Professor Per Morten Sandset was Vice-Rector of the University of Oslo for the period 2017–2025.
See also the following URL: http://ous-research.no/riim/
Publications
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Dybedal, Ingunn; Iversen, Nina; Jacobsen, Anne Flem; Bjørge, Line; Chaireti, Roza & Henriksson, Carola Elisabeth
[Show all 12 contributors for this article]
(2025).
Hereditary antithrombin deficiency and venous thrombosis in pregnancy–results of a retrospective multicenter study.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
23(9),
p. 2807–2818.
doi:
10.1016/j.jtha.2025.03.001.
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Background
The optimal anticoagulant regimen to prevent pregnancy-related venous thrombosis (VT) in women with antithrombin (AT) deficiency is unknown.
Objectives
This study aims to identify optimal doses of low-molecular-weight heparin (LMWH) to prevent pregnancy-related VT and to investigate if AT concentrate peripartum could reduce postpartum VT in women with AT deficiency.
Methods
This retrospective study includes 115 pregnancies in 57 women with subclassified AT deficiency treated with LMWH in Denmark, Norway, and Sweden (1991-2017).
Results
In pregnancies with high-risk AT deficiency, LMWH doses of <5000 IU/24 h, 5000 to 12 500 IU/24 h, and >12 500 IU/24 h revealed different VT risks (P = .02). The hazard ratios for VT were 1.0 (reference), 0.5 (95% CI [0.1, 2.3]), and 0 (95% CI [0, ∞]), correspondingly. Of the additional risk factors, only previous VT reached statistical significance. In 100 pregnancies with high-risk AT deficiency, 15 VTs occurred in contrast to none in the 15 pregnancies with low-/intermediate-risk AT deficiency. Six of the 12 antepartum VTs occurred before week 9. All had a prior VT, and 5 were hormone-associated. Of these 5, 1 had received a LMWH dose of 7500 IU/24 h and 3 had received a LMWH dose of 10 000 IU/24 h, respectively. AT concentrate, given peripartum in 66 of the 74 term pregnancies, resulted in 1 VT (1.5%). Without AT concentrate (8 pregnancies), 2 VTs occurred (25%; 95% CI [2, 61]). Peripartum hemorrhage (>1000 mL) occurred in 8 (11%) term pregnancies. Six had received therapeutic LMWH doses.
Conclusion
In high-risk AT deficiency pregnancies with previous VT, our results support prophylaxis with high prophylactic doses of LMWH from confirmed pregnancy. Hence, AT concentrate should be given peri-/postpartum
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Roman, Giacomo; Lauritzen, Knut Husø; Harrison, Sean Philip; Bhattacharya, Anindita; Andresen, Marianne Seierstad & Mowinckel, Marie-Christine
[Show all 16 contributors for this article]
(2025).
Ex vivo correction of severe coagulation Factor VII deficiency in patient-derived 3D liver organoids.
Haematologica.
ISSN 0390-6078.
doi:
10.3324/haematol.2025.288046.
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Coagulation factor (F) VII deficiency is the most frequent among the rare, inherited bleeding disorders and is predominantly caused by missense mutations in the F7 gene. The disease phenotype ranges from asymptomatic cases to extremely severe hemorrhagic forms, requiring prophylactic injections with plasma-derived or recombinant FVII concentrates.
In response, we have developed an autologous cell-based approach that corrects the disease-causing mutation in patient-derived induced pluripotent stem cells (iPSCs) and generates therapeutic, three-dimensional hepatic organoids (HOs). We report the CRISPRmediated correction of homozygous c.718G>C (p.G240R), a missense mutation associated with a severe, life-threatening bleeding phenotype. The HOs contain all liver cell types and exhibit key liver functions, including coagulation factor production. After correction, our data indicate that the patient-derived HOs secrete consistent amounts of functional FVII protein, resulting in improved thrombin generation times.
These results represent a significant milestone toward the establishment of an autologous cell-based therapy for patients with FVII- and other coagulation factor deficiencies.
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Svalastoga, Marte; Larsen, Trine-Lise; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Garresori, Herish
[Show all 15 contributors for this article]
(2025).
Effect of drug interactions with apixaban on clinical outcomes in cancer patients with venous thromboembolism.
Frontiers in Oncology.
15.
doi:
10.3389/fonc.2025.1520725.
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Introduction: It is unclear how drug-interaction with apixaban influences recurrent venous thromboembolism (VTE) and bleedings in cancer patients.
Methods: A post-hoc analysis of a single-arm interventional clinical trial on apixaban treatment of cancer patients with VTE to investigate whether the occurrence of any of the endpoints could be associated with the concurrent use of an interacting drug. Drugs taken by the patients during the trial period were categorized as either increasing bleeding risk, increasing thrombosis risk, both or neither.
Results: 298 patients were divided into groups based on whether they used no interacting drugs (controls, n=74), drugs increasing bleeding risk (n=55), drugs increasing thrombosis risk (n=8), or both (n=161). Odds ratios (OR) were calculated for recurrent VTE, clinically relevant non-major bleeding (CRNMB), and major bleeding during the 36-month follow-up period. Each patient took a median of 13 different drugs over the study period. 67% of the patients used drugs expected to both increase bleeding and thrombosis. The use of fluconazole appeared associated with CRNMB (OR 3.6, 95% confidence interval (CI) 0.99-13), but not with major bleeding (OR 0.56, 95% CI 0.06 - 4.8). Non-steroid anti-inflammatory drugs were not associated with CRNMB (OR 1.0, 95% CI 0.25-4.1) or major bleedings (OR 0.72, 95% CI 0.14 - 3.6). Use of antiplatelet therapy was not associated with CRNMB (OR 0.75, 95% CI, 0.22 - 2.58) or major bleeding (OR 0.2, 95% CI, 0.02-1.6). There were no major bleedings in 23 patients using aprepitant nor in the 10 patients taking macrolides. We found no association between drugs and recurrent VTE, except that there were no recurrent VTE in 19 patients using bevacizumab.
Conclusions: Despite the high number of drugs taken that could potentially interact with apixaban, none were found to clearly influence clinical outcomes, except that fluconazole may increase the risk of CRNMB.
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Tinholt, Mari; Tekpli, Xavier; Torland, Lilly Anne; Tahiri, Andliena; Geisler, Jürgen & Kristensen, Vessela N.
[Show all 8 contributors for this article]
(2024).
The breast cancer coagulome in the tumor microenvironment and its role in prognosis and treatment response to chemotherapy.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
22(5),
p. 1319–1335.
doi:
10.1016/j.jtha.2024.01.003.
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Background The procoagulant phenotype in cancer is linked to thrombosis, cancer progression, and immune response. A novel treatment that reduces the risk of both thrombosis and cancer progression without excess bleeding risk remains to be identified. Objectives Here, we aimed to broadly investigate the breast tumor coagulome and its relation to prognosis, treatment response to chemotherapy, and the tumor microenvironment. Methods Key coagulation-related genes (n = 35) were studied in a Norwegian cohort with tumor (n = 134) and normal (n = 189) tissue and in the Cancer Genome Atlas (n = 1052) data set. We performed gene set variation analysis in the Norwegian cohort, and in the Cancer Genome Atlas cohort, associations with the tumor microenvironment and prognosis were evaluated. Analyses were performed with cBioPortal, Estimation of Stromal and Immune cells in Malignant Tumors Using Expression Data, Tumor Immune Estimation Resource, the integrated repository portal for tumor–immune system interactions, Tumor Immune Single-cell Hub 2, and the receiver operating characteristic plotter. Six independent breast cancer cohorts were used to study the tumor coagulome and treatment response to chemotherapy. Results Twenty-two differentially expressed coagulation-related genes were identified in breast tumors. Several coagulome factors were correlated with tumor microenvironment characteristics and were expressed by nonmalignant cells in the tumor microenvironment. PLAT and F8 were independent predictors of better overall survival and progression-free survival, respectively. F12 and PLAU were predictors of worse progression-free survival. The PROCR-THBD-PLAT signature showed a promising predictive value (area under the curve, 0.75; 95% CI, 0.69-0.81; P = 3.6 × 10−17) for combination chemotherapy with fluorouracil, epirubicin, and cyclophosphamide. Conclusion The breast tumor coagulome showed potential in prediction of prognosis and chemotherapy response. Cells within the tumor microenvironment are sources of coagulome factors and may serve as therapeutic targets of coagulation factors.
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Shapiro, Amy D.; Nakar, Charles; Parker, Joseph M.; Thibaudeau, Karen; Crea, Roberto & Sandset, Per Morten
(2023).
Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1.
Haemophilia.
ISSN 1351-8216.
doi:
10.1111/hae.14849.
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Aim An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. Methods The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. Results The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2–5 days for 48 weeks and every 1–7 days for up to 124 weeks was well tolerated. Conclusion This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www.clinicaltrials.gov as #NCT02690714.
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Roman, Giacomo; Stavik, Benedicte; Lauritzen, Knut Husø; Sandset, Per Morten; Harrison, Sean & Sullivan, Gareth John
[Show all 7 contributors for this article]
(2023).
“iPSC-derived liver organoids and inherited bleeding disorders: Potential and future perspectives”.
Frontiers in Physiology.
14.
doi:
10.3389/fphys.2023.1094249.
