| 1. |
- Alfredsson, Joakim
(författare)
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Management and Outcome in Non ST-Elevation Acute Coronary Syndromes : Similarities and Differences Between Women and Men
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Non ST-elevation Acute Coronary Syndromes are the most frequent manifestations of acute ischemic heart disease. Gender differences in treatment intensity, including differences in level of care, have been reported. Also differences in benefit from certain treatments, especially invasive treatment, have been discussed. Finally, difference in outcome between men and women, have been proposed. Results have been inconsistent, partly depending on if and how adjustment for differences in background characteristics has been made. The aims of the studies in this thesis were to assess differences between the genders in baseline characteristics, level of care, medical treatment and non-invasive and invasive cardiac procedures. The aims were also to determine gender differences in short and long-term mortality, including impact of level of care, and to determine differences between the genders in benefit from an invasive strategy, with special reference to benefit in women.Method: We used prospectively collected data from the RIKS-HIA registry in two studies (Paper I and IV). In one study we merged data from patients admitted to general wards in the south-east region of Sweden (The AKUT registry), with data from patients admitted to CCU´s (RIKS-HIA) at participating hospitals during the same time (Paper II). We also randomly assigned women to a routine invasive or a selective invasive treatment strategy, and performed a meta-analysis, to determine gender differences in benefit from a routine invasive strategy (Paper III).Results: Women were older than men and more likely to have a history of diabetes and hypertension, while men were more likely to have a history of myocardial infarction and revascularisation. Women were also more likely to have normal coronary arteries on the angiogram. After adjustment for baseline differences there were only minor, and directionally inconsistent, differences between women and men in pharmacological treatment. Men were more often referred for coronary angiography, even after adjustment. While CABG-rate was lower in women, after adjustment PCI-rate was similar or even higher compared to men. After adjustment for differences in age, longterm outcome was better in women. In our small but randomised trial there was no benefit from a routine invasive strategy in women. A meta-analysis indicated interaction between gender and treatment strategy, with lack of benefit in women, in contrast to in men. However, our large observational study indicated no gender difference with an invasive strategy. Moreover, benefit was similar in women and men with invasive treatment.Conclusion: There are substantial differences between women and men in baseline characteristics that affect management and outcome more than gender per se. After adjustment women have better long-term outcome than men. There appear to be a difference in benefit from a routine invasive strategy between the genders, with less benefit in women, but in routine clinical management there was no difference between women and men managed with an invasive strategy.
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| 2. |
- Björklund, Fredrik, 1968-
(författare)
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Platelet reactivity and comorbidities in acute coronary syndrome
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background In the event of an acute coronary syndrome (ACS), the risk of death and complications such as stroke and re-infarction is high during the first month. Diabetes, impaired kidney function, elevated markers of systemic inflammation and high level of platelet reactivity have all been associated with worsened prognosis in ACS patients. Impaired kidney function is a condition with high cardiovascular morbidity and there is an established association between level of kidney function and outcome in the event of an ACS. Aims We sought to investigate the level of platelet reactivity during the first days of an ACS and specifically the level of platelet reactivity in patients with different conditions associated with worsened prognosis in the event of an ACS. We also wanted to investigate the prognostic impact of baseline levels of cystatin C as well as the importance of decreasing kidney function during the first days of an ACS. Methods We included 1028 unselected patients with ACS or suspected ACS during the years 2002 and 2003, of which 534 were diagnosed with an acute myocardial infarction (AMI). Blood samples for measuring platelet aggregation, cystatin C levels and other clinically important biomarkers were collected day 1, 2, 3 and 5 following admission. Platelet reactivity was measured using 2 different methods. Platelet aggregation was measured using Pa-200, a particle count method, based on scattering of laser light. PFA 100 is a method of measuring primary hemostasis in whole blood. Results Platelet aggregation and comorbidities. We found an increase in platelet aggregation when an ACS was complicated by an infection and there was an increased frequency of aspirin non-responsiveness in patients suffering from pneumonia during the first days of an ACS. Furthermore, we found an independent association between levels of C-reactive protein and platelet aggregation. During the first 3 days following an acute myocardial infarction, platelet aggregation increased despite treatment with anti-platelet agents. Platelet aggregation was found to be more pronounced in patients with diabetes. Patients with impaired kidney function, showed increased platelet aggregation compared to patients with normal renal function, however, this difference was explained by older age, higher prevalence of DM and levels of inflammatory biomarkers. We found no independent association between chronic kidney disease (CKD) and levels of platelet aggregation. Kidney function and outcome Serum levels of cystatin C on admission had an independent association with outcome following an acute myocardial infarction. With a mean follow-up time of 2.9 years, the adjusted HR for death was 1.62 (95% CI 1.28-2.03; p<0.001) for each unit of increase in cystatin C on admission. The level of dynamic changes in cystatin C during admission for an acute myocardial infarction was independently associated with prognosis in patients with normal or mild impairment of renal function. The adjusted HR for death was 10.1 (95% CI 3.4-29.9; p<0.001). Conclusion In patients suffering from an AMI platelet aggregation increases during the first days, despite anti-platelet treatment. Diabetes, age and biomarkers of inflammation are independently associated with platelet aggregation. Admission levels of cystatin C as well as changes in cystatin C levels during hospitalisation are independently associated with outcome.
