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

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01397513
• Other study ID #: 151:2005/76316
• Secondary ID: 2005/1403-31/2
• Status: Completed
• Phase: Phase 4
• First received: July 14, 2011
• Last updated: July 18, 2011
• Start date: March 2006
• Est. completion date: February 2011

Study information

• Verified date: March 2006
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Karolinska Institutet
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: February 2011
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1

Intervention

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

Locations

Country	Name	City	State
Sweden	Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital	Stockholm

Sponsors (1)

Lead Sponsor	Collaborator
Karolinska Institutet

Country where clinical trial is conducted

Sweden, 

References & Publications (18)

Antovic A, Perneby C, Ekman GJ, Wallen HN, Hjemdahl P, Blombäck M, He S. Marked increase of fibrin gel permeability with very low dose ASA treatment. Thromb Res. 2005;116(6):509-17. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2006 Aug 17. — View Citation

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. — View Citation

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. Epub 2007 Oct 24. — View Citation

Dunn EJ, Philippou H, Ariëns 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. Epub 2006 Mar 16. — View Citation

Ganda OP, Arkin CF. Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care. 1992 Oct;15(10):1245-50. — View Citation

Jörneskog G, Egberg N, Fagrell B, Fatah K, Hessel B, Johnsson H, Brismar K, Blombäck M. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia. 1996 Dec;39(12):1519-23. — View Citation

Lütjens A, te Velde AA, vd Veen EA, vd Meer J. Glycosylation of human fibrinogen in vivo. Diabetologia. 1985 Feb;28(2):87-9. — View Citation

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. — View Citation

Rooth E, Wallen NH, Blombäck 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. — View Citation

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

Tehrani S, Mobarrez F, Antovic A, Santesson P, Lins PE, Adamson U, Henriksson P, Wallén NH, Jörneskog 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. — View Citation

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. Epub 2006 Dec 5. Review. — View Citation

Williams S, Fatah K, Hjemdahl P, Blombäck M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998 Nov;19(11):1666-72. — View Citation

Yngen M, Ostenson CG, Hu H, Li N, Hjemdahl P, Wallén 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):537-40. Epub 2004 Feb 13. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fibrin network permeability	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	No
Secondary	Fibrin network permeability	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	No
Secondary	Platelet microparticles	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	No