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The bleeding phenotype of hereditary coagulation disorders is caused by the low or undetectable activity of the proteins involved in hemostasis, due to a broad spectrum of genetic alterations. Most of the affected coagulation factors are produced in the liver. Therefore, two-dimensional (2D) cultures of primary human hepatocytes and recombinant overexpression of the factors in non-human cell lines have been primarily used to mimic disease pathogenesis and as a model for innovative therapeutic strategies. However, neither human nor animal cells fully represent the hepatocellular biology and do not harbor the exact genetic background of the patient. As a result, the inability of the current in vitro models in recapitulating the in vivo situation has limited the studies of these inherited coagulation disorders. Induced Pluripotent Stem Cell (iPSC) technology offers a possible solution to overcome these limitations by reprogramming patient somatic cells into an embryonic-like pluripotent state, thus giving the possibility of generating an unlimited number of liver cells needed for modeling or therapeutic purposes. By combining this potential and the recent advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, it allows for the generation of autologous and gene corrected liver cells in the form of three-dimensional (3D) liver organoids. The organoids recapitulate cellular composition and organization of the liver, providing a more physiological model to study the biology of coagulation proteins and modeling hereditary coagulation disorders. This advanced methodology can pave the way for the development of cell-based therapeutic approaches to treat inherited coagulation disorders. In this review we will explore the use of liver organoids as a state-of-the-art methodology for modeling coagulation factors disorders and the possibilities of using organoid technology to treat the disease.
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Harrison, Sean Philip; Siller, Richard; Tanaka, Yoshiaki; Dugarte, Maria Eugenia Chollet; Morena-Barrio, María Eugenia de la & Xiang, Yangfei
[Show all 36 contributors for this article]
(2023).
Scalable production of tissue-like vascularized liver organoids from human PSCs.
Experimental and Molecular Medicine.
ISSN 1226-3613.
55,
p. 2005–2024.
doi:
10.1038/s12276-023-01074-1.
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Abstract The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology.
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Cui, Xueyan; Stavik, Benedicte; Thiede, Bernd; Sandset, Per Morten & Kanse, Sandip
(2022).
FSAP Protects against Histone-Mediated Increase in Endothelial Permeability In Vitro.
International Journal of Molecular Sciences.
ISSN 1661-6596.
23(22).
doi:
10.3390/ijms232213706.
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Factor-VII-activating protease (FSAP) is involved in the regulation of hemostasis and inflammation. Extracellular histones play a role in inflammation and the conversion of latent pro-FSAP into active FSAP. FSAP has been shown to regulate endothelial permeability, but the mechanisms are not clear. Here, we have investigated the effects of FSAP on endothelial permeability in vitro. A mixture of histones from calf thymus stimulated permeability, and the wild-type (WT) serine protease domain (SPD) of FSAP blocked this effect. WT–SPD–FSAP did not influence permeability on its own, nor that stimulated by thrombin or vascular endothelial growth factor (VEGF)-A165. Histones induced a large-scale rearrangement of the junction proteins VE-cadherin and zona occludens-1 from a clear junctional distribution to a diffuse pattern. The presence of WT–SPD–FSAP inhibited these changes. Permeability changes by histones were blocked by both TLR-2 and TLR4 blocking antibodies. Histones upregulated the expression of TLR-2, but not TLR-4, in HUVEC cells, and WT–SPD–FSAP abolished the upregulation of TLR-2 expression. An inactive variant, Marburg I (MI)–SPD–FSAP, did not have any of these effects. The inhibition of histone-mediated permeability may be an important function of FSAP with relevance to sepsis, trauma, and stroke and the need to be investigated further in in vivo experiments.
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Etscheid, Michael; Hanschmann, Kay Martin; Sandset, Per Morten & Kanse, Sandip
(2022).
Development of a Factor VII Activating Protease (FSAP) generation assay and its application in studying FSAP in venous thrombosis.
Thrombosis Research.
ISSN 0049-3848.
220,
p. 24–34.
doi:
10.1016/j.thromres.2022.09.027.
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Human genetic studies based on the Marburg I polymorphism in the factor VII activating protease (FSAP) encoding gene, analysis of FSAP activity in plasma and biochemical characterization of FSAP substrates indicate a possible causal link between FSAP activity and venous thrombosis. We hypothesized that a direct standardized assay to measure FSAP activity in plasma could provide convincing arguments for or against such a potential link. Using Ac-Pro-DTyr-Lys-Arg-AMC as a highly specific and sensitive substrate, histones as a trigger to activate pro-FSAP and plasma-purified active FSAP as a calibrator, we have developed a fluorogenic kinetic assay that reveals the FSAP generating potential in human plasma in real time. This assay is similar to the thrombin generation assay and allows analysis of lag phase, time to peak and velocity, as well as peak FSAP and the endogenous FSAP potential (EFP) of plasma samples. Carriers of the Marburg I polymorphism showed clearly delayed FSAP generation and lower peak FSAP and EFP level. There were no significant differences in all FSAP activity parameters between plasma from patients with a history of venous thrombosis and controls. When excluding Marburg I carriers, which were evenly distributed between groups, delayed FSAP generation significantly correlated with venous thrombosis in postmenopausal women. The novel FSAP activity assay is robust and easy to perform and will be a useful tool for analyzing plasma FSAP activity, also, in other pathophysiological conditions.
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Larsen, Trine-Lise; Garresori, Herish; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege & Jacobsen, Eva-Marie
[Show all 15 contributors for this article]
(2022).
Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients – 30 months follow-up.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
20(5),
p. 1166–1181.
doi:
10.1111/jth.15666.
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Background
There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial 6 months of full-dose treatment.
Methods
We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after 6 months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding.
Results
During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0%–11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1%–6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7%–12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41–1.6) at 2–6 months with full-dose apixaban, and 1.0% (95% CI 0.5–1.9) at 7–12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6–2.0) at 2–6 months, and 0.3% (95% CI 0.1–1.0) at 7–12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low.
Conclusion
Dose reduction of apixaban to 2.5 mg twice daily seems safe after 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.
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Skaga, Nils Oddvar; Holtan, Anders; Inger, Haug & Sandset, Per Morten
(2022).
KOAGULASJONSBOKS PÅ TRAUMESTUA I AKUTTMOTTAKET OSLO UNIVERSITETSSYKEHUS – ULLEVÅL (Versjon VI, 16.02.2022).
Kirurgen.
ISSN 1504-8888.
p. 21–25.
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Skaga, Nils Oddvar; Holtan, Anders; Haug, Inger & Sandset, Per Morten
(2022).
MEDIKAMENTBRUK VED KRITISK BLØDNING OG REVERSERING AV ANTITROMBOTISKE LEGEMIDLER – PROTOKOLL I TRAUMEMOTTAKET VED OUS ULLEVÅL.
Kirurgen.
ISSN 1504-8888.
p. 20–21.
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Garabet, Lamya Samir Noori; Eriksson, Anna Maria; Tjønnfjord, Eirik; Cui, Xueyan; Olsen, Magnus Kringstad & Jacobsen, Hege
[Show all 18 contributors for this article]
(2022).
SARS-CoV-2 vaccines are not associated with hypercoagulability in apparently healthy people.
Research and Practice in Thrombosis and Haemostasis (RPTH).
7(1).
doi:
10.1016/j.rpth.2022.100002.
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Background: SARS-CoV-2 adenoviral vector DNA vaccines have been linked to the rare but serious thrombotic postvaccine complication vaccine-induced immune thrombotic thrombocytopenia. This has raised concerns regarding the possibility of increased thrombotic risk after any SARS-CoV-2 vaccines. <p><p>Objectives: To investigate whether SARS-CoV-2 vaccines cause coagulation activation leading to a hypercoagulable state. Methods: This observational study included 567 health care personnel; 521 were recruited after the first dose of adenoviral vector ChAdOx1-S (Vaxzevria, AstraZeneca) vaccine and 46 were recruited prospectively before vaccination with a messenger RNA (mRNA) vaccine, either Spikevax (Moderna, n = 38) or Comirnaty (Pfizer-BioNTech, n = 8). In the mRNA group, samples were acquired before and 1 to 2 weeks after vaccination. In addition to the prevaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer levels, and free tissue factor pathway inhibitor (TFPI) levels were analyzed. <p>Results: No participant experienced thrombosis, vaccine-induced immune thrombotic thrombocytopenia, or thrombocytopenia (platelet count <100 × 10<sup>9</sup> /L) 1 week to 1 month postvaccination. There was no increase in thrombin generation, D-dimer level, or TFPI level in the ChAdOx1-S vaccine group compared with controls or after the mRNA vaccines compared with baseline values. Eleven of 513 (2.1%) participants vaccinated with ChAdOx1-S had anti-PF4/polyanion antibodies without a concomitant increase in thrombin generation. <p>Conclusion: In this study, SARS-CoV-2 vaccines were not associated with thrombosis, thrombocytopenia, increased thrombin generation, D-dimer levels, or TFPI levels compared with baseline or unvaccinated controls. These findings argue against the subclinical activation of coagulation post-COVID-19 vaccination.
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Morena-Barrio, Maria Eugenia de la; Suchon, Pierre; Jacobsen, Eva-Marie; Iversen, Nina; Miñano, Antonia & Morena-Barrio, Belén de la
[Show all 17 contributors for this article]
(2022).
Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays.
Blood.
ISSN 0006-4971.
140(2),
p. 140–151.
doi:
10.1182/blood.2021014708.
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Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional
methods. We have identified 2 new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in 4 unrelated thrombophilic patients with early and recurrent thrombosis that had normal
antithrombin activity. In one case, the mutation was identified by whole genome sequencing,
while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1
based on a single functional positive finding supporting deficiency. The 2 variants shared a
common functional defect, an impaired or null N-glycosylation of Asn224 according to a
eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities but
impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the
plasma for 1 hour at 41°C. Moreover, the b glycoform of the variants, lacking 2 N-glycans,
had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential
dominant–negative effect. These results explain the increased thrombin generation
observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon
have in impairing the efficacy of N-glycosylation. Our study shows new elements involved in the regulation of
N-glycosylation, a key posttranslational modification that, according to our results, affects folding, secretion, and
function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and
genetic tests to diagnose this severe thrombophilia.
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Andresen, Marianne Seierstad; Sletten, Marit; Sandset, Per Morten; Iversen, Nina; Stavik, Benedicte & Tinholt, Mari
(2021).
Coagulation Factor v (F5) is an Estrogen-Responsive Gene in Breast Cancer Cells.
Thrombosis and Haemostasis.
ISSN 0340-6245.
122(8),
p. 1288–1295.
doi:
10.1055/a-1707-2130.
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Engeseth, Marit; Enden, Tone Rønnaug; Sandset, Per Morten & Wik, Hilde Skuterud
(2021).
Predictors of long-term post-thrombotic syndrome following high proximal deep vein thrombosis: a cross-sectional study.
Thrombosis Journal.
19:3,
p. 1–7.
doi:
10.1186/s12959-020-00253-8.
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Background Post-thrombotic syndrome (PTS) is a frequent chronic complication of proximal deep vein thrombosis (DVT) of the lower limb, but predictors of PTS are not well established. We aimed to examine predictors of PTS in patients with long-term PTS following proximal DVT. Methods During 2006–09, 209 patients with a first time acute upper femoral or iliofemoral DVT were randomized to receive either additional catheter-directed thrombolysis or conventional therapy alone. In 2017, the 170 still-living participants were invited to participate in a cross-sectional follow-up study. In the absence of a gold standard diagnostic test, PTS was defined in line with clinical practice by four mandatory, predefined clinical criteria: 1. An objectively verified DVT; 2. Chronic complaints (> 1 month) in the DVT leg; 3. Complaints appeared after the DVT; and 4. An alternative diagnosis was unlikely. Possible predictors of PTS were identified with multivariate logistic regression. Results Eighty-eight patients (52%) were included 8–10 years following the index DVT, and 44 patients (50%) were diagnosed with PTS by the predefined clinical criteria. Younger age and higher baseline Villalta score were found to be independent predictors of PTS, i.e., OR 0.96 (95% CI, 0.93–0.99), and 1.23 (95% CI, 1.02–1.49), respectively. Lack of iliofemoral patency at six months follow-up was significant in the bivariate analysis, but did not prove to be significant after the multivariate adjustments. Conclusions In long-term follow up after high proximal DVT, younger age and higher Villalta score at DVT diagnosis were independent predictors of PTS.
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Delluc, Aurélien; Ghanima, Waleed; Kovacs, Michael J.; Shivakumar, Sudeep; Kahn, Susan R. & Sandset, Per Morten
[Show all 9 contributors for this article]
(2021).
Statins for venous event reduction in patients with venous thromboembolism: A multicenter randomized controlled pilot trial assessing feasibility.
Research and Practice in Thrombosis and Haemostasis (RPTH).
20(1),
p. 126–132.
doi:
10.1111/jth.15537.
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Andersen, Elisabeth; Dugarte, Maria Eugenia Chollet; Bernardi, Francesco; Branchini, Alessio; Baroni, Marcello & Mariani, Guglielmo
[Show all 12 contributors for this article]
(2021).
The factor vii variant p.A354v-p.p464hfs: Clinical versus intracellular and biochemical phenotypes induced by chemical chaperones.
Applied Sciences.
11(13).
doi:
10.3390/app11135762.
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(1) Background: Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. Patients with modest differences in FVII levels may display large differences in clinical severity. The variant p.A354V-p.P464Hfs is associated with reduced FVII antigen and activity. The aim of the study was to investigate the clinical manifestation of this variant and the underlying molecular mechanisms. (2) Methods: Analyses were conducted in 37 homozygous patients. The recombinant variant was produced in mammalian cells. (3) Results: We report a large variation in clinical phenotypes, which points out genetic and acquired components beyond F7 mutations as a source of variability. In contrast, patients displayed similarly reduced FVII plasma levels with antigen higher than its activity. Comparative analysis of the recombinant variant and of plasma samples from a subset of patients indicated the presence of an elongated variant with indistinguishable migration. Treatment of cells with the chemical chaperone 4-phenylbutyrate (4-PBA) improved the intracellular trafficking of the variant and increased its secretion to the conditioned medium up to 2-fold. However, the effect of 4-PBA on biological activity was marginal. (4) Conclusions: Chemical chaperones can be used as biochemical tools to study the intracellular fate of a trafficking-defective FVII variant.
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Bøhn, Siv Kjølsrud; Thune, Inger; Flote, Vidar Gordon; Frydenberg, Hanne; Bertheussen, Gro Falkener & Husøy, Anders
[Show all 12 contributors for this article]
(2021).
Effects of a One-Year Physical Activity Intervention on Markers of Hemostasis among Breast Cancer Survivors - A Randomized Controlled Trial.
TH Open.
5(1),
p. e14–e23.
doi:
10.1055/s-0040-1721782.
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Introduction: Physical activity may reduce the development of breast cancer. Whereas hypercoagulability has been linked to adverse outcomes in breast cancer patients, the effects of physical activity on their hemostatic factors are unknown. The study aimed to assess whether long-term (1 year) physical activity can affect hemostatic factors in breast cancer patients.
Methods: Fifty-five women (35–75 years) with invasive breast cancer stage I/II were randomized to a physical activity intervention (n = 29) lasting 1 year or to a control group (n = 26), and analyzed as intention to treat. Fibrinogen, factor VII antigen, tissue factor pathway inhibitor, and von Willebrand factor (VWF) antigen as well as prothrombin fragment 1 + 2, the endogenous thrombin potential and D-dimer, were measured in plasma before intervention (baseline), and then after 6 and 12 months.
Results: Maximal oxygen uptake (measure of cardiorespiratory fitness) decreased the first 6 months among the controls, but remained stable in the intervention group. We found no significant differences between the two study groups regarding any of the hemostatic factors, except a significantly higher increase in factor VII antigen in the intervention group. The effect of the intervention on VWF was, however, significantly affected by menopausal stage, and a significant effect of the intervention was found on VWF among postmenopausal women, even after adjustment for dietary intake.
Conclusion: Long-term physical activity had no effect on the majority of the hemostatic factors measured, but led to increased plasma concentrations of factor VII antigen and prevented an increase in VWF concentration after breast cancer treatment in postmenopausal women. The clinical impact of these findings for risk of vascular thrombosis warrants further studies.
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Cui, Xueyan; Tjønnfjord, Geir Erland; Kanse, Sandip; Dahm, Anders Erik A; Iversen, Nina & Myklebust, Christiane Filion
[Show all 12 contributors for this article]
(2021).
Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.
Scientific Reports.
11.
doi:
10.1038/s41598-021-84695-8.
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Abstract The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.
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Ihle-Hansen, Håkon; Hagberg, Guri; Sandset, Else Charlotte; Ihle-Hansen, Hege; Amundsen, Erik Koldberg & Sandset, Per Morten
[Show all 7 contributors for this article]
(2021).
Reversering av antikoagulerende legemidler ved hjerneblødning.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
141(14),
p. 1–6.
doi:
10.4045/tidsskr.21.0063.
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Antikoagulerende legemidler kan effektivt forebygge og behandle blodpropper, men gir samtidig økt risiko for hjerneblødning. Ved hjerneblødning anbefales rask reversering av den antikoagulerende effekten. Reverserende behandling må imidlertid velges ut ifra antikoagulasjonsmidlenes ulike virkningsmekanismer, og spesifikk antidot foretrekkes hvis tilgjengelig.
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Jacobsen, Anne Flem & Sandset, Per Morten
(2021).
Prior Thromboembolic Disease and Assisted Reproductive Therapy.
Seminars in Reproductive Medicine.
ISSN 1526-8004.
doi:
10.1055/s-0041-1732375.
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Abstract Assisted reproductive therapy (ART) increases the risk of venous thrombosis (VT) by 2- to 4-fold, whereas pregnancy increases the risk by 5- to 10-fold. Women with a history of VT undergoing ART are often suggested thromboprophylaxis. The literature is scarce and international guidelines are lacking. We made a review of the literature and base our suggestions primarily on expert opinions. We suggest women with a prior VT to use low-molecular-weight heparin as thromboprophylaxis starting from ovarian stimulation, throughout pregnancy, and 6 weeks postpartum. Assessment of VT risk should be done prior to ART. Adjustment of treatment to minimize the thrombotic risk, such as preventing ovarian hyperstimulation syndrome, single-embryo transfer, cryopreservation, and transfer of frozen embryos instead of fresh embryo in high-risk women, is suggested. Women with previous arterial thrombosis should continue aspirin during ART treatment, pregnancy, and postpartum.
