Tomas Lindahl - Profile on Academia.edu (original) (raw)
Papers by Tomas Lindahl
Platelets, Aug 14, 2012
Stroke is worldwide a leading cause of death and disability. Its etiology is regarded as heteroge... more Stroke is worldwide a leading cause of death and disability. Its etiology is regarded as heterogeneous. Platelets are implicated in its pathophysiology, but our understanding of their specific role is incomplete. Only sparse and conflicting information exists about platelet reactivity and activity in acute stroke. Some scientists take the view that platelets activate in conjunction with acute cerebral infarctions. Others put forward evidence corroborating the contrary notion. Increased soluble P-selectin as a sign of platelet and/or endothelial activity seems to be a feature of the disease. The latter point of view is opposed by other researchers. Due to these conflicting opinions, this study is devoted to platelet characteristics in acute cerebral infarctions. We studied subjects (n ¼ 72; age 74 AE 10(SD) years; 31 females) having acute stroke. As controls served atrial fibrillation (AF) patients (n ¼ 58; age 69 AE 7(SD) years; 12 females) subject to electrical cardioversion, a flow cytometer was put to use for measuring platelet reactivity and activity. After agonist provocation, both platelet bound P-selectin and fibrinogen were employed as estimates of platelet reactivity. Dilutions of a thrombin-receptor-activating peptide (TRAP-6) (74 and 57 mmol/l) (P-selectin and fibrinogen) and ADP (8.5 and 1.7 mmol/l) (fibrinogen only) were put to use as platelet agonists. Membrane-bound P-selectin without agonist stimulation served as a measure of in vivo platelet activation. Soluble P-selectin, as determined from a commercial ELISA, was used to assess platelet and/or endothelial activity. In acute stroke neither platelet-bound P-selectin nor fibrinogen after stimulation, i.e. reactivity, differed from AF controls. In contrast, lower platelet activity as judged from surface attached and circulating P-selectin without agonist stimulation proved to be a feature of cerebral infarctions. The p-values were p < 0.001 and p < 0.01, respectively. It is concluded that acute stroke is not associated with platelet reactivity platelets circulate less activated during the disease. It is evident that the mechanisms reflecting platelet reactivity and activity being investigated in this study play minor roles in stroke pathophysiology. New powerful platelet inhibitory drugs are currently introduced. To avoid major bleeding studies on platelet, behavior in acute stroke are necessary before including these medications in stroke treatment protocols.
Frontiers in Cardiovascular Medicine, Sep 29, 2021
Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In ... more Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the effects of heparin/antithrombin and bivalirudin on PAR1-and PAR4-mediated intracellular calcium mobilization, aggregation, α-granule release, and procoagulant membrane exposure in platelets exposed to thrombin concentrations likely to be encountered in the thrombus microenvironment during thrombosis. At physiological antithrombin levels, heparin treatment resulted in complete and sustained inhibition of thrombin-induced PAR4-mediated platelet activation, but transient PAR1 signaling was sufficient to elicit significant α-granule release and platelet aggregation. In contrast, bivalirudin treatment resulted in rapid and profound inhibition of signaling from both PAR receptors, followed by a delayed phase of PAR4-mediated platelet activation, resulting in a robust prothrombotic response. Combination treatment with bivalirudin and subtherapeutic concentrations of heparin completely inhibited the residual platelet activation observed with single drug treatment at all time-points. Our results show that heparin and bivalirudin have different and complementary inhibitory effects on the activation of PAR1 and PAR4 by thrombin.
Clotting time by free oscillation rheometry and visual inspection and a viscoelastic description of the clotting phenomenon
Scandinavian Journal of Clinical & Laboratory Investigation, Oct 1, 2003
An automated procedure for determination of clotting time in whole blood was validated by direct ... more An automated procedure for determination of clotting time in whole blood was validated by direct comparison with the reference method, visual clotting time determination. The procedure was based on a 10 Hz free oscillation rheometer (FOR) of our design, the ReoRox 4. Recalcified citrated blood samples (n = 30), clotting in the range 4 to 20 min, were used in the validation. Every 30 s of the analysis, as the change in stiffness (deltaG*) of the sample was monitored by FOR, the sample cup was shortly removed from the FOR and its contents inspected for first signs of clotting, i.e. visual clotting time determination. Various FOR clotting criteria were attempted. Best correlation to visual clotting time was found when deltaG* reached 0.01 Pa, which yielded linear regression slope, intercept and r2 of 0.98, 0.09 min and 0.98, respectively. For comparison, six plasma samples were analyzed in the same way and gave almost the same results. The accuracy of the FOR determinations was checked by also analyzing, in parallel, portions of the sample with a conventional oscillation rheometer, a Bohlin VOR. The rationale is given for preferring deltaG* over G* as a FOR monitoring function in coagulation tests and for including median filtration of the primary FOR data. An extension of the FOR theory to include deltaG* and evidence in support of inhomogeneous blood clotting are also given.
