M. Mowinckel - Academia.edu (original) (raw)

Papers by M. Mowinckel

Research paper thumbnail of OC 07.5 Modeling and Correcting FVII Deficiency using Human Stem Cell-Derived Hepatic Organoids

Research and Practice in Thrombosis and Haemostasis

Research paper thumbnail of The performance of STA-Liatest D-dimer assay in out-patients with suspected pulmonary embolism

British Journal of Haematology, 2006

Plasma d-dimers are cross-linked fibrin derivatives produced when fibrin is degraded by plasmin. ... more Plasma d-dimers are cross-linked fibrin derivatives produced when fibrin is degraded by plasmin. Elevated levels of d-dimer are found in conditions that lead to the activation of coagulation and fibrin formation (Gaffney et al, 1988), e.g. patients with acute thromboembolism, but also in any other condition associated with fibrin formation, such as cancer, pregnancy, surgery, and inflammatory disease. In general, d-dimer testing has high sensitivity, but poor specificity to detect venous thromboembolism (VTE). Several d-dimer assays are commercially available. However, these d-dimer assays differ with regard to the specificity of antibodies and the methodology (Dempfle et al, 2001; Gardiner et al, 2005). As a result, different assays exhibit variable performance and test characteristics, and therefore test results of the various assays are not interchangeable (Anderson & Wells, 2000; van der Graff et al, 2000). Three d-dimer formats are presently available: enzymelinked immunosorbent assay (ELISA), whole blood agglutination assay, and latex agglutination assay. Those based on an ELISA exhibit the highest sensitivity (94-100%) to detect VTE, and are generally considered to be the gold standard for d-dimer testing (Perrier et al, 1999; Anderson & Wells, 2000; van der Graff et al, 2000; Dunn et al, 2002; Perrier et al, 2004). The whole blood agglutination tests have lower sensitivity (80%), but substantially higher specificity (90-95%) (van der Graff et al, 2000). Immuno-turbidimetric assays have sensitivities (90-100%) and specificities (30-50%) approximate to that of the ELISA-based tests (Perrier

Research paper thumbnail of Effect of Thrombopoietin Receptor Agonists (Tpo-Ras) on Endothelial Cells and Neutrophil Extracellular Trap (Net) Formation in Immune Thrombocytopenia (Itp)

Research paper thumbnail of Antiphospholipid antibodies are associated with low levels of complement C3 and C4 in patients with systemic lupus erythematosus

Scandinavian Journal of Immunology, 2016

Complement activation and low complement levels are common in systemic lupus erythematosus (SLE).... more Complement activation and low complement levels are common in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are found in about 30‐40% of patients with SLE. This study aimed to investigate the association between aPL and complement levels in patients with SLE. Serum samples were collected from 269 patients with SLE enrolled in the Norwegian Systemic Connective Tissue and Vasculitis Registry (NOSVAR) during 2003‐2009, and from 353 controls. All samples were analysed for anti‐β2 glycoprotein 1 (anti‐β2GP1) and anticardiolipin antibodies (aCL), C‐reactive protein (CRP) and complement components C3 and C4. Median CRP level was significantly higher in cases than in controls (2.06 versus 0.90 mg/l; P < 0.0001). No significant difference in CRP was found between SLE patients with or without aPL (2.09 versus 1.89; P = 0.665). Median C3 levels were similar in cases (1.03 g/l) and controls (1.00 g/l), whereas median C4 levels were 0.16 g/l in cases versus. 0.19 in controls (P < 0.0001). However, aPL‐positive SLE patients had significantly lower median C3 levels (0.92 versus. 1.07 g/l; P = 0.001) and C4 levels (0.11 versus 0.16 g/l; P < 0.0001) compared to aPL‐negative patients. Lower C3 and C4 values in aPL‐positive SLE patients may reflect a higher consumption of C3 and C4 due to more pronounced complement activation in aPL‐positive SLE patients compared to SLE patients without aPL.

