liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Platelets: with special reference to platelet density subpopulations, stable coronary heart disease and atrial fibrillation
Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 85 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1220
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-62630ISBN: 978-91-7393-272-1 (print)OAI: oai:DiVA.org:liu-62630DiVA: diva2:373666
Public defence
2010-12-10, K3, Campus Norrköping, Linköpings univeristet, Norrköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-12-01 Created: 2010-12-01 Last updated: 2010-12-01Bibliographically approved
List of papers
1. Identification of low-density plate and elevated let populations with increased reactivity alpha-granule content
Open this publication in new window or tab >>Identification of low-density plate and elevated let populations with increased reactivity alpha-granule content
Show others...
2003 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 111, no 01-Feb, 75-80 p.Article in journal (Refereed) Published
Abstract [en]

The present study examines biochemical and functional characteristics of platelet density subpopulations together with their ability to mobilise intracellular fibrinogen when activated. Platelets from three healthy volunteers were investigated. The total platelet population was separated according to density in a linear Percoll(TM) gradient in a plasma-free milieu containing EDTA that binds soluble Ca2+. Subsequently, platelets from each individual were divided according to density into 11 or 12 aliquots. In all fractions, we determined platelet count, intracellular P-selectin and the ADP-evoked platelet fibrinogen binding as a measure of platelet reactivity together with the platelet dense body content. The work demonstrates that platelets use stored intracellular fibrinogen when activated. It also shows that the platelet-fibrinogen binding can be initiated in a surrounding depleted of Ca2+ and fibrinogen. Moreover, the study demonstrates subpopulations of light platelets having increased reactivity and more alpha-granules but less dense bodies. The biological significance of the findings needs to be elucidated. (C) 2003 Elsevier Ltd. All rights reserved.

Keyword
platelets, platelet density, dense bodies, fibrinogen, P-selectin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46312 (URN)10.1016/j.thromres.2003.08.019 (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13
2. Platelet Density Distribution in Essential Thrombocythemia
Open this publication in new window or tab >>Platelet Density Distribution in Essential Thrombocythemia
Show others...
2010 (English)In: Pathophysiology of Haemostasis and Thrombosis, ISSN 1424-8832, E-ISSN 1424-8840, Vol. 37, no 1, 35-42 p.Article in journal (Refereed) Published
Abstract [en]

Essential thrombocythemia (ET) is characterized by high platelet counts and a slightly increased bleeding risk. Why severe hemorrhage does not occur more frequently is not known. Variations of platelet density (kg/l) depend mainly on cell organelle content in that high-density platelets contain more alpha and dense granules. This study compares ET patients (n = 2) and healthy volunteers (n = 2) with respect to platelet density subpopulations. A linear Percoll gradient containing prostaglandin E(1) was employed to separate platelets according to density. The platelet population was subsequently divided by density into 16 or 17 subpopulations. Determination of platelet counts was carried out. In each density fraction, platelet in vivo activity, i.e. platelet-bound fibrinogen, was measured using a flow cytometer. To further characterize platelet subpopulations, we determined intracellular concentrations of CD40 ligand (CD40L) and P-selectin in all fractions. Patients and controls demonstrated similar density distributions, i.e. 1 density peak. High-density platelets had more surface-bound fibrinogen in conjunction with signs of platelet release reactions, i.e. with few exceptions they contained less CD40L and P-selectin. Peak density platelets showed less surface-bound fibrinogen. These platelets contained less CD40L and P-selectin than nearby denser populations. The light platelets had more surface-bound fibrinogen than peak platelets together with elevated concentrations of CD40L. In ET, the malignant platelet production could exist together with platelets originating from normal megakaryocytes. It is also possible that clonal megakaryocytes produce platelets covering the entire density span. The 'normal' density distribution offers a tenable explanation as to why serious bleedings do not occur more frequently.

