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H L Vos

Publications and source records attributed to H L Vos.

At least 55 records · Page 3Linked to original sources
PubMed1999

No indication for APTT screening in patients on oral anticoagulant therapy.

UNLABELLED: Patients on oral anticoagulant therapy (OAT) may bleed due to a very low factor IX level caused by a mutation at Ala-10 in the propeptide region of the factor IX gene. We evaluated screening of patients on OAT with an APTT to detect patients with this abnormality. In 734 patients an APTT was assessed. Twenty-three patients had a disproportionately prolonged APTT. In these patients the factor IX level, the mutation at Ala-10 and the frequency of bleeding complications were assessed. No severely lowered factor IX levels were found (1 patient with 5% factor IX). No mutations at Ala-10 were found and bleeding complications were not more frequent in these patients. CONCLUSION: Routine APTT screening of patients on OAT is not useful to detect patients with increased bleeding or with the Ala-10 mutation in the factor IX gene.

Administration, Oral↗
PubMed1999

Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions.

Factor VIII activity (factor VIII:C) levels > or =150 IU/dl are associated with a 5- to 6-fold increased risk of venous thrombosis compared to levels <100 IU/dl, and fibrinogen levels > or =5.0 g/l increase the thrombosis risk 4-fold. These high levels are present in 25% resp. 3% of the patients with a first episode of venous thrombosis. These findings were based on measurements after the thrombotic event, so the factor VIII and fibrinogen levels in thrombosis patients may have been influenced by acute phase reactions or ongoing inflammatory responses. In the present study we measured plasma C-reactive protein (CRP) as a sensitive marker of an acute phase reaction in 474 thrombosis patients and 474 age- and sex-matched healthy controls, that were part of the Leiden Thrombophilia Study (LETS). Mean and median CRP levels were higher in thrombosis patients than in the controls, suggesting inflammation in some patients. CRP affected both factor VIII and fibrinogen levels, in patients and controls alike. After adjustment for the effect of CRP, high factor VIII:C levels still increased the thrombosis risk 6-fold and high fibrinogen levels 4-fold, which is for both very similar to the risk before correction for CRP levels. These results show that although systemic inflammation may be present in some of the patients, elevated levels of factor VIII:C and fibrinogen were in general not caused by acute phase reactions. This further supports a causal relationship between both high factor VIII:C and fibrinogen levels and venous thrombosis.

Acute-Phase Reaction↗
PubMed1998

Two novel mutations in the prothrombin gene cause severe bleeding in a compound heterozygous patient.

Hypoprothrombinemia is a rare hereditary coagulation defect characterized by low levels of biologically active prothrombin. In this paper we report the laboratory and genetic analysis of a patient with a severe hypoprothrombinemia and some of her relatives. Laboratory analysis showed very low levels of prothrombin antigen. Molecular analysis of the prothrombin genes of the patient resulted in the identification of two novel sequence variations in heterozygous state, a 20079 G to A transition, which predicts a Trp 569-->Stop mutation, and a 1261C-->G change within intron B near the acceptor splice site. A cosegregation of prothrombin deficiency in family members with the two genetic defects was observed.

Adult↗
PubMed1998

Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A)

BACKGROUND AND PURPOSE: Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age. METHODS: We conducted a case-control study in western Washington state. Case patients were women aged 18 to 44 years with a first stroke (n = 106). Control subjects were women without stroke recruited from the same region by use of random-digit telephone dialing (n = 391). All were interviewed and provided blood specimens, which were genotyped for these mutations. RESULTS: Factor V Leiden was found in 0.9% of case patients, a single patient with a subarachnoid hemorrhage, and in 4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2 (95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant was found in 1.9% of case patients, 1 with a venous stroke and 1 with an ischemic stroke, and in 1.6% of control subjects. The OR for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types were also not statistically significant. CONCLUSIONS: In this study, neither factor V Leiden nor the prothrombin variant (G20210A) was an important risk factor for stroke in young women. In this setting, screening for these mutations cannot be recommended. Unanswered by this study is whether screening would be useful in select patients, such as those with a strong family history of thrombophilia or those with venous strokes.

Adult↗
PubMed1998

Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin.

