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Platelets and the inflammatory response in coronary heart disease
Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The thesis investigates a new invented computerised apparatus suitable for determining platelet density distribution and peak platelet density in undisturbed linear Percoll™ gradients. The device measures light transmission through test tubes containing density-separated platelets. The transmission reflects the distribution of platelets in the gradient. Coloured particles (density marker beads™) with known density are used as calibration. Consequently, the technique makes it possible to determine peak platelet density by comparing the position of the platelet peak in the gradient with the locations of the beads. The thesis describes the construction of the device and investigates its reliability (paper I). A subsequent article (II) compares platelet density alterations and changes of platelet reactivity as estimated from the ADP-evoked platelet fibrinogen binding. We examined individuals with stable angina pectoris (n=18) subject to coronary angiography. Sampling was carried out immediately before angiography and 24 hours thereafter. In a further study (paper III) platelet density was measured in patients having acute myocardial infarctions with ST-segment elevations (STEMI) (n=36). Platelet counts and volumes were also determined. Soluble P-selectin was used to assess platelet activity. The neutrophil and monocyte counts were used to estimate the inflammatory response. Myeloperoxidase and interleukin 6 (IL-6) were employed to quantify neutrophil and monocyte activity, respectively. All measures except platelet density were repeated after 6 months of recovery.

The second part of the thesis (papers IV and V) investigates Chlamydia pneumoniae in coronary heart disease. Paper IV studies a cohort (n=92) with stable angina pectoris. C. pneumoniae IgG was compared with disease severity i.e. the number of diseased coronary arteries (1-3) as determined by coronary angiography. Determination of the following was carried out before angiography: C. pneumoniae IgG, neutrophil count, myeloperoxidase and IL-6. Article V examines if the organism affects platelet activity in acute STEMI (n=I4). In this study C. pneumoniae IgM and IgG together with soluble P-selectin were determined on day I. Except for IgM the measures were repeated after 6 months. Finally, in the last article (paper VI) individual heterogeneity of platelet inhibition after a clopidogrel-loading dose was explored. Platelet reactivity as estimated from the ADP-evoked platelet fibrinogen binding was determined before angiography, stenting and the clopidogrel load (day I). The analysis was repeated after 24 hours (day 2). The thesis demonstrates that the optical apparatus is technically reliable (paper I). Healthy individuals repeatedly have platelet density subpopulations as evidenced from additional transmission peaks (paper I). The subpopulations frequently display enhanced a-granule content as expected from their positions in the gradient (paper I). The second paper shows that platelet density alterations are inversely related to changes of platelet reactivity (paper II). Decreased platelet count and an elevated inflammatory response are features of acute STEMI (paper III). We demonstrate that some patients have substantial inflammatory reactions whereas others had lower inflammatory responses. The difference persisted in the recovery. Compared to subjects with higher platelet density, individuals with lower/disturbed density displayed more severe inflammatory characteristics (paper III). Manuscript IV shows that C. pneumoniae is associated to the severity of coronary atherosclerosis as estimated from to coronary angiography. Paper V reveals that elevated C. pneumoniae IgM at the acute STEMI is related to enhanced soluble P-selectin. Both parameters proved to be associated with IgG both at the MI and after 6 months of recovery (paper V). Thus, enhanced soluble P-selectin at the STEMI is associated with a reactivation of a chronic C. pneumoniae infection. Finally, the thesis shows a substantial individual heterogeneity of platelet inhibition after a clopidogrel load (paper VI). Some individuals had strong inhibition most likely susceptible to bleedings. Others had weak reactions after clopidogrel exposure indicating elevated risk for thrombotic events.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 816
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27503Local ID: 12158ISBN: 91-7373-505-1 (print)OAI: oai:DiVA.org:liu-27503DiVA: diva2:248055
Public defence
2003-10-31, Elsa Brändström salen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-17Bibliographically approved
List of papers
1. Computerised method for recording platelet density distribution
Open this publication in new window or tab >>Computerised method for recording platelet density distribution
1995 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 54, no 5, 304-309 p.Article in journal (Refereed) Published
Abstract [en]

In the present study a computerized apparatus was employed for scanning light transmission variations along test tubes containing density-separated platelets. The device consists of a stepping motor, a stationary halogen lamp and a photopotentiometer connected to a personal computer. Anticoagulated whole blood was layered on a preformed continuous Percoll gradient having a density span from 1090 kg/l (bottom) to 1040 kg/l (top). After centrifugation at 3400g for 1.5 hours, high-density cells (i.e. erythrocytes) pass through to the bottom of the test tube and the lighter platelets remain in the gradient. The test tube is moved by the computer between the halogen lamp and the photopotentiometer. Transmission variations along the gradient were recorded and registered in the computer. Density markers beads were used as an internal standard and platelet peak density was determined. After perforating the test tube the gradient was divided into 45 aliquots. In all fractions determination of platelet counts and mean platelet volume was carried out. In addition, in the aliquots having a platelet count > 20 × 1012/l the ratio β-thromboglobulin per platelet was also determined. The platelet distribution in the gradient was illustrated graphically. A good agreement was found when comparing platelet distributions in the gradients and light transmission variations along the test tubes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84674 (URN)10.1111/j.1600-0609.1995.tb00690.x (DOI)
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2017-12-07Bibliographically approved
2. Inverse relationship between platelet density and reactivity alterations at coronary angiography
Open this publication in new window or tab >>Inverse relationship between platelet density and reactivity alterations at coronary angiography
Show others...
2001 (English)In: Haemostasis, ISSN 0301-0147, E-ISSN 1423-0038, Vol. 31, no 1, 55-60 p.Article in journal (Refereed) Published
Abstract [en]

