Información del artículo
La diabetes mellitus es un factor de riesgo conocido de enfermedad vascular. Las primeras fases de esta afección vascular implican la disfunción del endotelio vascular. El estudio funcional del endotelio supone una intervención demasiado laboriosa y costosa para formar parte de la valoración regular del paciente de riesgo. En consecuencia, ha crecido el interés en los últimos años en la valoración de la lesión endotelial por medio de la determinación de diferentes marcadores solubles. Los más estudiados son aquellos marcadores de síntesis predominantemente endotelial implicados en los procesos de trombosis y fibrinolisis. En este artículo se revisan aquellos que se han relacionado con la lesión endotelial en la diabetes: trombomodulina, tissue factor pathway inhibitor, factor von Willebrand, activador tisular del plasminógeno e inhibidor del activador del plasminógeno-1.
Palabras clave:
Lesión endotelial
Diabetes
Trombomodulina
Tissue factor pathway inhibitor
Diabetes mellitus is a known risk factor for vascular disease. Endothelial damage is an early event in this process. Endothelial dysfunction studies are too expensive and laborious for routine use in at-risk patients. Therefore, in the last few years interest has increased in soluble markers of endothelial damage, particularly in those involved in thrombosis and fibrinolysis. We review the markers of endothelial damage that have been shown to be increased in diabetic patients: thrombomodulin, tissue-type factor pathway inhibitor, von Willebrand factor, tissue plasminogen activator, and plasminogen-activator inhibitor-1.
Key words:
Endothelial damage
Diabetes
Thrombomodulin
Tissue factor pathway inhibitor
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Biblografía
[1.]
P.Z. Zimmet.
Kelly West Lecture 1991 Challenges in diabetes epidemiology-from West to the rest.
Diabetes Care, 15 (1992), pp. 232-252
[2.]
M. Laakso, S. Lehto.
Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance.
Atherosclerosis, 137 (1998), pp. S65-S73
[3.]
P.Z. Zimmet, K.G.M.M. Alberti.
The changing face of macrovascular disease in non-insulin-dependent diabetes mellitus: an epidemic in progress.
Lancet, 350 (1997), pp. 1-4
[4.]
I. Juhan-Vague, S.G. Thompson, J. Jespersen.
Invovelment of hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris.
Arterioscler Thromb, 13 (1993), pp. 1865-1873
[5.]
S. Mäkimattila, A. Virkamäki, P.H. Groop, J. Cockcroft, T. Utriainen, J. Fagerudd, et al.
Chronic Hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus.
Circulation, 94 (1996), pp. 1276-1282
[6.]
R. De Catterina.
Endothelial dysfunctions: common denominators in vascular disease.
Cur Opin Lipidol, 11 (2000), pp. 9-23
[7.]
A. Panza, A.A. Quyyumi, J.E. Brush Jr, S.E. Epstein.
Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.
N Engl J Med, 323 (1990), pp. 22-27
[8.]
K.E. Sorensen, D.S. Celermajer, D. Georgakopoulos, G. Hatcher, D.J. Betteridge, J.E. Deanfield.
Impairement of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level.
J Clin Invest, 93 (1994), pp. 50-55
[9.]
H. Takahashi, S. Ito, M. Hanano, K. Wada, H. Niwano, Y. Seki, et al.
Circulating thrombomodulin as a novel endothelial cell marker: comparison of its behavior with von Willebrand factor and tissue-type plasminogen activator.
Am J Hematol, 41 (1992), pp. 32-39
[10.]
J.H. Jansson, B. Norberg, T.K. Nilsson.
Impact of acute phase on concentrations of tissue plasminogen activator and plasminogen activator inhibitor in plasma after deep-vein thrombosis or open-heart surgery.
Clin Chem, 35 (1989), pp. 1544-1545
[11.]
S.G. Thompson, J. Kienast, S.D. Pyke, F. Haverkate, J.C. van de Loo.
Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.
N Engl J Med, 332 (1995), pp. 635-641
[12.]
A.D. Blann, C.N. McCollum.
von Willebrand factor and soluble thrombomodulin as predictors of adverse events among subjects with peripheral or coronary atherosclerosis.
