The influence of direct thrombin inhibitors on the formation of platelet-leukocyte aggregates and tissue factor expression.
BACKGROUND
High concentrations of platelet-monocyte aggregates (PMAs) have been found in patients with myocardial infarction (MI). Oral direct thrombin inhibitors (DTIs) are under evaluation as long-term antithrombotic treatment. The aim was to evaluate whether DTIs affect the formation of platelet-leukocyte aggregates, TF expression and procoagulant microparticles (MPs).


METHODS
DTIs were added to an experimental whole blood model before platelet activation with thrombin or ADP. The concentrations of PMAs, platelet-granulocyte aggregates (PGAs), the amount of platelets bound per leukocyte and MPs were investigated by flow cytometry. TF mRNA and activity were recorded in all settings. TF activity was evaluated in a MI population treated with or without an oral DTI.


RESULTS
In vitro, thrombin and ADP increased the formation of PMAs and PGAs as well as TF mRNA expression. DTIs reduced the amount platelets bound to monocytes (p=0.02) and to granulocytes (p=0.001) upon thrombin stimulation together with a reduction of TF mRNA. In contrast, the ADP-induced formation of PMAs, PGAs and TF mRNA was not affected by the DTIs. Both thrombin and ADP stimulation increased the amount of TF-expressing MPs, which was effectively inhibited by the DTIs (p=0.02-0.002). In the MI population, the DTI reduced the TF activity (p<0.001).


CONCLUSIONS
DTIs modulate the formation of PMAs, PGAs and the TF production therein. Together with a reduction of procoagulant MPs, these results may contribute to the clinical benefit found of oral DTIs. Targeting different mechanisms in platelet and coagulation activation may be of importance due to the lack of effect of DTIs on ADP-induced platelet-leukocyte aggregates and TF production.
Christersson
Christina
C
Department of Medical Sciences, Cardiology, Uppsala University, Sweden. christina.christersson@akademiska.se
Johnell
Matilda
M
Siegbahn
Agneta
A
D000991:Antithrombins / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D055252:Cell-Derived Microparticles / Q000187:drug effects* / Q000378:metabolism; D000069604:Dabigatran; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D013925:Thromboplastin / Q000235:genetics*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000991:Antithrombins; D001384:Azetidines; D001562:Benzimidazoles; D001596:Benzylamines; D012333:RNA, Messenger; D015091:beta-Alanine; C109573:melagatran; C426686:ximelagatran; D013925:Thromboplastin; D000069604:Dabigatran