“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.

 

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Keywords

inherited platelet disorders - guideline - diagnosis

Introduction

Inherited platelet disorders (IPD) are a heterogeneous group of diseases causing bleeding of variable severity that can either be associated with complex systemic diseases or occur as isolated entities.[1] The diagnosis of these disorders is comprehensive and often challenging. Many IPD, particularly those without a reduction in platelet count below 100,000/µL, often remain undetected until bleeding symptoms manifest.[2] The clinical consequences of IPD typically result in a mild to moderate bleeding tendency. However, co-factors such as medications, surgeries, or other hemostatic challenges can lead to clinically significant bleeding. Typical symptoms of IPD include mucocutaneous bleeding such as epistaxis, menorrhagia, hematomas, petechiae, and bleeding during invasive procedures and surgeries. Additionally, bleeding can occur suddenly and unpredictably.[3] [4]

To assess platelet function, a diagnostic algorithm is recommended. Despite the availability of numerous testing methods, only a few are suitable for clinical practice.[3] The application of different laboratory diagnostic tests is dependent on the patient's history, clinical presentation, and local resources, which frequently require close collaboration with specialized hemostasis centers and molecular genetics laboratories for the following:

• To facilitate the diagnosis of IPD as close to the patient's residence as possible.

• To limit the diagnostic process to the essential steps.

• To ensure that the diagnosis provides tangible benefits including adequate treatment to the patient.

• To support the counseling of affected individuals and their families.

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 Platelet Disorders” (AWMF Registry Number 086–003), which is summarized here in this manuscript.

ThromKid, initiated in 2004 as a project of the Permanent Pediatric Commission of the GTH, aims to improve the diagnosis and treatment of patients with IPD. These efforts have led to the development of two guidelines for Germany, Austria, and Switzerland, providing information on standardized diagnostic procedures and consensus-based treatment recommendations.[5] [6] The ThromKidplus group, which now also includes recommendations for adult patients, further focuses on refining existing guidelines, establishing criteria for quality control in specialized hemostasis laboratories, and designating competence or reference centers to support other centers in diagnosis and therapy.[7] [8] [9] [10] [11] Another important aspect of this initiative is the establishment of a patient registry for IPD,[12] contributing to the overall effort to enhance patient care and outcomes.

 

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Methods

Literature Basis of the Guideline

As an S2k guideline, the recommendations are derived from expert consensus and current literature. The references cited in this manuscript were selected based on their relevance, but no systematic literature search was performed. Original studies and systematic reviews supporting the recommendations and aligning with current clinical and laboratory standards were prioritized.

 

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Determination of Consensus Strength for Recommendations

In the context of the AWMF guideline development, the consensus strength for the recommendations was determined through a structured voting process. The recommendations were presented to eligible participants, followed by an opportunity for questions and suggestions for modifications. Voting was conducted either on the original recommendations or proposed amendments. If necessary, discussions led to alternative proposals, followed by a final vote. Voting options included “agree,” “disagree,” or “abstain.” The strength of the consensus was classified based on the percentage of agreement among participants:

• Strong consensus: >95% of participants agreed.

• Consensus: >75% agreement.

• Majority agreement: >50 to 75% agreement.

• No majority agreement: <50% agreement.

The consensus process involved experts from the ThromKidplus study group as well as representatives from various medical societies. The consensus conferences and voting were moderated neutrally by a member of the AWMF, ensuring an unbiased discussion and adherence to formal consensus methodology. This approach ensured that the final recommendations reflected a broad consensus among the expert panel, with all relevant expert opinions considered during the guideline development process.

The guideline includes a total of 42 recommendations, covering various diagnostic aspects. In this manuscript, only the key recommendations are highlighted, which received a strong directive ('should' recommendations), to focus on the most relevant and actionable guidance.

