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Thromb Haemost 2017; 117(09): 1671-1678
DOI: 10.1160/TH17-04-0259
Coagulation and Fibrinolysis
Schattauer GmbH

Interplay between elevated cellular fibronectin and plasma fibrin clot properties in type 2 diabetes

Małgorzata Konieczyńska  
1   John Paul II Hospital, Krakow, Poland
,
Agata Hanna Bryk  
1   John Paul II Hospital, Krakow, Poland
2   Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
,
Krzysztof Piotr Malinowski
3   Faculty of Health Science, Jagiellonian University Medical College, Krakow, Poland
,
Katarzyna Draga
4   INC Research LLC, Central Nervous System Department, Krakow, Poland
,
Anetta Undas
1   John Paul II Hospital, Krakow, Poland
2   Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland
› Author Affiliations Financial support: The study was supported by Jagiellonian University Medical College grant to A. U. (K/ZDS/005802).
Further Information

Publication History

Received: 12 April 2017

Accepted: 09 May 2017

Publication Date:
28 November 2017 (online)

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Summary

Type 2 diabetes is associated with faster formation of poorly lysable, denser fibrin clots and elevated cellular fibronectin (cFn), a marker of vascular injury. We investigated whether cFn affects clot properties in type 2 diabetes. In 200 consecutive patients with type 2 diabetes and 100 control subjects matched for age and sex, we determined plasma cFn along with clot formation and degradation using turbidimetric and permeability assays. Diabetic patients had elevated cFn (median, 3.99 [interquartile range, 2.87–4.81] µg/ml]), increased clot density (MaxAbsC) and prolonged lysis time (LysT) compared with those without type 2 diabetes (all p<0.01). Diabetic patients with documented cardiovascular disease (CVD, n=127, 63.5 %) had increased cFn (4.53 [3.68–4.95] µg/ml), decreased clot permeability (Ks) and increased MaxAbsC compared with those without CVD (all p<0.001). Diabetic patients with cFn in the top quartile (>4.81 µg/ml) were two times more likely to have CVD compared with those in the lowest quartile (odds ratio 1.80, 95 % confidence interval 1.41–2.46, p<0.001). No differences in cFn were observed in relation to microvascular complications. After adjustment for potential confounders, cFn accounted for 10.2 % of variance in Ks, 18.2 % of variance in clot density and 10.2 % of variance in AUC in diabetic patients. This study shows that elevated cFn is associated with unfavourably modified clot properties in type 2 diabetes, especially with concomitant CVD, which indicates novel links between vascular injury and prothrombotic alterations in diabetes. Coagulation, cellular fibronectin, type 2 diabetes, cardiovascular disease.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Coagulation - cellular fibronectin - type 2 diabetes - cardiovascular disease

* M. K. and A. B. equally contributed to this work.


 