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Wik, Hilde Skuterud; Kahn, Susan; Eriksson, Henry; Morrison, David; Ghanima, Waleed & Schulman, Sam
[Show all 7 contributors for this article]
(2021).
Post-thrombotic syndrome in patients with venous thromboembolism treated with dabigatran or warfarin: A long-term cross-sectional follow-up of RE-COVER study patients.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
p. 1–9.
doi:
10.1111/jth.15449.
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Background Studies suggest that the direct factor Xa inhibitor rivaroxaban compared to warfarin reduces the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT), but this has not been evaluated for oral direct thrombin inhibitors. Objectives To compare the long-term prevalence of PTS, recurrent venous thromboembolism (VTE), and health-related quality of life (HRQoL) in patients with acute DVT and/or pulmonary embolism (PE), randomized to treatment with dabigatran or warfarin in the phase III RE-COVER studies. Methods We conducted a cross-sectional follow-up study of patients randomized in Canada, Norway, and Sweden. PTS was assessed by the patient-reported Villalta scale (PRV) and HRQoL by EQ-5D and VEINES-QOL/Sym. Results We included 349 patients between December 2015 and November 2018; 166 were treated with dabigatran and 183 with warfarin. DVT (+/− PE) was index event in 255 patients, whereas 94 patients had PE only. Mean time from index event was 8.7 (standard deviation 1.4) years. PTS was diagnosed in 63% of patients with DVT and in 46% of patients with PE only, and did not differ between the treatment groups; the crude odds ratio (OR) for PTS in patients treated with dabigatran compared with warfarin was 1.1 (95% confidence interval [CI] 0.6–1.8) after DVT and 1.2 (95% CI 0.5–2.6) after PE only. The prevalence of recurrent VTE was 21% in both treatment groups. HRQoL scores did not differ between groups. Conclusion In this long-term cross-sectional study, the prevalence of PTS, recurrent VTE, and HRQoL were similar in patients treated with dabigatran and warfarin.
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Martin, Karlyn A.; Beyer-Westendorf, Jan; Davidson, Bruce L.; Huisman, Menno V.; Sandset, Per Morten & Moll, S.
(2021).
Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
19(8),
p. 1874–1882.
doi:
10.1111/jth.15358.
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Tinholt, Mari; Stavik, Benedicte; Tekpli, Xavier; Garred, Øystein; Borgen, Elin & Kristensen, Vessela N.
[Show all 9 contributors for this article]
(2020).
Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer.
Oncoimmunology.
ISSN 2162-4011.
9:e1824644(1),
p. 1–12.
doi:
10.1080/2162402X.2020.1824644.
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Background Factor (F) V is an essential cofactor in blood coagulation, however, F5 expression in breast tumors has also been linked to tumor aggressiveness and overall survival. The specific role of FV in breast cancer is yet unknown. We therefore aimed at dissecting the biological relevance of FV in breast cancer. Methods Gene expression data from a Scandinavian breast cancer cohort (n = 363) and the cancer genome atlas (TCGA) (n = 981) and 12 replication cohorts were used to search for F5 co-expressed genes, followed by gene ontology analysis. Pathological and bioinformatic tools were used to evaluate immune cell infiltration and tumor purity. T cell activation, proliferation and migration were studied in FV treated Jurkat T cells. Results F5 co-expressed genes were mainly associated with immune system processes and cell activation. Tumors with high expression of F5 were more infiltrated with both lymphoid (T cells, NK cells, and B cells) and myeloid cells (macrophages and dendritic cells), and F5 expression was negatively correlated with tumor purity (ρ = −0.32). Confirming a prognostic role, data from the Kaplan-Meier plotter showed that high F5 expression was associated with improved relapse-free survival. The strongest association was observed in basal-like breast cancer (HR = 0.55; 95% CI, 0.42–0.71). Exogenous FV did not substantially affect activation, proliferation or migration of human T cells. Conclusions F5 was identified as a novel marker of immune cell infiltration in breast cancer, and the prognostic role of F5 was verified. FV emerge as an interesting immunological biomarker with potential therapeutic relevance for the cancer-inflammation-thrombosis circuit.
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Godolphin, Peter J.; Bath, Philip M.; Partlett, Christopher; Berge, Eivind; Brown, Martin M & Eliasziw, Misha
[Show all 9 contributors for this article]
(2020).
Outcome assessment by central adjudicators in randomised stroke trials: Simulation of differential and non-differential misclassification.
European Stroke Journal.
ISSN 2396-9873.
5(2),
p. 174–183.
doi:
10.1177/2396987320910047.
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Introduction Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results. Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000–10,000), overall event rate (10%–50%) and treatment effect (0.67–0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level. Results For the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered. This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant. Discussion: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment. Conclusion: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary.
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Andresen, Marianne Seierstad; Stavik, Benedicte; Sletten, Marit; Tinholt, Mari; Sandset, Per Morten & Iversen, Nina
[Show all 7 contributors for this article]
(2020).
Indirect regulation of TFPI-2 expression by miR-494 in breast cancer cells.
Scientific Reports.
10:4036,
p. 1–10.
doi:
10.1038/s41598-020-61018-x.
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Abstract TFPI-2 has been shown to be involved in breast cancer pathogenesis by inhibiting extracellular matrix degradation, and low levels are associated with disease progression. As microRNA-494 (miR-494) protects against breast cancer progression, we investigated whether miR-494 is involved in the regulation of TFPI-2 in MCF-7 breast cancer cells. TFPI-2 mRNA and protein levels increased after transfection with miR-494 mimic, and TFPI-2 mRNA and miR-494 levels correlated positively in tumors from breast cancer patients. No specific binding sites for miR-494 in the 3′-untranslated region (UTR) of TFPI2 were identified; however, miR-494 was predicted in silico to bind 3′-UTR of the transcription factors AHR and ELF-1, which have potential binding sites in the TFPI2 promoter. ELF-1 mRNA was downregulated whereas AHR mRNA levels were upregulated after transfection with miR-494 mimic. Knockdown of ELF-1 and AHR increased and reduced TFPI-2 mRNA levels, respectively. Increased luciferase activity was seen when TFPI-2 promoter constructs containing the potential AHR or ELF-1 binding sites were co-transfected with miR-494 mimic. In conclusion, TFPI-2 mRNA levels were upregulated by miR-494 in MCF-7 breast cancer cells most likely by an indirect association where miR-494 targeted the transcription factors AHR and ELF-1. This association was supported in a breast cancer cohort.
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Thorsen, Lene; Haugnes, Hege Sagstuen; Fosså, Sophie Dorothea; Brydøy, Marianne; Tandstad, Torgrim & Wisløff, Torbjørn
[Show all 13 contributors for this article]
(2020).
Thromboembolic events after high-intensity training duringcisplatin-based chemotherapy for testicular cancer: Casereports and review of the literature.
International Journal of Cancer.
ISSN 0020-7136.
147(11),
p. 3189–3198.
doi:
10.1002/ijc.33151.
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The randomized “Testicular cancer and Aerobic and Strength Training trial” (TAST‐trial) aimed to evaluate the effect of high‐intensity interval training (HIIT) on cardiorespiratory fitness during cisplatin‐based chemotherapy (CBCT) for testicular cancer (TC). Here, we report on an unexpected high number of thromboembolic (TE) events among patients randomized to the intervention arm, and on a review of the literature on TE events in TC patients undergoing CBCT. Patients aged 18 to 60 years with a diagnosis of metastatic germ cell TC, planned for 3 to 4 CBCT cycles, were randomized to a 9 to 12 weeks exercise intervention, or to a single lifestyle counseling session. The exercise intervention included two weekly HIIT sessions, each with 2 to 4 intervals of 2 to 4 minutes at 85% to 95% of peak heart rate. The study was prematurely discontinued after inclusion of 19 of the planned 94 patients, with nine patients randomized to the intervention arm and 10 to the control arm. Three patients in the intervention arm developed TE complications; two with pulmonary embolism and one with myocardial infarction. All three patients had clinical stage IIA TC. No TE complications were observed among patients in the control arm. Our observations indicate that high‐intensity aerobic training during CBCT might increase the risk of TE events in TC patients, leading to premature closure of the TAST‐trial.
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Hannevik, Trine-Lise; Brekke, Jorunn; Enden, Tone Rønnaug; Frøen, Hege; Ahmed, Herish & Jacobsen, Eva-Marie
[Show all 15 contributors for this article]
(2020).
Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.
Thrombosis Research.
ISSN 0049-3848.
196,
p. 238–244.
doi:
10.1016/j.thromres.2020.08.042.
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Introduction: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. Materials and methods: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. Results: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1–6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8–7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3–11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5–12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1–6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3–16%). Conclusion: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.
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Andersen, Nina Gjerde; Mowinckel, Marie-Christine; Sunde, Kjetil; Sandset, Per Morten & Beitland, Sigrid
(2020).
Utility of coagulation analyses to assess thromboprophylaxis with dalteparin in intensive care unit patients.
