Open access peer-reviewed chapter
Abstract
Individuals with diabetes mellitus (DM) are at high risk of thrombosis in which hyperactive platelets are implicated. The platelet hyperactivity has been linked to hyperglycemia. This hypothesis is supported by studies in type II diabetes mellitus showing increased sensitivity of platelets to stimulating agonists in the context of tissue resistance to high-circulating insulin. However, controversy still exists regarding the altered platelet functions in type 1 diabetes mellitus (T1DM) and the link to modifying factors such as blood glucose, hyperlipidemia, metabolic acidosis and insulin treatment. Moreover, increased insulin dosage or treatment appears to have antagonistic actions: diminished functions at low doses and enhanced activation at high doses, the switch being attributable to insulin-like growth factor. The physiological role of insulin in suppressing platelet activation is lost in T1DM, a scenario that favors increased platelet sensitivity to stimulating agonists. Furthermore, the response to antiplatelet agents and statins is sub-optimal in diabetics presenting clinical and research knowledge gap regarding the ideal antiplatelet treatment in DM in general and T1DM in particular. This chapter reviews the unique characteristics of platelet functions in T1DM highlighting the controversial areas linking unique behavior of platelets and the abnormal response to therapeutic interventions.
Keywords
- type 1 diabetes mellitus
- platelets
- hyperactivity
- thrombosis
- platelet functions
1. Introduction
Diabetes mellitus (DM) is a metabolic disorder characterized by high blood glucose levels. There are two major types: type 1DM (T1DM) or insulin-dependent DM (IDDM) due to insulin deficiency or absence; and type 2 DM (T2DM) or non-insulin-dependent DM (NIDDM) is due to insulin resistance.
Diabetes mellitus and impaired glucose tolerance are associated with cardiovascular risk [1, 2] and thrombosis [3] considered to be platelet in origin [4]. Data on platelet functions have largely been derived from T2DM, since it is the most prevalent. However, T1DM is unique in that platelets are exposed to hyperglycemia in the absence of insulin, while in T2DM they are exposed to both hyperglycemia and hyperinsulinemia. It is increasingly debatable the roles of these factors in alteration of platelet functions in T1DM owing to the acuteness and short duration of exposure. More so, the role of insulin on platelet functions is controversial [5] given the paucity of its receptors [6], and that the platelet glucose transporters are independent of it [6].
2. Platelet Indices and Morphology in T1DM
2.1 Platelet indices
Platelet indices such as platelet count, mean platelet volume (MPV), platelet distribution width (PDW), and platelet large cell ratio (P-LCR) are elevated in patients with IDM type 1 than non-diabetic controls [7] and are associated with cardiovascular complications [8]. These strongly correlate with duration of blood sugar control as assessed by extent of HbA1c [9] suggesting link with metabolic impairment. Notably, MPV size positively correlated with fasting blood glucose and HbA1C [10]. However, as to whether these changes are due to glucose and attendant osmotic effects or part of disease process remains largely unexplored.
2.2 Bone Marrow and megakaryocytes in T1DM
Changes in platelet indices in DM correlate with mekaryocyte DNA content or ploidy [11] reflecting direct influence on bone marrow function even prior to systemic circulation observations. The thrombopoiesis associated with T1DM releases an enormous amount of hyperactive platelets from the bone marrow into circulation [12]. Moreover, the newly released large but immature platelets from bone marrow have increased synthetic capacity for thromboxane and thrombospondin, have enhanced membrane surface expression of receptors such as GPIIbIIIa, CD61, and CD63, [13, 14], and have enhanced aggregation [14, 15]. In DM, the hyperglycemia acts through neutrophils to stimulate thrombopoietin (TPO) production in the liver and enhance megakaryocyte thrombopoiesis [16]. In T1DM, increased circulating TPO has been shown to be linked to elevated blood sugar levels and HbA1c HbA1C [17] providing evidence linking bone marrow megakaryopoiesis and metabolic state.
2.3 Platelet morphology and ultrastructure in T1DM
Peripheral blood smears of patients with diabetic complications show occasional giant platelets [8]. Biochemical examination has revealed altered membrane lipid composition, as well as Na +-K+ ATPase and Ca++-ATPase, which are sensitive to glucose concentrations compared with control from non-diabetic subjects [18].
Ultra structural examinations show prominence of dense granules.
3. Platelet hemostatic functions in T1DM
Diabetes mellitus is a pro-thrombotic condition and platelets are implicated. This has been confirmed by number of laboratory methods such adhesion to immobilized surfaces, granule content secretion, aggregation, clot retraction, and membrane surface expression of activation biomarkers.