Blood Coagul Fibrinolysis, 10 (1999), pp. 375-380
[13.]
H. Ishii, M. Uchiyama H Kazama.
Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells.
Thromb Haemost, 63 (1990), pp. 157-162
[14.]
H. Ishii, P.W. Majerus.
Thrombomodulin is present in human plasma and urine.
J Clin Invest, 76 (1985), pp. 2178-2181
[15.]
Y. Morikawa, A. Morikawa, I. Makino.
Relationship of thyroid states and serum thrombomodulin (TM) levels in Graves' disease: TM, a possible new marker of the peripheral activity of thyroid hormones.
J Clin Endocrinol Metab, 76 (1993), pp. 609-614
[16.]
J.L. Reverter, J.C. Reverter, D. Tàssies, F. Rius, J. Monteagudo, J. Rubiés-Prat, et al.
Thrombomodulin and induced tissue factor expression on monocytes as markers of diabetic microangiopathy: A prospective study on hemostasis and lipoproteins in insulin-dependent diabetes mellitus.
Am J Hematol, 56 (1997), pp. 93-99
[17.]
A.D. Blann, C.N. McCollum.
von Willebrand factor and soluble thrombomodulin as predictors of adverse events among subjects with peripheral or coronary atherosclerosis.
Blood Coagul Fibrinolysis, 10 (1999), pp. 375-380
[18.]
A.D. Blann, J. Amiral, C.N. McCollum.
Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease.
Eur J Haematol, 59 (1997), pp. 115-120
[19.]
V. Salomaa, C. Matei, N. Alecsik, L. Sansores-Garcia, A.R. Folsom, H. Juneja, et al.
Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study.
Lancet, 353 (1999), pp. 1729-1734
[20.]
T. Matsuoka, Y. Yamasaki, T. Watari, M. Kubota, T. Kamada.
Serum soluble thrombomodulin as a marker of diabetic macroangiopathy.
Diabetes, 18 (1995), pp. 731
[21.]
A.D. Blann, A. Farrell, A. Picton, C.N. McCollum.
Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease.
Thromb Res, 97 (2000), pp. 209-216
[22.]
J. Constans, A.D. Blann, V. Guerin, C. Conri.
Soluble thrombomodulin in hypercholesterolemic patients.
Lancet, 355 (2000), pp. 145
[23.]
N. Tani, K. Hada, A. Kitami, M. Nakano, H. Takahashi, S. Ito, et al.
Effects of salicylic acid and cilostazol administration on serum thrombomodulin concentration in diabetic patients.
Thromb Res, 69 (1993), pp. 153-158
[24.]
J. Boldt, M. Papsdorf, B. Kumle, S. Piper, G. Hempelmann.
Influence of angiotensin-converting enzyme inhibitor enalaprilat on endothelial-derived substances in the critically ill.
Crit Care Med, 26 (1998), pp. 1663-1670
[25.]
P. Ambrosi, M.F. Aillaud, G. Habib, B. Kreitmann, D. Metras, R. Luccioni, et al.
Fluvastatin decreases soluble thrombomodulin levels in cardiac recipients.
Thromb Haemost, 83 (2000), pp. 46-48
[26.]
M. Nakano, M. Furutani, H. Shinno, T. Ikeda, K. Oida, H. Ishii.
Elevation of soluble thrombomodulin antigen levels in the serum and urine of streptozotocin-induced diabetes model rats.
Thromb Res, 99 (2000), pp. 83-91
[27.]
A. Tanaka, H. Ishii, S. Hiraishi, M. Kazama, H. Maezawa.
Increased thrombomodulin values in plasma of diabetic men with microangiopathy.
Clin Chem, 37 (1991), pp. 269-272
[28.]
Y. Iwashima, T. Sato, K. Watanabe, E. Ooshima, S. Hiraishi, H. Ishii, et al.
Elevation of plasma thrombomodulin level in diabetic patients with early diabetic nephropathy.
Diabetes, 39 (1990), pp. 983-988
[29.]
