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

July 18, 2011 updated by: Karolinska Institutet

Effects of Low and High Doses of Aspirin Treatment on Fibrin Network Formation in Patients With Type 1 Diabetes and Possible Influence of the Glycemic Control.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

48

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
      • Stockholm, Sweden, 18288
        • Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Aspirin 75mg
Drug: Aspirin
Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.
Other Names:
  • Trombyl
Active Comparator: Aspirin 320mg
Drug: Aspirin
Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.
Other Names:
  • Trombyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fibrin network permeability
Time Frame: At the start and end of each 4-week treatment period
Changes in fibrin network permeability after 4 weeks of treatment with either aspirin 75 or 320mg.
At the start and end of each 4-week treatment period

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fibrin network permeability
Time Frame: At the start and end of each 4-week treatment period
Subgroup analyses comparing the treatment effects of aspirin 75 or 320mg on fibrin network permeability in patients with good and poor glycemic control, respectively.
At the start and end of each 4-week treatment period
Platelet microparticles
Time Frame: At the start and end of each 4-week treatment period
Changes in plasma concentrations of platelet microparticles after 4 weeks of treatment with either aspirin 75 or 320mg.
At the start and end of each 4-week treatment period

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Karolinska Institutet

Investigators

  • Principal Investigator: Gun Jörneskog, MD PhD, Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2006

Primary Completion (Actual)

July 1, 2010

Study Completion (Actual)

February 1, 2011

Study Registration Dates

First Submitted

July 14, 2011

First Submitted That Met QC Criteria

July 18, 2011

First Posted (Estimate)

July 19, 2011

Study Record Updates

Last Update Posted (Estimate)

July 19, 2011

Last Update Submitted That Met QC Criteria

July 18, 2011

Last Verified

March 1, 2006

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 151:2005/76316
  • 2005/1403-31/2 (Other Identifier: Ethics Committe in Stockholm)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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