afibrinogenaemia, autosomal recessive disorders, factor VIII, factor XI, factor XIII.
Abstract-Single-point mutations in the gene coding for prothrombin (factor II:A20210) or factor V (factor V:A1691) are associated with an increased risk of venous thromboembolism. The use of oral contraceptives is also a strong and independent risk factor for the disease, and the interaction between factor V:A1691 and oral contraceptives greatly increases the risk. No information is available about the interaction between oral contraceptives and mutant prothrombin. We investigated 148 women with a first, objectively confirmed episode of deep vein thrombosis and 277 healthy women as controls. Fourteen patients (9.4%) were carriers of factor II:A20210, 24 (16.2%) of factor V:A1691, and 4 (2.7%) of both defects. Among controls, the prevalence was 2.5% for either factor II:A20210 or factor V:A1691, and there was no carrier of both the mutations. The relative risk of thrombosis was 6-fold for factor II:A20210 and 9-fold for factor V:A1691. The most prevalent circumstantial risk factor in patients and the only one observed in controls was oral contraceptive use, which per se conferred a 6-fold increased risk of thrombosis. The risk increased to 16.3 and 20.0 when women with factor II:A20210 or factor V:A1691 who used oral contraceptives were compared with noncarriers and nonusers. These figures indicate a multiplicative interaction between the genetic risk factors and oral contraceptives.No difference in the type of oral contraceptives was observed between patients and controls, those of third generation being the most frequently used (73% and 80%
Summary. Factor X (FX) deficiency is a rare autosomal recessive disorder. The phenotype and genotype of 15 Iranian patients with FX deficiency from 13 unrelated families with a high frequency of consanguinity were analysed. Five different assays identified four patients from three families with a discrepancy between low-FX coagulant activity (FX:C) and higher-FX antigen (FX:Ag) (a type II deficiency). The remaining 11 patients had parallel reductions of FX:C and FX:Ag (a type I deficiency). Nine different homozygous candidate mutations were identified, of which eight were novel. The four type II cases were associated with an Arg()1)Thr missense mutation in the prepropeptide: Arg()1) is highly conserved in all vitamin K-dependent proteins. Four type I mutations (Gly78Asp, Cys81Tyr, Gly94Arg and Asp95Glu) were localized to the EGF-1 and EGF-2 domains, for which molecular views showed that the protein folding would be disrupted. The type I mutation Gly222Asp was localized in the catalytic domain of FX, and is sufficiently close to the Asp-His-Ser catalytic triad to disrupt its correct protein folding. The two type I splice site mutations were IVS1+3, A fi T and IVS2-3, T fi G. These novel homozygous FX mutations were consistent with their phenotypes and agree with experimental data from knockout mice, indicating that FX is an essential protein for survival.
We have recently identified in two unrelated patients with bleeding tendency a homozygous mutation causing a deletion of one of the two contiguous Lys 9 /Lys 10 residues in the A-chain of ␣-thrombin (⌬K9). We used in vitro expression analysis to clarify the role of the deletion of Lys 9 or Lys 10 in the thrombin function. The k cat /K m value of the hydrolysis by ⌬K9 of the synthetic substrate PhePip-Arg-p-nitroanilide (where Pip represents L-pipecolyl) and fibrinopeptide A was 18-and 60-fold lower, respectively, compared with wild type (WT). Interaction with antithrombin was also reduced in the mutant, the association rate being about 20-fold lower than in the WT thrombin. The sensitivity to sodium ion of ⌬K9 was found significantly attenuated compared with the WT form. ⌬K9 has a very weak platelet-activating capacity, attributed to a severely defective PAR1 interaction, whereas the binding to the platelet glycoprotein Ib␣ was unaffected. Likewise, the interaction with protein C was severely impaired, whereas interaction with thrombomodulin had a normal K d value. At variance with these findings, both low affinity (basic pancreatic trypsin inhibitor) and high affinity (N-␣-[2-naphthylsulfonyl-glycyl]-4-amidinophenylalanine-piperidide) thrombin inhibitors displayed a better binding to ⌬K9 than to the WT form, indicating a better accommodation of these inhibitors into the catalytic pocket of ⌬K9. A molecular dynamics simulation of the ⌬K9 thrombin in full explicit water solvent provided support to the role of the Achain