Acta Anaesthesiologica Scandinavica.
ISSN 0001-5172.
p. 1–10.
doi:
10.1111/aas.13748.
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Background The aim of this study was to evaluate the utility of coagulation analyses to assess thromboprophylaxis with dalteparin in intensive care unit (ICU) patients. Methods Prospective observational study of ICU patients receiving dalteparin prophylaxis at Oslo University Hospital in Norway. Trough and peak antithrombin, protein C, anti‐factor Xa activity (aFXa), d‐dimer, thromboelastography, calibrated automated thrombogram and microparticles were analysed. Levels were compared in patients with and without venous thromboembolism (VTE), major bleeding, acute kidney injury (AKI) with use of renal replacement therapy (RRT) and variable dalteparin dose. Results Among 50 included patients (76% male, mean age 62 years) five (10%) developed VTE and eight (16%) major bleeding. Median through aFXa level was 0.03 (0.02‐0.05) IU/mL, and 48 (96%) of patients were within and two (4%) above target range. Peak aFXa level was 0.21 (0.13‐0.29) IU/mL, the number of patients below, within and above prophylactic range were 21 (42%), 25 (50%) and four (8%). Peak aFXa levels were similar in patients with and without VTE (0.18 vs 0.21 IU/L, P = .72), major bleeding (0.22 vs 0.21 IU/mL, P = .38) and AKI with RRT (0.18 vs 0.24, P = .13), but lower in patients receiving dalteparin 5000 IU od compared to 7500 IU od (0.19 vs 0.30 IU/mL, P < .01). Conclusions Intensive care unit patients receiving dalteparin prophylaxis had half of patients within prophylactic peak aFXa target range. Peak aFXa levels was affected by administered dalteparin dose, but not presence of VTE, major bleeding or AKI with RRT.
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Garabet, Lamya Samir Noori; Henriksson, Carola; Lozano, Maria Luisa; Ghanima, Waleed Khalid; Bussel, James & Brodin, Ellen Elisabeth
[Show all 11 contributors for this article]
(2019).
Markers of endothelial cell activation and neutrophil extracellular traps are elevated in immune thrombocytopenia but are not enhanced by thrombopoietin reseptor agonists.
Thrombosis Research.
ISSN 0049-3848.
185,
p. 119–124.
doi:
10.1016/j.thromres.2019.11.031.
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Introduction Patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis, which seems to be further enhanced by treatment with thrombopoietin-receptor-agonists (TPO-RAs). The underlying mechanisms of thrombosis in ITP are not fully understood. Endothelial cell activation and neutrophil extracellular traps (NETs) play important roles in thrombosis, however, their roles in ITP itself, or in TPO-RA-treatment, have not yet been fully explored. We aimed to investigate whether endothelial cell activation and NETs are involved in the hypercoagulable state of ITP, and whether TPO-RA-treatment enhances endothelial cell activation and NET formation. Material and methods We measured markers of endothelial cell activation including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and thrombomodulin in 21 ITP patients, and E-selectin in 18 ITP patients. Markers of NET formation, citrullinated histone H3-DNA (H3Cit-DNA) and cell-free DNA (cfDNA), were measured in 15 ITP patients. All markers were measured before, and 2 and 6 weeks after initiation of TPO-RA-treatment in ITP patients, and in matched controls. Results Higher levels of ICAM-1, thrombomodulin, and H3Cit-DNA were found in ITP patients, both before and after TPO-RA-treatment, compared with controls. No differences were found for VCAM-1, E-selectin or cfDNA. TPO-RA-treatment did not further increase markers of endothelial cell activation or NET formation. Conclusions This study showed that ITP patients have increased endothelial cell activation and NET formation, both of which may contribute to the intrinsic hypercoagulable state of ITP. TPO-RA-treatment, however, did not further increase endothelial cell activation or NET formation indicating that other drug-associated prothrombotic mechanisms are involved.
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Godolphin, Peter J.; Bath, Philip M.; Algra, Ale; Berge, Eivind; Brown, Christopher Martin & Chalmers, John
[Show all 19 contributors for this article]
(2019).
Outcome assessment by central adjudicators versus site investigators in stroke trials: A systematic review and meta-analysis.
Stroke.
ISSN 0039-2499.
50(8),
p. 2187–2196.
doi:
10.1161/STROKEAHA.119.025019.
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Background and Purpose—
In randomized stroke trials, central adjudication of a trial’s primary outcome is regularly implemented. However, recent evidence questions the importance of central adjudication in randomized trials. The aim of this review was to compare outcomes assessed by central adjudicators with outcomes assessed by site investigators.
Methods—
We included randomized stroke trials where the primary outcome had undergone an assessment by site investigators and central adjudicators. We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, and Google Scholar for eligible studies. We extracted information about the adjudication process as well as the treatment effect for the primary outcome, assessed both by central adjudicators and by site investigators. We calculated the ratio of these treatment effects so that a ratio of these treatment effects >1 indicated that central adjudication resulted in a more beneficial treatment effect than assessment by the site investigator. A random-effects meta-analysis model was fitted to estimate a pooled effect.
Results—
Fifteen trials, comprising 69 560 participants, were included. The primary outcomes included were stroke (8/15, 53%), a composite event including stroke (6/15, 40%) and functional outcome after stroke measured on the modified Rankin Scale (1/15, 7%). The majority of site investigators were blind to treatment allocation (9/15, 60%). On average, there was no difference in treatment effect estimates based on data from central adjudicators and site investigators (pooled ratio of these treatment effects=1.02; 95% CI, [0.95–1.09]).
Conclusions—
We found no evidence that central adjudication of the primary outcome in stroke trials had any impact on trial conclusions. This suggests that potential advantages of central adjudication may not outweigh cost and time disadvantages in stroke studies if the primary purpose of adjudication is to ensure validity of trial findings.
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Eilertsen, Anette Løken; Dahm, Anders Erik A; Høibraaten, Else; Lofthus, Cathrine Marie; Mowinckel, Marie-Christine & Sandset, Per Morten
(2019).
Relationship between sex hormone binding globulin and blood coagulation in women on postmenopausal hormone treatment.
Blood Coagulation and Fibrinolysis.
ISSN 0957-5235.
30(1),
p. 17–23.
doi:
10.1097/MBC.0000000000000784.
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Engeseth, Marit; Enden, Tone Rønnaug; Andersen, Marit Helen; Sandset, Per Morten & Wik, Hilde Skuterud
(2019).
Does the Villalta scale capture the essence of postthrombotic syndrome? A qualitative study of patient experience and expert opinion.
Journal of Thrombosis and Haemostasis.
ISSN 1538-7933.
p. 1–8.
doi:
10.1111/jth.14557.
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Background The Villalta scale is recommended for diagnosing and grading of postthrombotic syndrome (PTS) in clinical studies, but with limitations in specificity and sensitivity. Objectives To explore the typical complaints of PTS through patients experience and expert opinion and relate this to the items of the Villalta scale. Patients/Methods A qualitative study design with focus group interviews including patients with PTS and health care workers experienced in PTS patient care. Results Typical PTS complaints were reflected within four main domains: (a) agonizing discomforts; patients without venous ulcers often described other discomforts than pain; (b) skin changes; these were common and sometimes present before deep vein thrombosis (DVT). Except for venous ulcers, skin changes were considered of less importance; (c) fluctuating heaviness and swelling during the day and with activity; (d) post‐DVT concerns; fear of DVT recurrence, health services failing to meet the patients’ expectations, and psychological and social restrictions. These findings are not necessarily captured or well reflected in the Villalta scale. Conclusion Our findings indicate that the Villalta scale does not capture typical PTS complaints or their importance to the patients. A revision of the diagnosis and grading should be considered.
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Beitland, Sigrid; Wimmer, Rolf Henning; Lorentsen, Torleif; Jacobsen, Dag; Drægni, Tomas & Brunborg, Cathrine
[Show all 9 contributors for this article]
(2019).
Venous thromboembolism in the critically ill: A prospective
observational study of occurrence, risk factors and outcome.
Acta Anaesthesiologica Scandinavica.
ISSN 0001-5172.
63(5),
p. 630–638.
doi:
10.1111/aas.13316.
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Background The aim of the study was to explore occurrence, risk factors and outcome of venous thromboembolism (VTE) in intensive care unit (ICU) patients. Methods Prospective observational study of ICU patients receiving thromboprophylaxis at Oslo University Hospital in Norway. Adult medical and surgical patients with ICU length of stay (LOS) longer than 48 hours were included. For detection of VTE, Doppler ultrasound screening of neck, upper and lower extremity veins was used, and computed tomography angiography when clinically indicated for any medical reason. Results Among 70 included patients, 79% were males and mean age was 62 (±12.1) years. All received thromboprophylaxis with dalteparin, and 44 (63%) used graduated compression stockings. VTE was found in 19 (27%) patients; deep vein thrombosis in 15 (21%) and pulmonary embolism in 4 (6%). Among the VTEs, 11 (58%) presented within the first 48 hours after admission, two (11%) were located in the lower limbs and five (26%) were symptomatic. Risk factors for VTE in multivariable analyses were malignancy, abdominal surgery and SAPS II score <41 with an AuROC (95% CI) of 0.72 (0.58‐0.85, P = 0.01). Patients with and without VTE had comparable ICU LOS (13 vs 11 days, P = 0.27) and mortality (16% vs 20%, P = 0.72). Conclusion Venous thromboembolism was observed in 27% of ICU patients receiving thromboprophylaxis. Factors associated with increased risk of VTE were malignancy, abdominal surgery and SAPS II score <41. Presence of VTE did not impact on patient outcome.