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| 3. |
- Milovanovic, Micha, 1966-
(författare)
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Platelets : with special reference to platelet density subpopulations, stable coronary heart disease and atrial fibrillation
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The current thesis was divided into two parts. Basic platelet research is the topic of the first section. The subsequent clinical part examines platelet reactivity in stable angina pectoris (AP) and in atrial fibrillation.Platelet heterogeneity was investigated in the first section (papers 1 and 2). The cells were separated according to density using linear Percoll™ (a density medium) gradients. The latter contained EDTA, prostaglandin E1 and theophylline to prevent platelet in vitro activity. The platelet population was then divided into density subpopulations (n = 16 - 20). Membrane attached fibrinogen was determined with a flow cytometer technique and used as a marker reflecting platelet in vivo activity. Platelet P-Selectin content was employed to estimate the quantity of platelet α-granules. Paper I examined healthy blood donors (n = 3). The second report (paper II) compared healthy volunteers (n = 2) and subjects with essential thrombocythemia (ET) (n = 2). The latter is a clonal disease being characterized by an excessive platelet production. Platelet counts were determined in all fractions. In manuscripts I and II determination of surface bound fibrinogen and intracellular P-Selectin was carried out in 12 and 16 platelet density fractions, respectively.High density platelets displayed more surface bound fibrinogen indicating in vivo activity. They also contained less P-Selectin. The latter finding implies platelet in vivo release reactions. Low density platelets circulated with more surface bound fibrinogen as well. Compared with peak density platelets, lighter cells contained more P-Selectin. ET was characterized by a similar platelet density pattern in that high and low density platelets displayed more surface bound fibrinogen. The similarity may explain why severe bleedings do not occur more frequently in ET. It is also obvious from the current thesis that the significance of platelet heterogeneity remains unclear and stimulates to further research. In particular, future work must involve more patients.The second part (papers III-VI) of the thesis was devoted to stable AP and atrial fibrillation. Determination of platelet reactivity i.e. platelet bound fibrinogen after stimulation was carried out in whole blood. A flow cytometer technique was employed (papers III-VI). Adenosine diphosphate (ADP) (1.7 and 8.5 μmol/L) and a thrombin-receptor activating peptide (TRAP-6) (57 and 74 μmol/L) were used as stimulating agents. Determination of peak platelet density (kg/L) was utilized as a further measure reflecting platelet reactivity (paper V). Surface bound and soluble P-Selectin were employed as platelet activity markers (paper VI).Gender differences with respect to platelet reactivity were investigated in paper III. Paper IV examined platelets in stable AP without significant coronary flow obstruction(s) as determined by coronary angiography. In a following study platelet reactivity was analysed in diabetes type II complicated by stable AP (paper V). Finally, long-term (more than 2 years) outcome of atrial fibrillation was related to platelet reactivity and activity (paper VI). In this study the subjects were investigated at the initial electrical cardioversion and the analysis were repeated after more than 2 years.Postmenopausal women with stable AP demonstrated more reactive platelets when stimulating with TRAP-6. They had higher platelet counts (paper III) as well. Stable AP without significant coronary flow obstruction(s) was associated with elevated platelet reactivity (paper IV). Diabetes type II was linked to higher peak platelet density and elevated platelet reactivity (paper V). Augmented platelet reactivity proved to be a feature of subjects remaining in atrial fibrillation more than 2 years after the electrical cardioversion (paper VI). In contrast, the irregular heart rhythm did not affect platelet activity.It is to assume that platelets at least partly are responsible for the sometimes atypical symptoms of females with stable AP. It is also conceivable to speculate that platelets contribute to chest pain in AP free from significant coronary flow obstruction(s). Theoretically, enhanced platelet reactivity could at least partly explain why diabetes type II affects the prognosis of coronary heart disease. The thesis further shows a possible theoretical link between atrial fibrillation, increased platelet reactivity and clot formation.
