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Semin Thromb Hemost 2009; 35(2): 127-130
DOI: 10.1055/s-0029-1220320
PREFACE

© Thieme Medical Publishers

Diagnostic Evaluation of Platelet Disorders: The Past, the Present, and the Future

Catherine P.M Hayward1 , 2 , Emmanuel J. Favaloro3
  • 1Departments of Medicine and Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  • 2The Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
  • 3Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, NSW, Australia
Further Information

Publication History

Publication Date:
30 April 2009 (online)

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Welcome to this special issue of Seminars in Thrombosis and Hemostasis, which is entirely devoted to the diagnostic evaluation of platelet function disorders. The issue provides a comprehensive update on the causes and the diagnostic evaluation of platelet function disorders, which are emerging to be one of the most, if not the very most common cause of bleeding. Among bleeding disorders, platelet function disorders are recognized to be the most challenging type of condition to evaluate both clinically and in the laboratory, from the perspective of diagnosis, testing, and quality assurance.[1] [2] This issue therefore covers an array of important topics that are relevant to the diagnosis of platelet function disorders, from standardization of their diagnostic evaluation in the clinic and the laboratory to the quality assessment, standardization, choices of screening and diagnostic assays for these conditions. The articles cover a broad scope, including the principles behind various methods for aggregometry, the challenges to test interpretation, and the value and uses of specialized assays, such as electron microscopy, platelet procoagulant activity assays, glycoprotein analysis, and genetic testing. The articles touch on several controversial aspects of diagnosing platelet function disorders, including how much testing is needed to exclude a platelet function disorder as a cause of bleeding and what assays provide the most information. This issue also addresses important related topics, such as how to approach the diagnostic evaluation of neonates and children for platelet function disorders, and some interesting specific conditions, such as MYH9-related platelet disorders. Together, the articles provide helpful information on the vast array of conditions that are now known to cause platelet function disorders and how these conditions can be diagnosed based on their laboratory features. This information should prove useful for clinical practice, laboratory practice, and educational and research purposes.

In the first article, by Pai and Hayward, the authors discuss the diagnostic evaluation of platelet function disorders and describe the unique challenges to standardizing both the clinical and laboratory assessments for these bleeding disorders.[3] Pai and Hayward discuss the application of standardized bleeding history assessments, and bleeding scores to platelet disorders, which has been attempted for only a few conditions.[3] Recent, important efforts to improve and standardize the laboratory assessment of platelet disorders worldwide are also discussed.[3] Also, a highlight of this article is a discussion of recent research on the diagnostic utility of commonly performed platelet function tests, which illustrates the usefulness of platelet aggregometry for the diagnostic evaluation of common bleeding disorders when performed by standardized procedures with validated reference intervals.[3]

The second article, by Favaloro, discusses the application of quality control and quality assurance processes to platelet function testing. In large part, this application has lagged far behind the implementation of quality processes for other diagnostic laboratory tests, even though aggregation tests have been performed by diagnostic laboratories for many years.[4] Favaloro discusses the practicalities, challenges, and strategies for applying quality processes to platelet function testing.[4] This article includes a helpful update on recent initiatives for internal and external quality assessment of platelet function testing, which have often been modified in interesting ways to deal with the fact that platelet function testing requires freshly collected blood samples.[4]

The Harrison and Mumford article then discusses current information on the use of screening or “global” assays of platelet function in the diagnostic evaluation of platelet function disorders.[5] This article focuses on several widely performed tests, namely the template bleeding time and the closure time measured by the Platelet Function Analyzer (PFA-100) from Siemens Diagnostics.[5] Harrison and Mumford summarize the principles, limitations, and appropriate uses of these tests and offer a compelling explanation for why normal results for bleeding or closure time should not preclude a further evaluation by more specialized assays for platelet function disorders.[5] The authors emphasize that clinicians and laboratories need to be aware that these assays have limited sensitivity and specificity for common platelet function disorders and provide a helpful review on the factors that can influence the test findings.[5]