Research paper thumbnail of 0.08b Reduced sensitivity to activated protein C in the absence of the factor V Leiden polymorphism is a risk factor for pregnancy related venous thrombosis

Thrombosis Research, 2011

Background/Aims: The long-term outcome of pregnancy related VT is not known. The purpose of this ... more Background/Aims: The long-term outcome of pregnancy related VT is not known. The purpose of this study was to assess long-term consequences of pregnancy related VT on the frequency of PTS and to identify predictors for PTS in this population. Materials and Methods: 531 women with a validated diagnosis of pregnancy related VT during 1990 through 2003 and 1092 controls matched for time of delivery were invited to further investigations in 2006. Total 313 women with their first lifetime VT and 353 controls answered a comprehensive questionnaire that included self-reported Villalta score. 15 patients and 4 controls had missing Villalta scores, 24 had VT in other location than deep veins or lungs, and were excluded from analyses. 204 patients had suffered DVT in the leg and 70 PE. The control group consisted of 349 women naive for VT at the time of index pregnancy. Results: 44% of cases with DVT in the lower extremity had Villalta score ≥5, which is suggestive of PTS. 8% of cases had Villalta score ≥15 (severe PTS). Proximal thrombosis was a strong predictor for PTS, but only when the DVT was postpartum. Regular smoking, age above 33 years at event, and para ≥1, but not BMI, were the other independent predictors for PTS. Conclusions: Three to 16 years after a diagnosis of pregnancy-related DVT in the leg, almost half the patients reported Villalta score ≥5 consistent with any grade of PTS. Proximal thrombosis when postnatal was the most important predictor for the development of PTS.

Research paper thumbnail of P57 Differential impact of conventional and low dose oral hormone therapy (HT), tibolone and raloxifene on sex hormone binding globulin (SHBG)

Thrombosis Research, 2009

Research paper thumbnail of Reduced peak, but no diurnal variation, in thrombin generation upon melatonin supplementation in tetraplegia

Thrombosis and Haemostasis, 2015

Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis... more Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005) peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin.

Research paper thumbnail of The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial

Thrombosis and haemostasis, 2001

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous ... more In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. ...

Research paper thumbnail of Circadian rhythms of hemostatic factors in tetraplegia: a double-blind, randomized, placebo-controlled cross-over study of melatonin

Spinal Cord, 2015

Study design:This is a double-blind, randomized, placebo-controlled cross-over study of melatonin... more Study design:This is a double-blind, randomized, placebo-controlled cross-over study of melatonin in complete tetraplegia.Objectives:Tetraplegic patients have an increased risk of venous thrombosis despite prophylaxis, blunted variations in melatonin and altered circadian variation of several hemostatic markers. To examine whether melatonin could modify the regulation of hemostasis, we measured plasma melatonin and several markers of hemostasis in tetraplegic subjects with or without melatonin supplement.Setting:The study was conducted in the Section for Spinal Cord Injury, Sunnaas Hospital, Nesoddtangen, Norway.Methods:Six subjects with long-standing complete tetraplegia were included in this cross-over study with 2 mg of melatonin or placebo given 4 days before sampling. We also included six able-bodied men without any intervention. Plasma samples were then collected frequently during a 24-h awake/sleep cycle. The plasma concentrations of melatonin and the various markers were analyzed using linear mixed models.Results:The 24-h profiles of prothrombin fragment 1+2 and von Willebrand factor, but not D-dimer, activated FVII, tissue factor pathway inhibitor and plasminogen activator inhibitor type 1, differed (P&lt;0.05) between tetraplegic patients and able-bodied subjects. The absolute plasma concentration of activated FVII was higher (P&lt;0.05) among the able-bodied compared with the tetraplegic groups. Supplementation of melatonin had no impact on these findings.Conclusions:We found differences in circadian variation of several hemostatic markers between able-bodied and tetraplegics. These differences were apparently unrelated to fluctuations in the melatonin concentrations, suggesting little or no role of melatonin in the regulation of hemostasis in tetraplegia.Sponsorship:Financial support was provided from the Throne Holst Foundation.Spinal Cord advance online publication, 3 February 2015; doi:10.1038/sc.2014.243.

