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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It appears that the binding of coagulation factor VIII to von Willebrand factor in plasma stabilizes the otherwise highly labile factor VIII. A mathematical model of factor VIII kinetics has been developed based upon this proposed effect of factor VIII binding. The model's kinetic parameter values have been estimated by fitting the model to data available in the medical literature. The model gives accurate quantitative predictions of the elevated steady-state concentrations of factor VIII in clinical conditions associated with the acute phase reaction and in pregnancy, the decreased steady-state concentrations of factor VIII in females heterozygous for hemophilia, the decreased steady-state concentrations of factor VIII in patients with type 1 (heterozygous) and type 3 (homozygous) von Willebrand disease, and the variable half-life of factor VIII in factor replacement therapy for hemophilia and von Willebrand disease.
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PMID:A mathematical model of coagulation factor VIII kinetics. 897 43

Molecular genetic characterization of the hemostatic system began more than 15 years ago, and, as a result, our knowledge of the genetic pathology of inherited bleeding disorders is well advanced. However, molecular testing for hemophilia and von Willebrand disease (vWD) has been impeded by the large size and complex genomic organization of the genes involved, and by the heterogeneity of the mutations underlying these disorders. Such limitations have significantly reduced the ability to provide diagnostic testing for these conditions through direct mutation detection. Many diagnostic laboratories continue to utilize linkage analysis with highly informative intragenic polymorphisms for the investigation of hemophilia. The one important exception to this trend has been the factor VIII inversion mutation, which provides a definitive test for the mutant allele in approximately 45% of severe hemophilia A patients. In contrast to patients with bleeding disorders, characterization of the factor V Leiden and prothrombin 20,210 variants has dramatically improved the diagnostic yield for patients with inherited thrombophilia. One of these two genotypes is now found in greater than 60% of patients with a clinical history of familial thrombophilia. Finally, recent studies indicate that molecular genetic analysis is beginning to permit preliminary progress in the identification of arterial thrombotic risk. Further advances in characterizing the multigenic basis of thrombotic disease and the application of new technologies to aid in the assessment of genetic variability predict an increasingly important role for molecular diagnostic approaches to the evaluation of disorders of hemostasis.
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PMID:Molecular diagnosis of inherited bleeding disorders and thrombophilia. 1053 Jul 16

During the course of investigations we encountered 11 patients with haemophilia A who had severe factor VIII deficiency as measured by one-stage assay but had surprisingly mild clinical presentation. Four of these patients had either a brother, nephew or maternal uncle with severe clinical manifestations. Two patients had low protein S levels, and one was heterozygous for the factor V Leiden mutation. One patient had a combined deficiency of protein C and antithrombin III. Four patients had a two-stage factor VIII assay value that was much higher than the one-stage assay value. Five patients were heterozygous for the MTHFR gene C677T polymorphism, of whom two patients were also deficient for protein S and one had two-stage factor assay values higher than the one-stage assay values. The patient who was both factor VIII deficient and heterozygous for factor V Leiden had mild clinical presentation as compared to his maternal uncle who was only factor-VIII deficient. The maternal cousin of the same patient was heterozygous for factor V Leiden and had suffered two thrombotic episodes. Thus, the present study advocates that the physiological inhibitors of blood coagulation also play an important role in cases of haemophilia A in the final outcome of haemostasis in vivo.
Haemophilia 2001 Jan
PMID:Milder clinical presentation of haemophilia A with severe deficiency of factor VIII as measured by one-stage assay. 1113 74

There is considerable variability in bleeding patterns of severe haemophilia (<1% factor VIII). Knowledge of the contribution of thrombophilic factors in these patterns may improve individually tailored treatment strategies. We reviewed the literature regarding the relation between prothrombotic factors and clinical phenotype of severe haemophilia. Medline and EMBASE were searched for relevant articles. 9369 articles published between 1963 and September 2003 were screened and seven relevant papers were retrieved. Each of these reported on a different combination of thrombophilic factors. Presence of the factor V Leiden mutation appears to decrease the severity of severe haemophilia most consistently. Findings on other thrombophilic factors were inconclusive. There is a clear need for additional research on potential determinants of phenotypes of severe haemophilia before such knowledge can be translated into individual care for severe haemophilia patients with confidence.
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PMID:Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature. 1526 26

The role of factor V Leiden (FVL) as a modifier of the severe hemophilia phenotype is still unclear. We used mice with hemophilia A or B crossed with FVL to elucidate in vivo parameters of hemostasis. Real-time thrombus formation in the microcirculation was monitored by deposition of labeled platelets upon laser-induced endothelial injury using widefield microscopy in living animals. No thrombi formed in hemophilic A or B mice following vascular injuries. However, hemophilic mice, either heterozygous or homozygous for FVL, formed clots at all injured sites. Injection of purified activated FV into hemophilic A or B mice could mimic the in vivo effect of FVL. In contrast to these responses to a laser injury in a microvascular bed, FVL did not provide sustained hemostasis following damage of large vessels in a ferric chloride carotid artery injury model, despite of the improvement of clotting times and high circulating thrombin levels. Together these data provide evidence that FVL has the ability to improve the hemophilia A or B phenotype, but this effect is principally evident at the microcirculation level following a particular vascular injury. Our observations may partly explain the heterogeneous clinical evidence of the beneficial role of FVL in hemophilia.
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PMID:Factor V Leiden improves in vivo hemostasis in murine hemophilia models. 1635 10

