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Biomedical subjects

E Berntorp

Publications and source records attributed to E Berntorp.

At least 55 records · Page 3Linked to original sources
PubMed2001

Clinical spectrum of hepatitis C-related liver disease and response to treatment with interferon and ribavirin in haemophilia or von Willebrand disease.

Our aim was to evaluate the severity of liver disease resulting from chronic hepatitis C in haemophilia or von Willebrand disease and the efficacy of 6 months treatment with interferon alpha and ribavirin. Fifty-five liver biopsies were performed in 43 patients without any bleeding complications, as seen with ultrasound immediately after the biopsy and 48 h thereafter. Histological changes were mild, with low scores for both inflammation and fibrosis, in spite of long exposure to blood products (mean 27 years). Two patients had compensated cirrhosis. Thirty-five out of 39 included patients completed study treatment. Hepatitis C virus (HCV)-RNA was negative in 77% (30/39) of patients at the end of treatment, and 36% (14/39) achieved a complete sustained response at follow-up 6 months after treatment. Treatment failure was more frequent in patients with virus genotype 1 compared with non-1 (P = 0.0003). The response rate correlated well with that of non-haemophilic patients. In summary: (1) liver biopsy was safe with our regimen; (2) liver disease in our patients was usually mild and had a slow progress; (3) only HCV genotype 1 predicted treatment failure; (4) our treatment results agreed with those from non-haemophilic patients.

Adolescent↗
PubMed2001

Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis.

The aims of this study were to investigate possible age-related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4-56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer-simulated from the single-dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half-life of FIX:C showed no correlation with age, while in vivo recovery (in U dL(-1) per U kg(-1) given) tended to increase. Computer-predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg(-1)) and, conversely, doses (in U kg(-1)) needed to maintain a 1-U dL(-1) trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1-U dL(-1) trough level can normally be maintained by dosing every 2-3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.

Adolescent↗
PubMed2001

Immune tolerance induction: recombinant vs. human-derived product.

The ultimate goal in the treatment of high-responding inhibitors in congenital haemophilia is to induce immune tolerance (IT). Since the advent of highly purified factor VIII products, especially recombinant ones, the issue has been raised of whether the type of product has an impact on treatment success. It is clear that IT induction is possible to achieve with both recombinant products and human-derived products, but there is a lack of comparative studies. Different theoretical aspects indicate that human-derived concentrate, especially of low purity, and with a high content of von Willebrand factor, may have a better tolerizing effect.

Blood Coagulation Factors↗
PubMed2001

The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.

Chi-Square Distribution↗
PubMed2001

An approach to study the viral safety of plasma-derived products in previously treated, non-infected patients.

Using the polymerase chain reaction (PCR), we designed a study concept to evaluate the safety of plasma derivatives in previously treated patients who are non-infected by the specific viruses studied. Several product lots can be studied in a single patient, with a study period for each lot of 3 months. In the present study 19 patients were included for treatment with Baxter Hyland Immuno's PCR-screened factor VIII concentrate Immunate (n=7), factor IX concentrate Immunine (n=10), the by-passing agent FEIBA plus Immunine (n=1), and the protein C concentrate Ceprotin (n=1). PCR testing for hepatitis B, C or HIV genomic material in patient samples was done as well as serological testing. All patients remained negative for the tested markers. All seven Immunate patients completed three treatment periods with three different lots of the study drug. The median study period was 282 days and the median dose 115 000 units, with a median of 115 exposure days. Five of the 10 Immunine patients completed three treatment periods and four patients, two treatment periods. One Immunine patient was discontinued from the study for reasons unrelated to the study drug administration. The median study period was 305 days and the median total dose 82 200 units, with a median of 88 exposure days. Our study presents a new design to approach the evaluation of viral safety of new plasma derivatives in previously treated, non-infected patients (NIPs) and offers several advantages over the currently recommended studies using testing for serological markers of infection in previously untreated patients (PUPs).

Blood Coagulation Factors↗
PubMed2001

Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors.