3.1 Platelet Adhesion in T1DM
In T1DM, there is evidence of increased platelets adherence to surfaces such as collagen and fibrinogen [19, 20, 21], and this corresponds to elevated plasma vWF Ag and activity [22] and low ADAMTS-13 Ag and activity [23]. These features are related to glycemic control [24] and only if vWF is present and elevated in plasma [25]. However, it is not yet established whether the increased adhesiveness are linked to aggregation and linked to or derived from ensuing endothelial injury.
3.2 Aggregation
In DM, platelets exhibit hyperactivity and increased sensitivity to agonists such as ADP, AA, collagen, and epinephrine [26], which augments successive increased secretion of and response to prostaglandins [21, 27]. Specifically, there is greater platelet reactivity in T1DM compared with T2DM and healthy controls as evaluated by light transmission aggregometry (LTA) and platelet function analyzer-100 (PFA-100) [28, 29]. Notably, aggregation curves are biphasic at low agonist concentrations showing greater augmentation of second wave [26] indicating increased secretion of and response to prostaglandins [27]. The mechanism for the biphasic wave response is due to altered ATP/ADP metabolism [30], nucleotide and thromboxane secretion [31], and calcium fluxes [32]. These are because, upon agonist stimulation, there is an initial phase characterized by glycogenolysis with minimal ATP synthesis causing translocation of alpha granule-containing glucose transporter 3 (Glut-3) to the surface, followed by a second phase of enhanced Glut-3 glucose entry, glycolysis, and ATP synthesis leading to both alpha and delta granule translocation and degranulation [33]. These processes are exaggerated in the presence of high vWF, cholesterol and poor glycemic control in T1DM [24].
In contrast, others have found no change in ADP-induced platelet aggregation in T1DM [34, 35]. The lack of consistency with other studies probably suggests loss of adhesive molecules into platelet microparticles [36] or modulation by factors extrinsic to the platelets such as magnesium ions [37], insulin [38], and acidosis [39].
3.3 Membrane surface receptor expression and platelet-leukocyte aggregates (PLA)
Evaluation of platelets from T1DM patients has shown increased membrane surface expression of activation markers such as P-selectin, platelet-leukocyte aggregates (PLA)(platelet-monocyte, platelet-granulocytes) [17, 40, 41]. Importantly, it has been demonstrated that first relatives of T1DM patients at risk of T1DM have increased expression of P-selectin, CD63, and thrombospondin compared with at-no-risk controls [42]. Given that these changes are also observed in megakayryocytes, and peripherally, there is ongoing debate whether the changes are predetermined and intrinsic to disease process or epigenetic secondary to the altered metabolic milieu, are yet to be resolved.
3.4 Secretion and other soluble markers of activation
Urinary excretion of thromboxane B2 (TXB2) was found higher in DM than in healthy controls [35]. This is in contrast to another study that found decreased levels of TXB2, β-Thromboglobulin (BTG) and platelet factor-4 (PF-4) in diabetic patients with uncontrolled blood sugar and high HbA1C [34].
3.5 Platelet microparticle
Platelet microparticles (PMPs) or membrane-covered vesicles that bleb or vesiculate off in response to oxidative stress are elevated in T1DM [43]. The elevated PMP in T1DM compared with T2DM [44] has not been explained. Nevertheless, the levels are predictive of vasculopathy [1].
4. Platelet: inflammation cross talk in T1DM
There is cross talk between inflammation and platelets in T1DM where leukocytes and platelets activate each other [45] and both leukocytes, especially monocytes, and platelets are hyperactivated [41, 46]. Whereas platelets release cytokines [47], and increased levels of these factors have been found in circulation in individuals with T1DM [40], a cause and effect relationship has been questioned [48]. What is known is that cytokines, especially IL-6 and IL-8, are platelet activators [49], but whether they are the cause of platelet hyperactivity in T1DM remains largely unknown.
5. Modifiers of platelet function
Although platelet hyperactivity are vital to the pathophysiology of diabetes mellitus [42, 50, 51, 52], there are other factors in systemic circulation that modify disease progression. These factors include hyperglycemia and its control, insulin deficiency and therapy, acute metabolic acidosis, inflammatory markers that precede and coexist during disease states, and body calcium-magnesium fluxes levels.
5.1 Acute metabolic acidosis
Unlike in type 2 DM, acute metabolic diabetes keto-acidosis (DKA) characterized by lactic acidosis and ketonemia occurs in T1DM with a rate between 20 and 70% depending on the intensity of glucose control [53]. Subjects in DKA have increased blood levels of β-Thromboglobulin (β-TG), platelet factor-4 (PF-4), but their platelets are paradoxically less sensitive to aggregation agonists such as ADP and prostacyclin. The agonist sensitivity improves with glycemic control [54]. The initial depressed platelet function that improves with treatment is similar to previous findings by Janka [55] and Ileri et al [56].
