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Biomedical subjects

J Ingerslev

Publications and source records attributed to J Ingerslev.

At least 55 records · Page 3Linked to original sources
PubMed2000

Two novel type 2N von Willebrand disease-causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor.

Two novel mutations, a T-to-C transition at nucleotide 2612 and a T-to-G transversion at nucleotide 3923 of the von Willebrand factor (vWF) complementary DNA, were detected by analysis of the vWF gene in DNA from members of 2 families with atypical von Willebrand disease. The T2612C transition predicts substitution of cysteine by arginine at amino acid position 788 (C788R), and the T3923G transversion predicts substitution of cysteine by glycine at position 1225 (C1225G) of pre-pro-vWF. The patients homozygous for the C788R and C1225G mutations both had a partial vWF deficiency (0. 18 IU/mL and 0.07 IU/mL vWF antigen, respectively); vWF in plasma from patients homozygous for either the C788R or the C1225G mutation failed to bind factor VIII and lacked high molecular weight multimers. Recombinant (r) vWF molecules having the C788R or C1225G mutation were expressed in COS-7 cells. Both rvWF C788R and rvWF C1225G exhibited significantly impaired secretion and failed to bind factor VIII. Recombinant vWF C788R in COS-7 culture medium showed a severe reduction in high molecular weight multimers, whereas rvWF C1225G showed a very mild reduction in high molecular weight multimers when compared with wild-type rvWF. (Blood. 2000;95:2000-2007)

Animals↗
PubMed2000

Markers of thrombophilia in retinal vein thrombosis.

PURPOSE: To study the prevalence of risk factors for systemic thromboembolism in patients with retinal vein thrombosis (RVT). METHODS: Fifty-four patients younger than 70 years, diagnosed with a retinal vein thrombosis at the Department of Ophthalmology, Aarhus University Hospital, were examined for the presence of venous thrombosis risk factors. RESULTS: 23 patients had a central RVT, 26 had a branch RVT, and 4 had a macular RVT. Nineteen (35.2%) of the patients displayed increased levels of plasma homocysteine, one patient (1.9%) the Factor V Leiden mutation, and one patient (1.9%) displayed an antiphospholipid antibody. All other tests for thrombophilia rendered normal. In 15 of the patients with hyperhomocysteinemia, folic acid substitution returned plasma homocysteine to a normal value in 12 cases. CONCLUSION: A surprisingly high prevalence of hyperhomocysteinemia was detected in this cohort of RVT patients, clearly superseding the prevalence of around 17% found in patients suffering venous thromboembolism in other vascular compartments. Our finding points to the likelihood that hyperhomocysteinemia may be a significant risk factor for retinal vein thrombosis.

Adult↗
PubMed2000

Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family.

Factor VIII gene analysis in a large consanguinous Danish family comprising 24 affected males and four homozygously affected females revealed an Asn694Ile mutation within the A2 domain. The factor VIII gene mutation led to a mild haemophilia A phenotype with factor VIII function displaying discordance between one-stage clotting and chromogenic two-stage assays. In one-stage assays, values ranged from 0.05 to 0.30 IU/ml (males) and from 0.19 to 0.29 IU/ml (homozygous affected females), whereas the chromogenic two-stage assay produced values of around only 50% of the one-stage result [0. 02-0.12 IU/ml (males); 0.06-0.10 IU/ml (females)]. The differences are suggested to be caused by the effect of the mutation on the active cleaved form of the factor (F)VIII protein. As the original amino acid (Asn) is conserved in all known FVIII A2 sequences, but not in ceruloplasmin, we suggest that Asn694 is involved in an A2-specific functional role. Examination of a homology model of the A domains predicts that the Asn694Ile mutation (i) results in the loss of two potential hydrogen-bonding interactions and (ii) hampers the integration of the bulky side-chain of Ile into the A2 domain core, probably causing an altered stability and/or folding of the protein. Interestingly, the disease in this Danish family was originally proposed to be von Willebrand-Jürgens disease. However, the current study rules out the co-existence of either von Willebrand's disease or the presence of the Normandy variant of von Willebrand factor (type 2N).

Blood Coagulation↗
PubMed2000

Haemophilic patients with hepatitis C have higher viral load compared to other well-defined patient groups.

