“Diagnosis of Inherited Platelet Disorders”: Update of the Interdisciplinary S2k-Guideline [^[*]] of the Permanent Pediatric Commission of the Society of Thrombosis and Haemostasis Research (GTH e.V.)

Abstract

Inherited platelet disorders (IPD) are a heterogeneous group of diseases causing bleeding, which are often challenging to diagnose. To improve the diagnostic process for these disorders, the ThromKidplus study group of the Permanent Pediatric Commission of the Society for Thrombosis and Haemostasis Research (GTH) has updated the AWMF Guideline for the “Diagnosis of Inherited Platelet Disorders” (AWMF Registry Number 086–003).

Key updates in the guideline include a detailed diagnostic algorithm, emphasizing the use of standardized questionnaires, thorough patient history, and specific laboratory tests such as light transmission aggregometry (LTA), flow cytometry, and genetic testing. Updated guidelines for pre-analytics standardize sample preparation and handling to ensure reliable test results. Updated protocols for aggregometry and flow cytometry aim to enhance diagnostic accuracy. The integration of next-generation sequencing (NGS) provides comprehensive genetic analysis, and a new chapter on future developments highlights emerging technologies and research fields.

This guideline supports the diagnosis of IPD close to the patient's residence, limits the diagnostic process to essential steps, and assists in counseling affected individuals and their families, ensuring that the diagnosis provides especially quality of life benefits to the patient.

Keywords

inherited platelet disorders - guideline - diagnosis

Authors and Coordinators

The updated guideline was created under the overall responsibility of Werner Streif, Ralf Knöfler, and Jennifer Gebetsberger. Section coordinators and authors for the various chapters include:

• Diagnostic Algorithm: Doris Böckelmann, Jennifer Gebetsberger, Susanne Holzhauer, Beate Kehrel, Ralf Knöfler, Martin Olivieri, Werner Streif, and Barbara Zieger.

• Pre-analytics: Kerstin Jurk and Barbara Zieger.

• Aggregometry: Karina Althaus, Ingvild Birschmann, Kerstin Jurk, Michael Krause, Ralf Knöfler, Florian Prüller, and Oliver Tiebel.

• Flow Cytometry: Oliver Andres, Kerstin Jurk, Kristina Mott, Harald Schulze, and Barbara Zieger.

• Immunofluorescence Microscopy: Karina Althaus and Tamam Bakchoul.

• Specialized Analyses for Platelet Function Diagnostics: Lorenzo Alberio, Kerstin Jurk, and Beate Kehrel.

• Molecular Genetic Methods: Doris Böckelmann, Jennifer Gebetsberger, Kristina Mott, Anna Pavlova, Harald Schulze, and Barbara Zieger.

• Future Developments: Frauke Bergmann, Jennifer Gebetsberger, Ralf Knöfler, and Werner Streif.

^* AWMF-Register Nr. 086-003.