Thrombosis and Haemostasis, 2007
Thrombin is apivotalenzyme formedinthe coagulationcascade and an importanta nd potentp lateleta c... more Thrombin is apivotalenzyme formedinthe coagulationcascade and an importanta nd potentp lateleta ctivator.The twop rotease-activatedthrombin receptors on human platelets aredenoted PAR1 and PAR4.The physiologicalr elevanceo fP AR4 is still unclear,asb oth aggregation and secretion can be accom-plishedbyP AR1 activation alone. In the presentstudy we have investigatedthe role of PARs in plateletactivation, blood coagulation, clot elasticity and fibrinolysis. Flow cytometry,freeoscillationrheometry and thrombin generation measurements were used to analyzebloodorplatelet-rich plasma from healthyindividuals. Maximum PAR1 activation with thep eptide SFLLRN gave fewerf ibrinogen-binding platelets with lowerm eanf luorescent intensity than maximum PAR4 activation with AY PGKF.
Nutrients, 2021
A low intake of selenium is associated with increased cardiovascular mortality. This could be red... more A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q10. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly low...
Thrombosis and Haemostasis, 1988
SummaryGel-filtration experiments of mixtures of functionally active and inactive forms of plasmi... more SummaryGel-filtration experiments of mixtures of functionally active and inactive forms of plasminogen activator inhibitor (PAI) with human plasma or bovine serum albumin have provided evidence for the existence of a discrete binding protein of PAI in plasma. Most likely it is a glycoprotein with a molecular weight of approximately 150,000. The data suggest that it forms a very stable complex with functionally active forms of PAI, but not with the inactive or “latent” PAI. However, the PAI activity seems not to be significantly altered by the interaction with the binding protein. Assuming that a stoichiometric complex is formed, titration experiments suggest that a pool of normal human plasma contains about 40–50 mg of PAI-binding protein liter.
Upsala Journal of Medical Sciences, 2017
Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent ... more Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena's Simple Simon TM PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type. Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 mL end-to-end capillary used to add the citrated plasma sample to 200 mL of prothrombin time (PT) reagent by either a 20 mL or a 5 mL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons. Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 mL variant showed markedly higher PT results than the 5 mL. The effects were even more pronounced at room temperature than at þ37 C. In plasmas from patients treated with NOACs (n ¼ 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 mL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1-2.1 for dabigatran and apixaban, and INR 1.1-5.0 for rivaroxaban. Using an INR ratio between the 20 mL and 5 mL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 mg/L for apixaban, 60 mg/L for dabigatran, and 20 mg/L for rivaroxaban. Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.
Journal of Biological Chemistry, 2016
Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defe... more Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematological features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex hormone-binding globulin levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms as follows: (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 °C reduction in body temperature and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of a few key proteins. The comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation and have implications for our understanding of physiology in general. * This work was supported by Grant R126-2012-12408 from the Lundbech Foundation (to F. O. and M. T. O.) and by Aalborg University (to K. G. W. and R. H.). The authors declare that they have no conflicts of interest with the contents of this article. □ S This article contains supplemental Tables S1-S5 and the supplemental database Bear-protein-db-Febr2013.txt. The mass spectrometric raw data and spectral libraries associated with this manuscript are available from ProteomeXchange with the accession number PXD003946.
Thrombosis and haemostasis, Jan 2, 2014
CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. ... more CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.8...