Comparison of hepatitis C viral load between different patient populations has been hampered by the use of different technology in individual studies. We had the impression that haemophilic (HAEM) patients had a higher serum load of hepatitis C virus (HCV) compared to other HCV-infected patients. We therefore studied viral load and genotypes in active illicit drug users (IDU), HAEM patients and patients with post-transfusion hepatitis (PTH). The study comprises 225 HCV-RNA positive patients, 117 IDU, 60 HAEM patients and 48 PTH patients. All patients were anti-HIV negative. HCV-RNA was measured with a quantitative reverse transcription polymerase chain reaction (RT-PCR) method, HCV-genotypes were determined with genotype specific primers in RT-PCR in 221 patients. Four patients could not be genotyped with our assay and were excluded. Overall viral load was higher in genotypes 1 and 2 compared to genotype 3, median values of HCV-RNA were 1,400 x 10(3) geq ml(-1), 2,700 x 10(3) geq ml(-1) and 270 x 10(3) geq ml(-1), respectively. HAEM patients had significantly higher viral load for both genotypes 1 and 3 compared to the IDU and PTH patients. In a multiple linear regression model HCV-RNA viral load was independently associated with HAEM and genotype, but not to age, gender or disease duration. In conclusion, HAEM patients have higher viral load than IDU and PTH patients. The reason for this is unknown, but it may be due to host factors or mode of transmission with multiple inoculations.

Adult↗
PubMed2000

Efficacy and safety of recombinant factor VIIa in the prophylaxis of bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors.

Patients with hemophilia may develop alloantibodies (inhibitors) directed toward the substitution factor. In the long term, this complication significantly affects around 15% of hemophilia A patients and 2-5% of hemophilia B patients suffering the severe class of disease (critical functional factor level <0.01 IU/mL). The typical consequence of a newly developed inhibitor is that the patient can no longer take advantage of the principles of modern hemophilia management, including safe and early treatment of bleeding and prophylactic use of concentrate in prevention of bleeding. Moreover, problems that are normally solved by means of a surgical procedure covered by the usual concentrate will be regarded as difficult and are likely to be associated with risk of untoward bleeding if high-titer inhibitors are present. Over the past decade, considerable experience has been collected illustrating that surgery may be performed quite safely in the patient with inhibitors if hemostasis is assisted by a new hemostatic agent, an activated recombinant factor VII molecule (rFVIIa). Although only one controlled randomized surgical study has been presented, cumulated data from this and from other, less formal studies on the use of rFVIIa in hemophilic inhibitor surgery have illustrated that a vast variety of different surgical procedures can be accomplished with none of the life-threatening bleeding complications that would be anticipated if no hemostatic treatment was administered. The aim of the present review is to present a multiplicity of surgical procedures that have been carried out during the clinical development of rFVIIa. Further, an update of 21 surgical procedures in inhibitor patients from the center of the author will be reviewed and discussed.

Autoantibodies↗
PubMed2000

Management and monitoring of recombinant activated factor VII.

Recombinant factor VIIa (rFVIIa) has recently been introduced as a new 'bypassing' agent to improve haemostasis in haemophilia patients with inhibitors to factor (F) VIII or FIX. In noninhibitor patients, levels of circulating FVIII or FIX can be used to assess the quality of substitution therapy. In contrast, laboratory monitoring of haemostatic efficacy in patients treated with rFVIIa has proved more complex. Evaluation of patient samples saved during rFVIIa treatment have revealed some correlation between FVII:C levels and improved haemostasis, while whole blood elasticity, as determined by thromboelastography, has been shown to improve following rFVIIa treatment. The investigation aimed to study the efficacy of rFVIIa in activating FX:C and in shortening the whole blood clotting time (WBCT) using the newly-developed roTEG coagulation instrument. Results indicated a substantial and apparently dose-dependent activation of FX:C by rFVIIa. In addition, the presence of FIX appeared to influence FX:C activation. In-vitro and ex-vivo roTEG thromboelastograph measurements showed that FVIIa shortened WBCT, although normalization did not occur. The results presented here are based on a small number of observations in a few patients and further studies should be planned to test the efficacy of these monitoring principles in clinical treatment practice with rFVIIa.

