Effects of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Aspirin
Intervention type(s): Drug
Intervention description(s): Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.
Other intervention name(s): Trombyl
Intervention MeSH terms: Aspirin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Fibrin network structure; Aspirin treatment; Platelet microparticles