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  • 1.
    Andraos, R.
    et al.
    Department of Clinical and Experimental medicine, Linköping University, Linköping, Sweden.
    Södergren, A.L.
    Department of Clinical and Experimental medicine, Linköping University, Linköping, Sweden.
    Öllinger, K.
    Department of Clinical and Experimental medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental medicine, Linköping University, Linköping, Sweden.
    Reactive oxygen species enhance generation of subpopulations of procoagulant platelets2014Conference paper (Refereed)
  • 2.
    Andraos, R.
    et al.
    Linköping University, Linköping, Sweden.
    Södergren, A.L.
    Linköping University, Linköping, Sweden.
    Öllinger, K.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Reactive oxygen species enhance generation of subpopulations of procoagulant platelets2014Conference paper (Refereed)
  • 3.
    Basabe-Desmonts, L.
    et al.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland; Biomedical Diagnostics Institute Programme, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Ramström, Sofia
    Biomedical Diagnostics Institute Programme, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Lopez-Alonso, A.
    Biomedical Diagnostics Institute Programme, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Somers, M.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Ricco, A. J.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Kenny, D.
    Biomedical Diagnostics Institute Programme, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Disposable bioanalytical microdevice for monitoring the effect of anti-platelet drugs2010In: 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 2010, 2010, p. 1388-1390Conference paper (Refereed)
    Abstract [en]

    We report a disposable self-powered integrated microfluidic chip that enables a rapid and simple platelet-function assay from small samples of whole blood. The chip integrates a single-cell adhesion assay with a microfluidic platform; it enables accurate quantification of platelet adhesion, and it controls whole blood flow rate, shear stress, volume of sample, and assay time.

  • 4.
    Basabe-Desmonts, L.
    et al.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Ramström, Sofia
    BDI Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Meade, G.
    BDI Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    O'Neill, S.
    BDI Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Riaz, A.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Lee, L. P.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland; Biomolecular Nanotechnology Center, Berkeley Sensor & Actuator Center, Department of Bioengineering, University of California, Berkeley CA, USA.
    Ricco, A. J.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Kenny, D.
    BDI Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Single-Step Separation of Platelets from Whole Blood Coupled with Digital Quantification by Interfacial Platelet Cytometry (iPC)2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 18, p. 14700-14706Article in journal (Refereed)
    Abstract [en]

    We report the efficient single-step separation of individual platelets from unprocessed whole blood, enabling digital quantification of platelet function using interfacial platelet cytometry (iPC) on a chip iPC is accomplished by the precision micropatterning of platelet-specific protein surfaces on solid substrates By separating platelets From whole blood using specific binding to protein spots of a defined size. iPC implements a simple incubate-and-rinse approach, without sample preparation, that enables (I) the study of platelets in the physiological situation of interaction with a protein surface, (2) the choice of the number of platelets bound on each protein spot, from one to many, (3) control of the platelet platelet distance, including the possibility to study noninteracting single platelets, (4) digital quantification (counting) of platelet adhesion to selected protein matrices, enabling statistical characterization of platelet subpopuladons from meaningfully large numbers of single platelets, (5) the study of platelet receptor expression and spatial distribution, and (6) a detailed study of the morphology of isolated single platelets at activation levels that can be manipulated To date, we have demonstrated 1-4 of the above list Platelets were separated from whole blood using tPC with fibrinogen, von Willebrand factor (VWF), and anti-CD42b antibody printed "spots" ranging from a fraction of one to several platelet diameters (2-24 full) The number of platelets captured per spot depends strongly on the protein matrix and the surface area of the spot, together with the platelet volume, morphology, and activation state Blood samples from healthy donors, a May-Hegglin-anomaly patient, and a Glanzmann's Thrombasthenia patient were analyzed via iPC to confirm the specificity of the interaction between protein matrices and platelets For example, the results indicate that platelets interact with fibrinogen spots only through the fibrinogen receptor (aIlb beta 3) and, relevant to diagnostic applications, platelet adhesion correlates strongly with normal versus abnormal platelet function A critical function of platelets is to adhere to regions of damage on blood vessel walls, in contrast to conventional flow cytometry, where platelets are suspended in solution, iPC enables physiologically relevant platelet bioassays based on platelet/protein-matrix inter actions on surfaces. This technology should be inexpensive to implement in clinical assay format, is readily integrable into fluidic microdevices, and paves the way for high-throughput platelet assays from microliter volumes of whole blood.

  • 5. Batakis, P.
    et al.
    Lopez-Alonso, A.
    Claesson, K.
    Kenny, D.
    Basabe-Desmonts, L.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Microcontact printing as a tool to study platelet adhesion2013Conference paper (Refereed)
  • 6.
    Boknas, N.
    et al.
    Linköping University, Linköping, Sweden.
    Faxalv, L.
    Linköping University, Linköping, Sweden.
    Lindahl, T. L.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents2014In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 4, p. 515-518Article in journal (Refereed)
    Abstract [en]

    Background: A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect.

    Objectives: To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. Methods Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin).

    Results: Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP-reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation.

    Conclusions: Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs.