The liver is an essential player in the pathway of coagulation in both primary and secondary haemostasis. Only von Willebrand factor is not synthetised by the liver, thus liver failure is associated with impairment of coagulation. However, recently it has been shown that the delicate balance between pro and antithrombotic factors synthetised by the liver might be reset to a lower level in patients with chronic liver disease. Therefore, these patients might not be really anticoagulated in stable condition and bleeding may be caused only when additional factors, such as infections, supervene. Portal hypertension plays an important role in coagulopathy in liver disease, reducing the number of circulating platelets, but platelet function and secretion of thrombopoietin have been also shown to be impaired in patients with liver disease. Vitamin K deficiency may coexist, so that abnormal clotting factors are produced due to lack of gamma carboxylation. Moreover during liver failure, there is a reduced capacity to clear activated haemostatic proteins and protein inhibitor complexes from the circulation. Usually therapy for coagulation disorders in liver disease is needed only during bleeding or before invasive procedures. When end stage liver disease occurs, liver transplantation is the only treatment available, which can restore normal haemostasis, and correct genetic clotting defects, such as haemophilia or factor V Leiden mutation. During liver transplantation haemorrage may occur due to the pre-existing hypocoagulable state, the collateral circulation caused by portal hypertension and increased fibrinolysis which occurs during this surgery.
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PMID:New insights into the coagulopathy of liver disease and liver transplantation. 1720 12

The role of natural anticoagulants, fibrinolytic cascade factors and common prothrombotic gene polymorphisms in modulating disease severity were studied in 35 'clinically mild' and 37 'clinically severe' haemophilia patients with severe factor VIII or IX deficiency (<0.01 IU/ml). Strong association of deficiencies of proteins C and S, antithrombin III, tissue factor pathway inhibitor and tissue plasminogen activator, together with factor V Leiden and endothelial protein C receptor 23 bp insertion polymorphisms were observed in the 'clinically milder' group as compared with the 'clinically severe' group. These results indicate a synergistic modulation of bleeding tendency in haemophilia patients by factors in the anticoagulant and fibrinolytic systems.
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PMID:Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients. 1765 55

Experimental animal studies as well as clinical trials have shown that interventions targeting the blood coagulation cascade inhibit cancer cell metastasis. These data support the hypothesis that congenital prothrombotic disorders, like factor V Leiden, facilitate metastasis whereas bleeding disorders, like haemophilia impede metastasis. To test this hypothesis, we subjected factor V Leiden and factor VIII deficient mice to a murine model of experimental lung metastasis. In this model, B16F10 murine melanoma cells are injected into the tail vein resulting in multiple lung metastases within 20 days. Both hemi- and homozygous factor VIII deficient mice were protected against lung metastasis compared to wild-type littermate controls. In contrast, homozygous factor V Leiden mice developed more metastases than wild-type littermates, whereas heterozygous carriers showed an intermediate number of pulmonary foci. Overall, these data show that a congenital susceptibility to either bleeding or thrombosis modifies the metastatic capacity of cancer cells in the bloodstream and suggest that procoagulant phenotypes are a risk factor for tumour metastasis.
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PMID:Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders. 1922 65

About 10% of patients with severe hemophilia exhibit a milder clinical phenotype with less frequent bleeds. Among many other factors, coinheritance of prothrombotic mutations have been proposed to act as modulators of clinical severity in severe hemophilia. We conducted a study to evaluate the impact of 3 prothrombotic mutations (factor V Leiden, factor II, and methylenetetrahydrofolate reductase mutations) on clinical phenotype of patients with severe hemophilia in our institution. For this purpose we compared the average annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. A total of 38 hemophilia A and B patients with factor levels less than 1 were recruited between October 2006 and October 2007. Prothrombotic mutations were detected in venous blood using polymerase chain reaction amplification technique. Eighteen patients (47%) carried no prothrombotic mutations. The remaining 20 patients (53%) were found to be carriers of either 1 or 2 mutations. Median age in both carrier and the non-carrier groups was 27 years. None of the patients in either group gave a history of thromboembolic event. Median annual factor concentrate consumptions in carriers and noncarriers were 610 +/- 530 units/kg and 770 +/- 670 units/kg, respectively (P = .203). Our results demonstrated no significant difference in annual factor concentrate consumption between carriers and noncarriers of prothrombotic mutations. Considering that average annual factor consumption is a surrogate indicator of clinical phenotype, we concluded that coinheritance of prothrombotic mutations was not associated with occurrence of different clinical phenotypes in severe hemophilia.
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PMID:The impact of prothrombotic mutations on factor consumption in adult patients with severe hemophilia. 1860 40

Molecular biological methods have become increasingly important not only in the diagnostics of inherited monogenetic diseases such as hemophilia A or B but also in the diagnostics of polygenetic diseases e.g. venous and arterial thrombosis. In haemophilia A, sequencing of the factor VIII gene has been established in addition to the analysis of the two most frequent genetic abnormalities, the inversions in intron 22 and intron 1, in several centers. Molecular testing has proved helpful to identify haemophilia patients at high risk to develop inhibitors as well as in carrier analysis. In patients with familial protein C or protein S deficiency mutation analysis contributes to the verification of the diagnosis. The frequently performed tests for the factor V Leiden mutation and the prothrombin 20210G>A variation can potentially support the estimation of the thrombotic risk as well as the risk of recurrence. However, any uncritical application of these genetic tests does not improve diagnostics nor does it support therapeutic decision making or counselling of the patient. Therefore, one should only do genetic tests with medical or therapeutic consequences. The applicability of mutation analysis in the daily routine is still limited in spite of the importance of molecular diagnostics in the understanding of pathomechanisms of haemostatic disorders. As has been demonstrated in large studies, the phenotypic effects of mutations can vary significantly between individuals. Endogenous and exogenous modulators that are still largely unknown, play a role. Currently, the understanding of these modulators is limited, and large multicenter studies and meta-analyses are needed for a better understanding of gene-gene and gene-environment interactions.
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PMID:[Molecular biology and haemostasis]. 1913 59


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