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| 4. |
- Skoglund, Caroline, 1981-
(författare)
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Platelets in inflammation : Role of complement protein C1q, C-reactive proteinand toll-like receptors
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelets are proven essential in haemostasis, however, they are now also increasingly recognized as cells with important immunomodulatory properties, e.g. through interaction with leukocytes and several species of bacteria and by release inflammatory mediators upon activation. Moreover, platelets express receptors involved in immunity and inflammation such as Fcγ‐receptor IIa, complement protein C1q‐receptors (gC1qR, cC1qR, CD93 and α2β1) and toll‐like receptors (TLR‐1, ‐2, ‐4, ‐6 and ‐9). C1q, C‐reactive protein (CRP) and TLRs are all pattern recognition molecules able to recognize non‐self structures and initiate an immune response. Uncontrolled or misdirected activation of platelets and the immune response is involved in the onset and progress of several conditions with an inflammatory component, such as coronary artery disease and autoimmune diseases.Hence, the aims of the present thesis were to investigate the effects and q mechanisms of C1and CRP on platelet activation, and to clarify the intracellular signaling events provoked by TLR‐2 stimulation of platelets. Platelet interaction with immune complexes is poorly understood, however by utilizing well‐characterized model surfaces with adsorbed IgG and microscopy, we show that both C1q and CRP are able to inhibit FcγR‐mediated platelet adhesion and spreading. Using isolated platelets in suspension and flow cytometry, we also found that C1q triggers a rapid, moderate and transient up‐regulation of P‐selectin that is sensitive to blockade of gC1qR and protein kinase C (PKC), but not blockade of α2β1. Additionally, subsequent platelet activation by collagen or collagen‐related peptide (GPVI specific) is inhibited by C1q, suggesting a role for GPVI in C1q‐mediated regulation of collagen‐induced platelet activation. Whole blood studies revealed that C1q inhibits total cell aggregation, formation of platelet‐leukocyte aggregates, and potentiates the production of reactive oxygen species (ROS), all in a platelet‐dependent manner. Furthermore, using the TLR‐2/1 agonist Pam3CSK4 we found that TLR‐2/1‐activation of platelets is mediated via a P2X1‐dependent increase in intracellular free Ca2+, P2Y1 and P2Y12 –receptor ligation, and activation of cyclooxygenase. We also found that platelets express IRAK‐1, however, without being rapidly phosphorylated upon Pam3CSK4 stimulation and thus probably not involved in the early aggregation/secretion response. Furthermore, TLR‐2/6 stimulation does not lead to platelet activation but instead inhibits TLR‐2/1‐provoked activation. Taken together, these findings further strengthen the role of platelets as key players in inflammatory processes.
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| 5. |
- Slätt, Johnny
(författare)
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Cyanoacetylation of indoles, pyrroles and amines, and synthetic uses of these products
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on an organic synthetic project aimed towards development of small molecules acting on the P2 receptor as well as development of synthetic methods to such molecules (primarily indoles and featuring isatogens in particular). The new methodology includes cyanoacetylation of indoles, pyrroles, amines, and enamines using cyanoacetic acid in acetic anhydride. The molecules obtained (e.g. 3-cyanoacetylindole) could be further functionalized by nitrosation followed by reduction. Cyanoacetylated anilines carrying an appropriate substituent (e.g NO2) could be cyclized to quinoxaline-N-oxides, a class of molecules which have been considered as analogues to isatogens. The molecule 2,2'-pyridylisatogen tosylate (PIT) is particularly interesting within this class because of its documented interaction with the P2 receptor.
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