Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children results of a multicenter study

Prothrombotic risk mutations and polymorphisms in patients with hemophilia A – a preliminary study / Polimorfismele și mutațiile cu risc protrombotic la pacienții cu hemofilie A - studiu preliminar

“…(24,25) There is raising evidence about the role of prothrombotic risk mutations or polymorphisms in modulating clinical phenotype of hemophilia, mitigating its expression and serving consequently as a marker for risk evaluation for bleeding, that could be important for a personalized therapy approach. (3)(4)(5) The frequency of F V, F II and PAI-1 genes alterations in our group of hemophilia patients is significantly higher than in normal population. Therefore, considering the uneven distribution in different ethnic groups and geographical regions, more extended studies are worthwhile to be performed, with a better design, with the inclusion of a larger number of patients and finally with the use of a control group with age-and sex -matched persons from our geographical region and from our ethnic group; an impact analyze of the investigated polymorphisms and mutations on the clinical outcomes of hemophilia are pending.…”

“…The question to be raised: is it a singular accidental situation or is it an evolutionary protective reaction, occurred over the centuries with the purpose of mitigating the hemorrhagic risk? (1)(2)(3)(4)(5) In order to try a reply to this question, special attention is focused on the main alterations, polymorphisms and mutations, more evidently connected to thromboembolic events: -factor V with the substitution of adenine (A) for guanine (G) at nucleotide position 1691 (G1691A) guanine: GG -wild type without harming effects; GA -heterozygous and AA homozygous factor V Leiden (FVL) (6,7) -prothrombin with the mutation of guanine (G) to adenine (A) transition at nucleotide position 20210 generating: GG -wild type (normal), GA -heterozygous and AA -homozygous type (7) -MTHFR structural changes with nucleotide at position 677 in the gene , generating two possibilities, cytosine (C) or thymine (T): 677CC represents the "normal" or "wild type" genotype, 677TT -the homozygous with mild MTHFR deficiency and 677CT -the heterozygote pattern with almost a normal activity (8,9) -PAI-1 gene mapped on chromosome 7 (q21.3-q22) with 4G/5G polymorphism (deletion/insertion of guanine in position 675 of the PAI-1 gene promoter) and three possible outcomes: homozygous genotype with normal or wild type -5G/5G and heterozygous genotype -4G/5G or homozygous genotype -4G/4G, both with abnormal activity (10,11). Aiming at evaluating the frequency of these mutations in persons with hemophilia (PwH), we started this single-center, analytical cross-sectional study supported by the Laboratory of Molecular Biology, Munster (Germany).…”

Tailoring of medical treatment: hemostasis and thrombosis towards precision medicine

“…The laboratory work-up revealed that, in addition to type I von Willebrand disease, she was homozygous for the prothrombin G20210A mutation, and the same thrombophilic mutation was found in other members of the family. Heterozygous factor V Leiden or the G20210A prothrombin mutation may compensate for low factor VIII or IX levels in hemophilia, resulting in more efficient thrombin generation and ensuing attenuation of clinical symptoms 1 and the risk of thrombotic complications. 2 This information was interpreted to account for the poor bleeding tendency of the patient.…”

“…The progress since last year cannot be overlooked. 1 The goal is to define patients in whom treatment can be stopped safely and to establish a strategy for treatment discontinuation. 2 This is not the first amazing success in some 50 years of basic and clinical research underlying the success story of CML: the detection of oncogenes and of kinase activity in many of them was fortuitous, since it was a byproduct of the search for human leukemia viruses.…”

Biological Rationale for New Drugs in the Bleeding Disorders Pipeline

“…Another recent report 58 has described the identification of an aptamer with activity against activated protein C, which could potentially allow for improved hemostasis in patients with hemophilia by virtue of therapeutic protein C inhibition, as has been described physiologically in children with severe hemophilia A with coinheritance of the factor V Leiden mutation. 59 NASPs Non-anticoagulant-sulfated polysaccharides (NASPs; also known as fucoidans) are heterogeneously sized, strongly anionic compounds with a fucose backbone that derive from marine plant sources (brown seaweed). NASPs have been investigated primarily for pharmacologic activity in anticancer, antiinflammation, antiangiogenesis, and even anticoagulant systems 60,61 ; selected NASPs may enhance hemostasis.…”