| 1. |
- Aulin, Julia, et al.
(författare)
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Serial measurement of interleukin-6 and risk of mortality in anticoagulated patients with atrial fibrillation : Insights from ARISTOTLE and RE-LY trials.
- 2020
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 18:9, s. 2287-2295
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF).OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF.METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression.RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P < .0001) in ARISTOTLE, and 1.11 (1.01-1.22, P = .0290) in RE-LY; with improved C index from 0.74 to 0.76 in ARISTOTLE, but not in the smaller RE-LY cohort. There were no consistent associations with second IL-6 and stroke or systemic embolism, or major bleeding.CONCLUSIONS: Persistent systemic inflammatory activity, assessed by repeated IL-6 measurements, is associated with mortality independent of established clinical risk factors and other strong cardiovascular biomarkers in anticoagulated patients with AF.
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| 2. |
- Basil, Nawfal, et al.
(författare)
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Severe alpha-1-antitrypsin deficiency increases the risk of venous thromboembolism
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : John Wiley & Sons. - 1538-7933 .- 1538-7836. ; 19:6, s. 1519-1525
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is associated with increased risk of liver disease and chronic obstructive pulmonary disease (COPD), but the risk of venous thromboembolism (VTE) is unknown. Our aim was to evaluate the risk of VTE in individuals with severe AATD compared with control subjects from the general population.Methods: Individuals with severe AATD (n = 1577) were recruited from the Swedish national AATD register. Control subjects (n = 5969) were selected from the OLIN (Obstructive Lung Disease in Northern Sweden) studies, that include a random general population sample. Longitudinal data on VTE and diagnoses were obtained from the Swedish National Patient Registry. Associations were analyzed using multivariable Cox regression.Results: At inclusion, 46% of the AATD individuals and 53% of the controls were never-smokers. COPD was present in 46% of the AATD individuals compared with 4% of the controls. During a median follow-up of 18 years, 116 (7%) of the AATD individuals and 89 (1%) of the control subjects developed VTE, unadjusted hazard ratio 6.5 (95% confidence interval 4.9–8.6). Risk factors for incident VTE were male gender, age, COPD, cancer, and liver disease. Adjusting for these factors, the AATD individuals had a significantly higher risk of incident VTE, adjusted hazard ratio 4.2 (95% confidence interval 2.9–6.2) as compared with the controls.Conclusion: Subjects with severe AATD have considerably increased risk of developing VTE compared with the general population, even after accounting for risk factors. This calls for optimized risk factor management and clinical follow-up of this patient group.
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| 3. |
- Brinkman, Herm Jan M., et al.
(författare)
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Pleiotropic anticoagulant functions of protein S, consequences for the clinical laboratory. Communication from the SSC of the ISTH
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 19:1, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary deficiencies of protein S (PS) increase the risk of thrombosis. However, assessing the plasma levels of PS is complicated by its manifold physiological interactions, while the large inter-individual variability makes it problematic to establish reliable cut-off values. PS has multiple physiological functions, with only two appearing to have significant anticoagulant properties: the activated protein C (APC) and tissue factor pathway inhibitor alpha (TFPIα) cofactor activities. Current clinical laboratory investigations for deficiency in PS function rely only on the APC-dependent activity. This communication presents an argument for reclassifying the qualitative PS deficiencies to differentiate the two major anticoagulant functions of PS. Reliable assays are necessary for accurate evaluation of PS function when making a specific diagnosis of PS deficiency based on the anticoagulant phenotype alone. This report emphasizes the pleiotropic anticoagulant functions of PS and presents evidence-based recommendations for their implementation in the clinical laboratory.
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| 4. |
- Chanzu, Harry, et al.
(författare)
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Platelet α-granule cargo packaging and release are affected by the luminal proteoglycan, serglycin
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : John Wiley & Sons. - 1538-7933 .- 1538-7836. ; 19:4, s. 1082-1095
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSerglycin (SRGN) is an intragranular, sulfated proteoglycan in hematopoietic cells that affects granule composition and function.ObjectiveTo understand how SRGN affects platelet granule packaging, cargo release, and extra-platelet microenvironments.MethodsPlatelets and megakaryocytes from SRGN−/− mice were assayed for secretion kinetics, cargo levels, granule morphology upon activation, and receptor shedding.ResultsMetabolic, 35SO4 labeling identified SRGN as a major sulfated macromolecule in megakaryocytes. SRGN colocalized with α-granule markers (platelet factor 4 [PF4], von Willebrand factor [VWF], and P-selectin), but its deletion did not affect α-granule morphology or number. Platelet α-granule composition was altered, with a reduction in basic proteins (pI ≥8; e.g., PF4, SDF-1, angiogenin) and constitutive release of PF4 from SRGN−/− megakaryocytes. P-Selectin, VWF, and fibrinogen were unaffected. Serotonin (5-HT) uptake and β-hexosaminidase (HEXB) were slightly elevated. Thrombin-induced exocytosis of PF4 from platelets was defective; however, release of RANTES/CCL5 was normal and osteopontin secretion was more rapid. Release of 5-HT and HEXB (from dense granules and lysosomes, respectively) were unaffected. Ultrastructural studies showed distinct morphologies in activated platelets. The α-granule lumen of SRGN−/− platelet had a grainy staining pattern, whereas that of wild-type granules had only fibrous material remaining. α-Granule swelling and decondensation were reduced in SRGN−/− platelets. Upon stimulation of platelets, a SRGN/PF4 complex was released in a time- and agonist-dependent manner. Shedding of GPVI from SRGN−/− platelets was modestly enhanced. Shedding of GP1b was unaffected.ConclusionThe polyanionic proteoglycan SRGN influences α-granule packaging, cargo release, and shedding of platelet membrane proteins.