This work investigates relationships between platelet density and reactivity. 21 individuals subject to coronary angiography were studied. Peak platelet density was analyzed using a newly developed electronic device. The apparatus measures light transmission through test tubes containing density-separated platelets, thus allowing an estimation of the platelet distribution in the gradient. A flow cytometry technique was used for determining platelet reactivity after stimulating with ADP. Platelet counts, mean platelet volumes, peak platelet density and platelet reactivity were determined immediately before (day 1) and 24 h after cardiac catheterization (day 2). For all parameters changes during the day of angiography were compared with platelet density alterations. The subjects were divided into two groups according to density changes at angiography. Group 1 individuals showed density alterations (i.e. day 2 – day 1 value) ≥–8 × 10–5 kg/l. In contrast, group 2 subjects either displayed density changes <–8 × 10–5 kg/l or grossly disturbed platelet density patterns on day 2. Before angiography both groups had similar platelet counts and volumes. Then platelet reactivity when stimulating with ADP did not differ significantly between the two groups. After angiography, the number of fibrinogen-positive cells when stimulating with ADP rose by 6 ± 8% for group 2 patients. The corresponding figure for group 1 was –1 ± 6%. The difference was significant (p = 0.01). No such relationships were found when comparing density alterations and changes of platelet counts and volumes. We conclude that in this study platelet density alterations at coronary angiography are inversely related to variations of platelet reactivity.

Place, publisher, year, edition, pages
Basel: S. Karger, 2001
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-74256 (URN)10.1159/000048045 (DOI)
Available from: 2012-01-22 Created: 2012-01-22 Last updated: 2017-12-08Bibliographically approved
3. Elevated inflammatory parameters are associated with lower platelet density in acute myocardial infarctions with ST-elevation
Open this publication in new window or tab >>Elevated inflammatory parameters are associated with lower platelet density in acute myocardial infarctions with ST-elevation
2000 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 100, no 6, 471-478 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Platelets and granulocytes play important roles in coronary disorders. We therefore, investigated platelet and granulocyte alterations in myocardial infarctions (MIs).

Patients and study design: A total of 36 individuals having MI with raised ST-segments who were receiving thrombolytic therapy were studied. Sampling was carried out after thrombolysis within 24 h after hospital admission. After 3 to 6 months of recovery, 25 patients were reinvestigated. At the infarction, peak platelet density was determined using a special designed computerised apparatus. In addition, we did counts on platelets, neutrophils and monocytes. Moreover, plasma levels of soluble P-selectin, myeloperoxidase and interleukin 6 were determined to estimate the degree of platelet, neutrophil and monocyte activation, respectively. Peak platelet density was analysed at the MI. All other parameters were determined at the acute event and at recovery.

Results: At the MI, compared to the recovery, platelet counts were lower (P<.001). In addition, increased neutrophil counts (P<.001), elevated monocyte counts (P<.001), enhanced myeloperoxidase (P<.001) and interleukin 6 (P<.001) levels were demonstrated. We failed to show elevated soluble P-selectin. Compared to individuals with ST-segment elevations and low platelet density (≤1.058 kg/l), patients having peak platelet densities >1.058 kg/l displayed lower neutrophil counts (P<.01) and decreased interleukin 6 levels (P<.01). Furthermore, we demonstrate that individuals with higher inflammatory response at the MI had higher neutrophil (r=.6; P<.01) and higher monocyte counts (r=.6; P<.001) at recovery.

Conclusion: We conclude that MI is associated with an inflammatory response. However, a subgroup of patients having MI with ST-elevations and low peak platelet density was identified. Compared to subjects with higher platelet density, they had more severe inflammatory characteristics. The differences persisted during recovery.

Keyword
interleukin 6, myocardial infarction, neutrophil granulocytes, platelets, platelet density, P-selectin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26960 (URN)10.1016/S0049-3848(00)00366-2 (DOI)11593 (Local ID)11593 (Archive number)11593 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. A significant relationship between Chlamydia pneumoniae seroreactivity and the severity of coronary atherosclerosis
Open this publication in new window or tab >>A significant relationship between Chlamydia pneumoniae seroreactivity and the severity of coronary atherosclerosis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background. Clinical evidence supporting a causal role of Chlamydia pneumoniae in the process of atherosclerosis is limited. It is also uncertain if the organism participates in the inflammatory response in stable angina pectoris. The current study investigates C. pneumoniae IgG and markers reflecting the inflammatory response in stable angina pectoris. The data were subsequently compared with the extent of coronary atherosclerosis.