  • 7. Boknäs, N.
    et al.
    Faxälv, L.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Phospholipid-containing reagents for the detection of tissue factor on microparticles by thrombin generation cause analytical errors by amplifying the contact activation pathway2013Conference paper (Refereed)
  • 8.
    Boknäs, N.
    et al.
    Linköping University, Linköping, Sweden.
    Faxälv, L.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    LLinköping University, Linköping, Sweden.
    Lindahl, T.
    Linköping University, Linköping, Sweden.
    Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S1, p. 401-402Article in journal (Refereed)
  • 9.
    Boknäs, Niklas
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sanchez Cenellas, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Wallstedt, Maria
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Thrombin-induced platelet activation via PAR4: pivotal role for exosite II2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 558-565Article in journal (Refereed)
    Abstract [en]

    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 alpha- and gamma-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 Ib alpha.

  • 10.
    Boknäs, Niklas
    et al.
    Linköping University, Linköping, Sweden .
    Faxälv, Lars
    Linköping University, Linköping, Sweden .
    Ström, Jakob O.
    Linköping University, Linköping, Sweden .
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Linköping, Sweden .
    Ramström, Sofia
    Linköping University, Linköping, Sweden .
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden .
    Platelets do not generate activated factor XII: how inappropriate experimental models have led to misleading conclusions2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, p. 1692-1694Article in journal (Refereed)
  • 11.
    Boknäs, Niklas
    et al.
    Department of Haematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
    Macwan, Ankit S.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Södergren, Anna L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Cardiovascular Research Centre, Örebro University, School of Medical Sciences, Örebro, Sweden.
    Platelet function testing at low platelet counts: When can you trust your analysis?2019In: Research and Practice in Thrombosis and Haemostasis, E-ISSN 2475-0379, Vol. 3, no 2, p. 285-290Article in journal (Refereed)
    Abstract [en]

    Background: Although flow cytometry is often brought forward as a preferable method in the setting of thrombocytopenia, the relative effects of low sample counts on results from flow cytometry-based platelet function testing (FC-PFT) in comparison with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) has not been reported.

    Objectives: To compare the effects of different sample platelet counts (10, 50, 100, and 200x10(9)L(-1)) on platelet activation measured with FC-PFT, LTA, and MEA using the same anticoagulant and agonist concentrations as for the commercial MEA test.

    Methods: Platelets were stimulated with two commonly used platelet agonists (ADP [6.5 mu molL(-1)] and PAR1-AP [TRAP, 32 mu molL(-1)]). The specified sample platelet counts were obtained by combining platelet-rich and platelet poor hirudinized plasma in different proportions with or without red blood cells.

    Results: For FC, P-selectin exposure and PAC-1 binding was reduced at 10x10(9)L(-1) after stimulation with PAR1-AP (by approximately 20% and 50%, respectively), but remained relatively unchanged when ADP was used as agonist (n=9). The platelet count-dependent effects observed with PAR1-AP were eliminated when samples were pre-incubated with apyrase, implying that reduced purinergic signaling was the main underlying factor (n=5). Both aggregometry-based PFTs showed a 50% reduction at 50x10(9)L(-1) and more than 80% reduction at 10x10(9)L(-1), irrespective of agonist used (n=7).

    Conclusions: Although FC-PFT is generally preferable to aggregometry-based PFTs in situations with low sample platelet counts, a careful optimization of experimental parameters is still required in order to eliminate platelet count-related effects.

  • 12.
    Boknäs, Niklas
    et al.
    Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 5, p. 512-519Article in journal (Refereed)
    Abstract [en]

    Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

  • 13. Börgeson, Emma
    et al.
    Lönn, Johanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bergström, Ida
    Brodin, Veronika Patcha
    Ramström, Sofia
    Linköping University, Linköping, Sweden .
    Nayeri, Fariba
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences.
    Lipoxin A(4) inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 4, p. 1489-1497Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A(4) (LXA(4)) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA(4) on the P. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione S-transferase pulldown assay. The study shows that P. gingivalis activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA(4). Furthermore, we found that LXA(4) significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA(4) was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA(4) antagonizes P. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.

  • 14.
    Centellas, Daniel Sanchez
    et al.
    Linköping University, Linköping, Sweden.
    Gudlur, Sushanth
    Linköping University, Linköping, Sweden; Nanyang Technology University, Singapore, Singapore..
    Vicente-Carrillo, Alejandro
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    A cluster of aspartic residues in the extracellular loop II of PAR 4 is important for thrombin interaction and activation of platelets2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 154, p. 84-92Article in journal (Refereed)
    Abstract [en]

    Thrombin activates platelets via proteolytic cleavage of protease-activated receptors (PARs) 1 and 4. The two PARs have distinct but complementary roles. The mechanisms responsible for PAR1 activation by thrombin have been extensively studied. However, much less is known regarding thrombin activation of PAR4, especially the potential involvement of regions of PAR4 other than the N-terminal, which is bound to the catalytic site of thrombin. We have studied PAR4 in S. cerevisiae strainMMY12, an expression system in which the GPCR receptors are connected to a Lac Z reporter gene resulting in increased beta-galactosidase activity. This approach was used to assess PAR4 mutants to evaluate the contribution of different aspartic residues in facilitating PAR4 activation. Furthermore, peptides mimicking parts of the PAR4 N-terminal and the second extracellular loop (ECLII) were tested for their ability to inhibit platelet activation by thrombin. Binding of these peptides to gamma-thrombin was studied by monitoring the decrease in tryptophan fluorescence intensity of thrombin. We conclude that not only the N-terminal but also the electronegative aspartic residues D224, D230 and D235 (located in ECLII) are be important for PAR4 binding to thrombin. We further suggest that they play a role for the tethered ligand binding to the receptor, as mutations also affected activation in response to a PAR4-activating peptide mimicking the new N-terminal formed after cleavage. This agrees with previous results on PAR1 and thrombin binding. We suggest that the ECLII of PAR4 could be a potential target for antithrombotic drug development.