Y. Sumida, H. Wada, M. Fujii, Y. Mori, T. Nakasaki, M. Shimura, et al.
Increased soluble fibrin monomer and soluble thrombomodulin levels in non-insulin-dependent diabetes mellitus.
Blood Coag Fibrinolysis, 8 (1997), pp. 303-307
[30.]
E.C. Gabazza, H. Takeya, H. Deguchi, Y. Sumida, O. Taguchi, K. Murata, et al.
Protein C activation in NIDDM patients.
Diabetologia, 39 (1996), pp. 1455-1461
[31.]
K. Oida, H. Takai, H. Maeda, S. Takahashi, T. Tamai, T. Nakai, et al.
Plasma thrombomodulin concentration in diabetes mellitus.
Diabetes Res Clin Pract, 10 (1990), pp. 193-196
[32.]
H. Shimano, K. Takahashi, M. Kawakami, T. Gotoda, K. Harada, M. Shimada, et al.
Elevated serum and urinary thrombomodulin levels in patients with non-insulin-dependent diabetes mellitus.
Clin Chim Acta, 225 (1994), pp. 89-96
[33.]
T. Inukai, Y. Fujiwara, K. Tayama, Y. Aso, Y. Takemura.
Clinical significance of urinary and serum thrombomodulins in patients with non-insulin-dependent diabetes mellitus.
Diabetes Res Clin Pract, 33 (1996), pp. 99-104
[34.]
Y. Aso, T. Inukai, Y. Takemura.
Mechanisms of elevation of serum and urinary concentrations of soluble thrombomodulin in diabetic patients: possible applications as a marker for vascular endothelial injury.
Metabolism, 47 (1998), pp. 362-365
[35.]
M. Rigla, J. Fontcuberta, J. Mateo, A. Caixas, J.M. Pou, A. de Leiva, et al.
Physical training decreases plasma thrombomodulin in type I and type II diabetic patients.
Diabetologia, 44 (2001), pp. 693-699
[36.]
S. Gabat, C. Keller, H.P. Kempe, J. Amiral, R. Ziegler, E. Ritz, et al.
Plasma thrombomodulin: a marker for microvascular complications in diabetes mellitus.
Vasa, 25 (1996), pp. 233-241
[37.]
M. Rigla, J. Mateo, J. Fontcuberta, J.C. Souto, A. de Leiva, A. Perez.
Normalisation of tissue factor pathway inhibitor activity after glycaemic control optimisation in type 1 diabetic patients.
Thromb Haemost, 84 (2000), pp. 223-227
[38.]
G. Gruden, G. Pagano, R. Romagnoli, D. Frezet, C. Olivetti, P. Cavallo-Perin.
Throm-bomodulin levels in insulin-dependent diabetic patients with microalbuminuria.
Diabet Med, 12 (1995), pp. 258-260
[39.]
M.A. Hoffman, B. Kohl, M.S. Zumbach, V. Borcea, A. Bierhaus, M. Henkels, et al.
Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.
Diabetes Care, 21 (1998), pp. 841-848
[40.]
P.B. Leurs, R. van Oerle, K. Hamulyak, B.H.R. Wolffenbuttel.
Tissue factor pathway inhibitor activity in patients with IDDM.
Diabetes, 44 (1995), pp. 80-84
[41.]
Y. Aso, Y. Fujiwara, K. Tayama, K. Takanashi, T. Inukai, Y. Takemura.
Relationship between plasma soluble thrombomodulin levels and insulin resistance syndrome in type 2 diabetes: a comparison with von Willebrand factor.
Exp Clin Endocrinol Diabetes, 109 (2001), pp. 210-216
[42.]
G.J. Brozle, J.P. Miletich.
Characterization of the inhibition of tissue factor in serum.
Blood, 69 (1987), pp. 150-155
[43.]
M.S. Bajaj, M.N. Kuppuswany, H. Saito, S.G. Spitzer, S.P. Bajaj.
Cultured normal human hepatocytes do not sinthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis.
Proc Natl Acad Sci USA, 87 (1990), pp. 8869-8873
[44.]
