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Effect Of Diabetes On Endothelial And Plateletts 2019 Pdf

effect of diabetes on endothelial and plateletts 2019 pdf

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Coagulatory Defects in Type-1 and Type-2 Diabetes

Diabetes both type-1 and type-2 affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory proteins, hyper-activation of platelets, changes in metal ion homeostasis, alterations in lipid metabolism leading to lipotoxicity in the heart and atherosclerosis , the presence of pro-coagulatory microparticles and endothelial dysfunction.

In this review, we explore the different mechanisms by which diabetes leads to an increased risk of developing coagulatory disorders and how this differs between type-1 and type-2 diabetes. In , combined occurrences of type-1 diabetes mellitus T1DM and type-2 diabetes mellitus T2DM were estimated at million individuals worldwide [ 1 ]. This number is predicted to rise to million by [ 1 ].

All forms of diabetes are characterised by defective signalling of insulin, the peptide hormone responsible for stimulating cellular glucose uptake. This results in a decrease of insulin production. T2DM is a polygenetic disease; it can be divided into two subtypes, with and without obesity, and several genes can predispose individuals to developing the disease.

It displays a heterogenous phenotype that is the consequence of resistance to insulin signalling, often due to defects associated with insulin receptors. At the beginning of the disease, insulin secretion is impaired and results in hyperinsulinemia.

Both T1DM and T2DM have wide-ranging consequences for the body as glucose levels are associated with many physiological processes. These include lipid metabolism and the regulation of inflammation, vasodilatation, basic cell growth and replication. Unmanaged diabetes and hyperglycaemia can worsen these physiological changes, potentially leading to diabetes-associated complications.

In particular, individuals with diabetes are two to three times more likely to develop cardiovascular diseases than those without diabetes [ 1 ]. Indeed, the vascular endothelium is altered in individuals with both these types of diabetes, and so hypertension, premature atherosclerosis and more extensive vascular diseases can be found in affected individuals compared to the general population, thus also increasing their risk of plaque rupture in the case of atherosclerosis and thrombus formation [ 4 , 5 , 6 ].

Furthermore, in individuals with diabetes, platelets are hyper-reactive, giving rise to increased activation of prothrombotic factors and decreased fibrinolysis which results in an increased risk of thrombosis [ 4 , 7 ]. In addition, the altered lipid profile found in individuals with diabetes affects cardiac function and can cause lipotoxicity in the heart [ 5 ].

The prognosis following a cardiovascular event remains poor for individuals with diabetes despite intensive research on the subject and the development of new therapies [ 4 , 9 ]. Thus, it is important to better understand the underlying mechanisms that drive the haemostatic changes observed in T1DM and T2DM. Despite the known increased risk of cardiovascular disease in individuals with diabetes, the pathophysiology underlying this relationship is complex and not completely understood.

Nevertheless, among the many physiological changes induced by diabetes that can impact on the cardiovascular system are changes in the concentrations of plasma proteins and metal ions, altered lipid metabolism and lipid composition resulting in altered metabolic regulation , cardiac lipotoxicity and atherosclerosis, endothelial dysfunction, platelet hyper-activation and the presence of pro-coagulatory particles in the blood.

Here, we review the molecular and cellular changes that can lead to the increased thrombotic risk observed in individuals with diabetes. T1DM and T2DM are associated with changes in blood coagulability, including alterations in clot structure and in the kinetics of clot formation and lysis. The factors responsible for these alterations include changes in the concentration and activity of numerous coagulatory proteins, resulting in defective thrombin generation and changes in the molecular make-up of fibrin clots.

Proteins identified as exhibiting an altered concentration in both T1DM and T2DM are summarised in Table 1 , while Figure 1 summarises the activity of those proteins in coagulation. Proteins with elevated concentrations in both types of diabetes include von Willebrand factor vWF [ 10 , 11 , 12 ], pre kallikrein [ 13 , 14 ], factor V [ 15 ], activated factor VII [ 15 , 16 , 17 ], factor VIII [ 15 , 18 ], factor X [ 15 ], factor XI [ 14 ], prothrombin [ 15 ], and fibrinogen [ 19 , 20 , 21 ] although a study has also reported its reduction in T1DM [ 22 ].

Simultaneously to changes in pro-coagulation proteins, several anticoagulation proteins have a reduced plasma concentration in both types of diabetes, including protein C [ 15 , 19 , 28 , 29 ] and protein S [ 30 ], but thrombomodulin [ 29 , 31 ] has an elevated concentration in both types of diabetes and tissue factor pathway inhibitor levels are elevated in T2DM [ 16 ]. A number of reports have examined antithrombin concentration in T2DM.