  • 15.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Umeå, Sweden.
    Sundberg, Erik
    Umeå University, Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Umeå, Sweden.
    Hultdin, Johan
    Umeå University, Umeå, Sweden.
    Baudin, Maria
    Umeå University, Umeå, Sweden.
    Larsson, Johanna
    Umeå University, Umeå, Sweden.
    Dunne, Eimear
    Royal Coll Surgeons Ireland, Dublin, Ireland.
    Kenny, Dermot
    Royal Coll Surgeons Ireland, Dublin, Ireland.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Nilsson, Sofie
    Umeå University, Umeå, Sweden.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background: Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation.

    Methods: Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications.

    Results: The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 16. Deb, S.
    et al.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Intracellular signaling in platelet sub-populations: a flow cytometry-based approach2014Conference paper (Refereed)
  • 17.
    Deb, S.
    et al.
    Linköping University, Linköping, Sweden.
    Sjöström, C.
    Linköping University, Linköping, Sweden.
    Tharmakulanathan, A.
    Linköping University, Linköping, Sweden.
    Boknäs, N.
    Linköping University, Linköping, Sweden.
    Lotfi, K.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Individual variation in hemostatic alterations caused by tyrosine kinase inhibitors: a way to improve personalized cancer therapy?2016In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 140, no Suppl. 1, p. S196-S197, article id PO-55Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: During the last two decades, Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukemia (CML), and are now considered standard treatment for this disease. However, TKIs can induce serious hemostatic side effects including cardiovascular disease and bleeding disorders. Blood platelet aggregation and formation of pro-coagulant platelets are important to allow a well-balanced hemostatic response. Therefore, a detailed understanding of what effect different TKIs exert on platelets and hemostasis could help to understand if there are differences of importance to minimize the risk of bleeding complications in treated patients.

    AIM: To investigate how TKIs used in CML (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) affect platelet activation and hemostasis.

    MATERIALS AND METHODS: We have developed a multi-parameter six color flow cytometry protocol to study different aspects of platelet function upon activation, e.g. formation of aggregatory (PAC-1-positive) and pro-coagulant (phosphatidylserine-exposing) platelets, exocytosis of alpha- and lysosomal granules and mitochondrial membrane potential.This protocol was performed in presence or absence of TKIs in blood from normal donors and in treated patients. Whole blood aggregometry (Multiplate®), thrombin generation in platelet-rich plasma and in vitro thrombus formation by free oscillation rheometry (ReoRox G2) was further evaluated in some situations.

    RESULTS: At clinically relevant concentrations, dasatinib significantly decreased the formation of procoagulant platelets. Ponatinib induced a slight decrease in formation of procoagulant platelets, whereas bosutinib and nilotinib showed opposite tendencies (n=7). Dasatinib also decreased platelet aggregation (n=4-6) and in vitro thrombus formation (n=3). Thrombin generation was not significantly affected by therapeutic levels of TKIs, whereas higher doses of dasatinib, bosutinib, ponatinib and imatinib significantly changed one or several of the thrombin generation parameters (n=7-8). Interestingly, large differences in response to the drugs were observed among the healthy donors, especially for dasatinib and bosutinib. Major inter-individual variations were also observed in dasatinib-treated patients, see Figure 1.

    CONCLUSIONS: Different TKIs show varying potency to affect platelet-based hemostasis. In addition, we found large inter-individual variations in how some drugs affected platelet function. Therefore, we suggest that development of a clinically useful protocol for platelet function testing could help to identify patients more susceptible to adverse drug reactions. Such a protocol could potentially help clinicians to gain insight into the risk of side effects, which could help to choose the most suitable drug for each individual patient.

  • 18. Faxälv, L.
    et al.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Soutukorva, K.
    Tengvall, P.
    Lindahl, T.L.
    Coagulation factor XII is not activated by platelets but facilitates platelet-driven propagation of coagulation 2012Conference paper (Refereed)
  • 19. Faxälv, L.
    et al.
    Wallstedt, M.
    Ramström, Sofia
    Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Dublin City University, Dublin, Ireland.
    A flow cytometric method to study platelet adhesion to protein-coated polystyrene beads2011Conference paper (Refereed)
  • 20.
    Faxälv, Lars
    et al.
    Linköping University, Linköping, Sweden.
    Boknäs, Niklas
    Linköping University, Linköping, Sweden.
    Ström, Jakob O.
    Linköping University, Linköping, Sweden.
    Tengvall, Pentti
    Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Müller et al has been cited >100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of <10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