P. Lesnik, A. Vonica, M. Guerin, M. Moreau, M.J. Chapman.
Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subespedies of LDL and HDL and with Lp(a).
Atheroscler Thromb, 1 (1993), pp. 066-075
[45.]
Y. Kamikura, H. Wada, A. Yamada, M. Shimura, K. Hiyoyama, H. Shiku, et al.
Increased tissue factor pathway inhibitor in patients with acute myocardial infarction.
Am J Hematol, 55 (1997), pp. 183-187
[46.]
P.B. Leurs, R. van Oerle, B.H.R. Wolffenbuttel, K. Hamulyak.
Increased tissue factor pathway inhibitor (TFPI) and coagulation in patients with insulin-dependent diabetes mellitus.
Thromb Haemost, 77 (1997), pp. 472-476
[47.]
H. Yokoyama, B. Myrup, P. Rossing, P.B. Ostergaard.
Increased tissue factor pathway inhibitor activity in IDDM patients with nephropathy.
Diabetes Care, 19 (1996), pp. 441-445
[48.]
F.C. Huvers, P.W. De Leeuw, A.J. Houben, C.H. De Haan, K. Hamulyak, H. Schouten, et al.
Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under nearnormoglycemic conditions.
Diabetes, 48 (1999), pp. 1300-1307
[49.]
K. Kario, T. Matsuo, H. Kobayashi, M. Matsuo, T. Sakata, T. Miyata.
Activation of tissue factor-induced coagulation and endothelial cell dysfunction in non-insulin-dependent diabetic patients with microalbuminuria.
Arterioscler Thromb Vasc Biol, 15 (1995), pp. 1114-1120
[50.]
P.M. Manucci.
Von Willebrand factor: a marker of endothelial damage?.
Atheroscler Thromb Vasc Biol, 18 (1998), pp. 1359-1362
[51.]
S.G. Thompson, J. Kienast, S.D. Pyke, F. Haverkate, J.C. van de Loo.
Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.
N Engl J Med, 332 (1995), pp. 635-641
[52.]
A.D. Blann, M. Seigneur, M. Steiner, M.R. Boisseau, C.N. McCollum.
Circulating endothelial cell markers in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease.
Eur J Clin Invest, 27 (1997), pp. 916-921
[53.]
A.J. Catto, A.M. Carter, J.H. Barrett, J. Bamford, P.J. Rice, P.J. Grant.
Von Willebrand factor and factor VIII: C in acute cerebrovascular disease: relationship to stroke, subtype and mortality.
Thromb Haemost, 77 (1997), pp. 1104-1108
[54.]
A. Jager, V.W. van Hinsberg, P.J. Kostense, J.J. Emeis, J.S. Yudkin, G. Nijpels, et al.
Von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study.
Arterioscler Thromb Vasc Biol, 19 (1999), pp. 3071-3077
[55.]
C.G. Schalkwijk, D.C. Poland, W. van Dijk, A. Kok, J.J. Emeis, A.M. Drager, et al.
Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation.
Diabetologia, 42 (1999), pp. 351-357
[56.]
P. Knöbl, G. Schernthaner, C. Schnack, P. Pietschmann, A. Griesmacher, R. Prager, et al.
Thrombogenic factors are related to urinary albumin excretion rate in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients.
Diabetologia, 36 (1993), pp. 1045-1050
[57.]
T. Jensen, J. Bjerre-Knudsen, B. Feldt-Rasmussen, T. Deckert.
Features of endothelial dysfunction in early diabetic nephropathy.
Lancet, 1 (1989), pp. 461-463
[58.]
B. Myrup, P. Rossing, T. Jensen, J. Gram, C. Klufft, J. Jespersen.
Procoagulant activity and intimal dysfunction in IDDM.
Diabetologia, 38 (1995), pp. 73-78
[59.]
S. Nielsen, A. Schmitz, T. Bacher, M. Rehling, J. Ingerslev, C.E. Mogensen.
Transcapillary escape rate and albuminuria in Type II diabetes. Effects of short-term treatment with low-molecular weight heparin.
Diabetologia, 42 (1999), pp. 60-67
[60.]
