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Biomedical subjects

L Tengborn

Publications and source records attributed to L Tengborn.

At least 19 recordsLinked to original sources
PubMed1999

[Centralized care is the basis of care programs for hemophilia patients].

Haemophilia is a rare and potentially life-threatening disease. In Sweden, with a population of approximately 8.5 million, about 350 people suffer from the more severe forms of haemophilia or von Willebrand disease. Meticulous management is important if the patients are to be spared chronic disability and serious treatment complications. The disease is lifelong and affects psychosocial aspects of life among patients and their families. With the help of a grant from the Swedish Board of Halth and Welfare, a care programme has been designed to guarantee Swedish haemophiliacs comparable and optimal care. The programme has been drawn up by representatives of the three haemophilia centres in Sweden (at University Hospital, Malmö, Sahlgrenska University Hospital, Gothenburg, and Karolinska Hospital, Stockholm) in co-operation with the World Federation of National Haemophilia Organisations. To ensure optimal individual application of the programme, individualised management strategies and patient information leaflets have been prepared.

Centralized Hospital Services↗
PubMed1999

Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.

The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3-5 and 15 at the age of 6-9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient. A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P<0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P=0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3-5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P=0.0002), whereas dose and infusion interval at start were not. Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.

Age Factors↗
PubMed1999

The effects of oestrogen replacement therapy on haemostatic variables in postmenopausal women with non-insulin-dependent diabetes mellitus.

Women with diabetes mellitus have an increased risk of developing coronary heart disease which may be related at least partially to unfavourable changes in haemostasis. The effect of oestrogen replacement therapy on haemostasis has not been studied systematically in women with non-insulin-dependent diabetes mellitus (NIDDM) and therefore this study was performed for that purpose. Twenty-five postmenopausal women with NIDDM were treated with 2 mg of 17-beta-oestradiol orally for 3 months in a double-blind, crossover, placebo-controlled trial. During the last 16 days of active treatment, 1 mg of norethisterone acetate was added for 10 days for endometrial protection. Blood samples were taken at baseline and after 68 days of active or placebo treatment. Treatment with oestradiol was followed by a marked decrease in the activity of plasminogen activator inhibitor, compared with placebo. The activity of tissue plasminogen activator increased significantly. Levels of antithrombin decreased during treatment with oestradiol, whereas no changes were seen in levels of fibrinogen, von Willebrand factor, prothrombin fragment 1+2, protein S, protein C or resistance to activated protein C. In conclusion, oestrogen replacement therapy in postmenopausal women with NIDDM improved the fibrinolytic activity, while only clinically insignificant alterations in the clotting system were seen. These changes in haemostasis may have a favourable impact on the risk for coronary heart disease in diabetic women.

Aged↗
PubMed1999

Comparison of various D-dimer tests for the diagnosis of deep venous thrombosis.

Analyses of D-dimers in plasma are frequently used as diagnostic tools for deep venous thrombosis (DVT). Enzyme-linked immunosorbent assays (ELISAs) are considered to be the method of choice for quantitative assays, but are time consuming. Therefore, we have assessed plasma levels of D-dimers in patients with clinically suspected DVT using quantitative (Asserachrom D-Di ELISA and TintElize), semiquantitative (Minutex latex, D-Di latex, NycoCard D-Dimer) and qualitative (INSTANT.I.A) assays. Phlebography was used as the gold standard to verify or exclude the suspected diagnosis. We conclude that the fast assays, INSTANT.I.A and Minutex, have essentially the same negative predictive value [91% and 89%, respectively, using a cut-off value < 0.5 mg/l fibrinogen equivalent units (FEU)] for excluding DVT as the Asserachrom D-Di ELISA and TintElize tests (92%). The D-Di Latex assay had a negative predictive value of 82% (cut-off < 0.5 mg/l FEU) and turned out to be less useful in our material. The NycoCard D-dimer assay had a negative predictive value of 100% when using the cut-off value < 0.5 mg/l FEU, but this was substantially lower when the cut-off was changed to < or = 0.5 mg/l. Thus, we conclude that several fast tests offer a simpler and more rapid way of determining plasma levels of D-dimer than conventional ELISA methods without loss of clinical usefulness in excluding DVT.

Biological Assay↗
PubMed1999

APC resistance and other haemostatic variables during pregnancy and puerperium.

Forty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type I and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

Activated Protein C Resistance↗
PubMed1998

Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm.