  • 21.
    Ignatova, A.
    et al.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Nikitin, E.
    Botkin City Clinical Hospital, Moscow, Russian Federation.
    Tharmakulanathan, A.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Linköping University, Linköping, Sweden; Department of Clinical Medicine, School of Medical Sciences, Örebro University, Örebro,.
    Poletaev, A.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Polokhov, D.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Fedotov, A.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Seregina, E.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Pshonkin, A.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Vorobiev, V
    Botkin City Clinical Hospital, Moscow, Russian Federation.
    Ptushkin, V.
    Botkin City Clinical Hospital, Moscow, Russian Federation.
    Panteleev, M.
    Dmitry Rogachev National Research Center of Pediatric Hematology Oncology and Immunology, Moscow, Russian Federation.
    Platelet Function and Ibrutinib Treatment in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma: Effects of Drug and of Disease Itself2017In: Research and Practice in Thrombosis and Haemostasis, ISSN 2475-0379, Vol. 1, no S1, p. 1344-1344Article in journal (Refereed)
  • 22.
    Lindahl, T. L.
    et al.
    Linköping University, Linköping, Sweden.
    Macwan, A. S.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 8, p. 1639-1641Article in journal (Refereed)
  • 23.
    Lindahl, Tomas L.
    et al.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Boknas, Niklas
    Linköping University, Linköping, Sweden; Region Östergötland, Linköping, Sweden..
    Faxalv, Lars
    Linköping University, Linköping, Sweden.
    Caveats in studies of the physiological role of polyphosphates in coagulation2016In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, no 1, p. 35-39Article in journal (Refereed)
    Abstract [en]

    Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets. Thus, proper use of inhibitors of the contact pathway and a careful choice of materials for plates and tubes is important to avoid artefacts. The use of phosphatases used to degrade polyP has an important drawback as it also degrades the secondary activators ADP and ATP, which are released from activated platelets. In addition, the use of positively charged inhibitors, such as polymyxin B, to inhibit polyP in platelet-rich plasma and blood is problematic, as polymyxin B also slows coagulation in the absence of polyP. In conclusion we hope awareness of the above caveats may improve research on the physiological roles of polyP in coagulation.

  • 24.
    Lindgren, M.
    et al.
    Dilaforette AB, Solna, Sweden.
    Meijers, J. C. M.
    University of Amsterdam, Amsterdam, Netherlands.
    Biemond, B. J.
    University of Amsterdam, Amsterdam, Netherlands.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Lindahl, T. L.
    Linköping University, Linköping, Sweden.
    Eriksson, P-O
    Dilaforette AB, Solna, Sweden.
    Leitgeb, A. M.
    Dilaforette AB, Solna, Sweden.
    Wahlgren, M.
    Karolinska Institute, Stockholm, Sweden.
    Hogwood, J.
    The National Institute for Biological Standards and Control (NIBSC), South Mimms, England.
    Gray, E.
    The National Institute for Biological Standards and Control (NIBSC), South Mimms, England.
    Holmer, E.
    Dilaforette AB, Solna, Sweden.
    Sevuparin: effects on hemostasis of a novel polysaccharide drug derived from heparin2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 369-369Article in journal (Refereed)
  • 25.
    Lopez, A.
    et al.
    Molecular and Cellular Therapeutics (MCT), Royal College of Surgeons, Dublin, Ireland.
    Kenny, D.
    Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Basabe-Desmonts, L.
    Molecular and Cellular Therapeutics (MCT), Royal College of Surgeons, Dublin, Ireland.
    Ramström, Sofia
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Jose, B.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Somers, M.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    A novel platelet assay that measures the effect of clopidogrel in vivo2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S2, p. 73-73Article in journal (Refereed)
  • 26.
    Lopez-Alonso, A.
    et al.
    NBIPI Program, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Basabe-Desmonts, L.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Ramström, Sofia
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Jose, B.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Sommers, M.
    Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    Redahan, L.
    Nephrology & Renal Transplant Medicine, Beaumont Hospital, Dublin, Ireland.
    Conlon, P.
    Nephrology & Renal Transplant Medicine, Beaumont Hospital, Dublin, Ireland.
    Kenny, D.
    NBIPI Program, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Biomedical Diagnostics Institute (BDI), Dublin City University, Dublin, Ireland.
    A novel platelet function assay that identifies bleeding risk and quantifies anti-platelet drug effect2012Conference paper (Refereed)
  • 27.
    Lopez-Alonso, Ana
    et al.
    Royal College of Surgeons in Ireland, Dublin, Ireland.
    Jose, Bincy
    Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland.
    Somers, Martin
    Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland.
    Egan, Karl
    Royal College of Surgeons in Ireland, Dublin, Ireland.
    Foley, David P.
    Division of Cardiology, Beaumont Hospital, Dublin, Ireland.
    Ricco, Antonio J.
    Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland.
    Ramström, Sofia
    Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Clinical and Experimental Medicine, Clinical Chemistry, Linköping University, Linköping, Sweden.
    Basabe-Desmonts, Lourdes
    Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland; CIC microGUNE, Polo Innovación Garaia, Arrasate-Mondragón, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    Kenny, Dermot
    Royal Coll Surgeons Ireland, Dublin, Ireland.
    Individual Platelet Adhesion Assay: Measuring Platelet Function and Antiplatelet Therapies in Whole Blood via Digital Quantification of Cell Adhesion2013In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 85, no 13, p. 6497-6504Article in journal (Refereed)
    Abstract [en]

    Widespread monitoring of platelet function and the effect of antiplatelet drugs will improve outcomes in cardiovascular patients, but platelet function testing is not routine in clinical practice. We report a rapid, accurate methodology to quantify platelet-protein interactions: a microarray of contact-printed 6-mu m fibrinogen dots on a transparent substrate binds platelets from whole blood, one platelet per dot. The fractional occupancy of an array of fibrinogen dots after a predefined incubation time quantitatively assays platelet adhesion to the protein matrix. We demonstrate this technique by measurement of platelet adhesion to fibrinogen as a means to quantify the effect of the P2Y(12) and alpha IIb beta 3 receptor inhibitors cangrelor and abciximab, respectively, both in vitro-by incubating the drug with a freshly drawn blood sample-and in blood from patients treated with antiplatelet agents. The effects of single- and dual-antiplatelet therapy are also assessed. Results from this platelet-binding assay are well correlated with standard techniques including flow cytometry and light transmission aggregometry. This assay technology, readily integrated with microfluidic platforms, is generally applicable to the assay of cell-protein interactions and promises more effective, rapid assay of drug effects in cardiovascular disease patients.