Although ketones contribute to acidosis in DKA, only effects of lactic acid on platelets are well studied. Lactic acid dose dependently reduces platelet secondary wave aggregation
5.2 Blood glucose and platelet functions in T1DM
Although platelet hyperactivity in T1DM has partly been ascribed to hyperglycemia, however, empirical evidence has been conflicting. Study results have ranged from no effects, decreased to increased platelet functions. The ambiguity may be attributed to confounders, depending on study designs, dose, and duration of exposure. Specifically, non-diabetic or healthy controls do not have the coexisting inflammatory biomarker seen in diabetics (T1DM from T2DM) who additionally have hyperlipidemia. Thus, in diabetics, duration of disease determines the level of non-enzymatic glycation. The route of glucose administration also matters. Oral intake is accompanied by post-prandial secretion of gut and counter regulatory hormones while direct or parenteral administration bypasses the gut, with
Bridges and coworkers [19] first demonstrated the link between blood glucose and platelet function. They showed that either a postprandial oral glucose load or intravenous infusion increased platelet stickiness in both diabetics and nob-diabetics. The observation has since been confirmed by others mostly in T2DM [68, 69, 70, 71]. Surprisingly, in one study of hyperglycemia platelet p-selectin expression was decreased during hyperglycemia compared with levels before oral intake [72]. These results are confounded other factors concurrently activating platelets such as postprandial hyperglycemia on counter regulatory hormones [73], procoagulant platelet microparticles [74], combined effect with insulin [75, 76], neutrophil-megakaryocyte thrombopoiesis [16], and hyperlipidemia [25, 77, 78].
In order to avoid the many confounders inherent in
The discordance in effects of glucose on platelets can be explained by the duration of exposure. While acute or short duration of exposure is associated with no or minimal effects, longer duration or chronic exposure stimulates thrombopoiesis in which reticulocytes increase adhesive receptors and are hyperactive to agonists [16]. The duration of glucose exposure correlates with HbA1c levels [86]. Contrary to popular belief, hyperactive platelets are evident even before observable metabolic features in individuals predisposed to T1DM with normal blood [41]. Early evidence of the influence of glucose on platelet functions via metabolic reactions was provided by Murer et al. [87] and Chaudhry et al. [88]. The two groups reported the presence of aggregation in media containing glucose or substitute substrates, the extent of which was related to glucose consumption and carbon dioxide production due to metabolism. In these experiments, addition of metabolic inhibitors inhibited aggregation. Moreover, alterations of membrane properties and energy requiring processes have been noted upon incubation of platelets with varying glucose concentrations [18] suggesting other mechanisms are at play.
Several preclinical animal studies have confirmed the dependency of platelet functions on glucose uptake and subsequent metabolism [33, 89]. Under resting conditions, the plasma membrane localized GLUT-1 glucose transporter facilitates glucose entry into platelets, activation glycolysis, and ATP production [90]. Upon stimulation with agonists such as thrombin, alpha granules containing both P-selectin and GLUT-3 translocate and fuse with plasma membrane to increase glucose uptake [91]. The resulting alpha granules degranulation, glucose influx, and increased ATP synthesis lead to P-selectin expression and aggregation [33, 92].
It appears that hyperglycemia in itself has little bearing on platelet activation unless accompanied by other changes. In a study of T1DM and T2DM, despite postprandial elevation of blood glucose in both types, however, markers of platelet activation were only increased in T2DM. Interestingly, insulin levels did not change in T1DM unlike in T2DM. Administration of insulin pre-meal was accompanied by increase of postprandial platelet activation markers [74, 76, 93]. However, platelet-activating effects of insulin in T1DM are evident only when there is concurrent hypoglycemia [94]. At low extracellular glucose, insulin potentiates action of thrombin to increase glucose entry via Glut-3 with concomitant increase in surface expression of P-selectin and aggregation. Conversely, at high glucose concentrations, insulin becomes inhibitory through its action on protein kinase B (PKB) and hampers thrombin activation mechanisms leading to decreased platelet activation and aggregation [92].
5.3 Hypertriglyceridemia/hyperlipidemia
In T1DM, the frequency of occurrence of hyperlipidemia is variable [95, 96, 97], but when it occurs is associated with platelet hyper-activation [46] and aggregation [98]. The link between post-prandial lipids and platelet secretions [99] and aggregations has been known for a long time [100]. The case was made stronger by observations that treatments lowering the plasma lipids led to normalization of platelet aggregation [101] and glycoprotein expression [102]. Hyper lipidemia associated with uncontrolled T1DM thus becomes an added dimension in platelet hyperactivity together with roles of glucose and insulin.