Continuing the theme on the diagnostic evaluation of platelet disorders, Cattaneo then provides a helpful review of the principles of light transmission aggregometry as the “gold standard” test for studying individuals with suspect defects of platelet function.[6] This article also illustrates that there are benefits to measuring platelet secretion to improve the detection of common platelet function disorders.[6] It is interesting that this opinion is in complete agreement with the opinions expressed in three other articles in this issue.[3] [7] [8] Cattaneo reviews the appropriate indications for aggregation testing in diagnostic laboratory settings and touches on the many factors that need to be carefully controlled and considered when performing aggregometry, including process control by test standardization.[6] He discusses why platelet function testing for “drug resistance” is not currently recommended outside of research settings.[6] Cattaneo also discusses the diagnostic applications for aggregometry and secretion tests, which he proposes are the best tests to perform for an initial investigation of individuals with suspected platelet function disorders.[6] This article contains a helpful description of the different types of aggregometry abnormalities that are seen with specific types of platelet function disorders when evaluated for responses to a panel of aggregation agonists.[6]

The next article, by McGlasson and Fritsma, discusses the history and current uses of lumiaggregometry and impedance-based whole blood aggregometry in considerable depth, including the advantages that these methodologies have over light transmittance aggregometry.[7] The authors provide a helpful and interesting update on the principles of luminescence assays of platelet secretion and whole blood aggregation tests and the range of findings for congenital and acquired alterations in platelet function (including those caused by drugs), including “hyperaggregability.”[7] The authors discuss platelet function testing for “drug resistance” and summarize information on some newer, whole blood testing assays of platelet function that have been developed to assess medication-induced effects on platelet function.[7]

Infants and children with platelet function disorders often pose unique clinical and laboratory diagnostic challenges, and the next article by Israels comprehensively covers this topic, from the clinical presentation to the laboratory evaluation.[9] This article covers the common diagnostic testing challenges that are faced when evaluating younger individuals with platelet function disorders, related to the need to test fairly large volumes of blood and the lack of well-established pediatric reference ranges for platelet disorders.[9] Israels also discusses the interesting ways that platelet function in neonates differs significantly from platelet function in older children and adults.[9] The article includes a helpful list of syndromes to consider when children and neonates present with features suspicious for a platelet function disorder.[9]

Congenital platelet disorders associated with thrombocytopenia often pose special diagnostic challenges to clinicians and diagnostic laboratories. In their article, Althaus and Greinacher review the current knowledge on inherited thrombocytopenia due to MYH9-related platelet disorders, which are very interesting genetic disorders of nonmuscle myosin heavy chain IIA, a cytoskeletal protein.[10] Their article provides an in-depth review of the clinical and laboratory features of the overlapping syndromes that comprise MYH9-related platelet disorders, including the mutations of the MYH9 gene that have been identified to cause these disorders.[10] The article provides a diagnostic algorithm to guide an evaluation of these conditions and discusses the current state of knowledge on best treatments.[10] The authors discuss the pitfalls of mistaking these conditions for other common disorders associated with thrombocytopenia.[10]

An up-to-date review on the molecular genetics of inherited platelet disorders is presented in the article by Nurden, Fiore, Pillois, and Nurden.[11] Their contribution to this issue of Seminars in Thrombosis and Hemostasis discusses the key features and characterized molecular defects for the heterogenous, inherited bleeding syndromes that are currently known to impair platelet function and/or production.[11] The article provides a helpful review on the spectrum of genetic abnormalities that are now known to cause Glanzmann thrombasthenia and Bernard-Soulier syndrome, two rare but well-studied, severe platelet function disorders.[11] The authors discuss the challenges and potential approaches to unearth the causes of other inherited platelet function disorders, including very common disorders that can be difficult to accurately classify.[11] They discuss a strategy to help unravel the genetic causes of common platelet disorders, which will hopefully inspire the research community.