Research paper thumbnail of PO-69 Activated protein C (APC) resistance in hematological malignancies

Thrombosis Research, 2007

Research paper thumbnail of Thrombin-inhibitor complexes in the blood during and after delivery

Thrombosis Research, 1996

Activation of coagulation leads to generation of thrombin which in turn is inactivated by the for... more Activation of coagulation leads to generation of thrombin which in turn is inactivated by the formation of thrombin-antithrombin (TAT) complexes, and thrombin-heparin cofactor complexes (T-HCII). These complexes were measured in plasma by ELISA methods, During normal delivery, the median TAT level in ten women increased from 4.1 to 7.8 times the median normal reference level. There was great individual variation, and levels 42 and 56 times normal median were found in two women shortly after normal delivery. The median T-HCII levels &eased only moderately from 2.3 to 3 1 times median normal reference. D-dimer values were elevated in 28 out of the 30 samples. In blood sampled 1-2 days after delivery, the median TAT level was 2.5 times the median normal reference. The median T-HCII level was now 5.6 times the median normal reference value. The values were stable during the first 4 days post par-turn, and there was little difference between those delivered vaginally or by Caesarean section (C-section). D-dimer values were above normal reference in all women, and higher in women delivered by C-section. In conclusion, increasing TAT levels during labour and delivery indicated generation of thrombin which was mainly inactivated by antithrombin. The T-HCII levels increased less during delivery. In the early post partum period, the T-HCII levels were relatively more increased than the TAT 1eveIs. These results suggest that intrav~c~arly generated thrombin is preferably inactivated by antit~ombin, even in parturient women. In the post partum period, formation of T-HCII complexes was more evident, possibly reflecting extravascular inactivation of thrombin. Key words: Thrombin, antithrombin, heparin cofactor II, dermatan sulfate, delivery, post partum period. 109 710 THRO~B~N-INHIBITOR COMPLEXES Vol. 82, No. 2 2. "After delivery." Samples were drawn 1 -2 days after delivery in four groups of women. Normal vaginal delivery (n=lO). Vaginal delivery with forceps or vacuum extractor (n=9). Delivery by C-section (n=13). Vaginal delivery of women with pathology in the pregnancy Vol. 82, No. 2 THRO~BIN-INHIBITOR COMPLEXES 111 112

Research paper thumbnail of 30 Differential effects of conventional and low dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

Thrombosis Research, 2007

Research paper thumbnail of 27 Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis

Thrombosis Research, 2007

Research paper thumbnail of Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis

Thrombosis Research, 2007

We have recently reported that different hormone regimens given to healthy post-menopausal women ... more We have recently reported that different hormone regimens given to healthy post-menopausal women had markedly different effects on activation of coagulation. Low-dose hormone therapy (HT) and raloxifene, as opposed to conventional-dose HT and tibolone, were associated with no or minor activation of coagulation. The aim of this study was to elucidate the mechanism(s) for differences in coagulation activation by analysing clotting and fibrinolytic factors and coagulation inhibitors. Materials and methods: 202 healthy women were randomly assigned to receive treatment for 12 weeks with either low dose HTcontaining 1 mg 17 β-estradiol + 0.5 mg norethisterone acetate (NETA) (n = 50), conventional dose HT containing 2 mg 17 β-estradiol and 1 mg NETA (n = 50), 2.5 mg tibolone (n = 51), or 60 mg raloxifene (n = 51) in an open-label design.

Research paper thumbnail of Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants

Journal of Thrombosis and Haemostasis, 2007

To cite this article: Liestøl S, Sandset PM, Mowinckel M-C, Wisløff F. Activated protein C resist... more To cite this article: Liestøl S, Sandset PM, Mowinckel M-C, Wisløff F. Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost 2007; 5: 2204-10.

Research paper thumbnail of Increased acquired activated protein C resistance in unselected patients with hematological malignancies

Journal of Thrombosis and Haemostasis, 2008

Research paper thumbnail of Structure and anticoagulant activity of fucosylated glycosaminoglycan degraded by deaminative cleavage

