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

NCT ID: NCT01397513

Last Updated: 2011-07-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-03-31
• Study Completion Date: 2011-02-28

Brief 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.

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Aspirin 75mg

Group Type: ACTIVE_COMPARATOR

Aspirin

Intervention Type: DRUG

Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.

Aspirin 320mg

Group Type: ACTIVE_COMPARATOR

Aspirin

Intervention Type: DRUG

Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.

Interventions

Aspirin

Tablets, 75 or 320mg once daily for 4 weeks. A 4-week wash-out period separated the two treatment periods.

Intervention Type: DRUG

Other Intervention Names

Trombyl

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Karolinska Institutet

OTHER

Sponsor Role: lead

Responsible Party

Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital

Principal Investigators

Gun Jörneskog, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital

Locations

Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital

Stockholm, , Sweden

Countries

Sweden

References

Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, Weisel JW. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol. 2000 May;20(5):1354-61. doi: 10.1161/01.atv.20.5.1354.

Reference Type: BACKGROUND

PMID: 10807754 (View on PubMed)

Collet JP, Allali Y, Lesty C, Tanguy ML, Silvain J, Ankri A, Blanchet B, Dumaine R, Gianetti J, Payot L, Weisel JW, Montalescot G. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2567-73. doi: 10.1161/01.ATV.0000241589.52950.4c. Epub 2006 Aug 17.

Reference Type: BACKGROUND

PMID: 16917107 (View on PubMed)

Rooth E, Wallen NH, Blomback M, He S. Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke. Thromb Res. 2011 Jan;127(1):51-6. doi: 10.1016/j.thromres.2010.09.011. Epub 2010 Oct 14.

Reference Type: BACKGROUND

PMID: 20950841 (View on PubMed)

Colle JP, Mishal Z, Lesty C, Mirshahi M, Peyne J, Baumelou A, Bensman A, Soria J, Soria C. Abnormal fibrin clot architecture in nephrotic patients is related to hypofibrinolysis: influence of plasma biochemical modifications: a possible mechanism for the high thrombotic tendency? Thromb Haemost. 1999 Nov;82(5):1482-9.

Reference Type: BACKGROUND

PMID: 10595642 (View on PubMed)

Jorneskog G, Egberg N, Fagrell B, Fatah K, Hessel B, Johnsson H, Brismar K, Blomback M. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia. 1996 Dec;39(12):1519-23. doi: 10.1007/s001250050607.

Reference Type: BACKGROUND

PMID: 8960835 (View on PubMed)

Cubbon RM, Gale CP, Rajwani A, Abbas A, Morrell C, Das R, Barth JH, Grant PJ, Kearney MT, Hall AS. Aspirin and mortality in patients with diabetes sustaining acute coronary syndrome. Diabetes Care. 2008 Feb;31(2):363-5. doi: 10.2337/dc07-1745. Epub 2007 Oct 24.

Reference Type: BACKGROUND

PMID: 17959865 (View on PubMed)

Antovic A, Perneby C, Ekman GJ, Wallen HN, Hjemdahl P, Blomback M, He S. Marked increase of fibrin gel permeability with very low dose ASA treatment. Thromb Res. 2005;116(6):509-17. doi: 10.1016/j.thromres.2005.02.007.

Reference Type: BACKGROUND

PMID: 16181986 (View on PubMed)

Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998 Nov;19(11):1666-72. doi: 10.1053/euhj.1998.1088.

Reference Type: BACKGROUND

PMID: 9857919 (View on PubMed)

Yngen M, Ostenson CG, Hu H, Li N, Hjemdahl P, Wallen NH. Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation. Diabetologia. 2004 Mar;47(3):537-540. doi: 10.1007/s00125-004-1352-4. Epub 2004 Feb 13.

Reference Type: BACKGROUND

PMID: 14963650 (View on PubMed)

Ganda OP, Arkin CF. Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care. 1992 Oct;15(10):1245-50. doi: 10.2337/diacare.15.10.1245.

Reference Type: BACKGROUND

PMID: 1425083 (View on PubMed)

Dunn EJ, Philippou H, Ariens RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia. 2006 May;49(5):1071-80. doi: 10.1007/s00125-006-0197-4. Epub 2006 Mar 16.

Reference Type: BACKGROUND

PMID: 16538489 (View on PubMed)

Nomura S, Suzuki M, Katsura K, Xie GL, Miyazaki Y, Miyake T, Kido H, Kagawa H, Fukuhara S. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis. 1995 Aug;116(2):235-40. doi: 10.1016/0021-9150(95)05551-7.

Reference Type: BACKGROUND

PMID: 7575778 (View on PubMed)

Undas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007 Mar 15;109(6):2285-92. doi: 10.1182/blood-2006-01-010645. Epub 2006 Dec 5.

Reference Type: BACKGROUND

PMID: 17148593 (View on PubMed)

Bjornsson TD, Schneider DE, Berger H Jr. Aspirin acetylates fibrinogen and enhances fibrinolysis. Fibrinolytic effect is independent of changes in plasminogen activator levels. J Pharmacol Exp Ther. 1989 Jul;250(1):154-61.

Reference Type: BACKGROUND

PMID: 2746495 (View on PubMed)

Lutjens A, te Velde AA, vd Veen EA, vd Meer J. Glycosylation of human fibrinogen in vivo. Diabetologia. 1985 Feb;28(2):87-9. doi: 10.1007/BF00279921.

Reference Type: BACKGROUND

PMID: 3920098 (View on PubMed)

Ardawi MS, Nasrat HN, Mira SA, Fatani HH. Comparison of glycosylated fibrinogen, albumin, and haemoglobin as indices of blood glucose control in diabetic patients. Diabet Med. 1990 Nov;7(9):819-24. doi: 10.1111/j.1464-5491.1990.tb01499.x.

Reference Type: BACKGROUND

PMID: 2148136 (View on PubMed)

Tehrani S, Mobarrez F, Antovic A, Santesson P, Lins PE, Adamson U, Henriksson P, Wallen NH, Jorneskog G. Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia. Thromb Res. 2010 Sep;126(3):e225-31. doi: 10.1016/j.thromres.2010.05.023. Epub 2010 Jul 15.

Reference Type: BACKGROUND

PMID: 20637495 (View on PubMed)

Siljander P, Carpen O, Lassila R. Platelet-derived microparticles associate with fibrin during thrombosis. Blood. 1996 Jun 1;87(11):4651-63.

Reference Type: BACKGROUND

PMID: 8639834 (View on PubMed)

Tehrani S, Antovic A, Mobarrez F, Mageed K, Lins PE, Adamson U, Wallen HN, Jorneskog G. High-dose aspirin is required to influence plasma fibrin network structure in patients with type 1 diabetes. Diabetes Care. 2012 Feb;35(2):404-8. doi: 10.2337/dc11-1302. Epub 2011 Dec 6.

Reference Type: DERIVED

PMID: 22148098 (View on PubMed)

Other Identifiers

2005/1403-31/2

Identifier Type: OTHER

Identifier Source: secondary_id

151:2005/76316

Identifier Type: -

Identifier Source: org_study_id