  • 28.
    Macwan, A.
    et al.
    Linköping University, Linköping, Sweden.
    Boknäs, N.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Berg, S.
    Linköping University, Linköping, Sweden.
    Faxälv, L.
    Linköping University, Linköping, Sweden.
    Lindahl, T.
    Linköping University, Linköping, Sweden.
    Gradient-dependent Modulation of Platelet Stimulatory G-protein Coupled Receptors (GPCR) Signaling2017In: Research and Practice in Thrombosis and Haemostasis, ISSN 2475-0379, Vol. 1, no S1, p. 1223-1223, article id PB568Article in journal (Refereed)
  • 29.
    Macwan, Ankit S.
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Boknäs, Niklas
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Hematology, Linköping University, Linköping, Sweden .
    Ntzouni, Maria P.
    Core Facility, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Gibbins, Jonathan M.
    Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 7Article in journal (Refereed)
    Abstract [en]

    As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent that is determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non- G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibit different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but share a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Further, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.

  • 30.
    Nylander, Martina
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Osman, Abdimajid
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Aklint, Emma
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Larsson, Anders
    Department of Medical Sciences, University Hospital, Uppsala, Sweden.
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets2012In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 129, no 4, p. E51-E58Article in journal (Refereed)
    Abstract [en]

    Introduction: Arterial thrombi contain more platelets than venous thrombi and are more resistant to fibrinolysis. This resistance could partly be due to plasminogen activator inhibitor 1 (PAI-1) secreted by platelets. The aim of this study was to elucidate differences between thrombin receptors protease-activated receptor (PAR) 1 and 4 and platelet storage, secretion and synthesis of platelet PAI-1, as compared to other platelet alpha-granule proteins such as VEGF and endostatin.

    Materials and methods: Human isolated platelets were incubated with thrombin (0.5 U/ml), PAR1-activating peptide (AP) (0.4-30 mu M) or PAR4-AP (1.5-300 mu M) for up to 24 hours. ELISA, western blot and fluorescence microscopy were used to measure secretion, contents and localization of PAI-1, VEGF and endostatin. Results: Our results show that PAI-1 and VEGF might be co-localized and that endostatin does not co-localize with either PAI-1 or VEGF. PAI-1 and VEGF show a similar secretion pattern, being more sensitive to low grade PAR1 activation, but secretion was also observed with higher concentrations of PAR4-APs. PAI-1 is secreted in an active form. PAI-1 mRNA was found in platelets, and elevated levels of PAI-1 were detected after 24 hours incubation of platelets.

    Conclusions: PAI-1 and VEGF, but not endostatin, might be stored in the same alpha-granule in human platelets. PAI-1 and VEGF also show a similar secretion pattern, being more sensitive to PAR1 than to PAR4 activation, but the secretion is not exclusively selective. Our results also show that platelet PAI-1 is increased if incubated for 24 hours, both with addition of PAR1-activating peptide and without activation, which could indicate de novo synthesis.

  • 31.
    Olsson, A.
    et al.
    Blekinge Institute of Technology, Karlskrona, Sweden; Linköping University, Linköping, Sweden; Blekinge Hospital, Karlskrona, Sweden.
    Alfredsson, J.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Svedjeholm, R.
    Linköping University, Linköping, Sweden.
    Kenny, D.
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
    Håkansson, E.
    Linköping University, Linköping, Sweden.
    Berglund, J. S.
    Blekinge Institute of Technology, Karlskrona, Sweden.
    Berg, S.
    Linköping University, Linköping, Sweden.
    Better platelet function, less fibrinolysis and less hemolysis in re-transfused residual pump blood with the Ringer’s chase technique: a randomized pilot study2018In: Perfusion, ISSN 0267-6591, E-ISSN 1477-111X, Vol. 33, no 3, p. 185-193Article in journal (Refereed)
    Abstract [en]

    Introduction: Residual pump blood from the cardiopulmonary bypass (CPB) circuit is often collected into an infusion bag (IB) and re-transfused. An alternative is to chase the residual blood into the circulation through the arterial cannula with Ringer’s acetate. Our aim was to assess possible differences in hemostatic blood quality between these two techniques.

    Methods: Forty adult patients undergoing elective coronary artery bypass graft surgery with CPB were randomized to receive the residual pump blood by either an IB or through the Ringer’s chase (RC) technique. Platelet activation and function (impedance aggregometry), coagulation and hemolysis variables were assessed in the re-transfused blood and in the patients before, during and after surgery. Results are presented as median (25-75 quartiles).