Carbohydrate Polymers, 2013

Fucosylated glycosaminoglycans (FGs) are complex glycosaminoglycans that exhibit potent anticoagu... more Fucosylated glycosaminoglycans (FGs) are complex glycosaminoglycans that exhibit potent anticoagulant activity. To study the relationship between molecular size and biological activity, oligosaccharides with (2,5)-anhydro-D-talose units at new reducing ends were prepared by hydrazine deacetylation and nitrous acid depolymerization. The product chemical structures were analyzed by one- and two-dimensional NMR methods. Additionally, anticoagulant activities were evaluated by clotting assay and chromogenic substrate cleavage. The results demonstrated that under mild deacetylation and deaminative cleavage conditions, both products were relatively homogeneous and sulfated fucose branch types and sulfate substituents remained stable. These depolymerized FGs with different molecular sizes had potent intrinsic anticoagulant activities, which were similar to those that were obtained by free-radical depolymerization with similar molecular weights. Decreasing molecular weight may weaken activity but not significantly affect factor Xase and heparin cofactor II (HCII)-mediated thrombin inhibition.

Research paper thumbnail of Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial

British Journal of Haematology, 2001

Recent studies suggest that low-dose oral contraceptives may cause acquired resistance to activat... more Recent studies suggest that low-dose oral contraceptives may cause acquired resistance to activated protein C (APC). The aims of this study were to determine whether hormone replacement therapy (HRT) may also induce acquired APC resistance and to study the effects of APC resistance on the risk of recurrent thrombosis. The patients comprised 140 females with at least one previous venous thromboembolism (VTE), who were randomized to receive continuous treatment with 2 mg 17-b-oestradiol and 1 mg norethisterone acetate (n 71) or placebo (n 69). Normalized APC sensitivity ratios (nAPCsr) were calculated by measurement of the effect of APC on thrombin generation in plasma collected at baseline and after 3 months of treatment. Of the 140 women, 121 had plasma samples collected both at baseline and after 3 months.

Research paper thumbnail of Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus

Archives of Disease in Childhood - Fetal and Neonatal Edition, 1996

Aim-Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue pla... more Aim-Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator (tPA) as a method of clearing blood from the cerebrospinal fluid, and thus preventing permanent hydrocephalus. Methods-Twenty two preterm infants, aged 7 to 26 days, with progressive posthaemorrhagic ventricular dilatation (ventricular width > 4 mm over 97th centile) received one to five intraventricular bolus injections of 1.0 mg or 0. 5 mg tPA at intervals of one to seven days. Results-The mean cerebrospinal fluid concentration of tPA 24 hours after 1 mg was 1860 tgIml. The half life of tPA in cerebrospinal fluid was about 24 hours. Twenty one (95%) infants survived, 12 (55%) without shunt surgery. One infant had secondary intraventricular haemorrhage. Conclusion-Intraventricular tPA resulted in survival without a shunt for most of the infants, but with some risk. Failure may have been due to plasminogen deficiency, an inhibitor, or late intervention. (Arch Dis Child 1996;75:F20-F26)

Research paper thumbnail of Low levels of plasminogen in cerebrospinal fluid after intraventricular haemorrhage: a limiting factor for clot lysis?

Acta Paediatrica, 1995

The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neon... more The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neonates with no infection or haemorrhage and in infants who had suffered intraventricular haemorrhage (IVH). A chromogenic substrate method was used. The 16 reference infants had a median CSF plasminogen level of 0.74% of that of normal adult plasma (range 0.17-1.1%). The 11 infants with IVH had a median CSF plasminogen level of 0.55% of normal adult plasma (range 0-4.4%). Six of the IVH infants went on to develop permanent hydrocephalus despite the use of intraventricular plasminogen activators. Endogenous fibrinolysis and the potential for fibrinolytic treatment in the CSF may be limited by low concentrations of plasminogen, and administration of recombinant plasminogen may assist attempts to clear intraventricular blood clots.

Research paper thumbnail of OC 07.5 Modeling and Correcting FVII Deficiency using Human Stem Cell-Derived Hepatic Organoids

Research and Practice in Thrombosis and Haemostasis

Research paper thumbnail of The performance of STA-Liatest D-dimer assay in out-patients with suspected pulmonary embolism