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| 5. |
- Dahlbäck, Björn, et al.
(författare)
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A hydrophobic patch (PLVIVG; 1481–1486) in the B-domain of factor V-short is crucial for its synergistic TFPIα-cofactor activity with protein S and for the formation of the FXa-inhibitory complex comprising FV-short, TFPIα, and protein S
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:5, s. 1146-1157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Factor V-short (FV756-1458) is a natural splice variant functioning in synergy with protein S as tissue factor pathway inhibitor alpha (TFPIα)–cofactor in inhibition of factor Xa (FXa). An exposed acid region (AR2; 1493–1537) in the B domain binds TFPIα. The preAR2 (1458–1492) is crucial for the synergistic TFPIα–cofactor activity between FV-short and protein S and for assembly of a trimolecular FXa-inhibitory complex among FV-short, protein S, and TFPIα. Objective: To identify which part of preAR2 is required for the synergistic TFPIα–cofactor activity between FV-short and protein S. Methods: A FXa-inhibition assay was used to test the synergistic TFPIα cofactor activity between protein S and new FV-short variants FV709-1476, FV712-1478, FV712-1481, FV712-1484, FV712-1487, and FV712-1490. A microtiter-based assay analyzed binding among FV-short variants, protein S, and TFPIα. Results: FV709-1476, FV712-1478, and FV712-1481 were fully active as synergistic TFPIα cofactors with protein S; FV712-1484 showed intermediate activity; and FV712-1487 and FV712-1490 were inactive. TFPIα interacted with all variants in the absence of protein S but FV712-1478 and FV712-1481 bound TFPIα with highest affinity. None of the FV-short variants bound directly to protein S in the absence of TFPIα. In the presence of TFPIα, efficient cooperative binding was demonstrated between protein S, TFPIα, and FV709-1476, FV712-1478, or FV712-1481. In contrast, no cooperativity among TFPIα, protein S, and FV712-1484, FV712-1487, or FV712-1490 was seen. Conclusion: A short hydrophobic patch in preAR2 (PLVIVG, 1481–1486) in FV-short is crucial for the synergistic TFPIα-cofactor activity between FV-short and protein S and for the assembly of a trimolecular FXa-inhibitory complex among FV-short, protein S, and TFPIα.
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| 6. |
- Dahlbäck, Björn
(författare)
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Natural anticoagulant discovery, the gift that keeps on giving : finding FV-Short
- 2023
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 21:4, s. 716-727
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Forskningsöversikt (refereegranskat)abstract
- The complex reactions of blood coagulation are balanced by several natural anticoagulants resulting in tuned hemostasis. During several decades, the knowledge base of the natural anticoagulants has greatly increased and we have also learned about antiinflammatory and cytoprotective activities expressed by antithrombin and activated protein C (APC). Some coagulation proteins have also been found to function as anticoagulants; e.g., thrombin when bound to thrombomodulin activates protein C. Another example is factor V (FV), which in addition to being a procofactor to FVa has emerged as an anticoagulant. The discovery of APC resistance, caused by FVLeiden, as a thrombosis risk factor resulted in the identification of FV as an APC cofactor working in synergy with protein S in the regulation of FVIIIa in the Xase complex. More recently, a natural anticoagulant FV splice isoform (FV-Short) was discovered when investigating the East Texas bleeding disorder. In FV-Short, the truncated B domain exposes a high-affinity binding site for tissue factor pathway inhibitor alpha (TFPIα), and together with protein S a high-affinity trimolecular complex is generated. The FXa-inhibitory activity of TFPIα is synergistically stimulated by FV-Short and protein S. The circulating FV-Short/protein S/TFPIα complex concentration is normally low (≈0.2 nM) but provides an anticoagulant threshold. In the East Texas bleeding, the concentration of the complex, and thus the threshold, is increased 10-fold, which results in bleeding manifestations. The anticoagulant properties of FV were discovered during investigations of individual patients and follow the great tradition of bed-to-bench and bench-to-bed research in the coagulation field.