C.D.A. Stehouwer, E.S.G. Stroes, W.H.L. Hackeng, P.G.H. Mulder, G.J.H. Den Ottolander.
Von Willebrand factor and development of diabetic nephropathy in IDDM.
Diabetes, 40 (1991), pp. 971-976
[61.]
M.E. Plater, I. Ford, M.T. Dent, F.E. Preston, J.D. Ward.
Elevated von Willebrand factor antigen predicts deterioration in diabetic peripheral nerve function.
Diabetologia, 39 (1996), pp. 336-343
[62.]
T.C. Vukovich, G. Schernthaner, P.N. Knöbl, U. Hay.
The effect of near-normoglycaemic control on plasma factor VII / von Willebrand factor and fibrin degradation products in insulindependent diabetic patients.
J Clin Endocrinol Metab, 69 (1989), pp. 84-89
[63.]
J. Loscalzo, E. Braunwald.
Tissue plasminogen activator.
N Engl J Med, 319 (1988), pp. 925-931
[64.]
M.C. Alessi, F. Peiretti, P. Morange, M. Henry, G. Nalbone, I. Juhan-Vague.
Production of plasminogen activator inhibitor 1 by human adipose tissue. Possible link between visceral fat accumulation and vascular disease.
Diabetes, 46 (1997), pp. 860-867
[65.]
J.H. Jansson, B. Norberg, T.K. Nilsson.
Impact of acute phase on concentrations of tissue plasminogen activator and plasminogen activator inhibitor in plasma after deep-vein thrombosis or open-heart surgery.
Clin Chem, 35 (1989), pp. 1544-1545
[66.]
I. Juhan-Vague, M.C. Alessi, P. Vague.
Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherotrombosis.
Diabetologia, 34 (1991), pp. 457-462
[67.]
I. Juhan-Vague, S.G. Thompson, J. Jespersen.
Invovelment of hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris.
Arterioscler Thromb, 13 (1993), pp. 1865-1873
[68.]
I. Juhan-Vague, M.F. Aillaud, M.C. Alessi, P. Vague, A. Rudnichi, M. Safar, et al.
Fibrinolytic anormalies associated with insulin resistance. Effect of Metformin. Result of the BIGPRO trial.
Fibrinolysis, 8 (1994), pp. 20-28
[69.]
R. Testa, A.R. Bonfigli, L. Piantanelli, S. Manfrini, I. Testa, F. Gregorio.
Relationship between plasminogen activator inhibitor type-1 plasma levels and the lipoprotein(a) concentrations in non-insulin-dependent diabetes mellitus.
Diabetes Res Clin Pract, 33 (1996), pp. 111-118
[70.]
J.B. McGill, D.J. Schneider, C.L. Arfken, C.L. Lucore, B.E. Sobel.
Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients.
Diabetes, 43 (1994), pp. 104-109
[71.]
J.P. Bastard, E. Bruckert, J.J. Robert, A. Ankri, A. Grimaldi, C. Jardel, et al.
Are free fatty acids related to plasma plasminogen activator inhibitor 1 in android obesity?.
Int J Obes Relat Metab Disord, 19 (1995), pp. 836-838
[72.]
F. Carmassi, M. Morale, R. Puccetti, F. De Negri, F. Monzani, R. Navalesi, et al.
Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus.
Thromb Res, 67 (1992), pp. 643-654
[73.]
R.E. Maser, D. Ellis, J.R. Erbey, T.J. Orchd.
Do tissue plasminogen activator-plasminogen activator inhibitor-1 complexes relate to the complications of insulin-dependent diabetes mellitus? Pittsburg Epidemiology of Diabetes Complications Study.
J Diabetes Complications, 11 (1997), pp. 243-249
[74.]
P.J. Grant.
The effects of medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes.
Diabetes Care, 19 (1996), pp. 64-66
[75.]
Y.T. Kruszynska, J.G. Yu, J.M. Olefsky, B.E. Sobel.
Effects of troglitazone on blood concentrations of plasminogen activator inhibitor-1 in patients with type 2 diabetes and in lean and obese normal subjects.
Diabetes, 49 (2000), pp. 633-639
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