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Engeseth, Marit; Enden, Tone Rønnaug; Sandset, Per Morten & Wik, Hilde Skuterud
(2019).
Limitations of the Villalta scale in diagnosing post-thrombotic syndrome.
Thrombosis Research.
ISSN 0049-3848.
184,
p. 62–66.
doi:
10.1016/j.thromres.2019.10.018.
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Introduction The Villalta scale is currently the recommended tool for diagnosing post-thrombotic syndrome (PTS) in clinical studies, but there is concern that the sensitivity and specificity of the scale might be low. We aimed to evaluate the diagnostic accuracy of the Villata scale using criteria in line with clinical practice as a reference. Material and methods We invited patients with a history of proximal DVT during 2006–09 to participate in a cross-sectional follow-up study of long-term complications after DVT. PTS was diagnosed by the Villalta scale, and by the following four mandatory and predefined clinical criteria used as a reference for PTS: 1. Objectively verified DVT; 2. chronic complaints (>1 month) in the DVT leg; 3. complaints appeared after the DVT; and 4. an alternative diagnosis was unlikely. Results We included 88 of 170 eligible patients (52%). With our clinical criteria as a reference the sensitivity and specificity of the Villalta scale for diagnosing PTS were 75% (95% CI 60–87%) and 66% (95% CI 50–80%), respectively. Fifteen patients were diagnosed with PTS by the Villalta scale only. These patients more often experienced pain or had comorbidity that could explain their leg symptoms and signs. Eleven patients diagnosed with PTS by the clinical criteria only, had more fluctuating heaviness and edema. Conclusions Our findings indicate that the diagnostic accuracy of the Villalta scale has limitations. Incorporating chronicity, whether the leg problems appeared following the DVT, fluctuations of heaviness and edema, and comorbidity in PTS assessment may improve the diagnostic accuracy.
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Garabet, Lamya Samir Noori; Ghanima, Waleed Khalid; Rangberg, Anbjørg; Teruel-Montoya, Raul; Martinez, Constantino & Lozano, Maria Luisa
[Show all 10 contributors for this article]
(2019).
Circulating microRNAs in patients with immune thrombocytopenia before and after treatment wirh thrombopoietin-receptor agonists.
Platelets.
ISSN 0953-7104.
p. 1–8.
doi:
10.1080/09537104.2019.1585527.
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MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of gene expression. Dysregulated expression of several miRNAs has been found in primary immune thrombocytopenia (ITP) suggesting that miRNAs are likely involved in the pathogenesis of ITP. We aimed to explore the differential expression of miRNAs in patients with ITP before and after starting treatment with thrombopoietin-receptor agonists (TPO-RAs) to clarify their roles in the pathophysiology of ITP, and as potential diagnostic and prognostic markers of this disorder. We performed a profiling study where 179 miRNAs were analyzed in eight ITP patients before and during treatment with TPO-RAs and in eight controls using miRNA PCR panel; 81 miRNAs were differentially expressed in ITP patients compared to controls, and 14 miRNAs showed significant changes during TPO-RA-treatment. Ten miRNAs were selected for validation that was performed in 23 patients and 22 controls using droplet digital PCR. Three miRNAs were found to be differentially expressed in ITP patients before TPO-RA-treatment compared to controls: miR-199a-5p was down-regulated (p = 0.0001), miR-33a-5p (p = 0.0002) and miR-195-5p (p = 0.035) were up-regulated. Treatment with TPO-RAs resulted in changes in six miRNAs including miR-199a-5p (p = 0.001), miR-33a-5p (p = 0.003), miR-382-5p (p = 0.004), miR-92b-3p (p = 0.005), miR-26a-5p (p = 0.008) and miR-221-3p (p = 0.023); while miR-195-5p remained unchanged and significantly higher than in controls, despite the increase in the platelet count, which may indicate its possible role in the pathophysiology of ITP. Regression analysis revealed that pre-treatment levels of miR-199a-5p and miR-221-3p could help to predict platelet response to TPO-RA-treatment. ROC curve analysis showed that the combination of miR-199a-5p and miR-33a-5p could distinguish patients with ITP from controls with AUC of 0.93. This study identifies a number of differentially expressed miRNAs in ITP patients before and after initiation of TPO-RAs with potential roles in the pathophysiology, as well as with a possible utility as diagnostic and prognostic biomarkers. These interesting findings deserve further exploration and validation in future studies.
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Andersen, Elisabeth; Dugarte, Maria Eugenia Chollet; Baroni, Marcello; Pinotti, Mirko; Bernardi, Francesco & Skarpen, Ellen
[Show all 8 contributors for this article]
(2019).
The effect of the chemical chaperone 4-phenylbutyrate on secretion and activity of the p.Q160R missense variant of coagulation factor FVII.
Cell & Bioscience.
9:69,
p. 1–10.
doi:
10.1186/s13578-019-0333-8.
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Background Congenital coagulation factor (F) VII deficiency is a rare bleeding disorder caused by mutations in the F7 gene. The missense factor FVII variant p.Q160R is the disease-causing mutation in all Norwegian FVII deficient patients and results in reduced biological activity and antigen levels of FVII in patient plasma. Previous in vitro studies on this variant demonstrated impaired intracellular trafficking and reduced secretion, possibly due to protein misfolding. The aim of the study was therefore to assess the impact of chemical chaperones on cellular processing and secretion of this variant using a cell model based on overexpression of the recombinant protein. Results Through screening of compounds, we identified 4-phenylbutyrate (4-PBA) to increase the secretion of recombinant (r) FVII-160R by ~ 2.5-fold. Additionally, treatment with 4-PBA resulted in a modest increase in specific biological activity. Intracellular localization studies revealed that upon treatment with 4-PBA, rFVII-160R was secreted through Golgi and Golgi reassembly-stacking protein (GRASP)-structures. Conclusions The present study demonstrates that the chemical chaperone 4-PBA, restores intracellular trafficking and increases the secretion of a missense FVII variant with functional properties in the extrinsic coagulation pathway.
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Dahm, Anders Erik A; Jacobsen, Eva-Marie; Wik, Hilde Skuterud; Jacobsen, Anne Flem; Mollnes, Tom Eirik & Kanse, Sandip
[Show all 7 contributors for this article]
(2019).
Elevated complement C3 and C4 levels are associated with postnatal pregnancy-related venous thrombosis.
Thrombosis and Haemostasis.
ISSN 0340-6245.
119(9),
p. 1481–1488.
doi:
10.1055/s-0039-1692426.
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High levels of complement C3 are associated with venous thrombosis (VT) in the general population. We investigated if high C3 and C4 levels were associated with pregnancy-related VT. We undertook the Norwegian VIP study, a case–control study of VT in pregnancy or within 3 months postpartum (cases, n = 313) and women without pregnancy-related VT (controls, n = 353). Determinants of C3 and C4 in the control women were investigated with linear regression and the odds ratio (OR) for pregnancy-related VT was calculated with logistic regression. We found that levels of C3 and C4 were associated with body mass index (BMI), C-reactive protein (CRP); with the coagulation factors (F) fibrinogen, FVIII, and FIX; and with the coagulation inhibitors antithrombin, protein C, protein S, and tissue factor pathway inhibitor. These associations were influenced by CRP levels. The crude OR for pregnancy-related VT was 1.8 (95% confidence interval [CI], 1.1–3.0) for C3 above the 90th percentile and 2.0 (95% CI, 1.2–3.2) for C4 above the 90th percentile. Stratification in antenatal and postnatal VT showed that C3 and C4 were only associated with postnatal VT with an OR for high C3 of 3.0 (95% CI, 1.8–5.0), and for high C4 of 2.6 (95% CI, 1.5–4.6). Adjustment for high FIX and BMI reduced the ORs. We conclude that the association between postnatal VT and C3 and C4 suggests that there is clinically relevant crosstalk between the complement and the coagulation system.
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Gregersen, Ida; Høibraaten, Else; Holven, Kirsten Bjørklund; Løvdahl, Lene; Ueland, Thor & Mowinckel, Marie-Christine
[Show all 10 contributors for this article]
(2019).
Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women.
Thrombosis Research.
ISSN 0049-3848.
184,
p. 1–7.
doi:
10.1016/j.thromres.2019.10.005.