The genetic defects causing recessive type 1 and type 3 von Willebrand disease (VWD) in eight families from the northern part of Italy have been investigated. Mutations were identified in 14 of the 16 disease-associated von Willebrand factor (VWF) genes. Only one mutation, a stop codon in exon 45, was previously reported. Several new mutations were identified: one cytosine insertion in exon 42, one guanine deletion in exon 28, one probably complete VWF gene deletion, one substitution in the 3' splice site of intron 13, one possible gene conversion, and three candidate missense mutations. One missense mutation, the substitution of a cysteine in exon 42, was identified in all type 3 VWD patients that were previously characterized as a subgroup with significant increase of factor VIII procoagulant activity after desmopressin infusion. This paper demonstrates again that the molecular defects of quantitative VWD are diverse and located throughout the entire VWF gene.

DNA Mutational Analysis↗
PubMed1998

A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.

Thrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis. We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger "Study of Myocardial Infarctions Leiden" (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8. CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively. While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.

Age Factors↗
PubMed1997

A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.

Using specimens from a population-based case control study among women ages 18 to 44 years in western Washington, we assessed the relationship between carriership of a genetic clotting factor II variant (20210 G-->A) and myocardial infarction (MI). The factor II variant was previously shown to be present in 1% to 2% of the population, to increase the levels of factor II, and to be associated with venous thrombotic disease. Personal interviews and blood samples were obtained from 79 women with a first myocardial infarction and 381 control women identified through random-digit telephone dialing. Polymerase chain reaction (PCR) method was used to determine the factor II genotypes. The factor II 20210 G to A transition was present more often in women with MI (5.1%) than among control women (1.6%). The age-adjusted odds ratio for MI was 4.0 (95% confidence interval 1.1 to 15.1). The relative risk was high when another major cardiovascular risk factor was also present, such as smoking (odds ratio 43.3, 95% confidence interval 6.7 to 281), and the risk seemed limited to those with other risk factors. These results, in which the effect of major coronary risk factors is enhanced fourfold to sixfold by the prothrombin variant, are similar to those previously reported for another genetic clotting abnormality, factor V Leiden. We conclude that factor II 20210 G to A increases the risk of myocardial infarction in young women, especially in the women with other major risk factors for coronary heart disease.

Adolescent↗
PubMed1997

Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21.

Ecm1, the mouse gene encoding extracellular matrix protein 1, is highly expressed in bone and cartilage as well as in osteogenic, preosteoblastic and chondroblastic cell lines. Ecm1 was recently localized to a chromosomal region in mouse syntenic to human chromosome 1q21, establishing this gene as a prime candidate gene for pycnodysostosis, a rare, autosomal recessive sclerosing skeletal dysplasia. Shortly thereafter, it was determined that cathepsin K is the pycnodysostosis gene. We now report the radiation hybrid mapping of human ECM1 to 1q21, and the gene structure and coding sequence of human ECM1.

Amino Acid Sequence↗
PubMed1996

A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis.

Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in an arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.

Blotting, Southern↗
PubMed1995

Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease.

We have identified a murine gene, metaxin, that spans the 6-kb interval separating the glucocerebrosidase gene (GC) from the thrombospondin 3 gene on chromosome 3E3-F1. Metaxin and GC are transcribed convergently; their major polyadenylylation sites are only 431 bp apart. On the other hand, metaxin and the thrombospondin 3 gene are transcribed divergently and share a common promoter sequence. The cDNA for metaxin encodes a 317-aa protein, without either a signal sequence or consensus for N-linked glycosylation. Metaxin protein is expressed ubiquitously in tissues of the young adult mouse, but no close homologues have been found in the DNA or protein data bases. A targeted mutation (A-->G in exon 9) was introduced into GC by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease. A phosphoglycerate kinase-neomycin gene cassette was also inserted into the 3'-flanking region of GC as a selectable marker, at a site later identified as the terminal exon of metaxin. Mice homozygous for the combined mutations die early in gestation. Since the same amino acid mutation in humans is associated with mild type 1 Gaucher disease, we suggest that metaxin protein is likely to be essential for embryonic development in mice. Clearly, the contiguous gene organization at this locus limits targeting strategies for the production of murine models of Gaucher disease.

Amino Acid Sequence↗
PubMed1995

Is episialin/MUC1 involved in breast cancer progression?

Episialin, also designated MUC1, CA 15-3 antigen and PEM, is an established serum marker for breast cancer. Its function and possible involvement in tumor progression has not yet been completely established. The molecule is an extended rod-like molecule protruding high above the cell surface. It is often highly overexpressed in breast cancer relative to normal breast epithelium cells. Overexpression of episialin on cells in vitro reduces cell-cell and cell-extracellular matrix adhesion, because the rod-like molecule masks the adhesion receptors. Episialin also exerts its anti-adhesion effect in vivo. In certain human tumors, where episialin was present at the basal side of the cell, abnormal contacts between the plasma membrane and the stroma were observed. As a consequence of its anti-adhesion properties, episialin overexpression reduces the sensitivity of the cells for cytotoxic lymphocytes. This might be one of the reasons why episialin transfected cells are more potent to form experimental metastases after i.v. injection into nude mice.