Systemic administration of desmopressin (DDAVP) induces increased plasma levels of tissue-type plasminogen activator (t-PA), coagulation factor VIII, and von Willebrand factor (vWF). However, the mechanisms behind these responses are not known. We tested the hypothesis that DDAVP acts as a local stimulator of acute endothelial release of t-PA and vWF independently of central pathways. Healthy, young, nonsmoking male volunteers were studied. In a first study (n = 7), DDAVP and placebo were administered as randomized single-blind stepwise intrabrachial artery infusions (0.7, 7.0, and 70 ng/min). In a another subset of subjects (n = 4), a constant-rate DDAVP infusion of 70 ng/min was administered for 20 minutes in the brachial artery of the nondominant arm with the dominant arm as control. To rule out that the observed t-PA release was flow-dependent, 4 additional subjects received stepwise intra-arterial infusions of both DDAVP (7.0, 21, and 70 ng/min) and sodium nitroprusside (SNP; 0.5, 2.5, and 10 micrograms/min). Brachial venoarterial plasma concentration gradients and forearm plasma flow were used to determine net release/uptake rates of t-PA and vWF. At baseline, the average net release rate of t-PA was 6.7 ng/min across the whole forearm vascular bed, whereas there was no detectable basal release of vWF. Stepwise infusion of DDAVP induced a massive regulated release of t-PA with a peak after 15 minutes on the highest dose-step (ANOVA; P < .0001). The average maximum net release rate was 178 ng/min, and the total amount of t-PA released was, on the average, 3,000 ng. The majority was released in its active form. Constant-rate DDAVP infusion again markedly increased t-PA release in the infusion arm but had no effect whatsoever in the control arm. In contrast, DDAVP did not stimulate a local release of vWF in either study. Central hemodynamics were unchanged during infusions despite a local vasodilatory response with DDAVP. Endothelium-independent flow stimulation by SNP did not elicit any local t-PA release. We conclude that DDAVP induces a massive acute flow-independent release of t-PA, without the simultaneous release of vWF, in the human forearm vascular bed. The lack of a t-PA response in the control arm, as well as the unaltered central hemodynamics with DDAVP, confirms that the observed regulated t-PA release is local and independent of central mechanisms.

Adult↗
PubMed1998

Continuous infusion of factor IX concentrate to induce immune tolerance in two patients with haemophilia B.

Two patients with haemophilia B and high-responding inhibitor to factor IX were subjected to immune tolerance induction according to the Malmö protocol, including high dosage of factor IX, cyclophosphamide and intravenous gammaglobulin. In one of the patients the treatment was preceded by extracorporeal protein A adsorption. Both patients had previously been subjected to immune tolerance induction without success and as an attempt to improve the tolerance induction regimen and lower cost, factor IX was given as continuous infusion, with a dose of around 300 units per kg body weight daily for 3 weeks. The inhibitor level declined in one of the patients but tolerance was not achieved. In the second patient the inhibitor level remained high. Despite the failure of the treatment in these two cases, we propose that the constant antigen load provided by the continuous infusion of modern, safe, purified factor IX concentrate may theoretically be of greater benefit in immune tolerance induction than the varying load resulting from intermittent infusions. Larger study materials are needed to show if this is so.

Adolescent↗
PubMed1998

Anaphylactoid reactions and nephrotic syndrome--a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers.

Anaphylaxis/anaphylactoid reactions have recently been reported after few treatments with factor IX concentrates in patients with haemophilia B at the same time as inhibitors to factor IX were demonstrated. In some of these cases nephrotic syndrome has appeared during immune tolerance induction (ITI) with high doses of factor IX concentrates. Gene deletions seem to be associated with a high risk of developing antibodies to factor IX. This report presents two brothers with deletion of 1 bp in exon f of the factor IX gene. Both showed anaphylactoid reactions and they were desensitized using slow i.v. injections of factor IX. At the time of anaphylaxis, inhibitors of factor IX in a low titre could be demonstrated. The elder brother responded well after a short time on ITI and has no spontaneous bleedings on regular prophylaxis although in a somewhat higher dose than expected. On the other hand, in spite of comparable regimens, the younger brother has so far been resistant to ITI. Moreover, during treatment with extremely high doses of factor IX concentrate he developed nephrotic syndrome which only slowly subsided after treatment with corticosteroids and withdrawal of factor IX.

Anaphylaxis↗
PubMed1998

Port-A-Cath usage in children with haemophilia: experience of 53 cases.

Experience of the Port-A-Cath implantable venous access system in 53 children with severe or moderate haemophilia A or B from seven centres in five countries is reviewed. The cumulative duration of follow-up was 1578 months (median 30 months, range 1-114). Of the devices implanted, 70% (37/53) were used without complications (median follow-up 32 months; range 1-114) and the remaining 30% (16/53) were associated with various types of complication: infection, bacteraemia or septicaemia in 56% (9/16) of cases, i.e. a rate of 0.07 per follow-up year or 0.19 per 1000 patient days, or various technical complications occurring after a median of 32 months (range 4-75) of uncomplicated use in the remaining 44% (7/16). Of the patients with inhibitors, 64% (7/11) manifested complications. Both doctors and parents considered that the Port-A-Cath device can be used with an acceptable frequency and severity of complications, and that it enables regular prophylactic or on-demand home treatment of children with haemophilia to be begun at an early age.

Catheterization, Central Venous↗
PubMed1998

Three novel PROC gene lesions causing protein C deficiency.

Missense mutations, three of them novel (Asn210-->Val, Asn248-->Ile, Ala355-->Val), were found in the protein C (PROC) genes of 7 patients with inherited protein C deficiency associated with venous thrombosis. Comparison with the phenotypic effects of mutations in the analogous residues of factor IX causing haemophilia B and the use of molecular modelling has provided explanations as to how these lesions might alter either the structure, function or secretion of the protein C molecules encoded.

DNA Mutational Analysis↗
PubMed1998

The influence of a serine protease inhibitor, nafamostat mesilate, on plasma coagulation, and platelet activation during experimental Extracorporeal Life Support (ECLS).

INTRODUCTION: During extracorporeal circulation the contact between blood and the artificial surface of the circuit induces several changes in the hemostatic system. The objective of the present study was to assess the effect of a serine protease inhibitor--Nafamostat mesilate (FUT-175)--on coagulation and on platelets during experimental extracorporeal circulation. METHODS: Two identical Extra Corporeal Life Support (ECLS) circuits were primed with fresh, heparinized human blood and circulated for 24 h. FUT-175 was added to one of the paired circuits and the other was used as a control. The following FUT-175 concentrations were employed: (1) 7.1 mg/l/h, (2) 14.2 mg/l/h, (3) 14.2 mg/l/h + 85.5 mg given as an initial bolus, (4) 28.5 mg/l/h + 171 mg given as an initial bolus. Blood samples were collected from the circuits before the start of the perfusion and at 0.5, 1, 3, 12, and 24 h of perfusion, and analysed for platelet count, plasma betathromboglobulin (beta-TG), platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa expression, thrombin/antithrombin III complex (TAT), prothrombin fragment 1+2 (F1+2), fibrinogen, D-dimer, and plasminogen activator inhibitor 1 activity (PAI-1). RESULTS: Significantly higher platelet membrane GPIb expression and lower plasma beta-thromboglobulin levels were observed in the circuits holding FUT-175, suggesting a lower degree of platelet activation. Also, a reduced activation of the coagulation system was observed in the "FUT-circuits", as reflected by the levels of F1+2 and TAT, and the PAI-1 activity that was rapidly inactivated. CONCLUSION: FUT-175 reduces the activation of platelets and plasma coagulation in an in vitro ECLS model.

Anticoagulants↗
PubMed1997

Elevated fibrinogen levels decrease following treatment of acromegaly.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality from cardiovascular disease and from stroke in particular. Fibrinogen is an established risk factor for stroke and myocardial infarction and high levels of plasminogen activator inhibitor-1 (PAI-1) activity were predictive of a recurrent myocardial infarction. The aim of this study was to analyse fibrinogen and PAI-1 activity in patients with acromegaly before and after treatment. PATIENTS: Twenty patients with acromegaly were compared with healthy controls matched for sex (12 men, 8 women), age (mean 53 +/- 7 years), body mass index (mean 26.5 +/- 2.5 kg/m2) and smoking. Fibrinogen was also compared with a random population sample of men and women (n = 392), aged 25-64 years, from the WHO's MONICA Project, Göteborg, Sweden. RESULTS: The acromegalic patients had a higher lean body mass of 65 +/- 11 vs 59 +/- 11 kg (P < 0.05), lower body fat of 17 +/- 8 vs 25 +/- 10 kg (P < 0.01), higher plasma fibrinogen of 4.0 +/- 0.9 vs 2.4 +/- 0.5 g/l (P < 0.001) and plasma insulin of 15 +/- 14 vs 7 +/- 2 mU/l (P < 0.01), serum triglycerides of 1.5 +/- 0.5 vs 1.2 +/- 0.5 mmol/l (P < 0.05), as well as serum insulin-like growth factor-I (IGF-I) levels of 742 +/- 271 vs 168 +/- 51 micrograms/l (P < 0.001) compared with the matched controls. PAI-1 activity was similar, as was total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose and blood pressure for acromegalic patients compared with controls. All the acromegalic patients had higher fibrinogen levels (p < 0.001) than the population mean. Plasma fibrinogen correlated positively with serum IGF-I in acromegaly (r = 0.55, P < 0.05). Fibrinogen decreased to a mean value of 3.2 +/- 0.3 g/l on treatment. CONCLUSION: Acromegaly is associated with high fibrinogen levels which may be one explanation for the increased risk of cardiovascular events, and stroke in particular, in this disease. Fibrinogen levels decreased following treatment of acromegaly.