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Background Women develop cardiovascular disease (CVD) approximately 7–10 years later than men, but progress with similar risk after menopause. Recent studies suggest that hormone replacement therapy (HRT) is cardioprotective when initiated early after menopause, but the mechanisms involved are still unclear. Objective In the current study, we aimed to examine the effects of HRT treatment on the plasma atherogenicity in postmenopausal women. We studied the total lipid profile in blood samples collected in a randomized, double-blinded, placebo controlled clinical trial of women with a history of venous thrombosis (VT), the EVTET study. Methods One-hundred and forty postmenopausal women <70 years were included in EVTET and randomized either to active treatment (one tablet of 2 mg estradiol and 1 mg norethisterone acetate daily) (n = 71) or placebo (n = 69). Blood samples were taken at baseline and after 3 months and subjected to routine assessment of hemostatic factors and lipids. Results Our study show that HRT compared to placebo significantly reduced plasma levels of Lp(a), ApoA1, ApoB, total cholesterol (TC), HDL-C, LDL-C, TC/HDL-C and LDL-C/HDL-C ratio at 3 months. No effect was observed on ApoB/ApoA1 ratio or triglycerides. The change in Lp(a) was significantly and inversely correlated with the change in estradiol (r = −0.32; P = 0.001) and positively correlated to the change in lipids, tissue factor pathway inhibitor activity and antigen, protein C and fibrinogen (r between 0.26 and 0.45, p < 0.01). Conclusion In sum, this study confirms a strong effect of HRT on atherogenic lipids with a large reduction in the pro-thrombotic Lp(a), suggesting an overall favorable effect on thrombogenicity after HRT replacement therapy in post-menopausal women at risk of VT.
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Kostovski, Emil; Frigato, E; Savikj, Mladen; Dahm, Anders Erik A; Sandset, Per Morten & Mowinckel, Marie-Christine
[Show all 10 contributors for this article]
(2018).
Normalization of disrupted clock gene expression in males with tetraplegia: a crossover randomized placebo-controlled trial of melatonin supplementation.
Spinal Cord.
ISSN 1362-4393.
p. 1–8.
doi:
10.1038/s41393-018-0176-x.
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<i>Study design</i>: Crossover double blind, randomized placebo-controlled trial.<p> <p><i>Objectives</i>: Circadian oscillators are located both in the brain and in peripheral organs. Melatonin, the main brain-derived hormone governing circadian variations, is highly associated with daylight patterns. However, in subjects with tetraplegia the melatonin levels are blunted. Here we studied peripheral oscillators in peripheral blood mononuclear cells (PBMCs) in males with tetraplegia by examining how exogenous melatonin may influence the expression of clock gene mRNAs.<p> <p><i>Setting</i>: Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway.<p> <p><i>Methods</i>: Six males with tetraplegia received 2 mg of melatonin or placebo 4 days before the study period. We also included six able-bodied men sleeping or kept awake during the night. Plasma samples were collected four times during a 24-h period. The mRNA expression levels of the clock genes <i>PER1</i>, <i>PER2</i>, <i>BMAL1</i>, and <i>REV-ERBα </i>were quantified in PBMCs using quantitative RT-PCR.<p> <p><i>Results</i>: The mRNA expression levels of <i>PER-1 and –2</i> and <i>REV-ERBα</i> were increased at 04:00 h compared with the ablebodied controls (<i>p</i> < 0.05). Melatonin supplementation changed mRNA peak-time toward the time of supplementation.<p> <p><i>Conclusions</i>: Several peripheral clock genes displayed distorted expression levels in tetraplegia. Supplementation with melatonin changed the mRNA expression levels of these genes toward those observed among able-bodied.
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Utne, Kristin Kornelia; Dahm, Anders Erik A; Wik, Hilde Skuterud; Jelsness-Jørgensen, Lars-Petter; Sandset, Per Morten & Ghanima, Waleed Khalid
(2018).
Rivaroxaban versus warfarin for the prevention of post-thrombotic syndrome.
Thrombosis Research.
ISSN 0049-3848.
163,
p. 6–11.
doi:
10.1016/j.thromres.2018.01.013.
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Sacco, Simona; Merki-Feld, Gabriele S.; Ægidius, Karen Lehrmann; Bitzer, Johannes; Canonico, Marianne & Gantenbein, Andreas R.
[Show all 19 contributors for this article]
(2018).
Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: A consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH).
The Journal of Headache and Pain.
ISSN 1129-2369.
19(76).
doi:
10.1186/s10194-018-0896-5.
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We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.
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Wik, Hilde Skuterud; Enden, Tone Rønnaug; Ghanima, Waleed Khalid; Engeseth, Marit; Kahn, Susan R. & Sandset, Per Morten
(2018).
Diagnostic scales for the post-thrombotic syndrome.
Thrombosis Research.
ISSN 0049-3848.
164,
p. 110–115.
doi:
10.1016/j.thromres.2017.10.022.
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Gravensteen, Ida Kathrine; Jacobsen, Eva-Marie; Sandset, Per Morten; Helgadóttir, Linda Björk; Rådestad, Ingela & Sandvik, Leiv
[Show all 7 contributors for this article]
(2018).
Anxiety, depression and relationship satisfaction in the pregnancy following stillbirth and after the birth of a live-born baby: A prospective study.
BMC Pregnancy and Childbirth.
18(41).
doi:
10.1186/s12884-018-1666-8.
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Background Experiencing a stillbirth can be a potent stressor for psychological distress in the subsequent pregnancy and possibly after the subsequent birth. The impact on women’s relationship with her partner in the subsequent pregnancy and postpartum remains uncertain. The objectives of the study were 1) To investigate the prevalence of anxiety and depression in the pregnancy following stillbirth and assess gestational age at stillbirth and inter-pregnancy interval as individual risk factors. 2) To assess the course of anxiety, depression and satisfaction with partner relationship up to 3 years after the birth of a live-born baby following stillbirth. Methods This study is based on data from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort. The sample included 901 pregnant women: 174 pregnant after a stillbirth, 362 pregnant after a live birth and 365 previously nulliparous. Anxiety and depression were assessed by short-form subscales of the Hopkins Symptoms Checklist, and relationship satisfaction was assessed by the Relationship Satisfaction Scale. These outcomes were measured in the third trimester of pregnancy and 6, 18 and 36 months postpartum. Logistic regression models were applied to study the impact of previous stillbirth on depression and anxiety in the third trimester of the subsequent pregnancy and to investigate gestational age and inter-pregnancy interval as potential risk factors. Results Women pregnant after stillbirth had a higher prevalence of anxiety (22.5%) and depression (19.7%) compared with women with a previous live birth (adjusted odds ratio (aOR) 5.47, 95% confidence interval (CI) 2.90–10.32 and aOR 1.91, 95% CI 1.11–3.27) and previously nulliparous women (aOR 4.97, 95% CI 2.68–9.24 and aOR 1.91, 95% CI 1.08–3.36). Gestational age at stillbirth (> 30 weeks) and inter-pregnancy interval < 12 months were not associated with depression and/or anxiety. Anxiety and depression decreased six to 18 months after the birth of a live-born baby, but increased again 36 months postpartum. Relationship satisfaction did not differ between groups. Conclusion Women who have experienced stillbirth face a significantly greater risk of anxiety and depression in the subsequent pregnancy compared with women with a previous live birth and previously nulliparous women.
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Gravensteen, Ida Kathrine; Jacobsen, Eva-Marie; Sandset, Per Morten; Helgadóttir, Linda Björk; Rådestad, Ingela & Sandvik, Leiv
[Show all 7 contributors for this article]
(2018).
Healthcare utilisation, induced labour and caesarean section in the pregnancy after stillbirth: a prospective study.
BJOG: An International Journal of Obstetrics and Gynaecology.
ISSN 1470-0328.
125(2),
p. 202–210.
doi:
10.1111/1471-0528.14750.
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Objective To investigate healthcare utilisation, induced labour and caesarean section (CS) in the pregnancy after stillbirth and assess anxiety and dread of childbirth as mediators for these outcomes. Design Population-based pregnancy cohort study. Setting The Norwegian Mother and Child Cohort Study. Sample 901 pregnant women; 174 pregnant after stillbirth, 362 pregnant after live birth and 365 previously nulliparous. Methods Data from questionnaires answered in the second and third trimesters of pregnancy and information from the Medical Birth Registry of Norway. Main outcome measures Self-reported assessment of antenatal care, register-based assessment of onset and mode of delivery. Results Women with a previous stillbirth had more frequent antenatal visits (mean 10.0; 95% confidence interval [CI] 9.4 - 10.7) compared with women with a previous live birth (6.0; 5.8 - 6.2) and previously nulliparous women (6.3; 6.1 - 6.6). Induced labour and CS, elective and emergency, were also more prevalent in the stillbirth group. The adjusted odds ratio for elective CS was 2.5 (95% CI 1.3 – 5.0) compared with women with previous live birth and 3.7 (1.8 - 7.6) compared with previously nulliparous women. Anxiety was a minor mediator for the association between stillbirth and frequency of antenatal visits, while dread of childbirth was not a significant mediator for elective CS. Conclusions Women pregnant after stillbirth were more ample users of healthcare services and had more often induced labour and CS. The higher frequency of antenatal visits and elective CS could not be accounted for by anxiety or dread of childbirth. The file is under embargo until 2018-05-18
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Amundsen, Erik Koldberg; Skadberg, Øyvind; Ghanima, Waleed Khalid; Frønæs, Synne Grønvold; Dahm, Anders Erik A & Tøsdal, Margunn Bye
[Show all 9 contributors for this article]
(2018).
D-Dimer: Aldersjusterte beslutningsgrenser ved diagnostikk av venøs tromboembolisme?
Klinisk Biokemi i Norden.
ISSN 1101-2013.
30(1),
p. 26–36.