 

Place, publisher, year, edition, pages
Basel, Switzerland: S. Karger, 2010
Keyword
Essential thrombocythemia, Flow cytometry, Plateletactivity, Platelet density
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-59581 (URN)10.1159/000314964 (DOI)000208040900005 ()20484885 (PubMedID)
Note

Original Publication: Micha Milovanovic, Kourosh Lotfi, Tomas Lindahl, Claes Hallert and Petter Järemo, Platelet Density Distribution in Essential Thrombocythemia., Pathophysiology of Haemostasis and Thrombosis, 2010. http://dx.doi.org/10.1159/000314964 Copyright: Karger http://www.karger.com/

Available from: 2010-09-29 Created: 2010-09-21 Last updated: 2017-12-12Bibliographically approved
3. Gender and stable angina pectoris: Women have greater thrombin-evoked platelet activity but similar adenosine diphosphate-induced platelet responses
Open this publication in new window or tab >>Gender and stable angina pectoris: Women have greater thrombin-evoked platelet activity but similar adenosine diphosphate-induced platelet responses
2005 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, no 1, 227-228 p.Other (Other academic)
Publisher
227-228 p.
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-48196 (URN)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12
4. Elevated platelet reactivity in stable angina pectoris without significant coronary flow obstruction
Open this publication in new window or tab >>Elevated platelet reactivity in stable angina pectoris without significant coronary flow obstruction
2008 (English)In: Journal of Cardiovascular Medicine, ISSN 1558-2027, Vol. 9, no 2, 129-130 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

There are many different causes of angina pectoris without significant coronary flow obstruction in major coronary arteries. Examples include Prinzmetal angina and small vessel atherosclerotic disease.

METHODS:

We investigated individuals with stable angina pectoris subject to elective coronary angiography. To keep the study group as homogeneous as possible, patients with diabetes mellitus were excluded. Subjects with normal coronary angiograms (n = 13) or insignificant (< 50%) coronary flow obstruction(s) (n = 4) were grouped together. The remaining cohort (n = 96) with at least one significant (> or = 50%) flow obstruction in at least one major coronary artery served as controls.

RESULTS:

Before angiography, platelet activity in vitro on stimulation with a thrombin-receptor activating peptide (TRAP-6) (57 micromol/l and 74 micromol/l) and ADP (1.7 micromol/l and 8.5 micromol/l) was determined. Angina pectoris individuals without significant flow obstruction in major coronary arteries had enhanced platelet reactivity both when stimulated with TRAP-6 and ADP (P < 0.01 for both TRAP-6 concentrations and P < 0.05 for both ADP concentrations, respectively.

CONCLUSIONS:

It is concluded that angina pectoris without significant flow impediment in major epicardial arteries is associated with augmented platelet reactivity.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2008
Keyword
angina pectoris; flow cytometry; platelets; platelet reactivity
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-44108 (URN)10.2459/JCM.0b013e3280c56d46 (DOI)18192803 (PubMedID)75552 (Local ID)75552 (Archive number)75552 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-01-07Bibliographically approved
5. Letter: Elevated platelet density and enhanced platelet reactivity in stable angina pectoris complicated by diabetes mellitus type II
Open this publication in new window or tab >>Letter: Elevated platelet density and enhanced platelet reactivity in stable angina pectoris complicated by diabetes mellitus type II
2009 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 3, 373-374 p.Article in journal, Letter (Other academic) Published
Abstract [en]

The prognosis of coronary heart disease (CHD) has changed for the better. Type II diabetes mellitus (T2DM) complicates CHD and is associated with less favorable prospects and higher rates of coronary recurrence.

149 individuals below 75 years of age subject to elective coronary angiography to evaluate chest pain were consented. Patients were eligible if they did not have a history of rheumatic disease. 51 individuals treated medically for T2DM were compared with the remaining subjects (n = 98). Blood samples were obtained before elective coronary angiography.A special designed optical apparatus was used to analyze peak platelet density. Platelet bound fibrinogen after provocation reflecting the activation of the GPIIb-IIIa receptor i.e. platelet reactivity was determined with the use of a flow cytometer.