Acromegaly↗
PubMed1997

The effects of transdermal oestradiol and oral progestogens on haemostasis variables.

OBJECTIVE: To evaluate the effects of 1 g (1 mg oestradiol) transdermal oestradiol gel continuously combined with 10 mg medroxyprogesterone acetate orally 12 days either monthly or every third month on haemostasis variables. DESIGN: An open, parallel stratified study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: A total of 48 peri- and postmenopausal women less than 65 years of age participated in this study. Twenty-seven women, who had from 2 months to 3 years since their last period were included in group I. Twenty-one women, who were more than 3 years postmenopausal, comprised group II. MAIN OUTCOME MEASURES: The following parameters were determined: von Willebrand factor antigen, factor VII antigen, fibrinogen, antithrombin, protein C, protein S, plasminogen activator inhibitor activity, tissue plasminogen activator antigen, prothrombin fragment 1 + 2, thrombin-antithrombin complex and platelets. RESULTS: Both regimens decreased fibrinogen, factor VII antigen as well as antithrombin. CONCLUSIONS: These changes were mainly 'in an anti-thrombotic direction'. The overall impression is that the transdermally administered oestrogen in combination with an oral progestogen induced favourable, although slight changes in the haemostatic system. The possible influence of these changes on the risk of cardiovascular disease remains yet to be studied.

Administration, Cutaneous↗
PubMed1997

Recombinant, B-domain deleted factor VIII (r-VIII SQ): pharmacokinetics and initial safety aspects in hemophilia A patients.

The pharmacokinetics of a second-generation recombinant B-domain deleted factor VIII (FVIII) preparation (r-VIII SQ) were studied in 36 patients with severe hemophilia A. In contrast to full-length recombinant FVIII, no albumin needs to be added to stabilize the final formulation of this B-domain deleted FVIII preparation. The in vivo recovery and half-life of r-VIII SQ were similar to those of plasma-derived (pd) FVIII (mean half-life of r-VIII SQ, 11.7 h). The volume of distribution and clearance were slightly, but significantly, higher for r-VIII SQ than for pdFVIII (p < 0.05). Peak plasma levels of FVIII were consistently related to the administered dose of r-VIII SQ (r = 0.94, p < 0.0001). The pharmacokinetic profile of r-VIII SQ remained essentially unchanged in a dose range of 25-100 IU/kg body weight and could be reproduced after repeated doses. r-VIII SQ was well tolerated. In conclusion, deletion of the B-domain of FVIII does not influence its in vivo pharmacokinetics.

Adolescent↗
PubMed1997

Sympathoadrenal activation and muscarinic receptor stimulation induce acute release of tissue-type plasminogen activator but not von Willebrand factor across the human forearm.

We have previously shown that both mental stress and administration of the muscarinic receptor agonist methacholine induce an acute release of tissue-type plasminogen activator (t-PA) across the human forearm. There are data indicating that the regulated acute release of t-PA from the endothelium is closely interrelated with release of von Willebrand factor (vWF). The aim of the present study was to simultaneously determine basal and stimulated in vivo release rates of t-PA and vWF in an intact human muscle vascular bed. Eighteen healthy young males were studied at rest and during 10 min of mental stress (forced arithmetic). A subsample of ten subjects also received a step-wise i.a. infusion of methacholine (0.1-0.8-4.0 microg/min). Forearm blood flow was determined by venous occlusion plethysmography and interconverted to forearm plasma flow (FPF) using individual hematocrits. Net release/uptake rates of t-PA and vWF were calculated as the product of the arteriovenous concentration gradient and FPF. At rest there was a net release of both t-PA antigen and activity. In contrast, there was no significant local net release of vWF antigen across the forearm. Net release rates of t-PA roughly doubled in response to the stress test (0.4 to 0.8 and 0.2 to 0.5 ng x min(-1) x 100 ml(-1) for t-PA antigen and activity, respectively, p <0.05 for both). Local administration of methacholine induced a more than 10-fold increase in the net release rates of t-PA (0.6 to 9.6 and 0.3 to 6.6 ng x min(-1) x 100 ml(-1) at the highest dose step for antigen and activity respectively, p <0.01 for both). In contrast, neither mental stress nor local administration of methacholine induced a significant net release of vWF antigen across the forearm. The results demonstrate that the processes of acute release of t-PA and vWF are not necessarily linked in vivo in man.

Adrenal Glands↗