Platelets and the inflammatory response in coronary heart disease

• 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.

Nyckelord

MEDICINE

MEDICIN

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)