British Journal of Haematology, 2006

Plasma d-dimers are cross-linked fibrin derivatives produced when fibrin is degraded by plasmin. ... more Plasma d-dimers are cross-linked fibrin derivatives produced when fibrin is degraded by plasmin. Elevated levels of d-dimer are found in conditions that lead to the activation of coagulation and fibrin formation (Gaffney et al, 1988), e.g. patients with acute thromboembolism, but also in any other condition associated with fibrin formation, such as cancer, pregnancy, surgery, and inflammatory disease. In general, d-dimer testing has high sensitivity, but poor specificity to detect venous thromboembolism (VTE). Several d-dimer assays are commercially available. However, these d-dimer assays differ with regard to the specificity of antibodies and the methodology (Dempfle et al, 2001; Gardiner et al, 2005). As a result, different assays exhibit variable performance and test characteristics, and therefore test results of the various assays are not interchangeable (Anderson & Wells, 2000; van der Graff et al, 2000). Three d-dimer formats are presently available: enzymelinked immunosorbent assay (ELISA), whole blood agglutination assay, and latex agglutination assay. Those based on an ELISA exhibit the highest sensitivity (94-100%) to detect VTE, and are generally considered to be the gold standard for d-dimer testing (Perrier et al, 1999; Anderson & Wells, 2000; van der Graff et al, 2000; Dunn et al, 2002; Perrier et al, 2004). The whole blood agglutination tests have lower sensitivity (80%), but substantially higher specificity (90-95%) (van der Graff et al, 2000). Immuno-turbidimetric assays have sensitivities (90-100%) and specificities (30-50%) approximate to that of the ELISA-based tests (Perrier

Research paper thumbnail of Effect of Thrombopoietin Receptor Agonists (Tpo-Ras) on Endothelial Cells and Neutrophil Extracellular Trap (Net) Formation in Immune Thrombocytopenia (Itp)

Research paper thumbnail of Antiphospholipid antibodies are associated with low levels of complement C3 and C4 in patients with systemic lupus erythematosus

Scandinavian Journal of Immunology, 2016

Complement activation and low complement levels are common in systemic lupus erythematosus (SLE).... more Complement activation and low complement levels are common in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are found in about 30‐40% of patients with SLE. This study aimed to investigate the association between aPL and complement levels in patients with SLE. Serum samples were collected from 269 patients with SLE enrolled in the Norwegian Systemic Connective Tissue and Vasculitis Registry (NOSVAR) during 2003‐2009, and from 353 controls. All samples were analysed for anti‐β2 glycoprotein 1 (anti‐β2GP1) and anticardiolipin antibodies (aCL), C‐reactive protein (CRP) and complement components C3 and C4. Median CRP level was significantly higher in cases than in controls (2.06 versus 0.90 mg/l; P < 0.0001). No significant difference in CRP was found between SLE patients with or without aPL (2.09 versus 1.89; P = 0.665). Median C3 levels were similar in cases (1.03 g/l) and controls (1.00 g/l), whereas median C4 levels were 0.16 g/l in cases versus. 0.19 in controls (P < 0.0001). However, aPL‐positive SLE patients had significantly lower median C3 levels (0.92 versus. 1.07 g/l; P = 0.001) and C4 levels (0.11 versus 0.16 g/l; P < 0.0001) compared to aPL‐negative patients. Lower C3 and C4 values in aPL‐positive SLE patients may reflect a higher consumption of C3 and C4 due to more pronounced complement activation in aPL‐positive SLE patients compared to SLE patients without aPL.

Research paper thumbnail of 0.08b Reduced sensitivity to activated protein C in the absence of the factor V Leiden polymorphism is a risk factor for pregnancy related venous thrombosis

Thrombosis Research, 2011

Background/Aims: The long-term outcome of pregnancy related VT is not known. The purpose of this ... more Background/Aims: The long-term outcome of pregnancy related VT is not known. The purpose of this study was to assess long-term consequences of pregnancy related VT on the frequency of PTS and to identify predictors for PTS in this population. Materials and Methods: 531 women with a validated diagnosis of pregnancy related VT during 1990 through 2003 and 1092 controls matched for time of delivery were invited to further investigations in 2006. Total 313 women with their first lifetime VT and 353 controls answered a comprehensive questionnaire that included self-reported Villalta score. 15 patients and 4 controls had missing Villalta scores, 24 had VT in other location than deep veins or lungs, and were excluded from analyses. 204 patients had suffered DVT in the leg and 70 PE. The control group consisted of 349 women naive for VT at the time of index pregnancy. Results: 44% of cases with DVT in the lower extremity had Villalta score ≥5, which is suggestive of PTS. 8% of cases had Villalta score ≥15 (severe PTS). Proximal thrombosis was a strong predictor for PTS, but only when the DVT was postpartum. Regular smoking, age above 33 years at event, and para ≥1, but not BMI, were the other independent predictors for PTS. Conclusions: Three to 16 years after a diagnosis of pregnancy-related DVT in the leg, almost half the patients reported Villalta score ≥5 consistent with any grade of PTS. Proximal thrombosis when postnatal was the most important predictor for the development of PTS.