OBJECTIVES: To evaluate effects of postmenopausal hormone replacement therapy (HRT) on von Willebrand factor, factor (F)VIII, factor (F)VII, fibrinogen, antithrombin (AT) III, prothrombin fragments 1 and 2, protein C, total and free protein S, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and resistance to activated protein C. DESIGN: Part 1: double blind randomized trial for 3 months. Part 2: open study for 9 months. SETTING: Department of Endocrinology, University Hospital, Malmö, Sweden. SUBJECTS: Fifty-one postmenopausal women with a history of amenorrhoea of at least 6 months and body mass index > or = 24 kg m-2 participated in part 1 and 46 participated in part 2. INTERVENTION: Randomization for placebo (n=24) or HRT (n=27). HRT was given as 2 mg oestradiol valerate for the first 3 months, with the addition of 10 mg medroxyprogesterone for 10 days every third month thereafter. MEASUREMENTS: At baseline and after 3 and 12 months. RESULTS: During 0-3 months in the HRT group, FVII increased (P < 0.01), whereas fibrinogen, AT III and total protein S all decreased (P < 0.001 for all). Changes in variables were expressed as Delta-values. After 3 months Delta-values differed between groups for fibrinogen (P < 0.05), AT III (P < 0.001), total protein S (P < 0.001), and PAI-1 (P < 0.001). During 0-12 months, fibrinogen, total protein S, tPA (P < 0.01 for all) and AT III (P < 0.05) decreased. In the control group, all variables were unchanged during the study, except for increases (P < 0.05) in total protein S after 3 and 12 months, and a decrease (P < 0.01) in FVIII after 12 months. After 12 months Delta-values differed for fibrinogen (P < 0.05), AT III (P < 0.05) and total protein S (P < 0.001). CONCLUSIONS: Unopposed oestrogen substitution was associated with both potentially beneficial effects, such as decreases in fibrinogen, and potentially thrombogenic effects such as decreasing AT III and protein S and increasing FVII. During prolonged follow-up and addition of progesterone, differences between groups concerning FVII were attenuated. These data suggest that effects of HRT upon coagulation are most pronounced early after institution of unopposed treatment.

Blood Coagulation↗
PubMed2001

Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia.

Haemophilia is a recessively inherited coagulation disorder, in which an X-chromosome mutation causes a deficiency of either coagulation factor VIII (FVIII) in haemophilia A, or factor IX (FIX) in haemophilia B. Intravenous administration of FVIII or FIX can be used to control a bleeding episode, to provide haemostasis during surgery or for long term prophylaxis of bleeding. In special cases, activated factor VII (FVIIa) may be used instead of FVIII or FIX. The aim of this work is to review the pharmacokinetics of FVIII, FIX and FVIIa and to give an outline of the use of pharmacokinetics to optimise the treatment of patients with haemophilia. The pharmacokinetics of FVIII are well characterised. The systemic clearance (CL) of FVIII is largely determined by the plasma level of von Willebrand factor (vWF), which protects FVIII from degradation. Typical average CL in patients with normal vWF levels is 3 ml/h/kg, with an apparent volume of distribution at steady state (Vss) that slightly exceeds the plasma volume of the patient, and the average elimination half-life (t1/2) is around 14 hours. There are still some discrepancies in the literature on the pharmacokinetics of FIX. The average CL of plasma-derived FIX seems to be 4 ml/h/kg, the Vss is 3 to 4 times the plasma volume and the elimination t1/2 often exceeds 30 hours. FVIIa has a much higher CL (average of 33 ml/h/kg), and a short terminal t1/2 (at 2 to 3 hours). The Vss is 2 to 3 times the plasma volume. Since the therapeutic levels of coagulation factors are well defined in most clinical situations, applied pharmacokinetics is an excellent tool to optimise therapy. Individual tailoring of administration in prophylaxis has been shown to considerably increase the cost effectiveness of the treatment. Dosage regimens for the treatment of bleeding episodes or for haemostasis during surgery are also designed using pharmacokinetic data, and the advantages of using a constant infusion instead of repeated bolus doses have been explored. The influence of antibodies (inhibitors) on the pharmacokinetics of FVIII and FIX is in part understood, and the doses of coagulation factor needed to treat a patient can tentatively be calculated from the antibody titre. In conclusion, therapeutic monitoring of coagulation factor levels and the use of clinical pharmacokinetics to aid therapy are well established in the treatment of patients with haemophilia.

Animals↗
PubMed2000

[Use the entire "analysis package" when investigating patients with venous thrombosis! Don't forget the relatives...].

During the last few years several genetic markers have been discovered that contribute to an increased risk of venous thrombosis. Patients who have several genetic markers are at a considerably higher risk of being affected than patients with only one marker. Recommendations are made as to which patients should be investigated, with appropriate laboratory analyses, when an increased risk of venous thrombosis is suspected. Most of the analyses can be done even if the patient is undergoing warfarin treatment.

Activated Protein C Resistance↗
PubMed2000

Correlation between different intensities of anti-vitamin K treatment and coagulation parameters.

In order to study the effect of different intensities of anti-vitamin K treatment on coagulation parameters, 23 patients with venous thromboembolism were given, after the initial treatment period, warfarin at doses giving an International Normalised Ratio of 1.3-2.0 for 4 weeks, and of 1.1-1.3 for another 4 weeks. Blood samples were taken at the end of each of these periods and 4 weeks after the end of warfarin treatment. The vitamin K-dependent coagulation factors VII, IX, and X, as well as the inhibitor protein C and its cofactor protein S, all showed a highly significant correlation with treatment intensity. This was to some extent also true for the coagulation activation markers, prothrombin fragment 1+2 and thrombin-antithrombin complex. Ratios of pro- and anticoagulant factors in some instances showed a decrease at therapeutical (International Normalised Ratio) levels, and also sometimes with reduced warfarin treatment intensity. Taken together, our results encourage further research addressing issues of varying treatment intensity with warfarin and alternative methods for monitoring of anti-vitamin K treatment.