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Tikkinen, Kari A.O.; Craigie, Samantha; Agarwal, Arnav; Violette, Philippe D.; Novara, Giacomo & Cartwright, Rufus
[Show all 16 contributors for this article]
(2018).
Procedure-specific risks of thrombosis and bleeding in urological cancer surgery: systematic review and meta-analysis.
European Urology.
ISSN 0302-2838.
73(2),
p. 242–251.
doi:
10.1016/j.eururo.2017.03.008.
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Context Pharmacological thromboprophylaxis involves balancing a lower risk of venous thromboembolism (VTE) against a higher risk of bleeding, a trade-off that critically depends on the risks of VTE and bleeding in the absence of prophylaxis (baseline risk). Objective To provide estimates of the baseline risk of symptomatic VTE and bleeding requiring reoperation in urological cancer surgery. Evidence acquisition We identified contemporary observational studies reporting symptomatic VTE or bleeding after urological procedures. We used studies with the lowest risk of bias and accounted for use of thromboprophylaxis and length of follow-up to derive best estimates of the baseline risks within 4 wk of surgery. We used the GRADE approach to assess the quality of the evidence. Evidence synthesis We included 71 studies reporting on 14 urological cancer procedures. The quality of the evidence was generally moderate for prostatectomy and cystectomy, and low or very low for other procedures. The duration of thromboprophylaxis was highly variable. The risk of VTE in cystectomies was high (2.6–11.6% across risk groups) whereas the risk of bleeding was low (0.3%). The risk of VTE in prostatectomies varied by procedure, from 0.2–0.9% in robotic prostatectomy without pelvic lymph node dissection (PLND) to 3.9–15.7% in open prostatectomy with extended PLND. The risk of bleeding was 0.1–1.0%. The risk of VTE following renal procedures was 0.7–2.9% for low-risk patients and 2.6–11.6% for high-risk patients; the risk of bleeding was 0.1–2.0%. Conclusions Extended thromboprophylaxis is warranted in some procedures (eg, open and robotic cystectomy) but not others (eg, robotic prostatectomy without PLND in low-risk patients). For “close call” procedures, decisions will depend on values and preferences with regard to VTE and bleeding. Patient summary Clinicians often give blood thinners to patients to prevent blood clots after surgery for urological cancer. Unfortunately, blood thinners also increase bleeding. This study provides information on the risk of clots and bleeding that is crucial in deciding for or against giving blood thinners.
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Sandset, Per Morten & Befring, Anne Kjersti
(2025).
Personlig ansvar er begrenset i ny helseforskningslov.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
145(Ttidsskriftet).
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Svar til statssekretær Kristian Bekeng om hva endringene i helseforskningloven innbærer.
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Befring, Anne Kjersti & Sandset, Per Morten
(2025).
Uheldige konsekvenser av ny helseforskningslov.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
145(15).
doi:
10.4045/tidsskr.25.0653.
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Motivasjonen for å endre helseforskningsloven var ifølge lovproposisjonen å legge til rette for mer og bedre forskning, styrke forskningsdeltakeres rettsvern og sikkerhet samt forenkle formelle prosesser knyttet til forskning.
Vi mener at den nye loven bryter med innarbeidet internasjonal lovgivning og anerkjente forskningsetiske normer, som den nylig reviderte Helsinkideklarasjonen . Også Datatilsynet, regionale komiteer for medisinsk og helsefaglig forskningsetikk, Universitetet i Oslo og NTNU er kritiske
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Lauritzen, Knut Husø; Bhattacharya, Anindita; Dugarte, Maria Eugenia Chollet; Sandset, Per Morten & Stavik, Benedicte
(2024).
Mitochondrial maturation in hepatic organoids.
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Wang, Heling; Siow, Richard; Schmauck-Medina, Tomás Alejandro; Zhang, Jianying; Sandset, Per Morten & Filshie, Clare
[Show all 38 contributors for this article]
(2024).
Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.
The journals of gerontology. Series A, Biological sciences and medical sciences.
ISSN 1079-5006.
79(4),
p. 1–10.
doi:
10.1093/gerona/glae029.
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Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.
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Larsen, Trine-Lise; Ghanima, Waleed; Sandset, Per Morten; Frøen, Hege; Jacobsen, Eva-Marie & Torfoss, Dag
[Show all 7 contributors for this article]
(2023).
Faktor Xa-hemmere til forebygging og behandling av venøs tromboembolisme ved kreft.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(1).
doi:
10.4045/tidsskr.22.0228.
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Venøs tromboembolisme er en hyppig komplikasjon ved kreftsykdom. Prevalensen varierer med krefttype og øker proporsjonalt med kreftstadium. De siste 15–20 årene har lavmolekylært heparin vært anbefalt som førstevalg ved behandling. Nye internasjonale retningslinjer åpner nå for å bruke direkte faktor Xa-hemmere både som profylakse mot og behandling av venøs tromboembolisme. Profylakse bør som hovedregel kun startes hos dem med moderat til høy risiko. Før man starter med antikoagulasjonsbehandling må man vurdere blødningsrisikoen. Både tromboseutvikling og blødningsrisiko kan endre seg og bør derfor vurderes fortløpende. I denne kliniske oversikten diskuteres bruk av antikoagulasjonsbehandling hos kreftpasienter, med særlig vekt på bruk av direkte faktor Xa-hemmere.
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Barrabes, Veronika; Fredriksen, Magne Wang; Ronæs, Johan; Getz, Linn Okkenhaug; Sandset, Per Morten & Tangen, Marte Kvittum
(2023).
Fremtidens helsetjenester - kollaps eller suksess?
Kommunal rapport.
ISSN 0801-6410.
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Cui, Xueyan; Myklebust, June Helen; Munthe, Ludvig A.; Schjesvold, Fredrik Hellem; Tjønnfjord, Geir Erland & Sandset, Per Morten
[Show all 7 contributors for this article]
(2022).
Low expression of coagulation inhibitors in the immune microenvironment in precursor stages of multiple myeloma.
Research and Practice in Thrombosis and Haemostasis (RPTH).
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Cui, Xueyan; Stavik, Benedicte; Sandset, Per Morten & Kanse, Sandip
(2022).
The role of FSAP in regulating endothelial permeability.
Research and Practice in Thrombosis and Haemostasis (RPTH).
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Andresen, Marianne Seierstad; Mowinckel, Marie-Christine; Stavik, Benedicte; Sandset, Per Morten & Dugarte, Maria Eugenia Chollet
(2022).
Evaluation of Pharmacological Enhancers of Mutated Factor VII Activity ex vivo.
Research and Practice in Thrombosis and Haemostasis (RPTH).
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Hernes, Toril A. Nagelhus; Sandset, Per Morten; Greve, Gottfried; Brekke, Camilla; Fitjar, Rune Dahl & Hannås, Gøril
(2022).
Vi har ikke tid til at finansiering av forskning settes på vent.
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Stavik, Benedicte; Andresen, Marianne Seierstad; Holm, Sverre; Skjelland, Mona; Tinholt, Mari & Sandset, Per Morten
[Show all 8 contributors for this article]
(2021).
Increased levels of coagulation factor V in atherosclerotic plaques - an immune regulated response?
Research and Practice in Thrombosis and Haemostasis (RPTH).
5.
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Andresen, Marianne Seierstad; Sletten, Marit; Sandset, Per Morten; Iversen, Nina; Stavik, Benedicte & Tinholt, Mari
(2021).
Coagulation factor V (F5) is an estrogen-responsive gene in breast cancer cells.
Research and Practice in Thrombosis and Haemostasis (RPTH).
5.
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andersen, elisabeth; Mowinckel, Marie-Christine; Stavik, Benedicte; Sandset, Per Morten & Dugarte, Maria Eugenia Chollet
(2021).
High-throughput Screening for Pharmacological Enhancers of Mutated Factor VII Activity.
Research and Practice in Thrombosis and Haemostasis (RPTH).
5.
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Stavik, Benedicte; Sagen, Ellen Lund; Cui, Xueyan; Holm, Sverre; Dahl, Tuva Børresdatter & Iversen, Nina
[Show all 8 contributors for this article]
(2020).
Tissue Factor Pathway Inhibitor induces secretion of pro-inflammatory cytokines in monocyte-derived macrophages.
Arteriosclerosis, Thrombosis and Vascular Biology.
ISSN 1079-5642.
40.
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Cui, Xueyan; Tjønnfjord, Geir Erland; Kanse, Sandip; Iversen, Nina; Dahm, Anders Erik A & Myklebust, Christiane Filion
[Show all 11 contributors for this article]
(2019).
Tissue factor pathway inhibitor enhances transendothelial migration of chronic lymphocytic leukemia cells trhough CXCL12/CXCR7 chemotaxis.
Research and Practice in Thrombosis and Haemostasis (RPTH).
3.
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Dugarte, Maria Eugenia Chollet; Andersen, Elisabeth; Skarpen, Ellen; Mowinckel, Marie-Christine; Stavik, Benedicte & Sullivan, Gareth
[Show all 7 contributors for this article]
(2019).
FVII: A human pluripotent stem cell derived hepatocyte model with potential therapeutic applications.
Research and Practice in Thrombosis and Haemostasis (RPTH).
3.
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July 2, 2025 9:35 AM
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Aug. 7, 2025 3:58 PM