Research paper thumbnail of P57 Differential impact of conventional and low dose oral hormone therapy (HT), tibolone and raloxifene on sex hormone binding globulin (SHBG)

Thrombosis Research, 2009

Research paper thumbnail of Reduced peak, but no diurnal variation, in thrombin generation upon melatonin supplementation in tetraplegia

Thrombosis and Haemostasis, 2015

Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis... more Tetraplegic patients have increased risk of venous thrombosis despite anti-thrombotic prophylaxis. Moreover, they have blunted plasma variations in melatonin and altered diurnal variation of several haemostatic markers, compared with able-bodied. However, whether healthy individuals and tetraplegic patients, with or without melatonin, display abnormalities in thrombin generation during a 24-hour (h) cycle, is unknown. We therefore used the Calibrated Automated Thrombogram (CAT) assay to examine diurnal variations and the possible role of melatonin in thrombin generation. Six men with long-standing complete tetraplegia were included in a randomised placebo-controlled cross-over study with melatonin supplementation (2 mg, 4 consecutive nights), whereas six healthy, able-bodied men served as controls. Ten plasma samples were collected frequently during a 24-h awake/sleep cycle. No significant diurnal variation of any of the measured CAT indices was detected in the three study groups. Whereas endogenous thrombin potential (ETP) was independent (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.05) of whether the tetraplegic men received melatonin or placebo, melatonin decreased (p = 0.005) peak values in tetraplegia compared with those given placebo. Able-bodied men had lower (p = 0.019) ETP and Lag-Time (p = 0.018) compared with tetraplegics receiving placebo. Neither the Time-to-Peak nor the Start-Tail was affected (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 0.05) by melatonin in tetraplegia. In conclusion, indices of thrombin generation are not subjected to diurnal variation in healthy able-bodied or tetraplegia, but peak thrombin generation is reduced in tetraplegic men receiving oral melatonin.

Research paper thumbnail of The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial

Thrombosis and haemostasis, 2001

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous ... more In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. ...

Research paper thumbnail of Circadian rhythms of hemostatic factors in tetraplegia: a double-blind, randomized, placebo-controlled cross-over study of melatonin

Spinal Cord, 2015

Study design:This is a double-blind, randomized, placebo-controlled cross-over study of melatonin... more Study design:This is a double-blind, randomized, placebo-controlled cross-over study of melatonin in complete tetraplegia.Objectives:Tetraplegic patients have an increased risk of venous thrombosis despite prophylaxis, blunted variations in melatonin and altered circadian variation of several hemostatic markers. To examine whether melatonin could modify the regulation of hemostasis, we measured plasma melatonin and several markers of hemostasis in tetraplegic subjects with or without melatonin supplement.Setting:The study was conducted in the Section for Spinal Cord Injury, Sunnaas Hospital, Nesoddtangen, Norway.Methods:Six subjects with long-standing complete tetraplegia were included in this cross-over study with 2 mg of melatonin or placebo given 4 days before sampling. We also included six able-bodied men without any intervention. Plasma samples were then collected frequently during a 24-h awake/sleep cycle. The plasma concentrations of melatonin and the various markers were analyzed using linear mixed models.Results:The 24-h profiles of prothrombin fragment 1+2 and von Willebrand factor, but not D-dimer, activated FVII, tissue factor pathway inhibitor and plasminogen activator inhibitor type 1, differed (P&lt;0.05) between tetraplegic patients and able-bodied subjects. The absolute plasma concentration of activated FVII was higher (P&lt;0.05) among the able-bodied compared with the tetraplegic groups. Supplementation of melatonin had no impact on these findings.Conclusions:We found differences in circadian variation of several hemostatic markers between able-bodied and tetraplegics. These differences were apparently unrelated to fluctuations in the melatonin concentrations, suggesting little or no role of melatonin in the regulation of hemostasis in tetraplegia.Sponsorship:Financial support was provided from the Throne Holst Foundation.Spinal Cord advance online publication, 3 February 2015; doi:10.1038/sc.2014.243.

