Effects of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes

The fibrin network is an important component of an arterial thrombus and its structure influences the degradation of the formed clot. A tighter and less permeable fibrin network, which is less susceptible to fibrinolysis, is formed in patients with manifest cardiovascular disease (CVD) or conditions associated with increased risk of atherothrombotic complications. In a previous study we have shown reduced fibrin network permeability in patients with type 1 diabetes, which may contribute to their increased risk of CVD. Low dose aspirin treatment is standard in management of CVD; however, the effect seems reduced in patients with diabetes. Our previous studies have shown that aspirin treatment alters the fibrin network in non-diabetic individuals and increases the fibrin network permeability. The effect of aspirin on fibrin network formation in patients with diabetes is unclear.

We hypothesized that patients with type 1 diabetes might need higher doses of aspirin than the recommended low dose (75mg) treatment to gain effects on fibrin network permeability, and that the effects of aspirin treatment on fibrin network in these patients are influenced by the glycemic control.

Diabetes is associated with increased platelet activation, elevated plasma fibrinogen levels and impaired fibrinolysis, factors which may contribute to the elevated risk of cardiovascular disease (CVD) in these patients. Increased platelet activation in patients with diabetes is reflected by elevated levels of platelet microparticles, which are small circulating procoagulant vesicles shed from the platelet membrane upon activation. CVD in these patients may start as early as in the age of 25-30 years and the course is often aggressive and with poor prognosis. Treatment with a daily low dose of acetylsalicylic acid (aspirin 75 mg) is one of the cornerstones in management of CVD in non-diabetic patients; however, the effect seems reduced in patients with diabetes. The mechanisms behind this treatment failure with aspirin in diabetes patients are unclear. Aspirin is a complex drug with multiple effects. The most well known is acetylation and inhibition of platelet cyclooxygenase (COX), but COX-independent mechanisms may also of importance in protection of cardiovascular complications. One such mechanism is alteration of the fibrin/fibrinogen properties and the fibrin network structure, possibly through acetylation of the lysine residues in the fibrinogen molecule involved in crosslinking of fibrin. The fibrin network structure seems important in development of atherothrombotic events, as individuals at high risk of CVD, including patients with type 1 diabetes, as well as patients with manifest CVD have a tighter and less permeable fibrin network structure. The altered fibrin network in patients with type 1 diabetes may in part be due to increased fibrinogen glycation, which may occur on lysine residues. Treatment with aspirin increases fibrin network permeability in non-diabetic subjects. However, the effect of aspirin on fibrin network permeability in patients with diabetes is unclear. Possible competition between acetylation and glycation on lysine residues in the fibrinogen molecule might contribute to the reduced preventive effect of aspirin in management of CVD in patients with diabetes and higher doses of aspirin might therefore be required in these patients.

Our hypothesis was that glycation and acetylation occur at the same binding sites in the fibrinogen molecule. Thus, poor glycemic control and increased glycation may lead to lower acetylation of the fibrinogen molecule than during good glycemic control in turn leading to an altered fibrin network.

The aims of the present study were to analyse the effects of low (75 mg) and high dose (320 mg) aspirin treatment on fibrin network formation in patients with type 1 diabetes (primary aim), and to investigate the possible influence of the glycemic control (secondary aim). As platelet microparticles may influence the fibrin formation \[17, 18\] and since aspirin has well-known effects on platelet function, we also measured plasma concentrations of platelet microparticles.

Eligibility Criteria:
Inclusion Criteria:

* Diabetes mellitus, type 1
* Levels of HbA1C (glycated hemoglobin) \<7.4% (NGSP standard)
* Levels of HbA1C \>8.4% (NGSP standard)

Exclusion Criteria:

* Prior aspirin treatment
* Treatment with anticoagulant drugs
* Ongoing treatment with NSAIDs or other antiplatelet drugs
* A history of macrovascular disease