Journal of the American College of Cardiology, 2012
Background: In the prospective, randomized TWENTE trial, the zotarolimus-eluting Resolute stent w... more Background: In the prospective, randomized TWENTE trial, the zotarolimus-eluting Resolute stent was at 1 year follow-up non-inferior to the everolimus-eluting Xience V stent for the primary endpoint target vessel failure. This composite endpoint consisted of cardiac death, clinically indicated target vessel revascularization, or target vessel-related myocardial infarction (MI). So far, few long-term data of prospective head-to-head comparisons between both DES have been reported. Methods: Patients requiring percutaneous coronary interventions (PCI) with DES implantation at Thoraxcentrum Twente in Enschede were randomization between Resolute (Medtronic Vascular, Santa Rosa, CA, USA) and Xience V (Abbott Vascular, Santa Clara, CA, USA) in a 1:1 fashion. Inclusion of all coronary or bypass graft lesions and all clinical settings was permitted except for primary PCI (i.e. acute ST-elevation myocardial infarction (STEMI) was an exclusion criterion). Both external monitoring and clinical event adjudication were performed by an independent external contract research organization (Cardialysis, Rotterdam, the Netherlands). Two year clinical follow-up was performed as indicated in the study protocol. Results: A total of 1,391 patients were enrolled in the TWENTE trial between June 2008 and August 2010. The study population comprised 21.6% diabetics with a vast majority of complex lesions and "off-label" indications for drug-eluting stents (77.4%). Patients presented with either stable angina (48.5%) or unstable angina/Non-STEMI (51.5%). Demographics, baseline angiographic and procedural data, and 2-year clinical follow-up data will be presented. This includes the primary endpoint of the study: Target vessel failure (TVF) at 2 year follow-up. Secondary endpoints include the individual components of the primary endpoint and the incidence of very late stent thrombosis. In addition, results of subgroup analyses will be reported. Conclusions: Results of pre-specified analyses of 2-year clinical outcome of the TWENTE trial will be presented at TCT 2012.
Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation
Journal of Thrombosis and Haemostasis, 2013
Thrombin generation in plasma measured with a commercial reagent for the detection of micropartic... more Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation
DivisionofClinicalChemistry,CardiovascularInflammationResearchCenter,LinkopingUniversity,LinkopingSE-58185Sweden andthe DepartmentofMedicalSciences,UniversityHospital,UppsalaSE-75105, Sweden
Nya svarsrutiner för protrombinkomplex
Vårdfacket, 1999
[Coordinated Swedish transfer is recommended during 1999. Prothrombin complex measurement should be indicated as a quota, not percent]
PubMed, May 19, 1999
Journal of Thrombosis and Haemostasis, Aug 1, 2016
To cite this article: Lindahl TL, Macwan AS, Ramstr€ om S. Protease-activated receptor 4 is more ... more To cite this article: Lindahl TL, Macwan AS, Ramstr€ om S. Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets.
Sevuparin : effects on hemostasis of a novel polysaccharide drug derived from heparin
Journal of Thrombosis and Haemostasis, 2015
Journal of Reproductive Immunology, May 1, 2012
Thrombosis and Haemostasis, Sep 1, 2014
Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Alth... more Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with α-and γ-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ibα.
Free oscillation rheometry detects changes in clot properties in pregnancy and thrombocytopenia
Platelets, 2008
Improved methods are needed to identify patients at risk for thrombotic or bleeding events. Free ... more Improved methods are needed to identify patients at risk for thrombotic or bleeding events. Free oscillation rheometry (FOR) is a technique that offers information on coagulation, based on contributions of all blood components, by measurement of clotting time and changes in clot elasticity. This is the first study that evaluates FOR parameters in subjects likely to represent hypercoagulability (pregnant women) and hypocoagulability (thrombocytopenic patients). Clotting time and blood clot elasticity were measured by FOR in blood samples obtained from women in different pregnancy trimesters (n = 58), in thrombocytopenic patients before and after a platelet transfusion (n = 20) and in healthy blood donors (n = 60). The clotting time was shorter and the clot elasticity higher in pregnant women compared to the non-pregnant female blood donors. The elasticity was higher in late pregnancy compared to early pregnancy. Compared to the blood donors, the thrombocytopenic patients had lower elasticity, which was increased by a platelet transfusion, but there was no difference in clotting time. The results suggest that FOR can provide new information on the haemostatic status of patients at risk of thrombotic or bleeding events as well as information on the haemostatic effect of a platelet transfusion.