Research paper thumbnail of PO-69 Activated protein C (APC) resistance in hematological malignancies

Thrombosis Research, 2007

Research paper thumbnail of Thrombin-inhibitor complexes in the blood during and after delivery

Thrombosis Research, 1996

Activation of coagulation leads to generation of thrombin which in turn is inactivated by the for... more Activation of coagulation leads to generation of thrombin which in turn is inactivated by the formation of thrombin-antithrombin (TAT) complexes, and thrombin-heparin cofactor complexes (T-HCII). These complexes were measured in plasma by ELISA methods, During normal delivery, the median TAT level in ten women increased from 4.1 to 7.8 times the median normal reference level. There was great individual variation, and levels 42 and 56 times normal median were found in two women shortly after normal delivery. The median T-HCII levels &eased only moderately from 2.3 to 3 1 times median normal reference. D-dimer values were elevated in 28 out of the 30 samples. In blood sampled 1-2 days after delivery, the median TAT level was 2.5 times the median normal reference. The median T-HCII level was now 5.6 times the median normal reference value. The values were stable during the first 4 days post par-turn, and there was little difference between those delivered vaginally or by Caesarean section (C-section). D-dimer values were above normal reference in all women, and higher in women delivered by C-section. In conclusion, increasing TAT levels during labour and delivery indicated generation of thrombin which was mainly inactivated by antithrombin. The T-HCII levels increased less during delivery. In the early post partum period, the T-HCII levels were relatively more increased than the TAT 1eveIs. These results suggest that intrav~c~arly generated thrombin is preferably inactivated by antit~ombin, even in parturient women. In the post partum period, formation of T-HCII complexes was more evident, possibly reflecting extravascular inactivation of thrombin. Key words: Thrombin, antithrombin, heparin cofactor II, dermatan sulfate, delivery, post partum period. 109 710 THRO~B~N-INHIBITOR COMPLEXES Vol. 82, No. 2 2. "After delivery." Samples were drawn 1 -2 days after delivery in four groups of women. Normal vaginal delivery (n=lO). Vaginal delivery with forceps or vacuum extractor (n=9). Delivery by C-section (n=13). Vaginal delivery of women with pathology in the pregnancy Vol. 82, No. 2 THRO~BIN-INHIBITOR COMPLEXES 111 112

Research paper thumbnail of 30 Differential effects of conventional and low dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

Thrombosis Research, 2007

Research paper thumbnail of 27 Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis

Thrombosis Research, 2007

Research paper thumbnail of Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis

Thrombosis Research, 2007

We have recently reported that different hormone regimens given to healthy post-menopausal women ... more We have recently reported that different hormone regimens given to healthy post-menopausal women had markedly different effects on activation of coagulation. Low-dose hormone therapy (HT) and raloxifene, as opposed to conventional-dose HT and tibolone, were associated with no or minor activation of coagulation. The aim of this study was to elucidate the mechanism(s) for differences in coagulation activation by analysing clotting and fibrinolytic factors and coagulation inhibitors. Materials and methods: 202 healthy women were randomly assigned to receive treatment for 12 weeks with either low dose HTcontaining 1 mg 17 β-estradiol + 0.5 mg norethisterone acetate (NETA) (n = 50), conventional dose HT containing 2 mg 17 β-estradiol and 1 mg NETA (n = 50), 2.5 mg tibolone (n = 51), or 60 mg raloxifene (n = 51) in an open-label design.

Research paper thumbnail of Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants

Journal of Thrombosis and Haemostasis, 2007

To cite this article: Liestøl S, Sandset PM, Mowinckel M-C, Wisløff F. Activated protein C resist... more To cite this article: Liestøl S, Sandset PM, Mowinckel M-C, Wisløff F. Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost 2007; 5: 2204-10.