Animals↗
PubMed1995

Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components.

Episialin (MUC1) is a transmembrane molecule with a large mucin-like extracellular domain protruding high above the cell surface. The molecule is located at the apical side of most glandular epithelial cells, whereas in carcinoma cells it is often present at the entire surface and it is frequently expressed in abnormally large quantities. We have previously shown that overexpression of episialin reduces cell-cell interactions. Here we show that the integrin-mediated adhesion to extracellular matrix of transfectants of a melanoma cell line (A375), a transformed epithelial cell line (MDCK-ras-e) and a human breast epithelial cell line (HBL-100) is reduced by high levels of episialin. This reduction can be reversed by inducing high avidity of the beta 1 integrins by mAb TS2/16 (at least for beta 1-mediated adhesion). The adhesion can also be restored by redistribution of episialin on the cell surface by monoclonal antibodies into patches or caps. Similarly, capping of episialin on ZR-75-1 breast carcinoma cells, growing in suspension, caused adherence and spreading of these cells. We propose that there is a delicate balance between adhesion and anti-adhesion forces in episialin expressing cells, which can be shifted towards adhesion by strengthening the integrin-mediated adhesion, or towards anti-adhesion by increasing the level of expression of episialin.

Animals↗
PubMed1994

Characterization and molecular cloning of a novel MUC1 protein, devoid of tandem repeats, expressed in human breast cancer tissue.

The human breast cancer marker protein, MUC1, is a polymorphic transmembrane molecule containing a large extracellular domain that is primarily composed of a variable number of highly conserved 20-amino-acid tandem repeats. We report here the detection of a novel invariantly sized 1.2-kb MUC1 mRNA, in addition to the large polymorphic mRNAs, by probing Northern blots with MUC1-cDNA-unique-sequence probes. The nucleotide sequence of this novel MUC1 mRNA demonstrates that it is identical to the MUC1 cDNA sequences downstream and upstream to the tandem-repeat array of the transmembrane form of MUC1. However, it contains neither the central tandem repeat array itself nor its directly flanking sequences that are deleted by a differential splicing event utilizing splice acceptor and donor sequences 5' and 3' to the tandem-repeat array. The splice event retains, downstream to the splice acceptor site, an open reading frame identical to that of the repeat-array-containing MUC1 thereby generating the novel MUC1/Y protein. Cells transiently transfected with the novel MUC1/Y cDNA express the MUC1/Y protein that is modified by glycosylation. The MUC1/Y protein is also readily detected in human breast cancer cells grown in vitro. Furthermore, primary breast cancer tissue samples demonstrate significant levels of the MUC1/Y protein whereas expression in tissue adjacent to the tumor is undetectable. Molecular characterization presented here, of the novel MUC1/Y molecule lacking the repeat array, suggests that it is likely to play a role distinct to that of the polymorphic repeat-array-positive MUC1 protein and that it may act as a new marker protein for human breast cancer.

Amino Acid Sequence↗
PubMed1993

Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction.

Episialin (MUC1) is a mucin-like glycoprotein abundantly expressed on most carcinoma cells. As a result of its extended and rigid structure, it reduces intercellular adhesion. We investigated whether this antiadhesion function allows tumor cells expressing high levels of episialin to escape from immune recognition. To test this hypothesis, we transfected episialin-negative (episialin-) melanoma cells (A375) with the MUC1 cDNA-encoding episialin. The results demonstrated that episialin-positive (episialin+) melanoma cells were significantly less susceptible to lysis than episialin- melanoma cells by both alloantigen or rIL-2-stimulated cytotoxic effector cells. In addition, cold target inhibition experiments with episialin+ and episialin- cells clearly demonstrated preferential lysis of episialin- cells. Furthermore, antibody blocking studies showed that lysis of episialin+, but not of episialin-, melanoma cells was predominantly dependent on the leukocyte function-associated Ag-1/intracellular adhesion molecule adhesion route, suggesting that episialin+ target cells adhere less efficiently to effector cells than episialin- target cells. This notion was supported by the observation that conjugate formation of the effector cells with episialin+ target cells was significantly impaired. From these results we conclude that over-expression of episialin as found on many tumor cells may indeed affect efficient lysis by cytotoxic lymphocytes and thus may contribute to escape from immune surveillance.

Antigens, CD↗