 

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Key Updates in the Guideline

Diagnostic Algorithm

The updated guideline introduces a structured diagnostic algorithm for IPD ([Fig. 1]), outlining a stepwise approach that integrates clinical assessment and laboratory testing to ensure accurate diagnosis. It emphasizes the importance of a thorough patient history and physical examination, alongside essential tests. The algorithm prioritizes clinical history and exclusion of plasmatic coagulation disorders. Blood counts and morphological platelet assessment can provide insights into size, granulation, and shape abnormalities. Advanced diagnostics, including aggregation assays, luminometry, flow cytometry, immunofluorescence microscopy, and genetic testing, may require referral to specialized centers. The workflow minimizes unnecessary visits by allowing and supporting blood or DNA samples to be sent to specialized laboratories for timely evaluation.

Fig. 1 Algorithm to support a rational approach to diagnose inherited platelet disorders. A structured approach consists of assessment of family history, clinical investigations, and laboratory tests. A standardized bleeding assessment tool (BAT), such as the ISTH-BAT for adults or pedISTH-BAT for children, should be used to evaluate bleeding symptoms. In girls and women with menorrhagia, the Pictorial Blood Assessment Chart (PBAC) may be more appropriate. Mean platelet volume (MPV) and immature platelet fraction (IPF) values are supportive for further investigations. Notably, MPV and IPF are device-dependent and require internal reference ranges. Blood smear examination provides essential morphological insights beyond platelet size and granularity, including abnormalities in erythrocytes and leukocytes. The term “unlikely” indicates that conditions such as immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and pseudothrombocytopenia should be excluded based on clinical and laboratory findings before proceeding with specialized diagnostics. NGS, next-generation sequencing.

 

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Key Recommendations for Diagnostic Algorithm

• A standardized questionnaire[13] [14] should be used to assess the patient's bleeding tendency (strong consensus, 96%). The pedISTH-BAT should be used for children and the ISTH-BAT for adults (consensus, 86%).

• In suspected IPD cases, a complete differential blood count, including platelet size distribution, mean platelet volume (MPV),[15] and quantification of the immature platelet fraction (IPF),[16] if available, should be conducted (strong consensus, 100%). As measurement methods may influence values, MPV and IPF results should be interpreted accordingly.

• A microscopic morphological cell assessment on routinely stained blood smears should be performed (strong consensus, 100%).

• In cases of repeated, clinically relevant, unexplained bleeding tendency, extended hemostasis diagnostics, including platelet tests listed in the guideline, should be performed (consensus, 91%).

Pre-analytics

Pre-analytics involves the initial steps of handling, preparing, and processing blood samples, with standardized procedures to ensure accuracy and minimize variability. The updated guideline provides recommendations on medication and dietary restrictions, blood collection, sample storage, and transportation to maintain sample integrity and ensure reliable results, particularly in platelet function testing.

 

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Key Recommendations for Pre-analytics

• Medications and nutritional supplements that impair platelet function should, where medically acceptable, be discontinued or paused in a timely manner before platelet function testing (strong consensus, 95%).

• Blood collection for platelet function diagnostics should not be performed immediately after venipuncture (consensus, 90%). Ideally, the first 3 to 4 mL of blood drawn should be discarded.

• During blood collection for platelet function analysis, bubble formation and overly rapid withdrawal should be avoided (strong consensus, 100%).

• Underfilled or overfilled blood collection tubes with citrate as an anticoagulant should not be processed further (strong consensus, 100%). According to the guideline, 3.2 or 3.8% citrate tubes should be used, maintaining a 9:1 blood-to-citrate ratio. Plastic (polypropylene) or siliconized glass tubes are recommended. Vacutainer® tubes should be avoided for flow cytometry due to the potential risk of platelet activation caused by the suction associated with this system.

• Blood samples should be transported at room temperature without shaking and mechanical stress (strong consensus, 100%).

• The shipment of blood samples for flow cytometric analysis should be restricted and only conducted after consultation with the analyzing laboratory (strong consensus, 100%).

• Analysis of platelet aggregation should be completed within 4 hours after blood collection (strong consensus, 100%).