Platelets, Aug 14, 2012
Stroke is worldwide a leading cause of death and disability. Its etiology is regarded as heteroge... more Stroke is worldwide a leading cause of death and disability. Its etiology is regarded as heterogeneous. Platelets are implicated in its pathophysiology, but our understanding of their specific role is incomplete. Only sparse and conflicting information exists about platelet reactivity and activity in acute stroke. Some scientists take the view that platelets activate in conjunction with acute cerebral infarctions. Others put forward evidence corroborating the contrary notion. Increased soluble P-selectin as a sign of platelet and/or endothelial activity seems to be a feature of the disease. The latter point of view is opposed by other researchers. Due to these conflicting opinions, this study is devoted to platelet characteristics in acute cerebral infarctions. We studied subjects (n ¼ 72; age 74 AE 10(SD) years; 31 females) having acute stroke. As controls served atrial fibrillation (AF) patients (n ¼ 58; age 69 AE 7(SD) years; 12 females) subject to electrical cardioversion, a flow cytometer was put to use for measuring platelet reactivity and activity. After agonist provocation, both platelet bound P-selectin and fibrinogen were employed as estimates of platelet reactivity. Dilutions of a thrombin-receptor-activating peptide (TRAP-6) (74 and 57 mmol/l) (P-selectin and fibrinogen) and ADP (8.5 and 1.7 mmol/l) (fibrinogen only) were put to use as platelet agonists. Membrane-bound P-selectin without agonist stimulation served as a measure of in vivo platelet activation. Soluble P-selectin, as determined from a commercial ELISA, was used to assess platelet and/or endothelial activity. In acute stroke neither platelet-bound P-selectin nor fibrinogen after stimulation, i.e. reactivity, differed from AF controls. In contrast, lower platelet activity as judged from surface attached and circulating P-selectin without agonist stimulation proved to be a feature of cerebral infarctions. The p-values were p < 0.001 and p < 0.01, respectively. It is concluded that acute stroke is not associated with platelet reactivity platelets circulate less activated during the disease. It is evident that the mechanisms reflecting platelet reactivity and activity being investigated in this study play minor roles in stroke pathophysiology. New powerful platelet inhibitory drugs are currently introduced. To avoid major bleeding studies on platelet, behavior in acute stroke are necessary before including these medications in stroke treatment protocols.
Frontiers in Cardiovascular Medicine, Sep 29, 2021
Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In ... more Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the effects of heparin/antithrombin and bivalirudin on PAR1-and PAR4-mediated intracellular calcium mobilization, aggregation, α-granule release, and procoagulant membrane exposure in platelets exposed to thrombin concentrations likely to be encountered in the thrombus microenvironment during thrombosis. At physiological antithrombin levels, heparin treatment resulted in complete and sustained inhibition of thrombin-induced PAR4-mediated platelet activation, but transient PAR1 signaling was sufficient to elicit significant α-granule release and platelet aggregation. In contrast, bivalirudin treatment resulted in rapid and profound inhibition of signaling from both PAR receptors, followed by a delayed phase of PAR4-mediated platelet activation, resulting in a robust prothrombotic response. Combination treatment with bivalirudin and subtherapeutic concentrations of heparin completely inhibited the residual platelet activation observed with single drug treatment at all time-points. Our results show that heparin and bivalirudin have different and complementary inhibitory effects on the activation of PAR1 and PAR4 by thrombin.
Clotting time by free oscillation rheometry and visual inspection and a viscoelastic description of the clotting phenomenon
Scandinavian Journal of Clinical & Laboratory Investigation, Oct 1, 2003
An automated procedure for determination of clotting time in whole blood was validated by direct ... more An automated procedure for determination of clotting time in whole blood was validated by direct comparison with the reference method, visual clotting time determination. The procedure was based on a 10 Hz free oscillation rheometer (FOR) of our design, the ReoRox 4. Recalcified citrated blood samples (n = 30), clotting in the range 4 to 20 min, were used in the validation. Every 30 s of the analysis, as the change in stiffness (deltaG*) of the sample was monitored by FOR, the sample cup was shortly removed from the FOR and its contents inspected for first signs of clotting, i.e. visual clotting time determination. Various FOR clotting criteria were attempted. Best correlation to visual clotting time was found when deltaG* reached 0.01 Pa, which yielded linear regression slope, intercept and r2 of 0.98, 0.09 min and 0.98, respectively. For comparison, six plasma samples were analyzed in the same way and gave almost the same results. The accuracy of the FOR determinations was checked by also analyzing, in parallel, portions of the sample with a conventional oscillation rheometer, a Bohlin VOR. The rationale is given for preferring deltaG* over G* as a FOR monitoring function in coagulation tests and for including median filtration of the primary FOR data. An extension of the FOR theory to include deltaG* and evidence in support of inhomogeneous blood clotting are also given.