Specialized investigative techniques have an important role in the diagnostic evaluation of some rare platelet disorders, and some of the important, specialized techniques are addressed by three separate articles in this issue.[12] [13] [14] In their article on electron microscopy, Clauser and Cramer-Bordé discuss platelet ultrastructure and how an electron microscopy evaluation of platelets has provided key insights into the pathogenesis of several inherited bleeding disorders, including gray platelet syndrome.[12] The authors provide illustrative examples of ultrastructural studies that provide clues to the pathogenesis of platelet disorders.[12] They also review the key features of several inherited platelet disorders, including conditions known to affect platelet granules, the platelet cytoskeleton, and the platelet membrane.[12]

The next article by Miller provides an update on the different types of glycoprotein assays that are now available for the diagnostic evaluation of platelet disorders.[13] Miller discusses the interesting spectrum and type of platelet glycoprotein abnormalities that can be seen in inherited and acquired hematologic disorders.[13] The article explains how glycoprotein assays can be used to ask questions about the quantity and quality (or function) of specific proteins in platelets and how they are altered by platelet function disorders.[13] The article touches on the application of some newer methodologies, including proteomics, to the diagnostic evaluation of platelet disorders.[13]

The subsequent article by Weiss provides a comprehensive review on the platelet disorders that alter platelet procoagulant function and the nature of the defects that impair these responses.[14] This article reviews the current knowledge on Scott syndrome as a prototypic disorder of platelet procoagulant function associated with abnormal, challenge-related bleeding.[14] Indeed, this condition provides the clinical proof that the procoagulant function of platelets is important for hemostasis.[14] Weiss also discusses the many different types of bleeding disorders that are associated with defective platelet procoagulant activity and the assays that have been used to detect these abnormalities.[14]

The final article in this issue, by Mezzano, Quiroga, and Pereira, addresses an important question: Exactly how much laboratory testing is required to confidently diagnose or exclude a platelet function disorder as the cause of a patient's bleeding?[8] This discussion is timely as more and more information emerges to indicate that platelet function disorders, as a group, represent a high proportion of bleeding causes worldwide.[8] This discussion is particularly interesting, given that almost all of the articles in this issue touch on the need to consider differences in sensitivity of available platelet function assays when choosing procedures that are most appropriate for diagnostic evaluations. The authors address current information and provide helpful opinions on the testing required to adequately detect common platelet function disorders, such as secretion defects.[8] They also point out that despite current testing, a large proportion of individuals presenting for a diagnostic evaluation of significant mucocutaneous bleeding will remain without a definitive laboratory diagnosis after extensive testing, a topic that was a focus of a recent article in Seminars in Thrombosis and Hemostasis.[2] [8] The discussion highlights that there is still much more to learn about platelet function.

In total, the collection of interesting articles that compose this issue of Seminars in Thrombosis and Hemostasis illustrate that a diagnostic evaluation of platelet function disorders involves a comprehensive and often complex process, given the spectrum of recognized disorders and the lack of standardized testing practices, diagnostic criteria, and algorithms to guide the diagnostic evaluations. It is remarkable that even in 2009, so much more is known about defects associated with some fascinating but very rare platelet function disorders (e.g., Glanzmann thrombasthenia and Bernard-Soulier syndrome) than about the common forms of platelet disorders that often present with mild bleeding problems. The lack of widely available, standardized tests has also been a problem with diagnosis of the common bleeding disorder von Willebrand disease,[15] but it is much more of a problem for platelet function disorders. This is hardly surprising; given that there are so many genes expressed by megakaryocytes,[16] [17] it is difficult to predict which one of these genes might potentially be the cause of defects in one or more aspects of platelet function. The new millennium has brought forth important initiatives and opportunities to tackle platelet function assay standardization and quality assessment and to translate the wealth of growing knowledge into improved diagnostic practices that will be of benefit to patients. The guest editors of this issue of Seminars in Thrombosis and Hemostasis would like to sincerely thank all the authors for their interesting and timely contributions. The issue offers many practical tips and expert opinions that we anticipate will be valued by clinicians, laboratories, and educators worldwide. We hope that you as readers enjoy this collation of articles on the diagnostic evaluation of platelet function disorders, a group of interesting and heterogenous disorders that deserve more attention as an important cause of bleeding.

REFERENCES

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