Page 34 - 2021_02-Haematologica-web

P. Nurden et al.
or their reproduction in mouse, zebrafish or other animal models.3,4,94 When no genetic diagnosis has been achieved with standard approaches, gene analysis should be expanded to evaluate complex copy number variations, deep variants in non-coding regions and secondary defects involving the action of microRNA or retrotransposons, as we have detailed elsewhere.11
Currently the diagnosis of IPD is based largely on the concept of a monogenic heritable platelet disease, but a proportion of these diseases may be di- or polygenic in origin. Families with unexplained heritability may have unrecognized variants or other changes in regulatory regions in combinations that only advanced technologies may help to resolve. Thus in a large cohort of patients with primary immunodeficiency, genome-wide associa- tion studies have revealed loci that modulate platelet func- tion with the co-localization of and interplay between novel high-penetrance monogenic variants and common variants.95 It is reassuring that IPD without thrombocy- topenia are not associated with a propensity to develop hematological malignancies or bone marrow aplasia or fibrosis, as in some inherited thrombocytopenias such as RUNX1-related disease and ETV6-related disease.
Current advances suggest the need to redefine the circuit for patient screening from the first consultation. An infor- mation-gathering first consultation, blood cell counts and basic coagulation screening remain essential as is assigning a bleeding score and determining whether the platelet function abnormalities are isolated or syndromic.96 But flow charts with extensive biological testing in order to select the gene(s) to analyze need to be revisited and the choice of extensive biological testing before genotyping questioned. Platelet aggregation, flow cytometry and the examination of blood smears provide early information to guide the diagnosis.75,97 Nevertheless, when clinical and biological data are in favor of an IPD, in selected cases upfront DNA analysis may save time, money and improve patients’ care: however longitudinal studies are required to substantiate this expectation. For patients without access
to a specialized platelet center, sending blood and DNA samples to expert centers is recommended. Validation of novel variant(s) on next-generation sequencing targeted gene platforms or after whole exome or whole genome sequencing requires confirmation by co-segregation or other studies as discussed above and it is here that selected biological phenotyping may be necessary.
As part of this roadmap, national centers regrouping platelet experts have a key inter-connecting role between the patients, local hematology laboratories and genomic platforms. In France, our creation of a Reference Center for IPD, led to the organization, on a national basis, of platelet studies with European links to next-generation sequencing and the preparation of personalized follow- up both for the patient and the local general practitioner. In this context it is indispensable that the medical person- nel directly responsible for the patient remain in control of the diffusion of information both to the patient and in the scientific literature and especially take into account ethical considerations.98 In everyday clinical practice a patient-centered approach governed by the overarching principle of patient utility versus in-depth, detailed labora- tory and genetic characterization is acceptable and in gen- erally sufficient for patients’ care.99 On the other hand, our understanding of these disorders cannot be expanded without advanced research involving modern technolo- gies. Here, informed explicit collaboration of the patient should be obtained.
Disclosures
No conflicts of interests to diclose.
Contributions
All the authors participated in the manuscript preparation. PN and ATN supervised the writing of the text.
Acknowledgment
We thank Xavier Pillois for his contribution to the section on GT and for the Pymol model of αIIbβ3.
References
1. Nurden P, Nurden AT. Congenital disorders associated with platelet dysfunctions. Thromb Haemost. 2008;99(2):253-263.
2. Favier R, Raslova H. Progress in understand- ing the diagnosis and molecular genetics of macrothrombocytopenias. Br J Haematol. 2015;170(5):626-639.
3.Heremans J, Freson K. High-throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding disorders. Int J Lab Hematol. 2018;40(Suppl):89-96.
4. Lentaigne C, Freson K, Laffan MA, et al. Inherited platelet disorders: towards DNA- based diagnosis. Blood. 2016;127(33):2814- 2823.
5. Johnson B, Lowe GC, Futterer J, et al. Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with second-
ary qualitative function defects. Haematologica. 2016;101(10):1170-1179.
6. Simeoni I, Stephens JC, Hu F, et al. A high- throughput sequencing test for diagnosing inherited bleeding, thrombotic and platelet disorders. Blood. 2016;127(23):2791-2803.
7.Downes K, Megy K, Duarte D, et al.
Diagnostic high-throughput sequencing of 2,396 patients with bleeding, thrombotic and platelet disorders. Blood. 2019;134(23): 2082-2091.
8. Megy K, Downes K, Simeoni I, et al. Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost. 2019;17(8):1253-1260.
9. Gunay-Aygum M, Zivony-Elboum Y, Gumruk F, et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood. 2010;116(23):4990-5001.
10. Hollopeter G, Jantzen AM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409(6817):202-207.
11. Nurden A, Nurden P. Inherited thrombocy- topenias: history, advances and perspectives. Haematologica. 2020;105(8):1-16.
12. Nurden AT, Fiore M, Nurden P, Pillois X. Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood. 2011;118(23):5996- 6005.
13. Coller BS, Shattil SA. The GPIIb/IIIa (inte- grin αIIbβ3) odyssey: a technology-driven
saga of a receptor with twists, turns, and
even a bend. Blood. 2008;112(8):3011-3025. 14. Mackman N, Bergmeier W, Stouffer GA, Weitz JI. Therapeutic strategies for throm- bosis: new targets and approaches. Nat Rev
Drug Disc. 2020;19(5):333-352.
15.Botero JP, Lee K, Branchford BR, et al.
ClinGen Platelet Disorder Variant Curation Expert Panel. Haematologica. 2020;105(4): 888-894.
16. Nurden AT. Acquired Glanzmann throm- basthenia: from antibodies to anti-platelet drugs. Blood Rev. 2019;36:10-22.
17.Nurden AT, Pillois X, Fiore M, et al. Expanding the mutation spectrum of the αIIbβ3 integrin in Glanzmann thrombasthe- nia: screening of the ITGA2B and ITGB3 genes in a large international cohort. Hum Mutat. 2015;36(5):548-61.
18.
19.
Nurden AT, Pillois X. ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia. Platelets. 2018;29(1):98- 101.
Pillois X, Nurden AT. Linkage disequilibrium amongst ITGA2B and ITGB3 gene variants in patients with Glanzmann thrombasthe- nia confirms that most disease-causing mutations are recent. Br J Haematol. 2016;175(4):686-695.
348
haematologica | 2021; 106(2)