| 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, Jovan P
(författare)
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Thrombin activatable fibrinolysis inhibitor (TAFI) in different hemorrhagic and thrombotic conditions
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Until recently the coagulation and fibrinolytic systems were usually considered as separate entities. Accounts of a fibrinolysis inhibitor that is generated by thrombin shed more light on this field and changed the concept by giving thrombin, the pivotal enzyme in hemostasis, another important role in the down-regulation of fibrinolysis. Thrombin Activatable Fibrinolysis Inhibitor (TAFI), also known as procarboxypeptidase B and procarboxypeptidase U, is a relatively recently described inhibitor of fibrinolysis that can be converted into its activated form which is a carboxypeptidase B- like enzyme, by the thrombin/thrombomodulin complex. In this study, the precursor of TAFI is denominated proTAFI (instead of TAFI or procarboxypeptidase U). Since this "inhibitor" of fibrinolysis is functional only in its active form, we reserve the term TAFI for the active form of the enzyme and suggest the term TAFli for the inactive form. Although the role of TAFI in pathology is not completely known, it is reasonable to expect that the level of TAFI is altered in various thrombotic and hemorrhagic diseases. Objective: The aim of the study is to investigate possible changes in different forms of TAFI and their influence on fibrinolysis in different clinical conditions associated with hypocoagulable states and decreased thrombin generation (e.g. hemophilia A and von Willebrand disease (VWD) as well as in hypercoagulable states such as APC resistance and conditions associated with complicated pregnancy and diabetes mellitus. Methods: Different forms of TAR were determined in patients with APC resistance due to FV Leiden mutation, in patients with hemophilia A and VWD, in patients with diabetes mellitus type I and in women with preeclampsia. Data were obtained on total thrombin activatable fibrinolysis inhibitor antigen (including pro-TAFI, its active form TAFI and its inactive form TAFIi), pro-TAFI activity, TAFl/TAFIi antigen, overall hemostatic potential (OHP) and overall fibrinolytic potential (OFP) in plasma, and clot lysis time (CLT) derived from this test. OHP and TAFI-dependent fibrinolysis were also determined in vitro in variously deficient plasmas after addition of different concentrations of rVIIa (NovoSeven). Results: A decrease in pro-TAFI, accompanied by no change in total TAFI antigen, was found in APC resistant patients. A significant decrease in TAFI antigen and impaired fibrinolysis that was not TAFI dependent were observed in women with preeclampsia compared to those with a normal pregnancy. Pro-TAFI levels did not differ between diabetic patients with or without microvascular complications and controls. TAFI antigen was lower (though not significantly so) in both groups of diabetic patients, while OHP was increased (significantly in the group with microvascular complications). Neither fibrinolysis itself nor TAFI-dependent fibrinolysis differed between the two groups of diabetic patients compared to controls. Pro-TAFI was decreased in hemophilia A, hemophilia B and VWD patients, together with no changes in total TAFI antigen. An increase in TAFI/TAFIi antigen was found in both hemophilia and VWD patients compared to controls. rFVIIa in a concentration of 2.4µg/mL improved the overall hemostasis in FV, FVIII and FIX deficient plasmas. Not even very high concentrations of rFVIIa (9.6µg/mL) induced hypercoagulation in deficient plasmas or in normal pooled plasma (NPP). It seems that flbrinolysis is also regulated by factors other than TAFI but higher concentrations of rVIIa do, at least partly, induce (most probably through increased thrombin generation) a TAFI-dependent down-regulation of fibrinolysis in FVIII and FIX deficient plasmas. Conclusions: TAFI contributes to an impairment of fibrinolysis in patients with APC resistance. TAFI does not induce a further down-regulation of initially impaired fibrinolysis in preeclampsia, most probably because it is reduced as a result of renal and hepatic disturbances. In patients with type I diabetes mellitus and microvascular complications, TAFI does not induce an impairment of fibrinolysis despite the presence of increased overall coagulation and hemostasis. The transformation of pro-TAFI into TAFI and TAFIi in hemophilia and VWD is most probably induced by plasmin and could partly counterbalance the up-regulation of fibrinolysis in these conditions. rVIIa improves overall hemostasis and fibrinolysis in hemophilia patients and in FVIII and FIX deficient plasma, but the improved down-regulation in overall fibrinolysis is only partly TAFI-dependent. The OHP assay seems to be a handy and inexpensive tool not only for the determination of overall hemostasis, coagulation and fibrinolysis but also for indirect estimation of TAFI-dependent fibrinolysis. TAFI obviously has a role as a link between coagulation and fibrinolysis but since it is activated by both thrombin and plasmin and is also inactivated by plasmin, both enzymes could regulate TAFIs role and influence the TAFI-dependent regulation of fibrinolysis. The definitive role of TAFI therefore remains to be proven.