  • References

  • 1 Viles-Gonzalez JF, Fuster V, Badimon JJ. Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J 2004; 25: 1197-1207.
    CrossrefPubMedGoogle Scholar
  • 2 Stratmann B, Tschoepe D. Atherogenesis and atherothrombosis - focus on diabetes mellitus. Best Pract Res Clin Endocrinol Metab 2009; 23: 291-303.
    CrossrefPubMedGoogle Scholar
  • 3 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
    CrossrefPubMedGoogle Scholar
  • 4 Undas A. Fibrin clot properties and their modulation in thrombotic disorders. Thromb Haemost 2014; 112: 32-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Bridge KI, Philippou H, Ariëns RAS. Clot properties and cardiovascular disease. Thromb Haemost 2014; 112: 901-908.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Bochenek M, Zalewski J, Sadowski J. et al. Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease. J Thromb Thrombolysis 2013; 35: 264-270.
    CrossrefPubMedGoogle Scholar
  • 7 Undas A, Wiek I, Stepien E. et al. Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome. Diabetes Care 2008; 31: 1590-1595.
    CrossrefPubMedGoogle Scholar
  • 8 Konieczynska M, Fil K, Bazanek M. et al. Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis. Thromb Haemost 2014; 111: 685-693.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Hess K, Alzahrani SH, Price JF. et al. Hypofibrinolysis in type 2 diabetes: The role of the inflammatory pathway and complement C3. Diabetologia 2014; 57: 1737-1741.
    CrossrefPubMedGoogle Scholar
  • 10 Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diabetes Vasc Dis Res 2010; 07: 260-273.
    CrossrefPubMedGoogle Scholar
  • 11 Undas A, Ariëns RA. Fibrin clot structure and function: A role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31: e88-99.
    CrossrefPubMedGoogle Scholar
  • 12 Soma P, Pretorius E. Interplay between ultrastructural findings and atherothrombotic complications in type 2 diabetes mellitus. Cardiovasc Diabetol 2015; 14: 96
    CrossrefPubMedGoogle Scholar
  • 13 Pretorius E, Bester J, Vermeulen N. et al. Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics. Cardiovasc Diabetol 2015; 14: 30
    CrossrefPubMedGoogle Scholar
  • 14 Du V, Huskens D, Maas C. et al. New Insights into the Role of Erythrocytes in Thrombus Formation. Semin Thromb Hemost 2014; 40: 72-80.
    PubMedGoogle Scholar
  • 15 Walus-Miarka M, Wolkow P, Cyganek K. et al. Altered fibrin-clot properties are associated with retinopathy in type 2 diabetes mellitus. Diabetes Metab 2012; 38: 462-465.
    CrossrefPubMedGoogle Scholar
  • 16 Wang Y, Gallant RC, Ni H. Extracellular matrix proteins in the regulation of thrombus formation. Curr Opin Hematol 2016; 23: 280-287.
    CrossrefPubMedGoogle Scholar
  • 17 To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair 2011; 04: 21
    CrossrefPubMedGoogle Scholar
  • 18 Corbett SA, Lee L, Wilson CL. et al. Covalent cross-linking of fibronectin to fibrin is required for maximal cell adhesion to a fibronectin-fibrin matrix. J Biol Chem 1997; 272: 2499-2505.
    PubMedGoogle Scholar
  • 19 Nair CH, Dhall DP. Studies on fibrin network structure: the effect of some plasma proteins. Thromb Res 1991; 61: 315-325.
    CrossrefPubMedGoogle Scholar
  • 20 Kanters SD, Banga JD, Algra A. et al. Plasma levels of cellular fibronectin in diabetes. Diabetes Care 2001; 24: 323-327.
    CrossrefPubMedGoogle Scholar
  • 21 van Keulen JK, de Kleijn DP, Nijhuis MM. et al. Levels of extra domain A containing fibronectin in human atherosclerotic plaques are associated with a stable plaque phenotype. Atherosclerosis 2007; 195: e83-91.
    CrossrefPubMedGoogle Scholar
  • 22 American Diabetes Association. 2. Classification and Diagnosis of Diabetes. Diabetes Care 2015; 38 (Suppl) S8-16.
    CrossrefPubMedGoogle Scholar
  • 23 Undas A, Szuldrzynski K, Stepien E. et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: Effects of inflammation and oxidative stress. Atherosclerosis 2008; 196: 551-557.
    CrossrefPubMedGoogle Scholar
  • 24 Undas A, Zawilska K, Ciesla-Dul M. et al. Altered fibrin clot structure / function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114: 4272-4279.
    CrossrefPubMedGoogle Scholar
  • 25 Carter AM, Cymbalista CM, Spector TD. et al. Heritability of clot formation, morphology, and lysis: The EuroCLOT study. Arterioscler Thromb Vasc Biol 2007; 27: 2783-2789.
    CrossrefPubMedGoogle Scholar
  • 26 Dunn EJ, Ariëns RA, de Lange M. et al. Genetics of fibrin clot structure: a twin study. Blood 2004; 103: 1735-1740.
    CrossrefPubMedGoogle Scholar
  • 27 Mills JD, Ariëns RA, Mansfield MW. et al. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation 2002; 106: 1938-1942.
    CrossrefPubMedGoogle Scholar
  • 28 Cho J, Mosher DF. Role of fibronectin assembly in platelet thrombus formation. J Thromb Haemost 2006; 04: 1461-1469.
    CrossrefPubMedGoogle Scholar
  • 29 Matuskova J, Chauhan AK, Cambien B. et al. Decreased plasma fibronectin leads to delayed thrombus growth in injured arterioles. Arterioscler Thromb Vasc Biol 2006; 26: 1391-1396.
    CrossrefPubMedGoogle Scholar
  • 30 Wang Y, Reheman A, Spring CM. et al. Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest 2014; 124: 4281-4293.
    CrossrefPubMedGoogle Scholar
  • 31 Makogonenko E, Tsurupa G, Ingham K. et al. Interaction of Fibrin(ogen) with Fibronectin: Further Characterization and Localization of the Fibronectin-Binding Site. Biochemistry 2002; 41: 7907-7913.
    CrossrefPubMedGoogle Scholar
  • 32 Wang Y, Ni H. Fibronectin: extra domain brings extra risk?. Blood 2015; 125: 3043-3044.
    CrossrefPubMedGoogle Scholar
  • 33 White ES, Baralle FE, Muro AF. New insights into form and function of fibronectin splice variants. J Pathol 2008; 216: 1-14.
    CrossrefPubMedGoogle Scholar
  • 34 Babaev VR, Porro F, Linton MF. et al. Absence of regulated splicing of fibronectin EDA exon reduces atherosclerosis in mice. Atherosclerosis 2008; 197: 534-540.
    CrossrefPubMedGoogle Scholar
  • 35 Maurer E, Schaff M, Receveur N. et al. Fibrillar cellular fibronectin supports efficient platelet aggregation and procoagulant activity. Thromb Haemost 2015; 114: 1175-1188.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Dunn EJ, Ariëns RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48: 1198-1206.
    CrossrefPubMedGoogle Scholar
  • 37 Dunn EJ, Philippou H, Ariëns RAS. et al. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49: 1071-1080.
    CrossrefPubMedGoogle Scholar
  • 38 Lados-Krupa A, Konieczynska M, Chmiel A. et al. Increased Oxidation as an Additional Mechanism Underlying Reduced Clot Permeability and Impaired Fibrinolysis in Type 2 Diabetes. J Diabetes Res 2015; 2015: 456189
    PubMedGoogle Scholar
  • 39 Kurdee Z, King R, Ajjan RA. The fibrin network in diabetes: Its role in thrombosis risk. Pol Arch Med Wewn 2014; 124: 617-627.
    PubMedGoogle Scholar
  • 40 Gerstein H, Jaeschke R. Drugs in diabetes in 2016 , changes in endocrinology in 2014. Dr. Hertzel Gerstein in an interview with Dr. Roman Jaeschke. Pol Arch Med Wewn 2016; 126: 907-908.
    PubMedGoogle Scholar