Bleeding Time↗
PubMed2000

Familial thrombophilia associated with homozygosity for the cystathionine beta-synthase 833T-->C mutation.

Severe hyperhomocysteinemia due to cystathionine beta-synthase (CBS) deficiency is a strong risk factor for premature cardiovascular disease. Among untreated patients, approximately 50% have suffered a thromboembolic event by 30 years of age. We report on 3 sisters with severe hyperhomocysteinemia due to homozygosity for the CBS 833T-->C mutation. These patients, who displayed no other known thrombophilic predisposition, had suffered single or multiple venous thrombosis before CBS deficiency was diagnosed relatively late in life. In this family, homozygosity for the 833T-->C mutation was associated with a mild phenotype with respect to other sequelae of CBS deficiency. Consequently, our results indicate that most cases with this genotype may remain undiagnosed. Investigated family members heterozygous for the 833T-->C mutation displayed normal total homocysteine in plasma (tHcy) levels, even when they were homozygous for the methylenetetrahydrofolate reductase 677C-->T polymorphism. The prevalence of homozygosity for the 833T-->C mutation has previously been estimated at no less than 1:20 500 in our population. Because a reduction of the severely elevated levels of tHcy in CBS deficiency reduces cardiovascular risk and because homozygosity for the 833T-->C mutation is more prevalent than previously thought, our results emphasize the importance of measuring tHcy routinely in thrombophilia screening.

Cardiovascular Diseases↗
PubMed2000

Absence of correlation between X chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of haemophilia A and B.

Haemophilia A and B are X-linked disorders which are due to a reduced activity of coagulation factor VIII or IX, respectively. Female carriers have a wide range of plasma concentration of factor VIII or factor IX, and may in rare cases have an affected phenotype. In order to investigate if this variation is related to X chromosome inactivation, we determined the X inactivation pattern in 31 haemophilia A and 15 haemophilia B carriers, using a PCR in the androgen receptor locus in blood DNA. Seven of the haemophilia A carriers and none of the haemophilia B carriers had a skewed pattern (> or =80:20). One of the skewed haemophilia A carriers had a low plasma concentration of factor VIII (0.15 U/ml), but the remaining 6 carriers did not differ in factor VIII concentration from that of carriers with a random X inactivation pattern. One carrier with a high factor VIII concentration (2.0 U/ml) did not have a skewed pattern. Similarly, for the haemophilia B carriers, there was no tendency to a more skewed X inactivation pattern in the carriers with low or high factor IX concentrations. In addition, we analysed a female with haemophilia B who was heterozygous for the mutation R180W in the factor IX gene. She had a random X chromosome inactivation pattern. We conclude that the wide range in plasma concentration of factor VIII and factor IX in haemophilia A and B carriers cannot in general be explained by the X chromosome inactivation pattern in peripheral blood cells.

Adolescent↗
PubMed2000

Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. In search of genetic factors causing elevated levels of total homocysteine in plasma (tHcy), we investigated a cohort of consecutively identified, unrelated thrombosis patients (n = 28) having intermediate or severe hyperhomocysteinemia (30 micromol/l 100 micromol/l, respectively). The methylene-tetrahydrofolate reductase (MTHFR) 677C-->T genotype, and the complete cystathionine beta-synthase (CBS) genotype was determined in all patients. We found that the MTHFR T/T genotype was strongly correlated with intermediate hyperhomocysteinemia, being present in 73.9% of those cases (17 of 23). In three of five patients with severe hyperhomocysteinemia, compound heterozygosity for CBS mutations was detected. Among the mutations, two novel missense mutations: 1265C-->T (S422L) and 1397C-->T (S466L) were detected. The phenotype in those patients was quite mild, thromboembolism apart. This indicates that a search for CBS mutations in patients with severe hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment. Co-existence of the MTHFR T/T genotype and the common CBS 844ins68 variant was significantly higher among patients (10.7%) as compared to controls (1.2%), indicating that this genotype combination is a thrombotic risk factor (P <0.05). In a few patients, hyperhomocysteinemia could not be explained by this genetic approach, suggesting that other genetic risk factors were implicated.

Adult↗
PubMed2000

Hemophilia. Strategies for the treatment of inhibitor patients.

