Coagulation Cascade

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Endothelial dysfunction is also characterized by an ongoing prothrombotic state and an increased risk of thrombotic events, and its persistence may represent a negative prognostic index. Patients with micro- and macroalbuminuria present an accentuated activation of the coagulative cascade [2]. It has been found that the simultaneous increase in circulating levels of vWF and tPA (that exceed 2 SD above control values) is associated with increased levels of prothrombin fragments 1 and 2 (F1 + 2) in children with T1DM. This finding seems to indicate that at the onset of the disease, young patients with diabetes may suffer from a sub-clinical coagulative, prothrombotic disorder. Increased F1 + 2 level is a marker of an unbalanced tissue factor/tissue factor inhibitor pathway, as well as an index of enhanced thrombin generation and of a hypercoagulable state. Diabetes is characterized by several coagulative disorders, such as an increase of factor VII activation and thrombin and fibrin generation, and a reduction of antithrombin III activity.

Structure and Function of von Willebrand Factor

The von Willebrand factor (vWF) is a glycoprotein involved in primary hemostasis and secreted mainly by endothelial cells and megakaryocytes. vWF is synthesized as a large 360-kDa precursor named pro-vWF. After many changes in the endoplasmic reticulum and the Golgi apparatus, this precursor undergoes cleavage into mature vWF and a large 97-kDa propeptide [3, 4]. Stimulation of exocytosis causes the release of equimolar amounts of vWF and its propeptide (vWF propeptide), which has a circulating halftime of 2 to 3 hours, compared with more than 12 hours for vWF itself. Propeptide concentrations are less influenced by factors such as blood groups, adhesive properties, and catabolism, whereas vWF concentrations can be influenced by ABO blood groups [3], exercise, and hypoxic reperfusion injury.

von Willebrand Factor and Diabetes Mellitus

Endothelial dysfunction represents an early feature of vascular disease, and several mechanisms may be involved in its pathogenesis. It has also been reported in young normotensive and normoglycemic first-degree relatives of patients with T2DM in association with insulin resistance, independent of age, sex, body mass index, serum insulin, and lipids. Abnormal markers of endothelial cell activation and impaired endothelium-dependent vasodilatation have been observed in children, adolescents, and young adults with T1DM without clinical evidence of vascular disease in the work of Elhadd, Kennedy, and others.

The increase in plasma concentration of vWF and vWF propeptide are found in patients with overt nephropathy [5] and in patients with microalbuminuria, whereas only the propeptide was increased in normoalbuminuric patients [3]. Assessment of propeptide concentrations is a valuable complement in studies of endothelial activation and also in chronic vasculopathies. Besides, it has been found that the increase of vWF and vWF propeptide in plasma precedes microalbuminuria. This increase can thus be useful to identify children with T1DM at risk of developing incipient nephropathy later in life, although not all authors are in agreement with this opinion.

Finally, the parallel determination of vWF and vWF propeptide does not add any useful information for the early prediction of the development of microalbuminuria.

It has been reported that the increase in plasma vWF precedes, and may therefore help to predict, the development of microalbuminuria in T1DM.

The type of endothelial dysfunction reflected by increased vWF and fibrinogen levels is closely related to microalbuminuria not only in T1DM [6], but also in T2DM

and essential hypertension. It is not clear, however, whether the prognostic value of vWF and vWF propeptide is related to their specific functions, that is, enhancement of platelet adhesion and factor VIII availability, or whether they are simply markers of endothelial injury and dysfunction.

High plasma levels of vWF and vWF propeptide are found also in patients with T2DM, and probably in T2DM patients an increased risk of new cardiovascular events is present only in patients with vWF concentrations above the median, but not in those with lower values. From the literature it is quite difficult to draw a clear conclusion about changes of vWF in T2DM patients because the data are discordant; therefore, larger and more complete studies are needed in order to really understand the value of vWF evaluation is T2DM subjects.

Glossary

Diabetic angiopathy: Represented mainly by microangiopathy, characterized by structural changes in the eye and renal glomeruli, and by macroangiopathy that consists of an accelerated form of atherosclerosis that increases the risk of cardiovascular disease.

Endothelial dysfunction: Long-term complication of diabetes melli-tus characterized by structural changes in small vessels.

T1DM: Type 1 diabetes mellitus; generally, the onset is in pediatric age. This is an autoimmune disease and the patients are insulin dependent.

T2DM: Type 2 diabetes mellitus; generally, the onset is in old age and obesity is one of the most frequent causes.

von Willebrand factor: A glycoprotein involved in primary hemosta-sis and secreted mainly by endothelial cells and megakaryocytes.

