Inherited bleeding disorders (IBDs) are a heterogeneous group of diseases that involve abnormalities of blood vessels, coagulation proteins, and platelets. The clinical manifestations of these disorders can vary from mild to severe. Some IBDs arise due to molecular abnormalities in genes encoding components of the pathways for platelet‐dependent homeostasis or fibrin clot generation and breakdown. Other IBDs result from deviations in the molecular pathology of genes that code for plasma coagulation factors; this group of IBDs includes common disorders such as hemophilia A, hemophilia B, or von Willebrand disease (VWD) as well as rare bleeding disorders such as deficiencies of coagulation factors fibrinogen, factor (F) II, FV, combined FV and FVIII, FVII, FX, FXI, and FXIII and congenital deficiency of vitamin K dependent factors.

Even with advances in technology, making an accurate diagnosis, especially in inherited platelet disorders (IPDs), continues to present a challenge to clinicians. The process is largely complicated by the heterogeneity in clinical and laboratory phenotypes, the limited specificity of currently available platelet function tests, and the large number of genes potentially responsible. Identifying the underlying molecular defect is necessary for definitively diagnosing IBDs, facilitating prognosis and clinical care, and identifying patients with severe clinical syndromes or at an increased risk for malignancy.

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However, despite the importance of molecular testing, molecular studies have historically been performed as the last step in the diagnostic workflow rather than upfront. In a new review published in Seminars in Thrombosis & Hemostasis, researchers reported on the development of molecular tools to aid accurate IBD diagnosis along with recent improvements in this field.

“To date, the most important aspect of establishing a diagnosis is still an accurate family and clinical history of the patient and the physical examinations,” said study author José María Bastida MD, PhD, from the hematology department of the University Hospital of Salamanca in Spain, in an interview with Hematology Advisor. “It is well known that molecular diagnosis of IBD confirms the final diagnosis, enables carrier status to be determined, and informs genetic counseling.”

DNA sequencing has been restricted until recently to Sanger sequencing (SS), which is selected according to the patient’s clinical and laboratory phenotype, for the analysis of candidate genes. However, multiple genes — even the entire genome — can now be simultaneously sequenced using high-throughput sequencing (HTS).

HTS has revolutionized DNA sequencing, Dr Bastida pointed out. “It is being established as the gold standard for identifying the molecular pathology underlying monogenic diseases, especially in patients with IBDs.”