Adult↗
PubMed2000

Molecular genetic analysis of severe protein C deficiency.

Severe protein C deficiency is a rare, early onset, venous thrombotic condition that is inherited as an autosomal recessive trait. The protein C (PROC) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro splicing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a good prognostic indicator of the age of onset or clinical severity of thrombotic symptoms. Other factors may thus complicate the relationship between genotype and clinical phenotype. Indeed, in two patients, the inheritance of either one or two Factor V Leiden alleles in addition to two PROC gene lesions could have served to precipitate the thrombotic events. No association was however apparent between clinical severity and the possession of a particular promoter polymorphism genotype. Despite the absence of a clear genotype-phenotype relationship, the molecular genetic analysis of the severe recessive form of protein C deficiency potentiates both the counselling of affected families and the provision of antenatal exclusion diagnosis.

Alternative Splicing↗
PubMed2000

Effect kinetics of desmopressin-induced platelet retention in healthy volunteers treated with aspirin or placebo.

Desmopressin is often used for haemostatic treatment in platelet dysfunction, but the effect kinetics of platelet responses and the mechanism of action are poorly known. This study aimed to determine the kinetics of platelet function responses induced by desmopressin in healthy volunteers treated with aspirin or placebo. Another aim was to correlate platelet responses to changes of von Willebrand factor (vWF) in plasma. We measured platelet function with a glass bead retention test, Ivy bleeding time, vWF:Ag and multimeric structure in plasma. Median baseline platelet retention was 12% (normal reference range 16-27%) during aspirin treatment and 18% during placebo. Median peak platelet retention after desmopressin was 33% during aspirin treatment and 34% during placebo. After about 3 h platelet function had returned to baseline. A second desmopressin dose after 3 h stimulated platelet retention to a similar extent as the first dose. There was no correlation between platelet responses and quantitative or qualitative changes of vWF in plasma. Platelet count did not change significantly. Thus, desmopressin's effect on platelet function lasts for about 3 h, but may be prolonged by a second dose immediately thereafter. These findings may have important clinical implications for patients with aspirin-induced platelet dysfunction undergoing surgery.

Adult↗
PubMed2000

The Malmö model for immune tolerance induction: impact of previous treatment on outcome.

Ten patients, who had been treated according to the Malmö model for immune tolerance induction (ITI), were analysed regarding treatment with clotting factors and chemotherapy during the time period between inhibitor detection and ITI. Of the patients who were successfully rendered tolerant (n=6) all but one had received treatment with FVIII, either alone (n=1), or combined with cyclophosphamide (n=4). Of the patients who did not become tolerant, three of four had received treatment with FVIII during the inhibitor period but only one with FVIII and chemotherapy. The total amount of treatment received was in general much lower in the group that did not become tolerant. In individual cases, it appeared very clear that the inhibitor level and anamnestic response was substantially reduced prior to the ITI using the Malmö treatment model. We conclude that treatment of acute bleeds during the inhibitor period may be of importance for ITI and that the different response rates published for different immune tolerance regimens most likely do not reflect the true response rate for the respective regimen.

Adult↗
PubMed2000

Recombinant FVIIa in the treatment of warfarin bleeding.

Patients receiving oral anticoagulant treatment have abnormally low levels of functional vitamin K-dependent coagulation proteins and consequently a clear risk of hemorrhagic complications. The incidence of hemorrhages has been reported to be around 0.6-0.7% per month at a therapeutic International Normalized Ratio (INR) and the incidence of major hemorrhagic events is substantial. Therefore, the ability to reverse the anti-vitamin K effect is of utmost importance, and if an immediate reversal is necessary, plasma or prothrombin complex concentrates are used. As plasma-derived products carry the risk of transmission of blood-borne viruses and also of thromboembolic complications, it is desirable to test new potential tools for oral anticoagulant reversal. Recombinant factor VIIa (FVIIa) has been tested in rats and humans treated with antivitamin K drugs with seemingly good effect on hemostasis and laboratory parameters. Even if more data are needed before any definite conclusions can be drawn, the outlook so far seems promising.

Anticoagulants↗
PubMed2000

NovoSeven in warfarin-treated patients.

Haemorrhages represent a major complication of treatment with vitamin K antagonists. In cases of severe bleeding, a prompt effect on the increased International Normalized Ratio value is vital to achieve haemostasis. As conventional treatment, that is plasma or plasma-derived concentrates, carries the risk of blood-borne virus transmission, new treatments are needed. An open, multicentre pilot trial is currently under way to determine the effect of recombinant activated factor VII (rFVIIa; NovoSeven) administered to patients experiencing a bleeding episode after receiving vitamin K antagonists. When rFVIIa was given to a patient with a warfarin-induced nosebleed, it had an immediate haemostatic effect and the International Normalized Ratio value virtually normalized.

Anticoagulants↗