The limitation of genetic testing in diagnosing patients suspected for congenital platelet defects

Blaauwgeers, Maaike W.; Asten, Ivar van; Kruip, Marieke J.H.A.; Beckers, Erik A.M.; Coppens, Michiel; Eikenboom, Jeroen; Galen, Karin P M van; Huisman, Albert; Korporaal, Suzanne J.A.; Amstel, Hans Kristian Ploos van; Tamminga, R. Y. J.; Urbanus, Rolf T.; Schutgens, Roger E. G.

doi:10.1002/ajh.25667

Cited by 7 publications

(13 citation statements)

References 10 publications

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“…We have previously shown that the self-administered BS obtained in the WiN study was comparable to the investigator obtained BS [14] . Lastly, blood samples were drawn to measure relevant coagulation factor levels in a central laboratory for each of the studies [ 13 , 15 , 18 , 21 , 22 ]. Laboratory measurements have been described in detail previously [ 13 – 16 ].…”

Section: Methodsmentioning

confidence: 99%

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

et al. 2021

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Background In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). Methods We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. Findings We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years ( p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Interpretation Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. Funding The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

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Section: Methodsmentioning

confidence: 99%

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

et al. 2021

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“…Different HTS studies for diagnostics of BPD have been published but for this review, we have only focussed on the studies that have used the guidelines for variant classification as formulated by the American College of Medical Genetics (ACMG) in 2015 [10]. Figure 2 provides an overview of the diagnostic rates obtained in these studies that however differ in terms of used HTS methods (TS or WES), studied pathologies (platelet disorders, coagulation disorders and bleeding of unknown etiology) and the number of genes and patients included [11][12][13][14][15][16][17][18][19][20][21]. In addition, these studies have used different inclusion criteria ranging from the selection of only patients with a known or suspected etiology (studies with typically high diagnostic rates) to patients with bleeding of unknown etiology and normal laboratory parameters (studies with very low diagnostic rates).…”

Section: Hts Technologies Used For Bpd Diagnosticsmentioning

confidence: 99%

“…10 Figure 2 provides an overview of the diagnostic rates obtained in these studies that however differ in terms of used HTS methods (TS or WES), studied pathologies (platelet disorders, coagulation disorders, and bleeding of unknown etiology), and the number of genes and patients included. [11][12][13][14][15][16][17][18][19][20][21] Most of these HTS studies provided no detailed information related to the detection of CNV. [11][12][13][14][15][16][17][18][19][20][21] The ThromboGenomics study reported a CNV in 40 of the 2396 tested patients; these were predicted to affect single exons (n = 11), multiple exons (n = 15), or whole genes (n = 14).…”

Section: Hts Technolog Ie S Us Ed For B Pd Diag Nos Tic Smentioning

confidence: 99%

“…33,34 In the studies using HTS approaches published so far, many variants were categorized as VUS. [11][12][13][14][15][16][17][18][19][20][21] The proportion of reported VUS, as high as 38% in the ThromboGenomics study, underlines the need for international data sharing efforts. 19 It is essential to annotate variants against databases of variants already implicated in rare diseases.…”

Section: S Treng Th S and Limitati On S Of Hts For D Iag Nos Ti C S Of B Pdmentioning

confidence: 99%

“…Most of these HTS studies provided no detailed information related to the detection of CNV 11‐21 . The ThromboGenomics study reported a CNV in 40 of the 2396 tested patients; these were predicted to affect single exons (n = 11), multiple exons (n = 15), or whole genes (n = 14).…”

Section: Hts Technologies Used For Bpd Diagnosticsmentioning

confidence: 99%

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Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders

Donck

Downes

Freson

2020

Journal of Thrombosis and Haemostasis

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Inherited bleeding and platelet disorders (BPD) are highly heterogeneous and their diagnosis involves a combination of clinical investigations, laboratory tests and genetic screening. This review will outline some of the challenges that geneticists and experts in clinical hemostasis face when implementing high-throughput sequencing (HTS) for patient care. We will provide an overview of the strengths and limitations of the different HTS techniques that can be used to diagnose BPD. A HTS test is cost efficient and expected to increase the diagnostic rate with a possibility to detect unexpected diagnoses and decrease the turnaround time to diagnose patients. On the other hand, technical shortcomings, variant interpretation difficulties and ethical issues related to HTS for BPD will also be documented. Delivering a genetic diagnosis to patients is highly desirable to improve clinical management and allow family counseling, but making incorrect assumptions about variants and providing insufficient information to patients before initiating the test could be harmful. Data-sharing and improved HTS guidelines are essential to limit these major drawbacks of HTS.

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A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders

Gandhi,

Zivkovic,

Østergaard

et al. 2024

Nat Cardiovasc Res

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Inherited bleeding disorders such as Glanzmann thrombasthenia (GT) lack prophylactic treatment options. As a result, serious bleeding episodes are treated acutely with blood product transfusions or frequent, repeated intravenous administration of recombinant activated coagulation factor VII (rFVIIa). Here we describe HMB-001, a bispecific antibody designed to bind and accumulate endogenous FVIIa and deliver it to sites of vascular injury by targeting it to the TREM (triggering receptor expressed on myeloid cells)-like transcript-1 (TLT-1) receptor that is selectively expressed on activated platelets. In healthy nonhuman primates, HMB-001 prolonged the half-life of endogenous FVIIa, resulting in its accumulation. Mouse bleeding studies confirmed antibody-mediated potentiation of FVIIa hemostatic activity by TLT-1 targeting. In ex vivo models of GT, HMB-001 localized FVIIa on activated platelets and potentiated fibrin-dependent platelet aggregation. Taken together, these results indicate that HMB-001 has the potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.

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The limitation of genetic testing in diagnosing patients suspected for congenital platelet defects

Cited by 7 publications

References 10 publications

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders

Strengths and limitations of high‐throughput sequencing for the diagnosis of inherited bleeding and platelet disorders

A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders

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