| 11. |
- Måseide, Ragnhild J., et al.
(författare)
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Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study)
- 2023
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Ingår i: Haemophilia. - 1351-8216. ; 30:1, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. Aim: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). Methods: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. Results: We report on 104 patients aged 15–84 years from the MoHem study. Overall, EQ-5D utility was.85 (median) (Q1–Q3 0.73–1.0) with corresponding visual analogue scale (VAS) 80 (70–90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41–50 years displayed lower utility (p =.02) and VAS (p <.01) than the Norwegian population norm. Patients on prophylaxis aged 35–54 years reported higher PA than those treated on-demand (p =.01). Conclusion: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.
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| 12. |
- Måseide, Ragnhild J., et al.
(författare)
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Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B – The MoHem study
- 2020
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 26:5, s. 891-897
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known. Aim: We evaluated joint health in Nordic patients in relation to their treatment modality. Methods: A cross-sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS). Results: We report on 145 patients: median age 28 years (IQR 13-52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2-4): lower for MHB (2 IU/dL, IQR 1-2) than MHA (3 IU/dL, IQR 2-4) (P <.01). Eighty-five per cent of MHA and 73% MHB had a history of haemarthrosis (P =.07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3-7) than MHB (7 years, IQR 5-12) (P =.01). Thirty-eight per cent received prophylaxis, started at median 10 years of age (IQR 4-24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0-1). Total HEAD-US captured 0/48 points (median) (IQR 0-2) and HJHS 4/120 points (IQR 1-10) with strong correlation between them (r =.72). FVIII/FIX:C ≤ 3 IU/dL was associated with higher HJHS (P =.04). Fifteen per cent had undergone orthopaedic surgery. Conclusion: The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy. FVIII/FIX:C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.
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| 13. |
- Nylander, Martina
(författare)
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The role of platelet thrombin receptors PAR1 and PAR4 in health and disease
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood cells are continuously flowing in our systems maintaining haemostasis in the arteries and veins. If a vessel is damaged, the smallest cell fragments in the blood (platelets) are directed to cover the wound and plug the leakage to prevent blood loss. Most of the time platelets stop the blood leak without any difficulties. During other, pathological, circumstances, platelets continue to form a thrombus, preventing the blood flow and may cause myocardial infarction or stroke.Thrombin is the most potent platelet agonist and is a product created in the coagulation cascade. This thesis is focused on the interactions between the two platelet thrombin receptors; protease activated receptors 1 (PAR1) and PAR4 in vitro. We have investigated potential differences between these receptors in several situations associated with cardiovascular disease.First we studied interactions between PAR1 and PAR4 and the oral pathogen Porphyromonas gingivalis (which secretes enzymes, gingipains, with properties similar to thrombin). Here we showed that P. gingivalis is signaling mainly, but not exclusively, via PAR4. Our second study showed that the cross-talk between the stress hormone epinephrine and thrombin occur exclusively through PAR4 if the key-substance ATP is present and cyclooxygenase-1 inhibited by aspirin. The third study investigated platelet secretion, with focus on the protein plasminogen activator inhibitor 1(PAI-1), an inhibitor of the fibrinolytic process responsible for dissolving a formed clot. Here we showed that PAI-1 secretion and synthesis was more sensitive to stimulation through PAR1 than PAR4. Finally this thesis describes differences between PAR1 and PAR4 in cell-signaling pathways regulating the stability of a platelet aggregate, where PAR4 seems to be of importance to create stable platelet aggregates and that this stability is dependent on ADP activation via P2Y12 and cell signaling via PI3-kinase.Until now, PAR1 has been considered to be the most important thrombin receptor, due to its high affinity for thrombin. However, there must be a reason why platelets express two different thrombin receptors. This thesis highlights several situations where PAR4 plays a complementary and important role in platelet signaling and haemostasis.In conclusion, this thesis suggests that PAR4 plays a major role in calcium signaling and the induction of sustained aggregation, while PAR1 shows a more prominent role in platelet secretion and synthesis. This thesis also reveals new interactions between platelet thrombin receptors and the ADP-, ATP- and epinephrine receptors. The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors and their interplay in situations such as infection, stress, fibrinolysis, and platelet aggregation.
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| 14. |
- Przybyla, Beata, et al.
(författare)
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Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD – A longitudinal study
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6–8 time points over three months. Results Overall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64–0.82, p<0.001) and between PC and AT (r = 0.62–0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation. Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
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| 15. |
- Rodeghiero, Francesco, et al.