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| 4. |
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| 5. |
- Bian, Li, et al.
(författare)
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Rutinmässig screening med APTT är inte indicerad före operation : [Routine screening with APTT is not indicated before surgery
- 2022
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Ingår i: Läkartidningen. - : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 119
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Forskningsöversikt (refereegranskat)abstract
- Activated partial thromboplastin time (APTT) is widely practiced in preoperative screening. The value of using this test to predict the risk of perioperative bleeding is not well documented in Sweden. In this article, a literature review is performed to determine whether unselected APTT testing can predict abnormal perioperative bleeding. The current literature does not support coagulation screening with APTT in routine perioperative bleeding assessment, as preoperative screening with APTT has a low sensitivity for detection of clinically significant bleeding disorder. While a comprehensive bleeding history is crucial, the APTT test should only be performed on patients with a history of increased bleeding tendency. The conclusion of this literature review is that patients with a negative bleeding history do not require routine screening with APTT prior to surgery, which, if implemented, would lead to a more cost-effective perioperative routine.
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| 6. |
- Iglesias, Maria Jesus, et al.
(författare)
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Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.
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| 7. |
- Lassila, Riitta, et al.
(författare)
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Practical Viewpoints on the Diagnosis and Management of Heparin-Induced Thrombocytopenia
- 2011
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Ingår i: Seminars in Thrombosis and Hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 37:3, s. 328-335
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Tidskriftsartikel (refereegranskat)abstract
- Heparin-induced thrombocytopenia (HIT, type II) is an immune-mediated disorder due to antibodies formed against heparin platelet factor 4 complexes, usually appearing at days 5 to 14 after initiation of heparin. It is important to recognize HIT because heparin prophylaxis or treatment paradoxically associates with new venous and/or arterial thrombosis. Early clinical suspicion and diagnosis together with proper pharmacotherapy and close laboratory monitoring are the cornerstones for successful management. This includes monitoring of Thrombocytopenia, its Timing to heparin administration, appearance of new Thrombosis or resistance to treatment, and differential diagnosis by exclusion of oTher causes (the 4T's). Specific attention should be paid to the absence or presence of thrombosis and to tailoring thromboprophylaxis or anticoagulant therapy with a nonheparin alternative. Even in the absence of HIT-associated thrombosis, an active policy for prolonged thromboprophylaxis is demanded. Rapid and reliable assays should be developed for diagnosis and anticoagulation monitoring to secure safe management with nonheparins. Semiquantitative testing for on-call hours should be available and later confirmed as clinically needed. Alternative therapeutic options are available, but because their use is infrequent, experienced coagulation treatment centers should provide guidance in the treatment and in laboratory monitoring. Most of the evidence in HIT is grade IC, and thus the best evidence is provided by clinical experience. New anticoagulants and platelet inhibitors may offer future alternatives in the management of HIT, but the current treatment options provide the best experience and benefit. The joint clinical and laboratory guidelines provided in this article along with two practical case scenarios were prepared by a Nordic expert panel. They will be valuable for hematologists and colleagues who do not routinely encounter HIT.
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| 8. |
- Ljungkvist, Marcus, et al.
(författare)
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Correlation to FVIII : C in two thrombin generation tests: TGA-CAT and INNOVANCE ETP
- 2017
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Ingår i: Mediterranean Journal of Hematology and Infectious Diseases. - : Institute of Hematology, Catholic University. - 2035-3006. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Several thrombin-generation tests are available, but few have been directly compared. Our primary aim was to investigate the correlation of two thrombin generation tests, thrombin generation assay-calibrated automated thrombogram (TGA-CAT) and INNOVANCE ETP, to factor VIII levels (FVIII:C) in a group of patients with hemophilia A. The secondary aim was to investigate inter-laboratory variation for the TGA-CAT method. Methods: Blood samples were taken from 45 patients with mild, moderate and severe hemophilia A. The TGA-CAT method was performed at both centers while the INNOVANCE ETP was only performed at the Stockholm center. Correlation between parameters was evaluated using Spearman's rank correlation test. For determination of the TGA-CAT inter-laboratory variability, Bland-Altman plots were used. Results: The correlation for the INNOVANCE ETP and TGA-CAT methods with FVIII:C in persons with hemophilia (PWH) was r=0.701 and r=0.734 respectively. The correlation between the two methods was r=0.546. When dividing the study material into disease severity groups (mild, moderate and severe) based on FVIII levels, both methods fail to discriminate between them. The variability of the TGA-CAT results performed at the two centers was reduced after normalization; before normalization, 29% of values showed less than ±10% difference while after normalization the number increased to 41%. Conclusions: Both methods correlate in an equal manner to FVIII:C in PWH but show a poor correlation with each other. The level of agreement for the TGA-CAT method was poor though slightly improved after normalization of data. Further improvement of standardization of these methods is warranted.
