Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders

Downes, Kate; Mégy, Karyn; Duarte, Daniel; Vries, Minka J A; Gebhart, Johanna; Hofer, Stefanie; Shamardina, Olga; Deevi, Sri V V; Stephens, Jonathan; Mapeta, Rutendo; Tuna, Salih; Hasso, Namir Al; Besser, Martin; Cooper, Nichola; Daugherty, Louise C.; Gleadall, Nick; Greene, Daniel; Haimel, Matthias; Martin, Howard; Papadia, Sofia; Revel‐Vilk, Shoshana; Sivapalaratnam, Suthesh; Symington, Emily; Thomas, Will; Thys, Chantal; Tolios, Alexander; Penkett, Christopher J.; Ouwehand, Willem H.; Abbs, Stephen; Laffan, Michael; Turro, Ernest; Simeoni, Ilenia; Mumford, Andrew D; Henskens, Yvonne; Pabinger, Ingrid; Gomez, Keith; Freson, Kathleen

doi:10.1182/blood.2018891192

Cited by 145 publications

(241 citation statements)

References 47 publications

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“…37 Recently, it has been shown that ThromboGenomics gives a diagnosis for a UBD in only 3.2% cases tested in a large cohort of patients (although these were not clearly patients with UBD). 38 This study and the normal ThromboGenomics in our cohort (45 patients) suggest further genetic research is required to establish the genetic basis of UBD.…”

Section: Discussionmentioning

confidence: 82%

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

MacDonald

Wright

Beuche

et al. 2019

Int J Lab Hematology

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Introduction There is an unmet need to characterize the diagnosis and management of patients with an unclassified bleeding disorder (UBD). Methods Retrospective review of registered patients with UBD at our centre. Assessment including rotational thromboelastometry (ROTEM) and thrombin generation (TG) were used. Results A total of 124 patients were identified; 91% female. Mean age of presentation was 38.3 years. Mean bleeding score was 8.8 (standard deviation [SD] 3.8); 6.6 in men (SD 1.4) and 9.7 in women (SD 3.3), which was significantly different (P < .05). In women, after deduction of scores for menorrhagia and postpartum haemorrhage, the mean score was 6.4 which was not significantly different to the male score (P = .11). Twenty‐three percent of patients have been transfused, 61% women had treatment for menorrhagia and 17% for epistaxis. TxA and desmopressin were effective at preventing bleeding in 69 procedures and 13 deliveries. TG revealed 26% patients with a long lag time and 19% with a decreased endogenous thrombin potential but no diagnostic pattern was seen. ROTEM (NATEM) was unable to characterize patients; 9% had a prolonged clot time or maximum lysis. ThromboGenomics was normal in 45 tested patients. Conclusions We provide data which shows the bleeding score is biased towards gynaecological bleeding but which remains elevated even when the bleeding score is deducted. Tranexamic acid and desmopressin are effective as haemostatic prophylaxis but there is an urgent need for clinical trials. In conclusion, we describe the use of the bleeding score in these patients and phenotype, diagnosis (including ThromboGenomic testing) and management with practice recommendations.

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Section: Discussionmentioning

confidence: 82%

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

MacDonald

Wright

Beuche

et al. 2019

Int J Lab Hematology

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“…In our study, 25 patients remain undiagnosed despite their clinical presentation with thrombocytopenia or a clinically relevant bleeding score. Even larger studies, like the recently published study by Downes et al including 2396 patients could only show a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal haemostasis test results . These patients may have acquired diseases or variants in unknown genes or regulatory regions.…”

Section: Discussionmentioning

confidence: 84%

“…All class 4 and 5 variants were found in children with thrombocytopenia, and directed functional testing was able to confirm the genetic findings. The overall diagnostic rate 27 and our own previously published adult cohort (n = 156),…”

Section: Significant Resultsmentioning

confidence: 96%

“…34 In our study, we chose to exclude the genes for RUNX1, ETV6 and ANKRD26 in our panel if not highly relevant for the patient/the family, as recommended by Greinacher et al 35 However, the selection of relevant genes in our study was made in a research setting, allowing not only diagnostic-grade tier 1 genes, as published by the ISTH, 6 ized by normal haemostasis test results. 27 These patients may have acquired diseases or variants in unknown genes or regulatory regions. Also, genetic findings might lack a specific functional test for confirmation.…”

Section: Discussionmentioning

confidence: 99%

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Genetic screening of children with suspected inherited bleeding disorders

et al. 2020

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Introduction Genetic screening using high‐throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear. Aim To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing. Methods After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes. Results A total of 68 heterozygous class 3‐5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009). Conclusion We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work‐up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.

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“…6 Cosegregation studies would support the genotype-phenotype correlation for our cases; however, we did not have access to samples from pedigrees. Concerning the possibility of other factors underlying the macrothrombocytopenia, it should be noted that all genes currently known for macrothrombocytopenia were evaluated in our patients using the ThromboGenomics gene panel test 5 and no other variants were found that could modify the phenotype.…”

Section: Letter To the Editormentioning

confidence: 99%

Autosomal dominant macrothrombocytopenia caused by a rare GPIBB variant: The importance of DNA sequencing

Kesel

Vantilborgh

Dierick

et al. 2019

Int J Lab Hematology

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Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders

Abstract: This paper reports on the use of a high-throughput diagnostic genetic screening for coagulation, platelet, or thrombotic disorders in a series of more than 2000 patients.

Cited by 145 publications

References 47 publications

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment

Genetic screening of children with suspected inherited bleeding disorders

Autosomal dominant macrothrombocytopenia caused by a rare GPIBB variant: The importance of DNA sequencing

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