The main pathogenetic mechanisms of hypercoagulation in diabetes and the possibility of its drug correction

Evgeny V. Kryukov; Крюков Евгений Владимирович; Alexey N. Kuchmin; Кучмин Алексей Николаевич; Elena P. Umanskaya; Уманская Елена Павловна; Mikhail B. Nagorny; Нагорный Михаил Борисович; Andrey A. Shevelev; Шевелёв Андрей Александрович

doi:10.17816/brmma64995

The main pathogenetic mechanisms of hypercoagulation in diabetes and the possibility of its drug correction

Authors: Kryukov E.V.¹, Kuchmin A.N.¹, Umanskaya E.P.¹, Nagorny M.B.¹, Shevelev A.A.¹
Affiliations:
1. Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russian Federation
Issue: Vol 23, No 2 (2021)
Pages: 165-174
Section: Reviews
URL: https://journals.eco-vector.com/1682-7392/article/view/64995
DOI: https://doi.org/10.17816/brmma64995
ID: 64995

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Abstract

Disorders in the blood coagulation system play an important role in the development of cardiovascular pathology in diabetes. Factors that cause them are hyperglycemia, insulin deficiency, insulin resistance, dyslipidemia, oxidative stress. The most significant changes are observed in the vascular-platelet link of hemostasis. Diabetes is characterized by morphological and functional changes in the endothelium of blood vessels. The activity of platelets increases, which is manifested by their high level of spontaneous aggregation and increased sensitivity to the action of activating factors. The role in the disturbance of hemostasis is played by increasing the activity of the von Willebrand factor, reflecting damage to endothelial cells. Diabetes is characterized by an increase in the activity of plasma clotting factors (I, II, III, VII, VIII, IX, XI, XII and XIII), activation of the callicrein-kinin system. In some cases, this correlates with the development of complications of diabetes. Characteristic disorders in the coagulation inhibition system are a decrease in the activity of antithrombin III, reduced formation of thrombin-antithrombin complexes, reduction of thrombomodulin and protein C. In diabetes, there is a decrease in fibrinolysis, due to a decrease in the expression of tissue activator plasminogen and an increase in the level of the inhibitor of the activator plasminogen. The possibilities of drug correction of hypercoagulation factors in diabetes are to achieve glycemic control with sugar-reducing drugs and elimination of dyslipidemia through hypolipidemic therapy. The most well-studied sugar-lowering drug that improves the state of the blood clotting system is metformin. The system of hemostasis in diabetic patients is positively affected by statins both due to the direct hypolipidemic effect, and by improving endothelial function and increasing fibrinolysis.

Keywords

diabetes mellitus, platelets, plasma clotting factors, inhibition of coagulation, fibrinolysis, glycemic control, dyslipidemia, metformin, statins

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Dysfunction of the interaction of the blood coagulation and anticoagulation systems against the background of metabolic disorders are considered to be the most important components of the progression of symptoms of impaired cardiovascular function in diabetes mellitus (DM) [1].
According to the presented results of studies carried out by leading specialists of the European Society of Cardiology on Diabetes Mellitus, Prediabetes and Cardiovascular Diseases and the European Association for the Study of Diabetes Mellitus, patients with diabetes have a significant, more than doubled, increase in the frequency of cardiovascular complications (CVD): the progression of symptoms of coronary heart disease, an increase in the number of ischemic stroke, cardiovascular outcomes, regardless of other risk factors [2].
The most common cause of adverse CVD in DM is atherothrombotic processes in the arterial system, among which the "lion's" share, about 75%, develops in the basin of the coronary arteries, and the share of cerebrovascular and peripheral thrombosis is the remaining 25% [3]. The formation of microthrombs in the vessels of the microvasculature of the myocardium in DM plays a significant role in the progression of cardiac insufficiency [4]. The most significant changes in the blood clotting system in patients with DM are observed in the vascular-platelet link. Disorders in the hemostatic system progress with the age of patients [5].
In DM, morphological and, consequently, functional changes occur in the vascular endothelium. As a result of chronic hyperglycemia, the mechanism of damage to intima proteins and proteoglycans of the basal membrane of blood vessels is triggered by the type of their non-enzymatic glycosylation, which underlies the formation and subsequent progression of anhidisfunction. The relationship between the level of glycosylated hemoglobin (HbA1c) in patients with DM and the development of endothelial-platelet dysfunction in them has been proven [6].
As a result of the persistent stimulating effect of glycation products on the synthesis of vascular endothelial adhesion molecules of type 1, interleukin 1, interleukin 6, tumor necrosis factor α, growth factors, smooth muscle cell proliferation develops, the content of type I and IV collagen molecules increases, fibronectin and proteoglycan complexes are additionally formed, and there is a decrease in the regenerative capabilities of endothelial cells. The formation of dysfunction of endothelial cells, monocytes, and macrophages triggers a cascade of physicochemical reactions, the result of which is an increase in the synthesis and activity of thromboplastin, which plays a fundamental role in the development of atherogenesis and atherothrombotic processes [7].
Glucose oxidation in the vascular wall under conditions of hyperglycemia and suppression of the activity of glycolysis enzymes occurs in alternative ways, resulting in oxidative stress. The resulting superoxide anion, interacting with nitric oxide (NO), ultimately inhibits its physiological activity, and the resulting peroxynitrite has a direct damaging effect on the deoxyribonucleic acid. As a result, the enzymatic activity of polyadenosine-diphosphate-ribose polymerase, an important nuclear enzyme, increases, which is accompanied by a natural decrease in the content of nicotinamide-adenine-nucleotide inside cells, slowing down glycolysis, reducing ADP synthesis, and ultimately leads to the development and subsequent aggravation of endothelial dysfunction [7]. It is proved that it is in DM that the glycosylation of antioxidants, such as superoxide dismutase and glutathione, leads to their inactivation, which is also an additional and important factor leading to endothelial dysfunction [8].
Differences in the severity of endothelial dysfunction in patients with type 2 diabetes (DM2) compared with patients with type 1 diabetes (DM1) with equally effective control of glycemia levels are characterized by a predominance of endothelial dysfunction in the group of patients with type 2 diabetes. At the same time, strict and effective control over the level of glycemia is associated with a qualitative improvement in the state of the endothelium in type 1 diabetes, and in type 2 diabetes, the severity of endothelial dysfunction remains almost unchanged [9]. It is possible that this difference is due to the insulin resistance associated with DM2, in which there is an increase in the content of low-density lipoproteins (LDL), oxidized as a result of hyperglycemia. It was found that oxidized LDL has a cytotoxic effect on the vascular endothelium [10].
DM is characterized by increased platelet activity, which is promoted by hyperglycemia, endothelial dysfunction, insulin deficiency or insulin resistance, dyslipidemia, oxidative stress, and inflammation [8].
Prolonged hyperglycemia against the background of absolute insulin deficiency and developed insulin resistance in combination with endothelial dysfunction, lipid metabolism disorders, inflammatory processes and oxidative stress trigger a cascade of reactions that lead to an increase in platelet aggregation properties.
Persistent hyperglycemia is accompanied by the processes of acceleration of megakryocytopoiesis, which leads to the appearance of large, "young" platelets in the blood of patients with DM, which have an increased ability to aggregate [11]. The increase of anaerobic glycolysis in platelets contributes to the enhancement of the aggregation properties of platelets [12].
Glycosylation of proteins on the surface of tromocytes, which occurs without the participation of enzymes, which is a key mechanism of tissue damage in DM, leads to an increase in the expression of glycoprotein proteins (GP) Ib and IIb/IIIa, which provide adhesive and aggregation properties. There is a correlation between the level of expression of glycoproteins Ib and IIb/IIIa and the content of HbA1c [13].
Increased levels of GP Ib and GP IIb / IIIa lead to increased spontaneous platelet aggregation [14]. In a multicenter prospective study of HAPARG [15], a higher level of spontaneous platelet aggregation was found in the group of patients with type 2 diabetes compared to the control group without DM, which was associated with a high risk of vascular occlusions.
The level of insulin in the blood determines the degree of sensitivity of platelet receptors to the action of a number of factors that stimulate aggregation: thrombin, collagen, ADP, epinephrine, serotonin, prostaglandins G2 and H2, arachidonic acid, thromboxane A2, etc. At the same time, one of the most important intracellular mechanisms of the effect of insulin on platelet activity is the inhibition of the release of Ca2+ into the cytosol from the cell, which leads to a decrease in the severity of agonist-stimulated aggregation [16].
Insufficient supply of insulin to platelets in DM due to absolute insulin deficiency or insulin resistance leads to their increased response to activating factors [8].
The influence of disorders in the lipid composition of the blood in DM on changes in the aggregation activity of platelets has been proven by a number of studies [2]. When combined with DM2, abdominal obesity, hypertension, the development of dyslipidemia is usually characterized by an increase in the level of triglycerides in the composition of very low-density lipids (VLDL) and a decrease in high-density lipoprotein cholesterol (HDL). The content of LDL cholesterol in patients with DM varies slightly, but the proportion of glycated LDL increases, which, by binding to the platelet membrane, modify its properties, increasing the sensitivity of platelets to epinephrine, ADP, and collagen molecules.
As a result of the conducted studies and the subsequent statistical analysis of the obtained data, a stable relationship between the level of collagen-stimulated platelet aggregation and the content of blood cholesterol was revealed. As a result of the formation of a complex of platelets with LDL, under the condition of sufficient platelet adhesion at the sites of local vascular damage, conditions are created for the activation of the flow of CS into the vascular wall by the type of saturation [17].
As a result of a violation of lipid metabolism in activated platelets, the production of thromboxane A2 increases, which stimulates the activation of new platelets and their aggregation activity [18].
The ability of platelet adhesion to areas with damaged vascular endothelium is mediated by a functionally important component of thrombocytic hemostasis - the plasma glycoprotein von Wiel-lebrand factor (VWF). It is proved that it interacts with the proteins of glycoproteins Ib and Ia, located on the platelet surface, and also participates in inter-platelet interaction through the process of binding of glycoproteins IIb/IIIa. An increase in mortality from cardiovascular complications can be caused by the influence of a complex mechanism, including progressive damage to vascular endothelial cells and chronic hyperglycemia against the background of increased VWF function [19].
At the same time, it is proved that the number of activated thrombocytes is increased in patients with different experience of diabetes compared to healthy individuals. With improved glycemic control, the number of activated platelet forms remained high [20].
In addition to changes in vascular-platelet hemostasis, in patients with DM, the activity of plasma clotting factors changes, the system of inhibition of coagulation and fibrinolysis is disrupted.
DM is characterized by an increase in the level of a number of plasma binding factors: II, III, VIII, IX, XI, XII, and XIII, and activation of the kallikrein-kinin system [12]. In some cases, there is a relationship between an increase in plasma clotting factors and the development of complications of diabetes. A correlation was found between the level of prekallikrein and the development of diabetic nephropathy and retinopathy. In patients suffering from proliferative retinopathy, the content of precallicrein is higher than in the initial stages of DM and significantly exceeds the indicators in healthy individuals [17]. When studying the level of precallicrein, it turned out that its lowest content is observed in healthy individuals, in the early stages of DM, its level increases and reaches a maximum in patients with microvascular complications, proliferative retinopathy.