References

1. De Vriese, A. N. S., Verbeuren, T. J., Van de Voorde, J., Lameire, N. H., and Vanhoutte, P. M. (2000). Endothelial dysfunction in diabetes. Br. J.

Pharmacol. 130, 963-974. This is a very clear and well done paper on the topic.

2. Ceriello, A. (1993). Coagulation activation in diabetes mellitus: The role of hyperglycemia and therapeutic prospects. Diabetologia 45, 471-477. One of the first and most complete papers on the relationship between coagulation and diabetes mellitus.

3. Vischer, U. M., Emeis, J. J., Bilo, H. J., Stehouwer, C. D., Thomsen, C., Rasmus, O., Hermansen, K., Wollheim, C. B., and Ingerslev, J. (1998). von Willebrand factor (vWF) as a plasma marker of endothelial activation in diabetes: Improved reliability with parallel determination of the vWF propeptide (vWf: AglI). Thromb. Haemost. 80, 1002-1007.

4. Visher, U. M., and de Moerloose, P. (1999). von Willebrand factor: From cell biology to the clinical management of von Willebrand's disease. Crit. Rev. Oncol. Hematol. 30, 93-109.

5. Zareba, W., Pancio, G., Moss, A. J., Kalaria, V. G., Marder, V. J., Weiss, H. J., Watelet, L. F., and Sparks, C. E. (2001). Increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients THROMBO Investigators. Thromb. Haemost. 86, 791-799.

6. Stehouwer, C. D. A., Stroes, E. S. G., Hackeng, W. H. L., Mulder, P. G. H., and den Ottolander, G. J. H. (1991). von Willebrand factor and development of diabetic nephropathy in insulin-dependent diabetes mellitus. Diabetes 40, 1746.

Further Reading

Elhadd, T. A., Kennedy, G., Hill, A., McLaren, M., Newton, R. W., Greene, S. A., and Belch, J. J. (1999). Abnormal markers of endothelial cell activation and oxidative stress in children, adolescents and young adults with type 1 diabetes with no clinical vascular disease. Diabetes Metab. Res. Rev. 15, 405-411.

Greaves, M., Malia, R. G., Goodfellow, K., Mattock, M., Stevens, L. K., Stephenson, J. M., and Fuller, J. H. (1997). Eurodiab IDDM complications study group. Fibrinogen and von Willebrand factor in IDDM: Relationships to lipid vascular risk factor, blood pressure, glycaemic control and urinary albumin excretion rate: The Eurodiab IDDM complications study. Diabetologia 40, 698-705. One of the largest studies about fibrinogen and von Willebrand factor in diabetes mellitus.

Huvers, F. C., De Leeuw, P. W., Houben, A. J. H. M., De Haan, C. H. A., Hamulyak, K., Schouten, H., Wolffenbuttel, B. H. R., and Schaper, N. C. (1999). Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type I diabetes under near-normoglycemic conditions. Diabetes 47, 1300-1307.

Verrotti, A., Greco, R., Basciani, F., Morgese, G., and Chiarelli, F. (2003). von Willebrand factor and its propeptide in children with diabetes. Relation between endothelial dysfunction and microalbuminuria.

Capsule Biography

Prof. Alberto Verrotti is associate professor at the University of Chieti, Italy, and his scientific activity is devoted to vascular mechanisms of microvascular complications of diabetes mellitus. He works in connection with many international research institutes. His research has been published in high-level journal and has been frequently supported by national and international grants.

Rita Greco graduated in 1995. She has specialized in pediatrics since 1999 at the University of Chieti, Italy. She is an active researcher in the field of endocrinology with special interest in diabetes mellitus and microcirculation. She has published many papers in international journals and is working at the Pediatry of Pescara Hospital.

Prof. Guido Morgese is full professor of pediatrics at the University of Siena, Italy. He dedicated himself for many years to research on childhood endocrinology and, in particular, on type 1 diabetes mellitus. In the past 20 years, he has published many papers in international journals, reporting his scientific data about the main aspects of pathophysiology of long-term complications of type 1 diabetes mellitus, with particular reference to microvascular complications. He is director of the Pediatric Clinic of the University Hospital in Siena, Italy.

Prof. Francesco Chiarelli is full professor of pediatrics at the University of Chieti, Italy. He spent many years researching childhood endocrinology and type 1 diabetes mellitus. Recently, he has studied in animal models and in humans the possible relationships between oxidative stress, coagulation abnormalities, and microvascular complications; his original data have been published in many international journals. He is director of the Pediatric Clinic of the University Hospital in Chieti, Italy, and he is the Secretary of the European Society of Pediatric Endocrinology.

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