Aggregometry

Aggregometry assesses platelet function by measuring light transmission (LT) changes in response to specific reagents (agonists/inducers). It is a key diagnostic tool for evaluating platelet function and identifying specific platelet disorders.[17] [18] [19] [20] Light transmission aggregometry (LTA) and impedance aggregometry (IA) are commonly used methods that provide quantitative data on platelet function.[21] [22]

LTA remains the recommended method for diagnosing IPD.[23] It indirectly measures platelet aggregation by detecting changes in LT as platelets form aggregates in response to agonists/inducers. IA is mentioned in the guideline, but due to its lower sensitivity compared with LTA, it is not recommended as a primary diagnostic tool for IPD.

The updated guidelines provide detailed instructions on using specific agonists to evaluate platelet aggregation responses. The recommended agonists/inducers and their standard final concentrations are as follows:

• Adenosine diphosphate (ADP): 2.0 to 3.0 µM (doubling of concentration if needed).

• Collagen: 2 µg/mL (higher concentration if needed and depending on the type of collagen, e.g., 5 µg/mL).

• Epinephrine: 5.0 µM (higher concentration if needed, e.g., 10 µM).

• Ristocetin: 0.5/0.6 mg/mL (to induce vWF binding to platelet GPIb for detection of von Willebrand disease—VWD of type 2B and platelet type VWD), and 1.2 to 1.5 mg/mL.

• Arachidonic acid: 1.0 to 1.5 mM (to assess cyclooxygenase pathway function).

• Thrombin receptor-activating peptide (TRAP): 10 µM (for PAR-1 activation).

The chapter also discusses the interpretation of results, potential pitfalls, and troubleshooting tips to address common challenges encountered during aggregometry testing.

 

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Key Recommendations for Aggregometry

• LTA should be used as the primary method for diagnosing IPD (consensus, 90%).

• In LTA, not only the maximum aggregation (%) but also the curve shape (lag time, aggregation rate, disaggregation) should be evaluated (strong consensus, 100%).

• Pathological aggregometry findings should be confirmed in a separate follow-up examination (consensus, 94%).

Flow Cytometry

Flow cytometry is a key diagnostic tool for analyzing membrane protein expression and post-exocytotic markers of platelets.[24] [25] It uses fluorescently labeled antibodies to detect specific surface markers, enabling the characterization of platelet receptor expression and activation status.

Flow cytometry is essential for diagnosing receptor defects, specifically Glanzmann thrombasthenia, Bernard-Soulier syndrome, and storage pool disorders (SPD; α-/δ-granules) as well as other rare IPD.[26]

While flow cytometry primarily assesses surface markers, the mepacrine assay enables evaluation of dense (δ)-granules.[27] [28] Mepacrine is a fluorescent dye that accumulates in δ-granules and is released upon platelet activation. The resulting decrease in intracellular fluorescence serves as a surrogate marker for granule content and secretion. The assay is robust and can be performed up to 24 hours after blood collection.[28]

Another important functional application of flow cytometry is annexin-V staining, which assess phosphatidylserine (PS) exposure, a key marker for procoagulant platelet activity.[29] Defects in PS exposure are characteristic of specific IPD, including Scott syndrome and Stormorken syndrome. In Scott syndrome, platelets exhibit defective PS exposure, which can be identified by reduced annexin-V binding upon activation. In contrast, Stormorken syndrome is characterized by increased basal annexin-V and CD62P staining, reflecting heightened platelet activation. These assays can be complemented by platelet-dependent thrombin generation tests to validate procoagulant defects.[30] [31]

Although IPD typically affect the entire platelet population, variability in subpopulations may occur due to residual protein expression, differential activation states, or compensatory mechanisms. Flow cytometric analysis of platelet subpopulations may therefore provide additional diagnostic insights.