Symptomatic treatment of patients with hemophilia A and hemophilia B has now reached high levels of safety and efficacy. In consequence, at present the most prominent clinical complication is the development of inhibitors, which are alloantibodies directed against the coagulation factor demanded for substitution therapy in the management and prevention of bleeds. When de novo inhibitors are detected for the first time in a patient, several questions are raised. Since the clinical picture with inhibitors is dominated by an excessive tendency to bleed and reduced or lost efficacy of the usual factor concentrate, acute bleeding will often be a problem. Major questions from the patient and his next of kin are whether the inhibitors will disappear, and whether there is a therapy available that can cure this complication. Over the last 20-25 years, treatment programs have been established that seem to offer a reasonably good chance of suppressing inhibitors in hemophilia. Some protocols suggest the use of very high daily doses of factor VIII, whereas others propose much lower doses of factor VIII, seemingly with quite comparable rates of success. Therefore, controlled prospective clinical studies, focusing on the dosage aspect, are urgently required. Control of bleeding is another issue of great importance. In inhibitor patients with a low responder state, substitution with increased doses of factor VIII or IX may successfully arrest bleeding. In some hemophilia A patients with a high responder state, but with actual inhibitor titers in the lower range, a porcine factor VIII concentrate could be useful. In these cases the patient's anti-factor VIII antibody should display no major cross-reactivity towards the porcine factor VIII molecule. In patients with high-responder inhibitors, so-called bypassing agents may be used to control bleeding. There are two major classes of bypassing agents. Concentrates have been produced for more than two decades derived from plasma and characterized by a high content of vitamin K-dependent coagulation factors. Examples are the prothrombin complex concentrates (PCC), and the activated prothrombin complex concentrates (aPCC). A newly introduced recombinant activated factor VII molecule (rFVIIa) has gained approval in numerous countries based primarily on results from emergency use in a substantial number of individuals with inhibitors. Other, still experimental, products have been proposed, but no human clinical studies are available as of yet Inhibitors remain a challenge to patients and their physicians.

Factor VIII↗
PubMed1999

Transcapillary escape rate and albuminuria in Type II diabetes. Effects of short-term treatment with low-molecular weight heparin.

The relation between urinary albumin excretion rate (UAE), transcapillary escape rate of albumin (TERalb), haemostatic factors, ambulatory blood pressure, and metabolic variables was investigated in 45 Type II (non-insulin-dependent) diabetic patients without overt nephropathy or uncontrolled blood pressure. We enrolled 44 patients in a placebo controlled study to test the effects of 3 week long treatment with low-molecular weight heparin (tinzaparin) on the same variables. BMI, 24 h systolic and diastolic blood pressure, plasma concentrations of triglycerides, fasting glucose, factor VIII, von Willebrand factor (vWf), fibrinogen, alpha-2 macroglobulin, and fibronectin were notably higher in patients with increased albuminuria compared with normoalbuminuric patients, whereas the TERalb was similar in the two groups. TERalb correlated with fasting plasma glucose. UAE correlated more closely than TERalb with 24 h ambulatory blood pressure, vWf, and factor VIII. Urinary albumin excretion rate was unchanged during tinzaparin [28.9+/-5.6 vs 28.1+/-6.0 microg/min (geometric mean (antilog SD)] vs placebo (18.0+/-5.4 vs 17.6+/-5.3 microg/min), and no change was found in TERalb [6.3+/-1.6 vs 6.0+/-1.5%/h (means +/- SD), and 6.3+/-1.5 vs 5.6+/-1.8%/h; tinzaparin versus placebo, respectively]. Only minor changes were observed in blood pressure, lipids, glycaemic control and haemostatic factors. This study shows no correlation between albuminuria and transcapillary escape rate in Type II diabetic patients without overt nephropathy or uncontrolled-blood pressure. UAE is related to markers of atherosclerosis, endothelial injury and dysfunction, and haemostatic factors. Moreover, UAE correlates much more than TERalb with 24 h ambulatory blood pressure, von Willebrand factor, and factor VIII. Finally, short-term treatment with tinzaparin does not change the transvascular or glomerular leakage of albumin. These results indicate that TERalb is not a sensitive marker of microvascular dysfunction in such patients and that factors other than abnormal glycosaminoglycan metabolism may contribute to the vascular damage of these patients.

