Soluble urokinase plasminogen activator receptor and incidence of venous thromboembolism

Summary

Raised plasma levels of the soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased incidence of cardiovascular diseases. Whether suPAR is associated with venous thromboembolism (VTE) is largely unknown. The purpose of the present study was to investigate the relationship between suPAR and incidence of VTE in a cohort study. suPAR was measured in 5,203 subjects (aged 46–68 years, 58 % women) from the general population, who participated in the Malmö Diet and Cancer (MDC) study between 1991 and 1994. Incident cases of VTE were identified from the Swedish patient register during a mean follow-up of 15.7 years. Of 5,203 subjects with measurements of suPAR, 239 had VTE during follow-up (127 venous thrombosis, 86 lung embolism, 26 both). Incidence of VTE was significantly higher in subjects with suPAR levels in the top quartile. Adjusted for age and sex, the HR (4^th vs 1^st quartile) was 1.74 (95%CI: 1.2–2.6, p for trend=0.003). After adjustments for risk factors, the HR was 1.66 (95 %CI: 1.1–2.5, p for trend=0.016). High level of suPAR was a risk indicator for incidence of VTE in this population-based cohort study. The causal relationships between suPAR and VTE remain to be explored.

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

Keywords

Epidemiological studies - venous thrombosis - pulmonary embolism - plasminogen activators

• References

• 1 Mustjoki S, Sidenius N, Vaheri A. Enhanced release of soluble urokinase receptor by endothelial cells in contact with peripheral blood cells. FEBS Lett 2000; 486: 237-242.
• 2 Plesner T, Behrendt N, Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells 1997; 15: 398-408.
• 3 Ploug M, Eriksen J, Plesner T. et al. A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal haemoglobinuria. Eur J Biochem 1992; 208: 397-404.
• 4 Plesner T, Ploug M, Ellis V. et al. The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. Blood 1994; 83: 808-815.
• 5 Pliyev BK. Activated human neutrophils rapidly release the chaemotactically active D2D3 form of the urokinase-type plasminogen activator receptor (uPAR/ CD87). Mol Cell Biochem 2009; 321: 111-122.
• 6 Pliyev BK, Menshikov MY. Release of the soluble urokinase-type plasminogen activator receptor (suPAR) by activated neutrophils in rheumatoid arthritis. Inflammation 2010; 33: 1-9.
• 7 Thunø M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers 2009; 27: 157-172.
• 8 Montuori N, Visconte V, Rossi G. et al. Soluble and cleaved forms of the uroki-nase-receptor: degradation products or active molecules?. Thromb Haemost 2005; 93: 192-198.
• 9 Persson M, Östling G, Smith G. et al. Soluble urokinase plasminogen activator receptor: a risk factor for carotid plaque, stroke, and coronary artery disease. Stroke 2014; 45: 18-23.
• 10 Persson M, Engström G, Björkbacka H. et al. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmö Diet and Cancer Study. Atherosclerosis 2012; 220: 502-505.
• 11 Eugen-Olsen J, Andersen O, Linneberg A. et al. Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296-308.
• 12 Borné Y, Persson M, Melander O. et al. Increased plasma level of soluble uroki-nase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. Eur J Heart Fail 2014; 16: 377-383.
• 13 Sloand EM, Pfannes L, Scheinberg P. et al. Increased soluble urokinase plasmi-nogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal haemoglobinuria (PNH) patients. Exp Hematol 2008; 36: 1616-1624.
• 14 Hedblad B, Nilsson P, Janzon L. et al. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmö, Sweden. Diabet Med 2000; 17: 299-307.
• 15 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539-553.
• 16 Ludvigsson JF, Andersson E, Ekbom A. et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11: 450.
• 17 Kofoed K, Schneider UV, Scheel T, Andersen O, Eugen-Olsen J. Development and validation of a multiplex add-on assay for sepsis biomarkers using xmap technology. Clin Chem 2006; 52: 1284-1293.
• 18 Howie BN, Donnelly P, Marchini J. A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies. PLoS Genet 2009; 5: e1000529.
• 19 Zöller B, Li X, Sundquist J, Sundquist K. Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden. Circulation 2011; 124: 1012-1020.
• 20 Rosengren A, Freden M, Hansson P-O et al.. Psychosocial factors and venous thromboembolism: a long-term follow-up study of Swedish men. J Thromb Haemost 2008; 6: 558-564.
• 21 Smith JG, Platonov PG, Hedblad B. et al. Atrial fibrillation in the Malmö Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol 2010; 25: 95-102.
• 22 Hammar N, Alfredsson L, Rosén M. et al. A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. Int J Epidemiol 2001; 30 (Suppl. 01) S30-34.
• 23 Isma N, Svensson PJ, Gottsäter A. et al. Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmö Thrombophilia Study (MATS). Thromb Res 2009; 124: 663-666.
• 24 Mondino A, Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 2004; 25: 450-455.
• 25 Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 2010; 11: 23-36.
• 26 Gyetko MR, Sud S, Sonstein J. et al. Antigen-driven lymphocyte recruitment to the lung is diminished in the absence of urokinase-type plasminogen activator (uPA) receptor, but is independent of uPA. J Immunol 2001; 167: 5539-5542.
• 27 Solberg H, Ploug M, Hoyer-Hansen G. et al. The murine receptor for urokinase-type plasminogen activator is primarily expressed in tissues actively undergoing remodeling. J Histochem Cytochem 2001; 49: 237-246.
• 28 Binder BR, Mihaly J, Prager GW. uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist’s view. Thromb Haemost 2007; 97: 336-342.
• 29 Zöller B, García de Frutos P, Dahlbäck B. A common 4G allele in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998; 79: 802-807.
• 30 Lijfering WM, Flinterman LE, Vandenbroucke JP. et al. Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. Semin Thromb Haemost 2011; 37: 885-896.
• 31 Petrauskiene V, Falk M, Waernbaum I. et al. The risk of venous thromboembol-ism is markedly elevated in patients with diabetes. Diabetologia 2005; 48: 1017-1021.
• 32 Squizzato A, Romualdi E, Büller HR. et al. Clinical review: Thyroid dysfunction and effects on coagulation and fibrinolysis: a systematic review. J Clin Endocri-nol Metab 2007; 92: 2415-2420.