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| 7. |
- Dahlbäck, Björn, et al.
(författare)
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The preAR2 region (1458–1492) in factor V-Short is crucial for the synergistic TFPIα-cofactor activity with protein S and the assembly of a trimolecular factor Xa-inhibitory complex comprising FV-Short, protein S, and TFPIα
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:1, s. 58-68
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Tidskriftsartikel (refereegranskat)abstract
- Background: Factor V-Short (FV756-1458) is a natural splice variant in which 702 residues are deleted from the B domain. It exposes an acid region (AR2; 1493–1537) that binds tissue factor pathway inhibitor alpha (TFPIα). Protein S also interacts with TFPIα and serves as TFPIα-cofactor in factor Xa (FXa) inhibition. FV-Short and protein S function as synergistic TFPIα-cofactors in inhibition of FXa. FV810-1492 is an artificial FV-Short variant that cannot synergize with protein S as TFPIα cofactor even though it contains AR2 and binds TFPIα. Objective: To elucidate the mechanisms for the synergism between FV756-1458 and protein S as TFPIα cofactors. Methods: Four FV-Short variants were created, FV756-1458 and FV712-1458 contained the preAR2 region (1458–1492), whereas FV810-1492 and FV713-1492 lacked this region. The synergistic TFPIα cofactor activity between FV-Short variants and protein S was analyzed by FXa-inhibition. A microtiter-based assay tested binding between FV-Short variants, protein S, and TFPIα. Results: The two preAR2-containing FV-Short variants were active as synergistic TFPIα cofactors, whereas the other two were inactive. All variants bound to TFPIα. None of the FV-Short variants bound directly to protein S. The combination of TFPIα and preAR2-containing FV-Short variants bound protein S, whereas TFPIα together with the preAR2-minus variants did not. Protein S potentiated TFPIα-binding to the preAR2-containing variants and binding between TFPIα and protein S was stimulated only by the preAR2-containing variants. Conclusion: The preAR2 region is demonstrated to be crucial for the synergistic TFPIα-cofactor activity between FV-Short and protein S and for the assembly of a trimolecular FXa-inhibitory complex comprising FV-Short, protein S, and TFPIα.
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| 8. |
- Frelinger, Andrew L., 3rd, et al.
(författare)
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Consensus recommendations on flow cytometry for the assessment of inherited and acquired disorders of platelet number and function : Communication from the ISTH SSC Subcommittee on Platelet Physiology
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : John Wiley & Sons. - 1538-7933 .- 1538-7836. ; 19:12, s. 3193-3202
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Tidskriftsartikel (refereegranskat)abstract
- Flow cytometry is increasingly used in the study of platelets in inherited and acquired disorders of platelet number and function. However, wide variation exists in specific reagents, methods, and equipment used, making interpretation and comparison of results difficult. The goal of the present study was to provide expert consensus guidance on the use of flow cytometry for the evaluation of platelet disorders. A modified RAND/UCLA survey method was used to obtain a consensus among 11 experts from 10 countries across four continents, on the appropriateness of statements relating to clinical utility, pre-analytical variables, instrument and reagent standardization, methods, reporting, and quality control for platelet flow cytometry. Feedback from the initial survey revealed that uncertainty was sometimes due to lack of expertise with a particular test condition rather than unavailable or ambiguous data. To address this, the RAND method was modified to allow experts to self-identify statements for which they could not provide expert input. There was uniform agreement among experts in the areas of instrument and reagent standardization, methods, reporting, and quality control and this agreement is used to suggest best practices in these areas. However, 25.9% and 50% of statements related to pre-analytical variables and clinical utility, respectively, were rated as uncertain. Thus, while citrate is the preferred anticoagulant for many flow cytometric platelet tests, expert opinions differed on the acceptability of other anticoagulants, particularly heparin. Lack of expert consensus on the clinical utility of many flow cytometric platelet tests indicates the need for rigorous multicenter clinical outcome studies.
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| 9. |
- Geisen, Christof, et al.
(författare)
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An HPA-1a–positive platelet–depleting agent for prevention of fetal and neonatal alloimmune thrombocytopenia : a randomized, single-blind, placebo–controlled, single-center, phase 1/2 proof-of-concept study
- 2023
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 21:4, s. 838-849
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. Objectives: To investigate whether a single dose of anti–HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA-1a–negative participants as compared with placebo. Methods: This randomized, single-blind, placebo–controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a– and HLA-A2–negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. Results: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment–emergent adverse events were possibly related to treatment, both in RLYB211–treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. Conclusion: These data support the hypothesis that anti–HPA-1a could be used as prophylaxis in women at risk of having an FNAIT–affected pregnancy.
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| 10. |
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