Adult↗
PubMed1999

Comparison of the effects of a monounsaturated fat diet and a high carbohydrate diet on cardiovascular risk factors in first degree relatives to type-2 diabetic subjects.

OBJECTIVE: Recent studies have demonstrated beneficial metabolic effects of dietary monounsaturated fatty acids (MUFA) in Type-2 diabetes mellitus (Type-2 DM). The question arises if dietary MUFA also has desirable effects on risk markers in subjects with high risk of developing Type-2 DM. SETTING: University department of endocrinology. SUBJECTS: Sixteen healthy, first-degree relatives (six men, 10 women, age (mean+/-s.d.): 35+/-2 years) with normal oral glucose tolerance tests. INTERVENTIONS: Randomised study with two 4-week treatment periods with either a carbohydrate-rich (CHO) diet (55 E% carbohydrate, 30 E% fat, 15 E% protein) or a diet rich in olive oil [MUFA 40 E% fat (25 E% as MUFA), 45 E% carbohydrate, 15 E% protein]. The periods were divided by a 4-week wash-out period. RESULTS: Similar lowering effects on total cholesterol, low density lipoprotein (LDL)-cholesterol, triglyceride and apoB levels were seen after the two diets. Slightly higher levels of high-density lipoprotein (HDL)-cholesterol (1.4+/-0.4 vs 1.3+/-0.4 mmol/l, P<0. 0001) and apoA-1 (1.2+/-0.3 vs 1.1+/-0.3 mmol/l, P<0.05) were found in the MUFA-diet. Furthermore, the insulin sensitivity, as assessed by Bergman's minimal model, and the first response insulin areas were similar, as were the 24-h blood pressures and the von Willebrand Factor (vWF) levels. CONCLUSIONS: Isocaloric diets rich in MUFA or rich in carbohydrate, respectively, seem to have similar effects on cardiovascular risk factors in persons at high risk of developing Type-2 DM. A potential risk, however, on body weight of high-fat diets should be kept in mind. SPONSORSHIP: This study was supported by grants from the Danish Diabetes Association, Institute of Clinical Experimental Research, Aarhus University, The Danish Heart Foundation, The Danish Medical Research Council, Velux Foundation, Poul and Erna Sehested Hansens Foundation, Mogens Svarre Mogensens Foundation.

Adult↗
PubMed1999

Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients.

The present study describes 403 patients with thrombosis, from a uniform ethnic and geographical background. Two-hundred-and-seven individuals had suffered mild or moderate stroke and 196 individuals suffered venous thromboembolism. We recorded levels of antithrombin, protein C and protein S, plasminogen and plasma homocysteine, and the presence of the factor V Leiden mutation, the prothrombin 20210G-->A variant, and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism. Controls for the mutation frequencies consisted of Guthrie card blood spots from a cohort of new-born babies. The cumulative prevalence of deficiencies in antithrombin, protein C, protein S or plasminogen was 2.4% in patients with stroke and 11.2% in patients with venous thrombosis. The factor V Leiden mutation was present in 11.1% of patients with stroke and 26.5% of patients with venous thrombosis, compared with 6.6% of controls (n = 4188; P < 0.05 and P < 0.0001, respectively). The prevalence of the prothrombin 20210A variant was 3.1% in patients with venous thrombosis, 1.9% in patients with stroke and 2.0% in controls (n = 500; P > 0.05). Hyperhomocysteinemia was present in 16.0% of patients with stroke and 17.6% of patients with venous thrombosis. The prevalence of the MTHFR 677T/T genotype was no different in patients with stroke (10.6%) and venous thrombosis (8.7%) than in controls (8.3%; n = 1084; P > 0.05); thus, it apparently contributed to thrombosis only via its influence on total plasma homocysteine, which was significantly increased in patients with the T/T genotype (P < 0.001). The MTHFR T/T genotype did not further increase the risk for thrombosis in carriers of the factor V Leiden mutation. Overall, thrombotic events were associated with a known risk factor in 27% of patients with stroke and 55% of patients with venous thrombosis.

Adolescent↗