(författare)
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Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders : An EHA Consensus Report
- 2019
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Ingår i: HemaSphere. - 2572-9241. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- Healthy subjects frequently report minor bleedings that are frequently 'background noise' of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non-severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus-based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild-to-moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient-centered initial diagnostic approach that will result in classification of MBD into distinct clinical-pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence-based, disease-specific guidelines under development by the IWG.
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| 16. |
- Szanto, Timea, et al.
(författare)
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Platelet function testing : Current practice among clinical centres in Northern Europe
- 2022
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 28:4, s. 642-648
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Platelet function tests are used to screen and diagnose patients with possible inherited platelet function defects (IPFD). Some acquired platelet dysfunction may be caused by certain drugs or comorbidities, which need to be excluded before testing. Aims: To identify current practice among centres performing platelet function tests in Northern Europe. Methods: A total of 14 clinical centres from Sweden (six), Finland (two), Denmark (two), Norway (one), Estonia (two) and Iceland (one) completed the survey questionnaire, the population capture area of about 29.5 million. Results: Six of the 14 (42.8%) centres providing platelet function assessment represent comprehensive treatment centres (EUHANET status). A Bleeding score (BS) or ISTH bleeding assessment tool (ISTH BAT score) is evaluated in 11/14 (78.6%) centres and family history in all. Five/14 centres (35.7%) use structured preanalytical patient instructions, and 10/14 (71.4%) recorded questionnaire on the preassessment of avoidance of any drugs or natural products affecting platelet functions. Preliminary investigations of screening tests of coagulation are performed in 10/14 (71.4%), while in 4/14 (28.6%), the diagnostic work-up of IPFD and von Willebrand disease (VWD) is performed simultaneously. The work-up of IPFD includes peripheral blood smear in 10/14 (71.4%), platelet aggregometry in all, flow cytometry in 10/14 (71.4%) and Platelet Function Analysis (PFA) in 3/11 (28.6%). Molecular genetic diagnosis is available in 7/14 (50%) centres. Conclusions: The considerable variability in the current practice illustrates the need for harmonization between the Northern European centres according to the international registers (i.e. EUHASS) and IPFD guidelines (ISTH, EHA).
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| 17. |
- Södergren, Anna, 1985-
(författare)
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Formation and Relevance of Platelet Subpopulations
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelets are important players in the hemostatic system, acting as guardians of vessel integrity. When they come across a breach in the vessel wall, they quickly adhere to the damaged surface, secrete activating and adhesive compounds from their secretory granules, recruit additional platelets into a growing platelet plug and support the action of the coagulation system. In the past decades, it has become clear that platelets form functionally different platelet subpopulations. The aggregatory platelets build the platelet plug, whereas the procoagulant subpopulation support and direct the actions of the coagulation system. The aim of this thesis was to examine the formation and features of the different platelet subpopulations, and elucidate their respective roles in hemostasis.Platelet lysosomal secretion is not well characterized. In Paper I, we found that lysosomal secretion, detected as LAMP-1 surface exposure, occur upon potent platelet stimulation including secondary activation by ADP. This is regulated by the endothelial platelet inhibitors nitric oxide and prostacyclin. As observed in Paper II, lysosomal secretion might also be of clinical relevance as a quality indicator for platelet concentrates used for transfusion, an area were quality control may become increasingly important in the future. Among several evaluated platelet activation markers, platelet LAMP-1 exposure and the ability to form procoagulant platelets may be useful as novel indicators of platelet responsiveness. Moreover, the ability to form procoagulant platelets varies extensively between individuals, something we established in Paper III. Here we also present a novel flow cytometry protocol enabling the simultaneous investigation of 6 different platelet activation markers. Using this protocol we investigate the formation of procoagulant platelets and reveal that only a subpopulation of platelets may become procoagulant. Further we show that this is dependent on the agonist stimulation applied. Finally in Paper IV, we explore the influence of the procoagulant platelet subpopulation on different aspects of hemostasis. While platelet aggregation was not affected, the fraction of procoagulant platelets was found to strongly correlate to peak thrombin generation, and to be associated with plasma cholesterol levels.In conclusion, this thesis presents evidence for the use of LAMP-1 surface exposure and the formation of a procoagulant platelet subpopulation as potential indicators of platelet activation potential. The formation of procoagulant platelets varies extensively between individuals, influence hemostasis and is associated with the known risk factor cholesterol. Thus, the formation of a procoagulant platelet subpopulation may be a candidate biomarker for cardiovascular disease, to be explored in the future.
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