One such study found reduced concentrations [ 32 ], whilst two other studies reported elevated concentrations of this protein associated with the disease [ 18 , 33 ].

The cause of this difference is not known; it may be due to a difference in methodology or to the individuals studied being at a different stage of progression of the disease. Antithrombin cofactors, the heparan sulphate glycosaminoglycans in the endothelium surface layer, are largely responsible for the anticoagulant properties of the endothelium [ 34 ]; the concentration of these molecules is decreased in the arteries of individuals with T2DM, especially in those with lesions [ 35 ].

The pro-fibrinolysis protein, tissue plasminogen activator has an increased concentration in individuals with glucose intolerance [ 36 ] and in individuals with T1DM [ 37 ] or T2DM [ 24 ], but its availability is decreased because of the elevated concentration of plasminogen activator inhibitor 1 PAI-1 associated with glucose intolerance in non-diabetic individuals [ 36 ] and with individuals with T2DM [ 10 , 19 , 20 , 24 , 38 ]. Again, the origin of this difference is not known but could be due to differences in methodology or to different stages of progression of the disease in the individuals studied.

Changes in plasma protein concentrations as well as plasma glucose levels lead to an increase in plasma viscosity in T2DM [ 44 ] and an increasing trend has been measured in T1DM, especially in individuals with bad glycaemic control [ 45 , 46 ]. Most but not all changes in the protein concentration of coagulatory proteins in plasma are due to uncontrolled glycaemia and so can often be reversed through control of blood glucose levels: for example, protein C, protein S and antithrombin concentrations have been demonstrated to increase in T2DM subjects following improvement in glycaemic control [ 47 ].

Some proteomic alterations are influenced by genetic factors. For example, the increase in fibrinogen concentration and factor VII coagulant activity in T2DM are also seen in first degree relatives of individuals without the disease [ 48 ].

In addition, chronic inflammation as is associated with both T1DM and T2DM leads to activation of both the complement system and the kinin—kallikrein system, resulting in the activation of factor XII and elevated concentrations of several proteins including factor VIII, tissue factor, prothrombin and fibrinogen [ 7 ]. Simplified schema of coagulation—activation, anticoagulation, fibrinolysis and anti-fibrinolysis by various mechanisms.

A Platelet activation. B Extrinsic pathway of coagulation. C Intrinsic pathway of coagulation. D Fibrinolysis. Anticoagulation and anti-fibrinolytic activities are indicated in red. All proteins inhibited by antithrombin are indicated in green. Summary of proteins that have exhibited an altered concentration or activity in individuals with type-1 diabetes mellitus T1DM or T2DM.

The concentration of coagulatory proteins is not the only factor that impacts on coagulation. Also, alterations in fibrin ogen function are also more complex than just a change in concentration: an examination of clots formed from fibrinogen purified from individuals with T2DM and controls found the T2DM-derived samples exhibited denser and less porous clots [ 53 ].

This can be explained by elevated glycation of fibrinogen in diabetes and can be abrogated with better glycaemic control [ 53 , 54 , 55 ]. Fibrinogen is not the only protein affected by poor glycaemic control; plasminogen, the precursor of plasmin, undergoes increased glycation in individuals with T1DM, thereby leading to a reduced fibrinolytic-activity of plasmin [ 51 ].

Furthermore, the activity of antithrombin is inhibited by methylglyoxal, a by-product of hyperglycaemia [ 56 ]. In addition, in healthy individuals subjected to combined hyperglycaemia and hyperinsulinemia, the tissue factor pathway has been shown to be increasingly activated compared to an euglycemia—hyperinsulinemia group , as reflected by elevated concentrations of activated factor VII and tissue factor pathway inhibitor, as well as in an increase in factor VII activity [ 57 ].

Thus, thrombin generation followed by measuring levels of the thrombin—antithrombin complex is increased in individuals with T2DM or T1DM [ 28 , 58 ]. Good glycaemic control is also important for anticoagulant activity, with better glycaemic control in T2DM leading to a reduction of thrombin generation [ 59 ] and an increase of the anticoagulant activity of antithrombin, protein C and protein S [ 47 ]. Thus, changes in both the concentrations and activities of coagulation proteins have important consequences on fibrin clot formation, clot lysis parameters and fibrin clot ultrastructure.

