Combined factor VIII/factor XI deficiency may cause intra-familial clinical variability in haemophilia A among Ashkenazi Jews

Berg, Lutz-Peter; Varon, Daryelle S.; Martinowitz, Uri; Wieland, Kerstin; Kakkar, Vijay V.; Cooper, David Neil

doi:10.1097/00001721-199402000-00009

Cited by 17 publications

(18 citation statements)

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“…13 In bleeding disorders, the frequently observed variability in the phenotypic expression even among persons carrying identical genetic mutations suggests the influence of multiple factors in the pathogenesis of these diseases. Thus, co-inheritance of genetic abnormalities has previously been reported for deficiencies of several coagulation factors, including FVIII and FXI, 14 as well as FXI and von Willebrand factor, 15 though reports of combined coagulation factor deficiencies are scant. The remarkably high prevalence of FV Leiden in the general population (2%-12%) 11 and the procoagulant state associated with this genetic change make FV Leiden a tantalizing possibility as a key factor in bleeding disorders.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage

Corral

Iniesta

Gónzález-Conejero

et al. 2001

Blood

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Intracranial hemorrhage is the third most frequent cause of cerebrovascular disease, but few genetic risk factors have been associated with its development. Recently, it has been reported that some polymorphisms that affect clotting factors increase the risk for thrombosis. However, reports have analyzed the effect of polymorphisms influencing the hemostatic state in bleeding disorders insufficiently. A case-control study was conducted of 201 patients with spontaneous intracranial hemorrhage and 201 control subjects matched for age, race, sex, and selected risk factors (hypertension, smoking, and alcohol consumption). Genomic polymerase chain reaction was used to analyze the prevalence of 4 polymorphisms: factor V Leiden, prothrombin 20210A, factor VII؊323 Del/Ins of a decanucleotide, and factor XIII V34L. Subjects with factor V Leiden had decreased risk for spontaneous intracranial hemorrhage (odds ratio, 0.19; 95% confidence interval, 0.03-0.95). The frequency of the prothrombin 20210A/G genotype was also lower among patients than controls (1.5% vs 3%, respectively). Moreover, carriers of the ؊323 Ins allele of factor VII had a 1.54-fold risk for intracranial hemorrhage (95% CI, 1.03-2.72). Finally, no significant differences were observed in the prevalence of factor XIII V34L polymorphism between patients and controls. Therefore, new genetic factors affecting the risk for spontaneous intracranial hemorrhage were identified. These data, together with the relevance of these polymorphisms in thrombotic diseases, support the idea that a polymorphism may play opposite roles in thrombosis and hemorrhage, suggesting an explanation for the high frequency of these polymorphisms in the general population.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage

Corral

Iniesta

Gónzález-Conejero

et al. 2001

Blood

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“…Further, individuals with hemostatic disease are likely to harbor a significant number of variants that act in concert thereby contributing to disease manifestation. Even for those diseases attributed to single-gene heredity (e.g., the hemophilias and von Willebrand disease), the severity, clinical course and response to treatment will all be influenced by other variants (Asatiani and Kessler 2007; Berg et al 1994; Ghosh et al 2001); in cases of hemophilia where thrombotic variants are also present, thrombosis can result from treatment designed to control bleeding (Nowak-Gottl et al 2003). We anticipate that the clinical application of “omics” technologies such as assessment of individual genome sequences (and perhaps also serum proteomes) are on the near horizon for medically important targets such as the Hemostaseome and that the application of these technologies on an individual basis will inform patient stratification and allow personalized treatment for a variety of hemostatic disorders.…”

Section: Discussionmentioning

confidence: 99%

Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

et al. 2011

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Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the `Hemostaseome,' and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.

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“…[3][4][5][6] One may assume that for these combined diseases there are also cargo receptors/cargo proteins acting in a similar way as in FV/FVIII disease. Other coagulation cascade combined diseases are considerably rarer; FVIII/XI has been hitherto described in three reports, FVIII/FIX (four reports), FVII/FVIII (four reports) and one report described FVIII/FXII.…”

Section: A Child With Haemophilia a And Shwachman-diamond Syndrome Wimentioning

confidence: 99%

“…3,[6][7][8] Apart from coagulation cascade, other combined HA/haematologic diseases also appear sporadic; HA/von Willebrand (five reports) and one report for each of the following: FVIII/Sickle cell anaemia, FVIII/hypofibrinogenemia, and FVIII/acute lymphatic leukaemia. Authors who frequently found such rare combined diseases (often in formefruste manner) were dissatisfied with clinical/ | e369 laboratory pattern of affected individual(s) and therefore conducted active search for them.…”

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confidence: 99%

A child with haemophilia A and Shwachman‐Diamond syndrome with literature review of combined haematologic diseases in children

et al. 2019

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Combined factor VIII/factor XI deficiency may cause intra-familial clinical variability in haemophilia A among Ashkenazi Jews

Cited by 17 publications

References 0 publications

Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage

Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage

Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

A child with haemophilia A and Shwachman‐Diamond syndrome with literature review of combined haematologic diseases in children

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