T2DM is associated with augmented platelet density (p < 0.001).Diabetic platelets displayed enhanced reactivity when stimulating with higher concentrations ADP (8.5 μmol/l) (p < 0.01) and TRAP-6 (74 μmol/l) (p < 0.001).

DTII patients with stable angina pectoris showed enhanced platelet density, augmented platelet reactivity and increased MPV. Platelets are more reactive in DTII. More aggressive platelets may offer a explanation as to why DTII has an impact upon the prognosis of CHD.

 

Place, publisher, year, edition, pages
Elsevier Ltd, 2009
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-59613 (URN)10.1016/j.thromres.2008.12.042 (DOI)19230957 (PubMedID)
Available from: 2010-09-21 Created: 2010-09-21 Last updated: 2017-12-12Bibliographically approved
6. Letter: Atrial fibrillation and platelet reactivity: in International Journal of Cardiology(ISSN 0167-5273)(EISSN 1874-1754)
Open this publication in new window or tab >>Letter: Atrial fibrillation and platelet reactivity: in International Journal of Cardiology(ISSN 0167-5273)(EISSN 1874-1754)
2010 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 145, no 2, 357-358 p.Article in journal, Letter (Other academic) Published
Abstract [en]

BACKGROUND: The impact of atrial fibrillation (AF) upon platelet reactivity has not been investigated.

METHODS: Subjects were 33 individuals with AF who consented to elective electrical cardioversion (ECV) immediately before ECV determination of surface-bound fibrinogen after stimulation i.e. platelet reactivity was carried out. A flow cytometer was employed. ADP (1.7 and 8.5mumol/L) and a thrombin receptor activating peptide (54 and 74mumol/L) were used as agonists. The analyses were repeated after 26+/-8(SD) months.

RESULTS: Compared to day 1 subjects with AF (n=18) had a trend towards lower platelet reactivity at study end. It reached significance when using 1.7mumol/L ADP. In contrast, after 26+/-8(SD) months sinus rhythm (SR) (n=15) was associated with significant lower reactivity with all agonists.

CONCLUSION: After 26+/-8(SD) months patients returning with AF had higher platelet reactivity than those who remained with SR.

Place, publisher, year, edition, pages
Ireland: Elsevier, 2010
Keyword
Atrial fibrillation, Flow cytometry, platelet reactivity, platelet activity
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-59612 (URN)10.1016/j.ijcard.2010.02.030 (DOI)
Note
Original Publication: Micha Milovanovic, Elisabeth Fransson, Claes Hallert and Petter Järemo, Letter: Atrial fibrillation and platelet reactivity, International Journal of Cardiology, 2010. http://dx.doi.org/10.1016/j.ijcard.2010.02.030 Copyright: ElsevierAvailable from: 2010-09-29 Created: 2010-09-21 Last updated: 2017-12-12Bibliographically approved

Open Access in DiVA

Platelets : with special reference to platelet density subpopulations, stable coronary heart disease and atrial fibrillation(1346 kB)1297 downloads
File information
File name FULLTEXT01.pdfFile size 1346 kBChecksum SHA-512
04ad3bf376cd33a2cb3b1d7930fb9a6eb3fa1dc86a63f25baa4a75f532ee12a8ec73a8d211a987629a63ae57288f02df0a1d82e9c078c301d97dc89a451dc322
Type fulltextMimetype application/pdf
Cover(436 kB)22 downloads
File information
File name COVER01.pdfFile size 436 kBChecksum SHA-512
f6e42f4c05f1c3f5c634188c9d2cea0dcc15bf46fbcf130d531128b4b90d229fb2ebd5162d8b368709661a04a0ec7aac75acee329257902d7b6d9045b319aba6
Type coverMimetype application/pdf

Authority records BETA

Milovanovic, Micha

Search in DiVA

By author/editor
Milovanovic, Micha
By organisation
Health, Activity, CareFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 1297 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 797 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf