Vascular damage is manifested as a violation of the endothelial relaxing factor and increased leukocyte adhesion to the epithelium surface. Rheological changes associated with increased adhesiveness of platelets are also of great importance in impaired microcirculation. Platelet adhesion and aggregation are significantly increased in patients with diabetes and in patients with hypertension. At the same time, the mechanisms responsible for platelet aggregation, under both conditions, are largely interrelated. At the moment, it is believed that the leading role here is played by the metabolism of divalent cations. In the early stages of platelet activation, the main role is played by intracellular calcium and magnesium ions. Platelet aggregation is associated with an increase in the content of intracellular calcium necessary for the initiation of this process.The increase in the content of intracellular magnesium in vitro has an inhibitory effect on platelet aggregation. When diabetes and hypertension increases the calcium content and decreases the concentration of magnesium in platelets, as shown in several studies. This is a decisive factor in the increase in platelet aggregation under these conditions.
Platelet abnormalities in patients with diabetes mellitus and arterial hypertension consist in the fact that adhesiveness and platelet aggregation increase, their life time decreases, production of platelet thromboxane and other vasoconstrictive prostanoids decreases, with a simultaneous decrease in their production of prostacycling and other vascular modifiers. the tendency to form blood clots in vitro increases. At the same time, there is also a violation of homeostasis of divalent cations in platelets (as mentioned above), and an increase in nonenzymatic glycolysis of platelet proteins, including glycoproteins, occurs.
Hypercoagulation and damage to the fibrinolysis system in combination with over-activation of platelets in patients with diabetes lead to hypertension, glycemic and lipidemic disorders with manifestations of vascular damage. A number of studies have shown that in patients with diabetes, especially in combination with endothelial cell damage, micro- and macrovascular disorders, and inadequate hypoglycemic therapy, there is an increase in the activity of some components of the coagulation system, including the von Willebrandt factor produced by the endothelium . The high concentration of components of factor VIII leads to hyperglycemia, an increase in the rate of thrombin formation and an increase in occlusive vascular lesions in patients with diabetes.
Increased fibrinogen binding and platelet aggregation in diabetic patients in response to the effects of adenosine diphosphate or collagen are mediated through an increase in the formation of prostaglandin H2, thromboxane A2, or both. A number of in vitro studies have noted that an increase in thromboxane production may be associated with high concentrations of glucose and lipids in the blood, and not with an increase in the interaction of platelets and the vessel wall. However, these observations require confirmation by further in vivo studies.
Evaluation of the state of the hemostasis system in diabetic patients is necessary for conservative treatment in order to prevent the progression of diabetic micro- and macroangiopathies.
Laboratory diagnosis of thrombophilic conditions is based on biochemical studies of the hemostasis system, which include coagulometric, photometric and enzyme immunoassay methods.
Coagulometric methods are most widely used, based on the determination of the clotting time of an experimental sample after incubation with a specific reagent, which makes it possible to evaluate the activity of the hemostatic cascade units. The indicators determined by this method include the prothrombin time (PTV), activated partial thrombo-plate time (APTT), thrombin time (TV), activated recalcification time (AVR), fibrinogen content.
In addition, enzyme immunoassay methods for the determination of the complex of thrombin-antithrombin and the prothrombin fragment 1 + 2 are used as specific markers of thrombinemia. Using specific chromogenic substrates, i.e. photometric methods assess the activity of fibrinolysis, including the determination of plasminogen, plasmin inhibitors, plasminogen activator.
Currently, studies are being disseminated based on the identification of molecular markers of those mutations that underlie the thrombophilic or hemorrhagic orientation of the pathology of hemostasis. These studies are especially important from the point of view that they can be used to diagnose thrombophilia, the cause of which is revealed by screening techniques, for example, in case of anomalies of factors VII, VIII or prothrombin. However, molecular techniques are rather expensive and not everywhere common, in particular, because of the duration of the analysis, therefore, photometric and immunoassay techniques are also most widely used along with traditional coagulometric methods.
In patients with diabetes and hypertension, hemodynamic disorders in the renal vessels and vessels of the systemic circulation are similar in many respects. Disturbances of autoregulation of the peripheral capillary blood flow correspond to the microcirculatory lesion of the glomerular apparatus. The transcapillary albumin release (TBA) indirectly reflects the transition of albumin from the blood plasma to the kidneys and other tissues and is considered as a marker of vascular damage in the microvasculature. The level of TBA is influenced by various factors. Thus, significant fluctuations in glycemia in a short time contribute to an increase in vascular permeability in patients with diabetes. A persistent increase in blood pressure causes an increase in TBA, with a direct correlation relationship between these indicators. Here it is necessary to note the following point:in cases of severe hypertension, an increase in TBA level more reflects hemodynamic disturbances in the microvasculature than damage to the filtration ability of the kidneys.
At present, the theory of generalized hyperperfusion is considered as the basis of the pathogenesis of diabetes mellitus complications in the form of retinal microangiopathy, glomeruli, and peripheral vascular bed. The long-term effects of severe hyperglycemia include an increase in extracellular fluid volume, leading to a decrease in the renin content and an increase in the natriuretic peptide content in the blood plasma, which together with the altered level of other vasoactive hormones lead to the generalization of the observed vasodilation. Generalized vasodilation causes a thickening of the basement membrane in all capillaries and a rise in capillary pressure in the kidneys and retina.
The presence of a high level of glycemia in diabetes has a multifaceted damaging effect on the state of the vascular wall and vascular tone, and thus plays a huge role in the development of hypertension. On the one hand, hyperglycemia activates protein kinase C in endothelial cells, which can cause an increase in the production of vasoconstrictive prostaglandins, endothelin and angiotensin-converting enzyme, which have a direct or indirect effect on the vasomotor reactivity. Moreover, hyperglycemia disrupts the production of matrix by endothelial cells, which can lead to an increase in the thickness of the main membrane. Hyperglycemia increases the synthesis of endothelial cells of type IV collagen and fibronectin with an increase in the activity of enzymes involved in the synthesis of collagen.In high concentrations, glucose has a direct (osmolarically independent) toxic effect on vascular endothelial cells. This toxic effect can lead to a decrease in endothelin-dependent vascular relaxation, an increase in vasoconstriction, and stimulation of hyperplasia. smooth muscle cells, vascular remodeling . Hyperglycemia also increases the formation of glycosylation products, which accumulate in the vascular wall. Non-enzymatic glycosylation of proteins goes through three stages, which in vivo depend on the degree and duration of hyperglycemia, the half-life of the protein and the permeability of tissues with respect to free glucose. Through a variety of mechanisms, non-enzymatic glycosylation proteins are able to affect the main processes of atherogenesis and vascular remodeling. The relationship between the accumulation of the final protein glycosylation products and vascular diseases is shown. Thus, the long-existing hyperglycemia leads to an increase in the production of extracellular matrix and proliferation of smooth muscle cells with hypertrophy and vascular remodeling. Hyperglycemia is associated with a decrease in the elasticity of the connective tissue of the arteriole walls and an increase in pulse pressure. Besides,hyperglycemia leads to an increase in filtration of glucose, which stimulates the work of the sodium transporter, glucose, in the proximal tubules.
Hypertension can develop as a result of a lack of vasodilating factors, and not an excess of vasoconstrictors (such as angiotensin and noradrenaline). In this regard, it is important to study the kallikrein system, which produces a powerful vasodilator bradykinin. It has been found that renal medulla extracts contain vasodilators, including neutral lipid and prostaglandin. Their absence, due to damage to the renal parenchyma or bilateral nephrectomy, contributes to an increase in blood pressure. The question of the state of the kallikrein-kinin system in patients with type 2 diabetes and hypertension is currently not fully understood. The presence of an increased functional activity of this system is demonstrated by a high level of calicrein in patients with diabetes and hypertension, more than 7 times the control indicators,and a decrease in the concentration of prekallikrein. This indicates the importance of the activation of this system in the regulation of blood pressure and, possibly, in the pathogenesis of hypertension in diabetes.