Research paper thumbnail of Increased acquired activated protein C resistance in unselected patients with hematological malignancies

Journal of Thrombosis and Haemostasis, 2008

Research paper thumbnail of Structure and anticoagulant activity of fucosylated glycosaminoglycan degraded by deaminative cleavage

Carbohydrate Polymers, 2013

Fucosylated glycosaminoglycans (FGs) are complex glycosaminoglycans that exhibit potent anticoagu... more Fucosylated glycosaminoglycans (FGs) are complex glycosaminoglycans that exhibit potent anticoagulant activity. To study the relationship between molecular size and biological activity, oligosaccharides with (2,5)-anhydro-D-talose units at new reducing ends were prepared by hydrazine deacetylation and nitrous acid depolymerization. The product chemical structures were analyzed by one- and two-dimensional NMR methods. Additionally, anticoagulant activities were evaluated by clotting assay and chromogenic substrate cleavage. The results demonstrated that under mild deacetylation and deaminative cleavage conditions, both products were relatively homogeneous and sulfated fucose branch types and sulfate substituents remained stable. These depolymerized FGs with different molecular sizes had potent intrinsic anticoagulant activities, which were similar to those that were obtained by free-radical depolymerization with similar molecular weights. Decreasing molecular weight may weaken activity but not significantly affect factor Xase and heparin cofactor II (HCII)-mediated thrombin inhibition.

Research paper thumbnail of Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial

British Journal of Haematology, 2001

Recent studies suggest that low-dose oral contraceptives may cause acquired resistance to activat... more Recent studies suggest that low-dose oral contraceptives may cause acquired resistance to activated protein C (APC). The aims of this study were to determine whether hormone replacement therapy (HRT) may also induce acquired APC resistance and to study the effects of APC resistance on the risk of recurrent thrombosis. The patients comprised 140 females with at least one previous venous thromboembolism (VTE), who were randomized to receive continuous treatment with 2 mg 17-b-oestradiol and 1 mg norethisterone acetate (n 71) or placebo (n 69). Normalized APC sensitivity ratios (nAPCsr) were calculated by measurement of the effect of APC on thrombin generation in plasma collected at baseline and after 3 months of treatment. Of the 140 women, 121 had plasma samples collected both at baseline and after 3 months.

Research paper thumbnail of Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus

Archives of Disease in Childhood - Fetal and Neonatal Edition, 1996

Aim-Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue pla... more Aim-Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator (tPA) as a method of clearing blood from the cerebrospinal fluid, and thus preventing permanent hydrocephalus. Methods-Twenty two preterm infants, aged 7 to 26 days, with progressive posthaemorrhagic ventricular dilatation (ventricular width > 4 mm over 97th centile) received one to five intraventricular bolus injections of 1.0 mg or 0. 5 mg tPA at intervals of one to seven days. Results-The mean cerebrospinal fluid concentration of tPA 24 hours after 1 mg was 1860 tgIml. The half life of tPA in cerebrospinal fluid was about 24 hours. Twenty one (95%) infants survived, 12 (55%) without shunt surgery. One infant had secondary intraventricular haemorrhage. Conclusion-Intraventricular tPA resulted in survival without a shunt for most of the infants, but with some risk. Failure may have been due to plasminogen deficiency, an inhibitor, or late intervention. (Arch Dis Child 1996;75:F20-F26)

Research paper thumbnail of Low levels of plasminogen in cerebrospinal fluid after intraventricular haemorrhage: a limiting factor for clot lysis?

Acta Paediatrica, 1995

The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neon... more The aim of this study was to measure plasminogen in the cerebrospinal fluid (CSF) of control neonates with no infection or haemorrhage and in infants who had suffered intraventricular haemorrhage (IVH). A chromogenic substrate method was used. The 16 reference infants had a median CSF plasminogen level of 0.74% of that of normal adult plasma (range 0.17-1.1%). The 11 infants with IVH had a median CSF plasminogen level of 0.55% of normal adult plasma (range 0-4.4%). Six of the IVH infants went on to develop permanent hydrocephalus despite the use of intraventricular plasminogen activators. Endogenous fibrinolysis and the potential for fibrinolytic treatment in the CSF may be limited by low concentrations of plasminogen, and administration of recombinant plasminogen may assist attempts to clear intraventricular blood clots.