K. Freson PhD

Advancements in thrombophilia testing: The role of multi-gene panels in venous thromboembolism

SUMMARY

Venous thromboembolism (VTE) is a prevalent condition with a significant acute and long-term morbidity and results from a complex interaction between genetic and environmental risk factors. About half of VTE cases are unprovoked, suggesting an underlying thrombophilia. Nevertheless, conventional thrombophilia tests, which assess deficiencies in antithrombin, protein C, and protein S, and the presence of the prothrombotic factor V Leiden and prothrombin G20210A variants, identify an underlying inherited predisposition in about 40% of VTE cases. These tests lack specificity for VTE and mostly fail to guide therapeutic decisions. Over the past decade, multi-gene panels utilising high-throughput sequencing have been developed to rapidly analyse a preselected set of VTE-risk genes of which most are involved in (anti)coagulation. Initial studies show that these panels can identify variants missed by conventional testing in approximately 40% of both patients with positive and negative thrombophilia workups. However, only about 10% of VTE patients carry previously undetected (likely) pathogenic variants that are of immediate relevance for counselling. The high prevalence of variants of uncertain significance (VUS) and oligogenic variants complicate data interpretation. Further research is necessary to characterise and reclassify these VUS and to evaluate the therapeutic implications of multi-gene panel testing.

(BELG J HEMATOL 2025;16(4):146–51)

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ThromboGenomics implementation in Belgium

SUMMARY

The international study ThromboGenomics has developed and tested a targeted high-throughput sequencing (HTS) multi-gene panel test for diagnostics of patients with rare bleeding, thrombotic or platelet disorders (BTPD). After the initial validation of this research platform, 2396 index patients were sequenced and a mean diagnostic rate of 49.2% was reached for all thrombotic, coagulation, platelet count and function disorder patients while this rate dropped to 3.2% for patients with unexplained bleeding disorders that were characterised by normal haemostasis test results. Since early 2019, a similar HTS test for BTPD has been implemented in Belgium in a clinical diagnostic setting. This test screens 96 diagnostic-grade genes and is updated yearly with novel genes. Upon inclusion, clinicians can opt for one of the three panels: 1) (anti)coagulation panel test for abnormal bleeding or thrombosis, 2) platelet disorder panel test for inherited thrombocytopenia or known platelet dysfunctions and 3) the unexplained bleeding panel test but with evidence for Ehlers-Danlos Syndrome or Rendu-Osler-Weber disease. Inclusion and exclusion criteria for patients eligible for such HTS will be discussed. The submission of detailed information about clinical phenotype, family history and laboratory test results is critical for the interpretation of the genetic results. The aim is to provide results to clinicians and patients with a detailed report that discusses variant interpretation.

(BELG J HEMATOL 2020;12(3):99-105)

 

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O09 VISUALIZING DENSE GRANULE FORMATION IN MEGAKARYOCYTES USING ADVANCED MICROSCOPY AND ITS APPLICATION FOR HERMANSKY-PUDLAK SYNDROME

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A-112 Causes of ‘Gray platelets’: from genetic studies of inherited thrombocytopenia to functional studies

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PEAR1 upregulation during megakaryopoiesis is dependent on changes in DNA methylation

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