Publication History

Received: 12 November 2024

Accepted: 05 June 2025

Article published online:
12 August 2025

• References

• 1 Zieger B, Boeckelmann D. Inherited platelet disorders: a short introduction. Hamostaseologie 2023; 43 (01) 52-59
• 2 Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol 2009; 29 (02) 130-136
• 3 Pecci A, Balduini CL. Inherited thrombocytopenias: an updated guide for clinicians. Blood Rev 2021; 48: 100784
• 4 Bury L, Falcinelli E, Gresele P. Learning the ropes of platelet count regulation: inherited thrombocytopenias. J Clin Med 2021; 10 (03) 533
• 5 Streif W, Knöfler R, Eberl W. et al; Paediatric Committee of the Society of Thrombosis and Haemostasis Research. [Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. Hamostaseologie 2014; 34 (04) 269-275 , quiz 276
• 6 Knöfler R, Eberl W, Schulze H. et al. [Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. Hamostaseologie 2014; 34 (03) 201-212
• 7 Knöfler R, Olivieri M, Weickardt S, Eberl W, Streif W. THROMKID Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung e.V. [First results of the THROMKID study: a quality project for the registration of children und adolescents with hereditary platelet function defects in Germany, Austria, and Switzerland]. Hamostaseologie 2007; 27 (01) 48-53
• 8 Althaus K, Zieger B, Bakchoul T, Jurk K. THROMKID-Plus Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) und der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH). Standardization of light transmission aggregometry for diagnosis of platelet disorders: an inter-laboratory external quality assessment. Thromb Haemost 2019; 119 (07) 1154-1161
• 9 Maurer M, Mesters R, Schneppenheim R, Knoefler R, Streif W. Platelet-type von Willebrand disease: diagnostic challenges. Flaws and pitfalls experienced in the THROMKID Quality Project. Klin Padiatr 2015; 227 (03) 131-136
• 10 Streif W, Oliveri M, Weickardt S, Eberl W, Knoefler R. Thromkid Study Group of GTH. Testing for inherited platelet defects in clinical laboratories in Germany, Austria and Switzerland. Results of a survey carried out by the Permanent Paediatric Group of the German Thrombosis and Haemostasis Research Society (GTH). Platelets 2010; 21 (06) 470-478
• 11 Stockklausner C, Duffert CM, Cario H, Knöfler R, Streif W, Kulozik AE. THROMKID-Plus Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) and of Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH). Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management. Ann Hematol 2021; 100 (07) 1647-1665
• 12 Ballmaier M, Germeshausen M, Schulze H, Andres O. THROMKIDplus Study Group. THROMKIDplus patient registry and biomaterial banking for children with inherited platelet disorders. Hamostaseologie 2024; 44 (04) 298-303
• 13 Gresele P, Orsini S, Noris P. et al; BAT-VAL study investigators. Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: a communication from the Platelet Physiology SSC. J Thromb Haemost 2020; 18 (03) 732-739
• 14 Magnay JL, O'Brien S, Gerlinger C, Seitz C. Pictorial methods to assess heavy menstrual bleeding in research and clinical practice: a systematic literature review. BMC Womens Health 2020; 20 (01) 24
• 15 Fixter K, Rabbolini DJ, Valecha B. et al. Mean platelet diameter measurements to classify inherited thrombocytopenias. Int J Lab Hematol 2018; 40 (02) 187-195
• 16 Ferreira FLB, Colella MP, Medina SS. et al. Evaluation of the immature platelet fraction contribute to the differential diagnosis of hereditary, immune and other acquired thrombocytopenias. Sci Rep 2017; 7 (01) 3355
• 17 Born GV, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168 (01) 178-195
• 18 Clayton S, Born GV, Cross MJ. Inhibition of the aggregation of blood platelets by nucleosides. Nature 1963; 200: 138-139
• 19 Born GV, Hume M. Effects of the numbers and sizes of platelet aggregates on the optical density of plasma. Nature 1967; 215 (5105): 1027-1029
• 20 Gebetsberger J, Prüller F. Classic light transmission platelet aggregometry: do we still need it?. Hamostaseologie 2024; 44 (04) 304-315
• 21 Halimeh S, Angelis Gd, Sander A. et al. Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents. Klin Padiatr 2010; 222 (03) 158-163
• 22 Le Blanc J, Mullier F, Vayne C, Lordkipanidzé M. Advances in platelet function testing—light transmission aggregometry and beyond. J Clin Med 2020; 9 (08) 2636
• 23 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; Epub ahead of print
• 24 Ramström S, Södergren AL, Tynngård N, Lindahl TL. Platelet function determined by flow cytometry: new perspectives?. Semin Thromb Hemost 2016; 42 (03) 268-281
• 25 Gresele P. Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13 (02) 314-322
• 26 Frelinger III AL, Rivera J, Connor DE. et al. Consensus recommendations on flow cytometry for the assessment of inherited and acquired disorders of platelet number and function: communication from the ISTH SSC Subcommittee on Platelet Physiology. J Thromb Haemost 2021; 19 (12) 3193-3202
• 27 Cai H, Mullier F, Frotscher B. et al. Usefulness of flow cytometric mepacrine uptake/release combined with CD63 assay in diagnosis of patients with suspected platelet dense granule disorder. Semin Thromb Hemost 2016; 42 (03) 282-291
• 28 Andres O, Henning K, Strauß G, Pflug A, Manukjan G, Schulze H. Diagnosis of platelet function disorders: a standardized, rational, and modular flow cytometric approach. Platelets 2018; 29 (04) 347-356
• 29 Josefsson EC, Ramström S, Thaler J, Lordkipanidzé M. COAGAPO study group. Consensus report on markers to distinguish procoagulant platelets from apoptotic platelets: communication from the Scientific and Standardization Committee of the ISTH. J Thromb Haemost 2023; 21 (08) 2291-2299
• 30 Wielders SJ, Broers J, ten Cate H, Collins PW, Bevers EM, Lindhout T. Absence of platelet-dependent fibrin formation in a patient with Scott syndrome. Thromb Haemost 2009; 102 (01) 76-82
• 31 Jurk K, Lahav J, VAN Aken H, Brodde MF, Nofer JR, Kehrel BE. Extracellular protein disulfide isomerase regulates feedback activation of platelet thrombin generation via modulation of coagulation factor binding. J Thromb Haemost 2011; 9 (11) 2278-2290
• 32 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 (07) 1511-1521
• 33 Zaninetti C, Leinøe E, Lozano ML. et al. Validation of immunofluorescence analysis of blood smears in patients with inherited platelet disorders. J Thromb Haemost 2023; 21 (04) 1010-1019
• 34 Zaninetti C, Greinacher A. Diagnosis of inherited platelet disorders on a blood smear. J Clin Med 2020; 9 (02) 539
• 35 Andres O, König EM, Althaus K. et al; THROMKIDplus Study Group of the Society of Paediatric Oncology Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie, GPOH) and the Society of Thrombosis Haemostasis Research (Gesellschaft für Thrombose- und Hämostaseforschung, GTH). Use of targeted high-throughput sequencing for genetic classification of patients with bleeding diathesis and suspected platelet disorder. TH Open 2018; 2 (04) e445-e454
• 36 Gebetsberger J, Mott K, Bernar A, Klopocki E, Streif W, Schulze H. State-of-the-art targeted high-throughput sequencing for detecting inherited platelet disorders. Hamostaseologie 2023; 43 (04) 244-251
• 37 Blavignac J, Bunimov N, Rivard GE, Hayward CP. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost 2011; 37 (06) 713-720
• 38 Paterson AD, Rommens JM, Bharaj B. et al. Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene. Blood 2010; 115 (06) 1264-1266
• 39 Homan CC, Scott HS, Brown AL. Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26. Blood 2023; 141 (13) 1533-1543
• 40 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 41 Matthijs G, Souche E, Alders M. et al. Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet 2016; 24 (10) 1515
• 42 Nurden AT, Nurden P. High-throughput sequencing for rapid diagnosis of inherited platelet disorders: a case for a European consensus. Haematologica 2018; 103 (01) 6-8
• 43 Bastida JM, Lozano ML, Benito R. et al. Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders. Haematologica 2018; 103 (01) 148-162