    Results: Total hemoglobin and platelet levels in the re-transfused blood were comparable with the two methods, as were soluble platelet activation markers P-selectin and soluble glycoprotein VI (GPVI). Platelet aggregation (U) in the IB blood was significantly lower compared to the RC blood, with the agonists adenosine diphosphate (ADP) 24 (10-32) vs 46 (33-65), p<0.01, thrombin receptor activating peptide (TRAP) 50 (29-73) vs 69 (51-92), p=0.04 and collagen 24 (17-28) vs 34 (26-59), p<0.01. The IB blood had higher amounts of free hemoglobin (mg/L) (1086 (891-1717) vs 591(517-646), p<0.01) and D-dimer 0.60 (0.33-0.98) vs 0.3 (0.3-0.48), p<0.01. Other coagulation variables showed no difference between the groups. Conclusions: The handling of blood after CPB increases hemolysis, impairs platelet function and activates coagulation and fibrinolysis. The RC technique preserved the blood better than the commonly used IB technique.

  • 32.
    Peng, Xiang
    et al.
    Department of Nephrology, Qingyuan City Hospital of Jinan University, Guangdong, China; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Experimental and Clinical Medicine, Linköping University, Linköping, Sweden.
    Kurz, Tino
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; .
    Segelmark, Mårten
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteinase 3 (PR3) is released from neutrophil azurophilic granules and exerts complex effects on the inflammatory process. PR3 catalyzes the degradation of a number of macromolecules, but the consequences on blood cells are less well defined. In the present study, the effect of PR3 on human platelets was thoroughly investigated.

    Methods: The experiments were performed on washed platelets freshly isolated from blood donated by healthy human volunteers. Platelets shape change and aggregation was measured on a Chrono-Log aggregometer. The phosphorylated form of MYPT1 was visualized by immunostaining. Platelet activation was further evaluated by flow cytometry.

    Results: PR3 induced platelet shape change but not aggregation. Flow cytometry analysis showed that PR3 induced no P-selectin expression or binding of fibrinogen to the platelets, and it did not change the activation in response to PAR1- or PAR4-activating peptides or to thrombin. Furthermore, Fura-2 measurement and immuno-blotting analysis, respectively, revealed that PR3 stimulated small intracellular Ca2+ mobilization and Thr696-specific phosphorylation of the myosin phosphatase target subunit 1 (MYPT1). Separate treatment of platelets with the Rho/Rho kinase inhibitor Y-27632 and the intracellular Ca2+ chelator BAPTA/AM reduced the shape change induced by PR3 whereas concurrent treatment completely inhibited it.

    Conclusion: The data shows that the neutrophil protease PR3 is a direct modulator of human platelets and causes shape change through activation of the Rho/Rho kinase and Ca2+ signaling pathways. This finding highlights an additional mechanism in the complex interplay between neutrophils and platelets.

  • 33.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635Article in journal (Refereed)
    Abstract [en]

    The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.

  • 34.
    Ramström, Sofia
    Linkoping University, Linköping, Sweden.
    Experiences with “spontaneous” contact activation and Microvesicles in Thrombin generation.: Invited presentation at a round table discussion, “Pre-analytical problems and solutions for assays sensitive to contact activation“2014Conference paper (Other academic)
  • 35.
    Ramström, Sofia
    et al.
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    O'Neill, Sarah
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Dunne, Eimear
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Kenny, Dermot
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Annexin V binding to platelets is agonist, time and temperature dependent2010In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 21, no 4, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Platelets bind annexin V when stimulated with combinations of platelet agonists such as collagen and thrombin. Previous studies have demonstrated significant heterogeneity of platelets binding annexin V. The relative role of the thrombin protease-activated receptors (PARs), PAR1 and PAR4, together with different methods of platelet preparation on annexin V binding to platelets is unclear. We therefore investigated the role of PAR1- and PAR4-activating peptides in combination with collagen-related peptide on annexin V binding. In diluted whole blood, PAR1- and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding. However, in washed platelets, PAR-activating peptides were less potent than thrombin at inducing annexin V binding. This difference was more pronounced when experiments were performed at 37 degrees C compared to room temperature. In studies of diluted whole blood, platelet rich plasma and washed platelets, platelets incubated at room temperature bound more annexin V than platelets incubated at 37 degrees C. We also saw a significant effect of time on annexin V binding, in that more annexin V bound to platelets with longer incubation times. In conclusion, PAR1 and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding in combination with collagen-related peptide in diluted whole blood and platelet rich plasma, but not in washed platelets. In addition, incubation temperature and time has a strong influence on annexin V binding to platelets. Thus variations in these conditions may explain the differences observed between previous studies.

  • 36.
    Ramström, Sofia
    et al.
    Linköping University, Linköping, Sweden.
    Södergren, Anna L.
    Linköping University, Linköping, Sweden.
    Tynngård, Nahreen
    Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    Platelet Function Determined by Flow Cytometry: New Perspectives?2016In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 42, no 3, p. 268-281Article, review/survey (Refereed)
    Abstract [en]

    Flow cytometry enables studies of several different aspects of platelet function in response to a variety of platelet agonists. This can be done using only a small volume of whole blood, and also in blood with low platelet counts. These properties, together with the increasing number of flow cytometers available in hospitals worldwide, make flow cytometry an interesting option for laboratories interested in studies of platelet function in different clinical settings. This review focuses on practical issues regarding the use of flow cytometry for platelet function testing. It provides an overview of available activation markers, platelet agonists, and experimental setup issues. The review summarizes previous experience and factors important to consider to perform high-quality platelet function testing by flow cytometry. It also discusses its current use and possibilities and challenges for future use of flow cytometry in clinical settings.

