPubMedGoogle Scholar
  • 56 Andres O, Henning K, Strauss G. et al. Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach. Platelets 2018; 29: 347-356
    CrossrefPubMedGoogle Scholar
  • 57 Westbury SK, Turro E, Greene D. et al. Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders. Genome Med 2015; 7: 36
    CrossrefPubMedGoogle Scholar