Genetics of haemostasis

Abstract

Summary. Congenital defects of platelets or plasma proteins involved in blood coagulation generally lead to bleeding disorders. In some of these disorders, patients with a severe phenotype are prone to spontaneous bleeds with critical consequences. This situation occurs more commonly in haemophilia A and haemophilia B and to a certain extent in severe forms (type 3) of von Willebrand disease. Defects in other plasma coagulation proteins and platelet factors are relatively rare, with an incidence of ≤1: 1–2 million. Molecular genetic studies of the human coagulation factors, especially factors VIII and IX, have contributed to a better understanding of the biology of these genetic disorders, the accurate detection of carriers and genetic counselling, and have also fostered new therapeutic strategies. This article reviews the evolution of genetics over the last five decades as a tool for bleeding disorder investigations, the recent advances in molecular techniques that have contributed to improved genetic diagnosis of this condition, and the development and utility of proficiency testing programmes and reference materials for genetic diagnosis of bleeding disorders.

Detection of mild inherited disorders of blood coagulation: current options and personal recommendations

“…Interestingly, molecular biology testing often offers an opportunity to precisely identify the nature of disease and thereby establishing the most appropriate preventive or therapeutic strategy (especially hemophilia A and B), but also for prenatal diagnosis [84,85].…”

“…It is now clearly established that different clinical phenotypes can emerge from an interaction between genetics and environment, as increasingly recognized for the common hemophilias [104] and also for hemostasis as we age [105]. As such, further advances in genomic technology [84,85] will make it possible to extend the database of mutations of all known hemorrhagic defects, more precisely understand the structure-function relationship of coagulation factors, bridge the gap between genotype and clinical or laboratory phenotype [106], plan specific therapies which are not only more likely to respond according to a specific genotype, but also obtain an early diagnosis during pregnancy or stillbirth, so that the mutation (or the haplotype) can be precisely identified at the time of prenatal diagnosis [107]. Genetic testing by means of high-throughput techniques such as next-generation sequencing will also enable the investigation of multiple coagulation factor genes simultaneously, so that the diffusion of these methods is expected to grow exponentially, even in clinical laboratories, in the next few years.…”

Epigenetics and stroke risk – beyond the static DNA code

“…Indeed, the involvement of genetic and epigenetic influences in these complementary events has been well argued. 118,119 The eNOS/NOS3 gene is very restricted in expression to ECs, where it provides the dominant source submit your manuscript | www.dovepress.com of nitric oxide in the vasculature. Nitric oxide is a vasodilator that plays a vital role in the maintenance of vascular homeostasis, by the virtue of potent antithrombotic and antiatherogenic activities.…”

Missense changes in the catalytic domain of coagulation factor X account for minimal function preventing a perinatal lethal condition

“…The coagulation pathway represents a suitable model for this investigation because of (a) several well‐characterized genes and proteins working in a common cascade‐shaped pathway, (b) huge number of variants described in the X‐linked members of the pathway (Haemophilia A, MIM# 306700; Haemophilia B, MIM# 306900) (http://www.factorix.org; http://www.factorviii-db.org/) and (c) ample differences in the effects of null variants affecting specific genes depending on the role of the encoded protein within the cascade, in addition to the type of inheritance (autosomal/X‐linked) …”

“…1 The coagulation pathway represents a suitable model for this investigation because of (a) several well-characterized genes and proteins working in a common cascade-shaped pathway, (b) huge number of variants described in the X-linked members of the pathway (Haemophilia A, MIM# 306700; Haemophilia B, MIM# 306900) (www.factorix.org; http://www.factorviii-db.org/) and (c) ample differences in the effects of null variants affecting specific genes depending on the role of the encoded protein within the cascade, in addition to the type of inheritance (autosomal/X-linked). 2 In this scenario, the relatively frequent and well-known haemophilia A or B do not permit to investigate natal or perinatal survival/ lethality because null variants, frequent in factor VIII (FVIII) and factor IX (FIX) mutational patterns, are associated with defective clot stabilization but are clearly compatible with coagulation initiation. 3 Differently, the complete deficiency of factor VII (FVII; 1:500.000; MIM# 227500) 4 or factor X (FX; 1:1.000.000; MIM# 227600), 5 both rare autosomal recessive conditions, might be virtually incompatible with life, as suggested by F7 or F10 knockout mouse models.…”