  • 37.
    Singh, Sukhi
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Damén, Tor
    Department of Anaesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiothoracic Anaesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nygren, Andreas
    Department of Anaesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiothoracic Anaesthesia and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Shams Hakimi, Caroline
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden; Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Dellborg, Mikael
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Lindahl, Tomas L.
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hesse, Camilla
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Regional Blood Bank, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Adrenaline Improves Platelet Reactivity in Ticagrelor-Treated Healthy Volunteers2019In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 119, no 5, p. 735-743Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Administration of agents that enhance platelet reactivity may reduce the perioperative bleeding risk in patients treated with the adenosine diphosphate (ADP)-receptor antagonist ticagrelor. Adrenaline potentiates ADP-induced aggregation and activation in blood samples from ticagrelor-treated patients, but it has not previously been evaluated in vivo.

    METHODS: Ten healthy male subjects were included in an interventional study. A loading dose of ticagrelor (180 mg) was administered, followed 2 hours later by a gradually increased intravenous adrenaline infusion (0.01, 0.05, 0.10 and 0.15 µg/kg/min; 15 minutes at each step). Blood pressure, heart rate, platelet aggregation (impedance aggregometry), platelet activation (flow cytometry), clot formation (rotational thromboelastometry) and adrenaline plasma concentration were determined before and after ticagrelor administration and at the end of each adrenaline step.

    RESULTS:  = 0.007).

    CONCLUSION: Infusion of adrenaline at clinically relevant doses improves in vivo platelet reactivity and clot formation in ticagrelor-treated subjects. Adrenaline could thus potentially be used to prevent perioperative bleeding complications in ticagrelor-treated patients. Studies in patients are necessary to determine the clinical importance of our observations.

    TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT03441412.

  • 38.
    Singh, Sukhi
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Malm, Carl Johan
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hesse, Camilla
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Regional Blood Bank, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor-treated patients2018In: Research and Practice in Thrombosis and Haemostasis, E-ISSN 2475-0379, Vol. 2, no 4, p. 718-725Article in journal (Refereed)
    Abstract [en]

    Background: Temporarily improved platelet reactivity may reduce the bleeding in patients on antiplatelet therapy who have ongoing bleeding or who are in need of acute surgery. Adrenaline can bind to adrenergic alpha(2A)-receptors on platelets and potentially enhance platelet reactivity.

    Objective: To assess if adrenaline can improve adenosine diphosphate (ADP)-induced platelet aggregation and activation in blood samples from patients on dual antiplatelet therapy with acetylsalicylic acid (ASA) and the ADP-receptor antagonist ticagrelor.

    Methods: Blood samples were collected from a total of forty acute coronary syndrome patients on dual antiplatelet therapy with ASA and ticagrelor. ADP-induced platelet aggregation (by impedance aggregometry) and activation (by flow cytometry) were assessed before and after supplementation with adrenaline and/or platelet concentrate.

    Results: Adrenaline supplementation (770 nmol L-1) increased median ADP-induced aggregation from 15 (25-75th percentiles: 10-20) to 26 (18-38) aggregation units. The effect was independent of concomitant platelet supplementation. Adrenaline also increased ADP-induced platelet activation: from 40% (36-54%) to 83% (74-88%) platelets with active fibrinogen receptor (binding PAC-1) and from 13% (7-21%) to 35% (18-50%) P-selectin-expressing platelets.

    Conclusions: Adrenaline potentiated ADP-induced platelet aggregation and activation in blood samples from ticagrelor-treated patients. Adrenaline infusion may be a new method to enhance platelet function in ticagrelor-treated patients who are in need of acute surgery or have ongoing bleeding. In vivo studies are needed to confirm the present results.

  • 39.
    Sodergren, Anna L.
    et al.
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Holm, Ann-Charlotte B. Svensson
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lindström, Eva G.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden; Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Öllinger, Karin
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances2016In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, no 1, p. 86-92Article in journal (Refereed)
    Abstract [en]

    Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.

  • 40. Sánchez Centellas, D.
    et al.
    Vicente-Carrillo, A.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Lindahl, T.L.
    Advances on yeast methods to study recombinant human PAR42014Conference paper (Refereed)
  • 41.
    Södergren, A. L.
    et al.
    Linköping University, Linköping, Sweden.
    Ollinger, K.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Subdivision according to size is necessary for correct interpretation of data regarding platelet expression of active GPIIb/IIIa and phosphatidylserine2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S1, p. 498-498Article in journal (Refereed)
  • 42.
    Södergren, A. L.
    et al.
    Linköping University, Linköping, Sweden.
    Tynngård, N.
    Linköping University, Linköping, Sweden.
    Berlin, G.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Responsiveness of platelets during storage studied with flow cytometry - formation of platelet subpopulations and LAMP-1 as new markers for the platelet storage lesion2016In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 110, no 2, p. 116-125Article in journal (Refereed)
    Abstract [en]