Thrombosis and Haemostasis, 2007
Thrombin is apivotalenzyme formedinthe coagulationcascade and an importanta nd potentp lateleta c... more Thrombin is apivotalenzyme formedinthe coagulationcascade and an importanta nd potentp lateleta ctivator.The twop rotease-activatedthrombin receptors on human platelets aredenoted PAR1 and PAR4.The physiologicalr elevanceo fP AR4 is still unclear,asb oth aggregation and secretion can be accom-plishedbyP AR1 activation alone. In the presentstudy we have investigatedthe role of PARs in plateletactivation, blood coagulation, clot elasticity and fibrinolysis. Flow cytometry,freeoscillationrheometry and thrombin generation measurements were used to analyzebloodorplatelet-rich plasma from healthyindividuals. Maximum PAR1 activation with thep eptide SFLLRN gave fewerf ibrinogen-binding platelets with lowerm eanf luorescent intensity than maximum PAR4 activation with AY PGKF.
Nutrients, 2021
A low intake of selenium is associated with increased cardiovascular mortality. This could be red... more A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q10. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly low...
Thrombosis and Haemostasis, 1988
SummaryGel-filtration experiments of mixtures of functionally active and inactive forms of plasmi... more SummaryGel-filtration experiments of mixtures of functionally active and inactive forms of plasminogen activator inhibitor (PAI) with human plasma or bovine serum albumin have provided evidence for the existence of a discrete binding protein of PAI in plasma. Most likely it is a glycoprotein with a molecular weight of approximately 150,000. The data suggest that it forms a very stable complex with functionally active forms of PAI, but not with the inactive or “latent” PAI. However, the PAI activity seems not to be significantly altered by the interaction with the binding protein. Assuming that a stoichiometric complex is formed, titration experiments suggest that a pool of normal human plasma contains about 40–50 mg of PAI-binding protein liter.
Upsala Journal of Medical Sciences, 2017
Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent ... more Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena's Simple Simon TM PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type. Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 mL end-to-end capillary used to add the citrated plasma sample to 200 mL of prothrombin time (PT) reagent by either a 20 mL or a 5 mL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons. Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 mL variant showed markedly higher PT results than the 5 mL. The effects were even more pronounced at room temperature than at þ37 C. In plasmas from patients treated with NOACs (n ¼ 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 mL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1-2.1 for dabigatran and apixaban, and INR 1.1-5.0 for rivaroxaban. Using an INR ratio between the 20 mL and 5 mL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 mg/L for apixaban, 60 mg/L for dabigatran, and 20 mg/L for rivaroxaban. Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.
Journal of Biological Chemistry, 2016
Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defe... more Brown bears (Ursus arctos) hibernate for 5-7 months without eating, drinking, urinating, and defecating at a metabolic rate of only 25% of the summer activity rate. Nonetheless, they emerge healthy and alert in spring. We quantified the biochemical adaptations for hibernation by comparing the proteome, metabolome, and hematological features of blood from hibernating and active free-ranging subadult brown bears with a focus on conservation of health and energy. We found that total plasma protein concentration increased during hibernation, even though the concentrations of most individual plasma proteins decreased, as did the white blood cell types. Strikingly, antimicrobial defense proteins increased in concentration. Central functions in hibernation involving the coagulation response and protease inhibition, as well as lipid transport and metabolism, were upheld by increased levels of very few key or broad specificity proteins. The changes in coagulation factor levels matched the changes in activity measurements. A dramatic 45-fold increase in sex hormone-binding globulin levels during hibernation draws, for the first time, attention to its significant but unknown role in maintaining hibernation physiology. We propose that energy for the costly protein synthesis is reduced by three mechanisms as follows: (i) dehydration, which increases protein concentration without de novo synthesis; (ii) reduced protein degradation rates due to a 6 °C reduction in body temperature and decreased protease activity; and (iii) a marked redistribution of energy resources only increasing de novo synthesis of a few key proteins. The comprehensive global data identified novel biochemical strategies for bear adaptations to the extreme condition of hibernation and have implications for our understanding of physiology in general. * This work was supported by Grant R126-2012-12408 from the Lundbech Foundation (to F. O. and M. T. O.) and by Aalborg University (to K. G. W. and R. H.). The authors declare that they have no conflicts of interest with the contents of this article. □ S This article contains supplemental Tables S1-S5 and the supplemental database Bear-protein-db-Febr2013.txt. The mass spectrometric raw data and spectral libraries associated with this manuscript are available from ProteomeXchange with the accession number PXD003946.
Thrombosis and haemostasis, Jan 2, 2014
CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. ... more CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.8...