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| 9. |
- Mobarrez, Fariborz, et al.
(författare)
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A multicolor flow cytometric assay for measurement of platelet-derived microparticles
- 2010
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 125:3, s. e110-e116
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Flow cytometry (FCM) is the most commonly used method for detection of platelet-derived microparticles (PDMPs), but it is poorly standardized and mainly used for “bedside” analyses in fresh samples. If PDMPs could be analyzed in previously frozen samples it would increase the usefulness of the method. However, cell membrane fragments from contaminating cells created during freezing/thawing may cause artifacts and disturb measurements. Materials and Methods: PDMPs were labeled with monoclonal antibodies directed against CD42a and CD62P, or CD42a and CD142. The PDMP gate was determined using forward scatter (FSC) and CD42a expression. The mean fluorescence intensities (MFIs) of CD62P or CD142 positive particles were translated into MESF-values (Molecules of Equivalent Soluble Fluorochrome) using a standard curve. FITC-labeled phalloidin (which binds to intracellular actin) was used to detect destroyed cells/cell fragments. Results: Phalloidin-positive particles were significantly more common in supernatants of frozen/thawed platelet rich and platelet poor plasma samples compared with supernatants of platelet free plasma. Highspeed centrifugation was then used to obtain PDMP samples with low contamination of cell fragments. Electron microscopy showed that these samples contained numerous round stained particles with cellular membranes of a size of 100-700 nm. Reproducibility experiments using plasma samples from healthy individuals showed that the coefficients of variation (CVs) of MESF values of CD62P and CD142 (both intra- and interassay) were <10%, and the variation between two cytometers in two different laboratories was <5%. We also found that PDMP expression of CD142 (i.e. tissue factor [TF]) and CD62P (i.e P-selectin) was around two times higher in samples from type 1-diabetes patients compared with those from healthy controls (p<0.001). Conclusions: The use of MESF values to quantify PDMP expression of P-selectin and TF yields reproducible data and enables comparison of data between laboratories. If high-speed centrifugation is performed, contamination of cell fragments is low in frozen/thawed samples. (C) 2009 Elsevier Ltd. All rights reserved.
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| 10. |
- Schmidt, David E., et al.
(författare)
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Clinical Implications of Discrepancy between One-Stage Clotting and Chromogenic Factor IX Activity in Hemophilia B
- 2024
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Ingår i: Thrombosis and Haemostasis. - : GEORG THIEME VERLAG KG. - 0340-6245 .- 2567-689X. ; 124:01, s. 032-039
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Tidskriftsartikel (refereegranskat)abstract
- Background Discrepancy in factor IX activity (FIX:C) between one-stage assay (OSA) and chromogenic substrate assay (CSA) in patients with hemophilia B (PwHB) introduces challenges for clinical management.Aim To study the differences in FIX:C using OSA and CSA in moderate and mild hemophilia B (HB), their impact on classification of severity, and correlation with genotype.Methods Single-center study including 21 genotyped and clinically characterized PwHB. FIX:C by OSA was measured using ActinFSL (Siemens) and CSA by Biophen (Hyphen). In addition, in vitro experiments with wild-type FIX were performed. Reproducibility of CSA was assessed between three European coagulation laboratories.Results FIX:C by CSA was consistently lower than by OSA, with 10/17 PwHB having a more severe hemophilia type by CSA. OSA displayed a more accurate description of the clinical bleeding severity, compared with CSA. A twofold difference between OSA:CSA FIX:C was present in 12/17 PwHB; all patients had genetic missense variants in the FIX serine protease domain. Discrepancy was also observed with diluted normal plasma, most significant for values below 0.10 IU/mL. Assessment of samples with low FIX:C showed excellent reproducibility of the CSA results between the laboratories.Conclusion FIX:C was consistently higher by OSA compared with the CSA. Assessing FIX:C by CSA alone would have led to diagnosis of a more severe hemophilia type in a significant proportion of patients. Our study suggests using both OSA and CSA FIX:C together with genotyping to classify HB severity and provide essential information for clinical management.
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