The updated guideline includes protocols for using flow cytometry to assess platelet surface markers, granule release, and platelet–leukocyte interactions. The guideline also covers the interpretation of flow cytometry data and the standardization of reporting results. Additionally, it highlights advanced techniques such as the use of specific fluorescently labeled antibodies and multi-parameter analysis for comprehensive characterization of platelet function.

 

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Key Recommendations for Flow Cytometry

• Flow cytometry should be used for the diagnosis of Glanzmann thrombasthenia, Bernard-Soulier syndrome, and SPD (strong consensus, 100%).

• For validation, flow cytometry should be combined with other specialized tests for platelet function analysis (consensus, 81%).

• Device- and method-specific, internal laboratory reference ranges should be established, and measurements should be conducted with regular control samples (consensus, 91%).

• Age should be considered in the evaluation of results (especially in young children) (strong consensus, 100%).

Immunofluorescence Microscopy

Immunofluorescence microscopy is considered a valuable supplementary tool for the detailed morphological analysis of platelet components and diagnosis of certain IPD. This technique involves the use of fluorescently labeled antibodies to detect specific receptor-, granule-, and cytoskeleton-related proteins within platelets, allowing for a detailed examination of platelet structure and potential activation in vivo.[32] [33] [34] The updated guideline provides expanded guidance on the use of immunofluorescence microscopy for diagnosing IPD. In contrast to other methods, both stained and unstained blood smears can be mailed to specialized laboratories for further evaluation.

 

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Key Recommendations for Immunofluorescence Microscopy

• Blood smears should only be prepared from fresh EDTA blood (at room temperature) (strong consensus, 100%).

• When performing staining, a control should always be included in the assessment (consensus, 82%).

Molecular Genetic Methods

Molecular genetic methods, including next-generation sequencing (NGS), provide a comprehensive analysis of multiple genes associated with IPD, including both platelet function defects (IPFD) and disorders affecting platelet number and structure.[35] [36] It is essential for confirming a suspected diagnosis and for characterizing the specific genetic background of an IPD. It is used for identifying heterozygous carriers and enabling precise sub-classification of specific disorders.

Genetic testing may be especially useful in patients with bleeding symptoms where an IPD is highly suspected, but standard platelet testing fails to provide clarity, e.g., Quebec platelet disorder.[37] [38] In complex diseases, where platelets are not the primary concern (“syndromes”), genetic testing may be prioritized. Furthermore, in cases of suspected inherited thrombocytopenia, e.g., ANKRD26-related thrombocytopenia, functional platelet assays may be of limited diagnostic value, and early genetic testing can facilitate diagnosis.[39] Conversely, when no clear diagnostic suspicion exists, functional platelet testing should be prioritized.

Extracted DNA is extremely stable and can be sent to specialized laboratories for further evaluation.

The updated guidelines incorporate NGS into the diagnostic workflow, offering recommendations for gene panel selection, data interpretation, and reporting in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines.[40] [41] [42] [43]

 

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Key Recommendations for Molecular Genetic Methods

• Molecular genetics should be used for the diagnosis of IPD (strong consensus, 95%).

• Molecular genetics should be used to identify heterozygous carriers of IPD (consensus, 78%).

Future Developments

The updated guideline includes a new chapter on future developments in the diagnosis of IPD. This chapter highlights emerging technologies and research fields that have the potential to further advance this topic. Topics covered include the use of artificial intelligence in diagnostics and novel biomarkers for platelet function. The goal is to provide a perspective on how the diagnosis of IPD may evolve in the upcoming years. The chapter also discusses the potential impact of personalized medicine and precision health approaches on the treatment and management of patients with IPD.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

We would like to express our heartfelt thanks to all the involved authors and professional societies for their valuable contributions and support. Their efforts have significantly contributed to the quality and relevance of this guideline.

For further information and to view the complete long and short versions of the guideline, please visit the AWMF Web site (https://register.awmf.org/de/leitlinien/detail/086-003).

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.

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Publication History

Received: 12 November 2024

Accepted: 05 June 2025

Article published online:
12 August 2025