Platelet tissue factor synthesis in type 2 diabetic patients is resistant to inhibition by insulin.
OBJECTIVE
Patients with type 2 diabetes have an increased risk of cardiovascular disease and show abnormalities in the coagulation cascade. We investigated whether increased synthesis of tissue factor (TF) by platelets could contribute to the hypercoagulant state.


METHODS
Platelets from type 2 diabetic patients and matched control subjects were adhered to different surface-coated proteins, and TF premRNA splicing, TF protein, and TF procoagulant activity were measured.


RESULTS
Different adhesive proteins induced different levels of TF synthesis. A mimetic of active clopidogrel metabolite (AR-C69931 MX) reduced TF synthesis by 56 +/- 10%, an aspirin-like inhibitor (indomethacin) by 82 +/- 9%, and the combination by 96 +/- 2%, indicating that ADP release and thromboxane A(2) production followed by activation of P2Y12 and thromboxane receptors mediate surface-induced TF synthesis. Interference with intracellular pathways revealed inhibition by agents that raise cAMP and interfere with phosphatidylinositol 3-kinase/protein kinase B. Insulin is known to raise cAMP in platelets and inhibited collagen III-induced TF premRNA splicing and reduced TF activity by 35 +/- 5 and 47 +/- 5% at 1 and 100 nmol/l. Inhibition by insulin was reduced in type 2 diabetes platelets resulting in an approximately 1.6-fold higher TF synthesis than in matched control subjects.


CONCLUSIONS
We characterized the extra- and intracellular mechanisms that couple surface activation to TF synthesis in adhering platelets. In healthy individuals, TF synthesis is inhibited by insulin, but in patients with type 2 diabetes inhibition is impaired. This leads to the novel finding that platelets from type 2 diabetic patients produce more TF than platelets from matched control subjects.
Gerrits
Anja J
AJ
Thrombosis and Haemostasis Laboratory, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
Koekman
Cornelis A
CA
van Haeften
Timon W
TW
Akkerman
Jan Willem N
JW
D000469:Alkaline Phosphatase / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000502:physiology*; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000503:physiopathology; D005170:Factor X / Q000187:drug effects / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000494:pharmacology*; D008875:Middle Aged; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
D000469:Alkaline Phosphatase; D005170:Factor X; D006442:Glycated Hemoglobin; D007328:Insulin; D012322:RNA Precursors; D011994:Recombinant Proteins; D013925:Thromboplastin