| 1. |
- Farm, Maria, et al.
(författare)
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Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers
- 2020
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Ingår i: TH open : companion journal to thrombosis and haemostasis. - : Thieme. - 2512-9465. ; 4:3, s. e178-e188
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Tidskriftsartikel (refereegranskat)abstract
- Introduction For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE. Objective This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE. Methods A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records. Results Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T lag were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay. Conclusion Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.
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| 2. |
- Taxiarchis, Apostolos, et al.
(författare)
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Extracellular vesicles in plasma and cerebrospinal fluid in patients with COVID-19 and neurological symptoms
- 2024
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Ingår i: International Journal of Laboratory Hematology. - : John Wiley & Sons. - 1751-5521 .- 1751-553X. ; 46:1, s. 42-49
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Tidskriftsartikel (refereegranskat)abstract
- Introduction:Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation.Methods:Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF).Results:A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19.Conclusion:The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection.
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| 3. |
- Antovic, Aleksandra
(författare)
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Determination of the overall haemostasis potential and fibrin gel permeability : method development and application in research and in clinical materials
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We have previously developed a laboratory method that may screen the Overall Haemostasis Potential (OHP) in plasma based on spectophotometric measurement of an area under the fibrin aggregation curve in citrated plasma samples to which tiny amounts of exogenous thrombin and tissue-plasminogen activator (t-PA) are added. When the fibrin aggregation curve is created, the fibrinogen originally present in plasma is gradually converted to fibrin by the generated thrombin. At the same time, plasminogen activation produces plasmin that in turn digests fibrin. Each absorbance value (Abs) represents the fibrin level at the corresponding time point, and the area under the curve, should reflect a balance between the generation and proteolysis of fibrin throughout the measurement period. To improve the assay sensitivity for the application in clinic or research work, various modifications were introduced. Thrombin in a decreased dose (0.04 IU/mL, compared to 0.2 IU/mL previously used) with or without t-PA was added to plasma. Areas under the two fibrin-aggregation curves i.e OHP and Overall Coagulation Potential (OCP) were thus created. A difference between the two parameters reflects the Overall Fibrinolysis Potential (OFP), calculated by (OCP-OHP)/OCP) x 100%. The modified method has shown its usefulness in detecting hypercoagulation in normal pregnancy, preeclampsia and coronary heart disease. Increased levels of OHP were also found in women with previous thromboembolim especially related to the presence of FV Leiden mutation. Moreover, assay of this parameter can screen immediate changes in the haemostatic system after the injection of low molecular mass heparin (dalteparin) and may be used for monitoring the anticoagulant effects. To ensure the sensitivity of the assay for determining different severity of hypocoagulation, further modifications were performed by introducing tissue factor and phospholipids to the reaction system. All the factors belonging to the two pathways of coagulation cascade, apart from FXII, affected the OHP outcome. This indicates that the modified assay system is similar to the haemostasis balance in circulating blood, and may thus become a laboratory too] to estimate bleeding tendency in haemophilic patients and distinguish prothrombotic cases among patients with FXII deficiency. OHP assay is thus a quantitative method to determine the fibrin level associated with combined potential of coagulation and fibrinolysis. However studies on fibrin gel porosity may give information about quality of the fibrin network which is important e.g. in atherosclerosis. We made modifications in a flow measurement previously established by B Blombäck et al and evaluated the resultant advantages. The essential equipment was simplified and the sample volume minimized which rendered the assay easier to apply in any clinical or research laboratory settings. By using different concentrations of thrombin with, or without phospholipids, it was possible to asses whether the fibrin gel porosity depends on both thrombin generation potential and fibrinogen clotting properties or only on the latter respectively. The modified flow measurement technique was used to determine the effects of acetylsalicylic acid (ASA, aspirin) effects on haemostasis. Fibrin gel porosity was more markedly increased during treatment with lower doses of ASA, compared to medium- / high-doses. These results are further confirmed by the findings in three-dimensional confocal microscopy where thicker fibrin fibers and larger network pores with irregular structure were observed during the low dose treatment. The greater increase in fibrin gel permeability and alterations in the structure of the fibrin network support the clinical findings of better prevention of arterial thrombosis such as in stroke and cardiovascular disease during treatment with low ASA doses such as 75mg daily, than with the higher doses.
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| 4. |
- Antovic, Aleksandra, et al.