    Background and ObjectivesStorage lesions may prevent transfused platelets to respond to agonists and arrest bleeding. The aim of this study was to evaluate and quantify the capacity of platelet activation during storage using flow cytometry and new markers of platelet activation. Materials and MethodsActivation responses of platelets prepared by apheresis were measured on days 1, 5, 7 and 12. In addition, comparisons were made for platelet concentrates stored until swirling was affected. Lysosome-associated membrane protein-1 (LAMP-1), P-selectin and phosphatidylserine (PS) exposure were assessed by flow cytometry on platelets in different subpopulations in resting state or following stimulation with platelet agonists (cross-linked collagen-related peptide (CRP-XL), PAR1- and PAR4-activating peptides). ResultsThe ability to form subpopulations upon activation was significantly decreased already at day 5 for some agonist combinations. The agonist-induced exposure of PS and LAMP-1 also gradually decreased with time. Spontaneous exposure of P-selectin and PS increased with time, while spontaneous LAMP-1 exposure was unchanged. In addition, agonist-induced LAMP-1 expression clearly discriminated platelet concentrates with reduced swirling from those with retained swirling. This suggests that LAMP-1 could be a good marker to capture changes in activation capacity in stored platelets. ConclusionThe platelet activation potential seen as LAMP-1 exposure and fragmentation into platelet subpopulations is potential sensitive markers for the platelet storage lesion.

  • 43.
    Södergren, A.L.
    et al.
    Linlöåin University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Linköping University, Linköping, Sweden.
    Platelet reactivity and receptor density in platelets with different MPV2017In: Research and Practice in Thrombosis and Haemostasis, ISSN 2475-0379, Vol. 1, no S1, p. 1235-1236, article id PB 1273Article in journal (Refereed)
  • 44. Södergren, A.L.
    et al.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Platelet subpopulations : do they exist? 2016Conference paper (Refereed)
  • 45.
    Södergren, A.L.
    et al.
    Linköping University, Linköping, Sweden.
    Tynngård, N.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Changes in platelet function during storage : evaluation of a flow cytometry method for studies of platelet adhesion and activation2012Conference paper (Refereed)
  • 46. Södergren, A.L.
    et al.
    Tynngård, N.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Changes in platelet function during storage: evaluation of a flow cytometry method for studies of platelet adhesion and activation2012Conference paper (Refereed)
  • 47.
    Södergren, Anna L.
    et al.
    Clinical Chemistry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry2017In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1594, p. 191-203Article in journal (Refereed)
    Abstract [en]

    Flow cytometry is a method that allows high throughput analysis of individual cells in suspension. By inclusion of fluorescently labelled antibodies, it is possible to analyze the abundance of one or more surface antigens, such as LAMP-1, without prior lysis of cells. Here we describe the special considerations required for the investigation of lysosomal exocytosis from platelets analyzed with flow cytometry.

  • 48.
    Södergren, Anna Linnea
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 1441Article in journal (Refereed)
    Abstract [en]

    It is recognised that platelets respond differently to activation, where a subpopulation of platelets adopt a procoagulant phenotype while others are aggregatory. However, it has not been thoroughly tested whether these subpopulations will remain in maximally activated samples, or if they are merely a result of different platelet sensitivities to agonist activation. Here platelets were activated with gradually increasing concentrations of thrombin and/or the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Platelet activation was investigated using a novel six-colour flow cytometry protocol evaluating exposure of phosphatidylserine, active conformation of the fibrinogen receptor αIIbβ3, α-granule and lysosomal release (P-selectin and LAMP-1 exposure), mitochondrial membrane integrity and platelet fragmentation. Upon activation by CRP-XL or thrombin+CRP-XL, platelets formed three differently sized subpopulations. Normal-sized platelets showed high exposure of aggregatory active αIIbβ3 and intact mitochondria, while the smaller platelets and platelet fragments showed high exposure of procoagulant phosphatidylserine. The distribution of platelets between the differently sized subpopulations remained stable despite high agonist concentrations. All three were still present after 30 and 60 min of activation, showing that all platelets will not have the same characteristics even after maximal stimulation. This suggests that platelet subpopulations with distinct activation patterns exist within the total platelet population.

  • 49.
    Tynngård, N.
    et al.
    Transfusion Medicine, Clinical and Experimental Medicine, Linköpings University, Linköping, Sweden.
    Ramström, Sofia
    Clinical Chemistry, Clinical and Experimental Medicine, Linköpings University, Linköping, Sweden.
    Berlin, G.
    Transfusion Medicine, Clinical and Experimental Medicine, Linköpings University, Linköping, Sweden.
    Adhesion Capacity of Platelets During Storage: Evaluation of a Flow Cytometric Adhesion Assay2012In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 52, no S3, p. 70A-70AArticle in journal (Refereed)
  • 50.
    Tynngård, Nahreen
    et al.
    Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Assays of different aspects of haemostasis: what do they measure?2015In: Thrombosis Journal, ISSN 1477-9560, E-ISSN 1477-9560, Vol. 13, article id 8Article, review/survey (Refereed)
    Abstract [en]

    Haemostasis is a complex process affected by many factors including both cellular and plasma components. It is a multistep process starting with platelet adhesion to damaged endothelium and ending in clot fibrinolysis. There are several methods available to study different aspects of haemostasis including adhesion, aggregation, coagulation and fibrinolysis. This review describes the different methods, what aspects of haemostasis they measure and their limitations. Methods discussed include methods to study adhesion (e.g. PFA-100, cone and platelet(let) analyzer and perfusion chambers) and aggregation (e.g. Multiplate, VerifyNow and Plateletworks). Furthermore the principles behind viscoelastic haemostatic assays are presented as well as methods that can analyse aspects of haemostasis in plasma or platelet-rich-plasma samples (thrombin generation, overall haemostasis potential and Thrombodynamics Analyzer).

12 1 - 50 of 51
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