Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation

Abstract

Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs.

Bleeding risk of surgery and its prevention in patients with inherited platelet disorders

“…Although IPDs are conventionally considered to be rare, at least 14,000 patients each year undergo investigations worldwide for a suspected IPD and over 5600 new diagnoses are made. 2 Therefore, cases in which a surgeon may have to deal with a patient with an IPD are not unexpected events, and knowledge of the bleeding risks associated with the distinct invasive procedures and the different platelet disorders may be of great help in guiding surgical management.…”

Dark chocolate modulates platelet function with a mechanism mediated by flavan-3-ol metabolites

“…In conclusion, due to the essential role played by platelets in the pathophysiology of both arterial and venous thrombosis, [41] we may conclude that dark chocolate consumption may be beneficial for subjects at increased risk of thrombosis and that its action may be mediated by the appearance of SREMs into systemic circulation. [42–44]…”

Use of Targeted High-Throughput Sequencing for Genetic Classification of Patients with Bleeding Diathesis and Suspected Platelet Disorder

“…Since the exact underlying defect cannot be identified in more than one-third of patients with confirmed platelet function abnormality and DNA sequencing costs have rapidly declined over recent years, HTS techniques open up new horizons in this field. 12 13 14 16 In 2015 and 2016 respectively, the Swiss and German public health systems introduced HTS analysis to the list of permitted genetic analyses for diagnostic reasons. By grouping the so far known and relevant genes for suspected pathophysiological mechanisms in platelet biogenesis or function, it becomes possible to have totally or at least partially reimbursed analytical efforts to confirm suspected diagnoses and genetically classify suspected but so far undefined entities of these rare diseases.…”

“…The authors consider that the presented NGS gene panel is capable of expanding molecular genetic testing to patients who have failed standard approaches to functionally diagnose or to genetically define IPD according to the published guidelines. 10 11 14 Our experiences and those of international initiatives have been implemented in the study design of the joint patient registry for IPD of the GTH and GPOH with respect to phenotyping by HPO, assurance of comprehensive functional testing, and biomaterial banking. We propose a selective proceeding within the diagnostic algorithm, dependent on the suspected group of IPD (compare Fig.…”

“…12 Since knowledge about genes, that are involved in either quantitative or qualitative platelet disorders, has increased rapidly and costs of high-throughput sequencing (HTS) technologies have declined simultaneously over the last decade, molecular genetic diagnosis of bleeding and platelet disorders (BPDs) is getting more and more valuable in diagnostic algorithms. 13 14 15…”