The elevated concentration of complement protein C3 found in T1DM results in the protein being increasingly incorporated into fibrin clots formed from fibrinogen purified from blood from those individuals with T1DM, leading to delayed fibrin clot lysis [ 60 ].

This has also been observed in T2DM [ 61 ]. In T1DM, both lysis time and the concentration of C3 improved with better glycaemic control [ 60 ]. Fibrin clots formed in individuals with T1DM, like with T2DM, are more compact in correlation with glycaemic control [ 63 ]. In both types of diabetes, fibrin clots are more resistant to fibrinolysis [ 10 , 53 , 63 ]. Diabetes duration also has an impact, with prolonged T2DM duration more than five years associated with increased thrombin generation, reduced fibrinolysis and a pro-thrombotic phenotype even with good glycaemic control [ 64 ].

PAI-1 and t-PA antigen levels are also higher in prolonged T2DM duration while fibrinogen, plasminogen, soluble thrombomodulin and thrombin-activatable fibrinolysis inhibitor antigen levels are unaffected [ 64 ]. In addition, differences in coagulatory protein levels and clot parameters were found between males and females with T1DM or T2DM: indeed, fibrinogen and PAI-1 concentrations are higher in females with T2DM than in males with T2DM, and after correcting for those factors, females still had more compact clots that were resistant to fibrinolysis than males [ 65 ], However, another study with fewer individuals found unchanged fibrinogen levels and reduced PAI-1 levels in females with T2DM [ 66 ].

In T1DM, clot density and fibrinogen concentration in females are the same as in males, while their factor XIII concentration is higher than in males [ 67 ].

When looking at a younger cohort with T1DM under 30 years old , females have a prolonged lysis time compared to males, but this is not the case for an older cohort [ 67 ]. Thus, in both types of diabetes, these combined changes result in an increase in pro-coagulation mechanism and a decrease in anticoagulation and fibrinolysis, leading to an elevated thrombosis risk.

Metal ions play numerous roles in blood plasma, which include structural and catalytic functions. This is important as many of these are necessary for the normal functioning of proteins involved in coagulation [ 69 , 70 , 71 , 72 , 73 ].

Chelating agents that bind calcium e. Several studies have found associations between high levels of calcium in the blood and risk of developing T2DM.

In addition, elevated total plasma calcium levels are also found in individuals with T2DM compared to healthy controls; no difference was observed between males and females and the duration of diabetes had no influence on calcium levels [ 78 ]. Serum calcium levels are unchanged in T1DM [ 79 , 80 ]. The effects of elevated calcium levels on coagulation in T2DM have not been fully characterised. In this study, calcium supplementation was found to also increase the risk of coronary artery calcification and atherosclerosis in both sexes [ 81 ].

However not all calcium taken in supplements will be absorbed and much of the absorbed excess calcium will be stored in bones. In individuals with T2DM, plasma calcium levels are elevated. Thus, further studies are necessary to determine if part of the hypercoagulability found in individuals with T2DM may be explained by alterations in plasma calcium concentration.

Zinc deficiency causes bleeding and platelet aggregation disorders [ 69 ]. Magnesium deficiency in humans and animals has been shown to cause hypercoagulability [ 94 ].

Magnesium deficiency has been observed in T1DM in both males and females, although the effect is more pronounced in females [ 68 ]. Magnesium deficiency in T1DM has been associated with delayed fibrinolysis and a higher thrombotic risk [ 39 ]. Individuals with T2DM are also at risk of magnesium deficiency and may therefore be affected by a similar mechanism [ 95 ]. Bad glycaemic control is associated with magnesium deficiency, as it reduces the tubular reabsorption of magnesium [ 68 ].

Levels of ceruloplasmin are elevated in individuals with T1DM, possibly due to inflammatory processes [ 96 ]. However, another study compared T2DM individuals without diabetic complications with T2DM individuals with complications and found the latter group to have higher ceruloplasmin levels [ 98 ].

In cases where high blood concentrations of ceruloplasmin has been observed, the protein has been shown to bind to activated protein C to reduce its anticoagulant activity and induce acquired activated protein C resistance—a state associated with a higher risk of venous thrombosis [ 70 , 71 ].

No direct study on the link between ceruloplasmin levels in diabetes and coagulation has been performed.