Setting. Department of Cardiology, Linköping University Hospital, Linköping, Sweden.

Experimental protocol. We investigated 92 patients with stable angina pectoris subject to coronary angiography to assess chest pain Before angiography C. pneumoniae IgG, neutrophil count and plasma levels of myeloperoxidase and interleukin 6 were analysed. The number of major coronary arteries (1-3) having at least one diameter narrowing(=> 50%) stenosis was determined. The patients were divided into two equal sized groups according to C. pneumoniae IgG levels.

Results. Subjects with higher antibody concentrations had a more severe disease. The number of diseased arteries was 2.1±0.8(SD) and 1.4±0.6(SD) for the two groups, respectively. The difference proved to he highly significant (p<0.0001). The groups did not differ with respect to inflammatory parameters.

Conclusion. This study with 92 consented individuals with stable angina pectoris suggests a causative relationship between C. pneumoniae IgG seroreactivity and the degree of coronary atherosclerosis. It does not, however, prove causality. Thus, it is likely that C. pneumoniae participates in the progression of atherosclerosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84675 (URN)
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2012-10-17Bibliographically approved
5. Evidence that Chlamydia pneumoniae affects platelet activity in patients with acute myocardial infarction and ST-segment elevations
Open this publication in new window or tab >>Evidence that Chlamydia pneumoniae affects platelet activity in patients with acute myocardial infarction and ST-segment elevations
2001 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 33, no 10, 747-748 p.Article in journal (Refereed) Published
Abstract [en]

This study concerns platelet activity at myocardial infarctions and possible relationships with Chlamydia pneumoniae seroreactivity. Fourteen patients with acute myocardial infarction and ST-segment elevations were enrolled. They all received thrombolytic therapy. The subjects were examined within 24 h after hospital admission (Day 1) and after 6 months of recovery. On Day 1, C. pneumoniae IgM antibody titres were analysed and on Day 1 and during recovery C. pneumoniae IgG and soluble P-selectin were determined. P-selectin was used to estimate platelet activation. C. pneumoniae IgM titres at the infarction were closely related to both Day 1 IgG titres (r = 0.6; p < 0.05) and to IgG levels after 6 months (r = 0.8; p < 0.01). These results indicate a possible reactivation of a chronic infection. C. pneumoniae IgM was related to platelet activation. The correlation coefficient was r = 0.7 (p < 0.01) when comparing IgM titres with Day 1 plasma P-selectin. A similar relationship was found when comparing IgM and recovery P-selectin (r = 0.8; p < 0.01). The pathogen appears to contribute to platelet responses occurring during myocardial infarctions with ST-segment elevations. It is concluded that an ongoing reactivation of a chronic infection is related to increased platelet activity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26961 (URN)10.1080/003655401317074545 (DOI)11594 (Local ID)11594 (Archive number)11594 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
6. Individual variations of platelet inhibition after loading doses of clopidogrel
Open this publication in new window or tab >>Individual variations of platelet inhibition after loading doses of clopidogrel
2002 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 252, no 3, 233-238 p.Article in journal (Refereed) Published
Abstract [en]

Objective.  To investigate individual variations of platelet inhibition after clopidogrel-loading doses.

Setting.  Department of Cardiology, Linköping University Hospital, Linköping, Sweden.

Subjects.  Individuals with stable angina pectoris (n = 18) subject to percutaneous coronary interventions (PCI) and subsequent stenting were investigated.

Methods and experimental protocol.  A 300-mg clopidogrel loading dose was administrated immediately after stenting (day 1) followed by an additional 75 mg clopidogrel after 24 h (day 2). The ADP-evoked platelet fibrinogen binding was analysed to estimate platelet reactivity immediately before angiography and on day 2. A flow cytometry technique was used with two ADP solutions (final concentrations 0.6 and 1.7 μmol L−1) employed as platelet activating agents. Soluble P-selectin was used as a marker of platelet activity.

Results.  When using 1.7 μmol L−1 ADP to activate platelets four individuals had a strong inhibition (i.e. platelet reactivity <10% of the day 1-value day 2). In contrast, five patients demonstrated a weak inhibition (i.e. platelet reactivity >60% of the day 1-value day 2). Similar results were obtained when using 0.6 μmol L−1 ADP as a platelet-activating agent. Clopidogrel, however, fails to suppress platelet activity as estimated from soluble P-selectin.

Conclusions.  Clopidogrel evoked platelet inhibition exhibits a considerable individual heterogeneity. Some individuals only had weak responses whereas others displayed strong platelet inhibition. The present flow cytometry technique appears suitable for identifying patients with abnormal reactions after clopidogrel exposure.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25248 (URN)10.1046/j.1365-2796.2002.01027.x (DOI)9687 (Local ID)9687 (Archive number)9687 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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