(författare)
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Microparticles Expressing Myeloperoxidase and Complement C3a and C5a as Markers of Renal Involvement in Antineutrophil Cytoplasmic Antibody-associated Vasculitis
- 2020
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 47:5, s. 714-721
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate expression of terminal complement components C3a and C5a on circulating myeloperoxidase (MPO)-positive microparticles (MPO+MP) in relation to disease activity and renal involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods. Forty-six clinically well-characterized patients with AAV and 23 age-and sex-matched healthy controls were included. The concentration of MPO+MP expressing C3a and C5a was analyzed from citrate plasma by flow cytometry. Serum levels of C3a and C5a were determined using commercial ELISA. The assessment of vasculitis disease activity was performed using the Birmingham Vasculitis Activity Score (BVAS). Among patients, 23 had active disease with BVAS >= 2 and 14 patients had active renal flares. Results. AAV patients had significantly increased expression of C3a and C5a on MPO+MP compared to controls (both p < 0.0001). When the group of patients with active AAV was divided according to the presence of renal activity, the concentration of MPO+MP expressing C3a and C5a was significantly higher in patients with renal involvement compared to patients with nonrenal disease and controls (p < 0.05 and p < 0.01, respectively). The serum levels of C3a were significantly decreased (p < 0.01) in the renal subgroup, while there were no changes in serum levels of C5a comparing the renal and nonrenal groups. There was significant correlation between the disease activity measured by BVAS and the levels of C3a and C5a expressed on MPO+MP. Conclusion. Determination of C3a and C5a on MPO+MP might be considered as a novel biomarker of renal involvement in patients with AAV and may be of importance in the pathogenetic process.
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| 5. |
- Grosso, Giorgia, et al.
(författare)
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The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies
- 2021
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 121:10, s. 1299-1309
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Tidskriftsartikel (refereegranskat)abstract
- Background Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. Objectives To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. Methods In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N =67), aPL++ individuals without clinical manifestations (aPL carriers, N =15), SLE-aPL++ ( N =118, among them, secondary [s] APS, N =56), aPL negative (-) SLE (SLE-aPL-, N =291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. Results Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) Conclusion Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.
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| 6. |
- Jonasdottir, Asta Dogg, et al.
(författare)
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Augmented thrombin formation is related to circulating levels of extracellular vesicles exposing tissue factor and citrullinated histone-3 in anti-neutrophil cytoplasmic antibody-associated vasculitides
- 2023
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Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTo study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV).MethodsWe have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS).ResultsThis study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS.ConclusionAugmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.
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| 7. |
- Kits, Annika, et al.
(författare)
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Fatal Acute Hemorrhagic Encephalomyelitis and Antiphospholipid Antibodies following SARS-CoV-2 Vaccination : A Case Report
- 2022
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Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Acute hemorrhagic encephalomyelitis (AHEM) is a rare hyperacute form of acute disseminated encephalomyelitis (ADEM). The disease is characterized by fulminant inflammation and demyelination in the brain and spinal cord and is often preceded by an infection or vaccination. This case report presents a 53-year-old male with rheumatoid arthritis and ongoing treatment with methotrexate and etanercept who developed fatal AHEM following the second dose of the COVID-19 vaccine. The disease course was complicated by multiorgan thromboembolic disease and the presence of high/moderate levels of cardiolipin IgG antibodies and anti-beta-2 glycoprotein 1 IgG antibodies suggesting a possible antiphospholipid syndrome. Treatment with immunosuppressive therapies failed to improve the course. The report comprises comprehensive clinical, neuroimaging, and neuropathological findings. The case highlights diagnostic challenges in a patient with several preceding risk factors, including autoimmune disease, immunotherapy, and vaccination, with possible pathophysiological implications. The temporal association with the COVID-19 vaccination may suggest possible causality although evidence cannot be ascertained. Reporting possible adverse events following COVID-19 vaccination is important to identify at-risk populations and to accomplish control of the current pandemic.
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| 8. |
- Lalic-Cosic, Sanja, et al.
(författare)
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Phosphatidylserine Exposing Extracellular Vesicles in Pre-eclamptic Patients
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pre-eclampsia (P-EC) is associated with systemic inflammation, endothelial dysfunction and hypercoagulability. The role of extracellular vesicles (EVs) in coagulation disturbances affecting the development and severity of P-EC remains elusive. We aimed to evaluate the concentration of EVs expressing phosphatidylserine (PS) and specific markers in relation to the thrombin and fibrin formation as well as fibrin clot properties, in pregnant women with P-EC in comparison to healthy pregnant women of similar gestational age.Methods: Blood samples of 30 pregnant women diagnosed with P-EC were collected on the morning following admission to hospital and after delivery (mean duration 5 days). The concentration of the PS-exposing EVs (PS+ EVs) from platelets (CD42a+, endothelial cells (CD62E+), and PS+ EVs expressing tissue factor (TF) and vascular cell adhesion molecule 1 (VCAM-1) were measured by flow cytometry. Further phenotyping of EVs also included expression of PlGF. Markers of maternal haemostasis were correlated with EVs concentration in plasma.Results: Preeclamptic pregnancy was associated with significantly higher plasma levels of PS+ CD42a+ EVs and PS+ VCAM-1+ EVs in comparison with normotensive pregnancy. P-EC patients after delivery had markedly elevated concentration of PS+ CD42a+ EVs, CD62E+ EVs, TF+ EVs, and VCAM-1+ EVs compared to those before delivery. Inverse correlation was observed between EVs concentrations (PS+, PS+ TF+, and PlGF+) and parameters of overall haemostatic potential (OHP) and fibrin formation, while PS+ VCAM-1+ EVs directly correlated with FVIII activity in plasma.Conclusion: Increased levels of PS+ EVs subpopulations in P-EC and their association with global haemostatic parameters, as well as with fibrin clot properties may suggest EVs involvement in intravascular fibrin deposition leading to subsequent microcirculation disorders.
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