Journal of the American College of Cardiology, 2012
Background: In the prospective, randomized TWENTE trial, the zotarolimus-eluting Resolute stent w... more Background: In the prospective, randomized TWENTE trial, the zotarolimus-eluting Resolute stent was at 1 year follow-up non-inferior to the everolimus-eluting Xience V stent for the primary endpoint target vessel failure. This composite endpoint consisted of cardiac death, clinically indicated target vessel revascularization, or target vessel-related myocardial infarction (MI). So far, few long-term data of prospective head-to-head comparisons between both DES have been reported. Methods: Patients requiring percutaneous coronary interventions (PCI) with DES implantation at Thoraxcentrum Twente in Enschede were randomization between Resolute (Medtronic Vascular, Santa Rosa, CA, USA) and Xience V (Abbott Vascular, Santa Clara, CA, USA) in a 1:1 fashion. Inclusion of all coronary or bypass graft lesions and all clinical settings was permitted except for primary PCI (i.e. acute ST-elevation myocardial infarction (STEMI) was an exclusion criterion). Both external monitoring and clinical event adjudication were performed by an independent external contract research organization (Cardialysis, Rotterdam, the Netherlands). Two year clinical follow-up was performed as indicated in the study protocol. Results: A total of 1,391 patients were enrolled in the TWENTE trial between June 2008 and August 2010. The study population comprised 21.6% diabetics with a vast majority of complex lesions and "off-label" indications for drug-eluting stents (77.4%). Patients presented with either stable angina (48.5%) or unstable angina/Non-STEMI (51.5%). Demographics, baseline angiographic and procedural data, and 2-year clinical follow-up data will be presented. This includes the primary endpoint of the study: Target vessel failure (TVF) at 2 year follow-up. Secondary endpoints include the individual components of the primary endpoint and the incidence of very late stent thrombosis. In addition, results of subgroup analyses will be reported. Conclusions: Results of pre-specified analyses of 2-year clinical outcome of the TWENTE trial will be presented at TCT 2012.
Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation
Journal of Thrombosis and Haemostasis, 2013
Thrombin generation in plasma measured with a commercial reagent for the detection of micropartic... more Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation
DivisionofClinicalChemistry,CardiovascularInflammationResearchCenter,LinkopingUniversity,LinkopingSE-58185Sweden andthe DepartmentofMedicalSciences,UniversityHospital,UppsalaSE-75105, Sweden
Nya svarsrutiner för protrombinkomplex
Vårdfacket, 1999
[Coordinated Swedish transfer is recommended during 1999. Prothrombin complex measurement should be indicated as a quota, not percent]
PubMed, May 19, 1999
Journal of Thrombosis and Haemostasis, Aug 1, 2016
To cite this article: Lindahl TL, Macwan AS, Ramstr€ om S. Protease-activated receptor 4 is more ... more To cite this article: Lindahl TL, Macwan AS, Ramstr€ om S. Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets.
Sevuparin : effects on hemostasis of a novel polysaccharide drug derived from heparin
Journal of Thrombosis and Haemostasis, 2015
Journal of Reproductive Immunology, May 1, 2012
Thrombosis and Haemostasis, Sep 1, 2014
Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Alth... more Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with α-and γ-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ibα.
Free oscillation rheometry detects changes in clot properties in pregnancy and thrombocytopenia
Platelets, 2008
Improved methods are needed to identify patients at risk for thrombotic or bleeding events. Free ... more Improved methods are needed to identify patients at risk for thrombotic or bleeding events. Free oscillation rheometry (FOR) is a technique that offers information on coagulation, based on contributions of all blood components, by measurement of clotting time and changes in clot elasticity. This is the first study that evaluates FOR parameters in subjects likely to represent hypercoagulability (pregnant women) and hypocoagulability (thrombocytopenic patients). Clotting time and blood clot elasticity were measured by FOR in blood samples obtained from women in different pregnancy trimesters (n = 58), in thrombocytopenic patients before and after a platelet transfusion (n = 20) and in healthy blood donors (n = 60). The clotting time was shorter and the clot elasticity higher in pregnant women compared to the non-pregnant female blood donors. The elasticity was higher in late pregnancy compared to early pregnancy. Compared to the blood donors, the thrombocytopenic patients had lower elasticity, which was increased by a platelet transfusion, but there was no difference in clotting time. The results suggest that FOR can provide new information on the haemostatic status of patients at risk of thrombotic or bleeding events as well as information on the haemostatic effect of a platelet transfusion.