in affecting conformation and catalytic properties of the B-chain, especially in some insertion loops of the enzyme, such as the 60-loop, as well as in the geometry of the catalytic triad residues.Recently, a homozygous deletion mutation of one of the two contiguous Lys 9 /Lys 10 residues 1 in the A-chain of ␣-thrombin was identified in two unrelated Iranian patients with severe prothrombin deficiency and hemorrhagic diathesis (1). The level of prothrombin antigen measured in plasma was 15%, whereas the coagulant activity ranged from less than 1% to about 2.5% (1). Prothrombin deficiency is an autosomal recessive bleeding disorder characterized by two phenotypes: hypoprothrombinemia, with concomitantly low levels of coagulant activity and antigen (type I), and dysprothrombinemia, with very low activity but subnormal or normal antigen levels (type II). These disorders are rare, and there is always residual prothrombin procoagulant activity measurable in patients, the phenotype found in prothrombin-deficient mice indicating that complete prothrombin deficiency may be lethal in humans (2, 3). To date, 38 defects in the prothrombin gene have been identified in patients with dysprothrombinemia or hypoprothrombinemia (1, 4 -7). Among these natural dysprothrombins, amino acid residues of the thrombin A-chain were found to be rarely involved (1, 4 -7).The A-chain in human thrombin is composed of 36 amino acid residues, which are connected to the catalytic B-chain by a single disulfide bond (8). This chain...
In a patient who presented with a severe coagulation deficiency in plasma contrasting with a very mild hemorrhagic diathesis a homozygous Arg67His mutation was identified in the prothrombin gene.
Recently, a homozygous deletion mutation of one of the two contiguous Lys9 ⁄ Lys10 residues in the A-chain of a-thrombin (DK9) was identified in patients with severe prothrombin deficiency and hemorrhagic diathesis [1,2].Compared with the wild-type (WT) form, the specificity constants of hydrolysis by DK9 of the synthetic substrate d-Phe-Pip-Arg-pNA and fibrinopeptide A were found to be 18-and 60-fold lower, respectively. The catalytic competence of the natural thrombin mutant with deletion of the Lys9 residue in the A-chain (DK9) was found to be severely impaired, most likely due to modification of the 60-loop conformation and catalytic triad geometry, as supported by long molecular dynamics (MD) simulations in explicit water solvent. In this study, the pH dependence of the catalytic activity and binding of the low-molecular mass inhibitor N-a-(2-naphthylsulfonyl-glycyl)-4-amidinophenylalanine-piperidine (a-NAPAP) to the wild-type (WT) and DK9 thrombin forms were investigated, along with their overall structural stabilities and conformational properties. Two ionizable groups were found to similarly affect the activity of both thrombins. The pK a value of the first ionizable group, assigned to the catalytic His57 residue, was found to be 7.5 and 6.9 in ligand-free DK9 and WT thrombin, respectively. Urea-induced denaturation studies showed higher instability of the DK9 mutant compared with WT thrombin, and disulfide scrambling experiments proved weakening of the interchain interactions, causing faster release of the reduced A-chain in the mutant enzyme. The sodium ion binding affinity was not significantly perturbed by Lys9 deletion, although the linked increase in intrinsic fluorescence was lower in the mutant. Essential dynamics (ED) analysis highlighted different conformational properties of the two thrombins in agreement with the experimental conformational stability data. Globally, these findings enhanced our understanding of the perturbations triggered by Lys9 deletion, which reduces the overall stability of the molecule, weakens the A-B interchain interactions, and allosterically perturbs the geometry and protonation state of catalytic residues of the enzyme.Abbreviations a-NAPAP, N-a-(2-naphthylsulfonyl-glycyl)-4-amidinophenylalanine-piperidine; Bis-Tris, (2-hydroxyethyl)iminotris(hydroxymethyl)methane;
Background Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19. Methods We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population. Results The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2–95.1) and a specificity of 96.1% (95.7–96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957–0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02–31.0; P = 0.04). Conclusion Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.
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