Individuals with T1DM are deficient in iron; diabetes duration or sex had no influence on iron deficiency, but the menstrual cycle did [ 99 , ]. The persistent presence of this parafibrin has been argued to cause chronic inflammation [ ]. Thus, the altered levels of plasma metal ions in individuals with T1DM and T2DM will impact on coagulation and the risk of developing cardiovascular diseases. Plasma cholesterol, low-density lipoprotein LDL and triglyceride concentrations are increased and high-density lipoprotein HDL concentration is decreased in individuals with T2DM, and in individuals with T1DM and bad glycaemic control [ , ].

Unchanged cholesterol levels in individuals with T1DM and good glycaemic control can be deceptive as lipid profiles and functioning are altered [ , ]. Traditionally, high levels of total cholesterol and LDL have been regarded as a major risk factor of atherosclerosis and cardiovascular disease in the general population.

However, a recent review of the literature by Ravnskov et al. They explain the difference between this new view and the traditional view as the failure of most meta-analyses to properly account for negative studies [ ]. They also argue that the associations between cardiovascular disease and LDL or cholesterol concentrations found in certain cohorts can be explained through different mechanisms. A possible explanation is that infections can cause cardiovascular disease and that LDL participates in immune functioning by adhering to and inactivating microorganisms and their toxic products [ ].

Another is that stress also causes cardiovascular diseases as increased production of adrenalin and noradrenaline contribute to hypertension and hyper-coagulation, and that cholesterol is a precursor for cortisol and other steroid stress hormones [ ].

Pathological effects of ionizing radiation: endothelial activation and dysfunction

Diabetes mellitus is associated with an enhanced risk for cardiovascular disease and its prevalence is increasing. Diabetes induces metabolic stress on blood and vascular cells, promoting platelet activation and vascular dysfunction. The level of vascular cell activation can be measured by the number and phenotype of microparticles found in the circulation. The aim of this study was to investigate the effect of a platelet-inhibitory dose of aspirin on the number and type of microparticles shed to the circulation.. Forty-three diabetic patients were enrolled in the study and received a daily dose of mg of aspirin for 10 days to cover the average platelet life-span in the circulation. Before and after the intervention period, circulating microparticles were characterized and quantified by flow cytometry.. Type 1 diabetic patients had about twice the number of tissue factor-positive circulating microparticles derived both from platelets and monocytes and endothelial-derived E-selectin positive microparticles than type 2 diabetic patients.

effect of diabetes on endothelial and plateletts 2019 pdf

main aspects of diabetes mellitus that possibly affect the atherogenic process and its relationship The blood vessel endothelium responds to the mechanical stress such as local platelet-mediated neutrophil activation, release of myeloperoxidase, toll-like receptor , 20, x FOR PEER REVIEW.

Platelets Are at the Nexus of Vascular Diseases

Box , Al-Ahsa, Saudi Arabia. Box , Doha, Qatar. Microparticles MPs are small vesicles shed from the cytoplasmic membrane of healthy, activated, or apoptotic cells.

Diabetes both type-1 and type-2 affects millions of individuals worldwide. A major cause of death for individuals with diabetes is cardiovascular diseases, in part since both types of diabetes lead to physiological changes that affect haemostasis. Those changes include altered concentrations of coagulatory proteins, hyper-activation of platelets, changes in metal ion homeostasis, alterations in lipid metabolism leading to lipotoxicity in the heart and atherosclerosis , the presence of pro-coagulatory microparticles and endothelial dysfunction.

The mean P2Y 12 reaction units PRU on empagliflozin was significantly less than without empagliflozin at baseline The mean difference in PRU was No patients experienced any serious adverse events SAEs.

 Информация уходит. - Вторжение по всем секторам. Сьюзан двигалась как во сне.

Там, за ней, его обратный билет. Остается только заполнить. Беккер снова вздохнул, решительно подошел к двери и громко постучал.

Стратмор также понимал, что первым делом нужно разрядить ситуацию. Выдержав паузу, он как бы нехотя вздохнул: - Хорошо, Грег. Ты выиграл. Чего ты от меня хочешь. Молчание.

Затем подошла еще одна группа, и жертва окончательно исчезла из поля зрения Халохота. Кипя от злости, тот нырнул в стремительно уплотняющуюся толпу. Он должен настичь Дэвида Беккера.


  1. Isod P.

    20.12.2020 at 18:46

    Although, effects of intensive glycemic control were well profound for prevention of micro-vascular complications as compared to macro-vascular.

  2. Juliane S.

    20.12.2020 at 21:02

    The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed.

  3. Thomas L.

    22.12.2020 at 18:55

    Platelets are important actors of cardiovascular diseases CVD.

  4. Malcon S.

    23.12.2020 at 23:55

    In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet.

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