5.4 Pharmacological treatments
5.4.1 Insulin treatment
Platelet hyperactivity, which largely occurs together with hyperglycemia and hyperinsulinemia, is well known in T2DM [103]. Notably, despite the absolute or relative deficiency of insulin in T1DM, platelet hyperactivity also occurs in T1DM. This phenomenon has elicited debate on the role of insulin in platelet functions. The data available on platelet functions in T1DM are usually at the beginning of insulin treatment or follow-up, which have reported mixed results: no change [86, 104, 105], reduced functions [38], or enhanced activity [24]. These discrepancies in study results can be accounted for by the differences in insulin dosages that produce hypoglycemia, duration of disease, individual peculiarities such as obesity, hyperlipidemia, and plasma calcium and magnesium balances.
Low dose or physiological levels of insulin inhibit platelet aggregation through several mechanisms [38, 106]. These include: decreasing intracellular cAMP levels [38], decreasing calcium mobilization [107] but increasing magnesium influx [108], nitric-oxide-mediated increase in cGMP [38], stimulation of prostacyclin synthesis [109]. Low-dose Insulin prevents second wave aggregation in diabetics, an effect augmented by calcium channel blockers [110]. It is therefore apparent that physiological levels of insulin suppress platelet function, effects that are reversed in its absence during diabetes mellitus type1.
The studies that showed increased platelet hyperactivity concurrent with hyperinsulinemia induced hypoglycemia [94], with attendant increase in counter-regulatory hormones such as adrenaline [111, 112] and increase in vWF-platelet adhesiveness [24], results which were similar to findings in T2DM [113].
Experimental
Whereas low-dose insulin decreases platelet aggregation, high dose increases platelet aggregation in vitro [115, 117]. These effects are mediated by paradoxical changes in intraplatelet cGMP levels [116] and co-operativity with insulin-like growth factor on platelets [118]. Indeed platelets pose few insulin receptors and responses are weak but potentiated by IGF-1 [118] in the presence of extracellular calcium [119]. This is because insulin and IGF-1 circulate together and share a lot of similarities in both structure and receptors [120, 121]. Thus, at high insulin concentrations, the effects of IGF-1 predominate, thus explaining the increased platelet aggregation and response to agonists in patients on hyperinsulinemia.
In healthy, non-diabetic non-obese subjects, insulin decreases platelet adherence to collagen surfaces, decreases agonist-induced (ADP, collagen, AA, and TRAP) platelet aggregation but increases intracellular cGMP. These responses are abolished or blunted in obese individuals [122].
5.4.2 Anti-platelet treatments
Aspirin suppressed platelet functions TXA secretion, LTA, and PFA although there are no observable differences between healthy and DM individuals [35]. In case of stable (>1 month) dual 100 mg aspirin and 75 mg clopidogrel, insulin-treated DM has elevated platelet reactivity as assessed by LTA and PFA compared with NIDM and non-diabetic controls [29]. The refractory effect of antiplatelets in the presence of insulin has been reported [123]. Aspirin has been shown to attenuate maximum aggregation in newly diagnosed T1DM via its effects on ADP, epinephrine, and thrombin. The effects are most marked in reducing the secondary [26] indicating propensity for secretory phase. The refractory state to anti-platelets responses of platelets to agonists in the presence of high glucose is dependent on the signaling pathways tested. For example, hyperglycemia blocks the NO-cGMP-protein kinase pathway but spares the thromboxane secretion [124].
5.4.3 Statins
In patients with hyperlipidemia type II, statins reduced ADP-induced platelet aggregation regardless of the type of drug. However, there was no change with collagen or ristocetin agonist. In addition, the changes were not observed in fibrinogen levels, spontaneous aggregation, and adhesion [125]. The effect of lipid lowering agents in attenuating platelet functions appears to be related to changes in fibrinogen levels [126], suggesting modulation through inflammatory mediators.
5.5 Inflammation
Inflammation is common to both T1DM and T2DM. However, in T1DM inflammation is upstream involving cellular interactions that release cytokines and fibrinogen [127]. The cytokines and fibrinogen have been found to influence platelet activation independent of hyperglycemia [123, 128]. Since fibrinogen is an acute phase protein associated with acute inflammatory conditions, its correlation with platelet functions points to the role of inflammation in the modulation platelet response after stimulation.
6. Mechanisms of altered platelet functions in T1DM
6.1 Oxidative stress
Owing to the absence or deficiency of insulin in T1DM glucose undergoes auto-oxidation with accumulation of reactive oxygen species [129]. The consequence is peroxidation of membrane lipids and proteins [130] promoting platelet aggregation [131].
However, it is still controversial whether oxidative stress is a consequence of metabolic complications in T1DM or the cause of the disease [47].
6.2 Hyperglycemia
Persistent hyperglycemia leads to formation of non-enzymatic glycation of proteins, so-called advanced glycation end products (AGEs). Accumulation of these products facilitates cytoskeletal reorganization causing externalization of membrane phosphatidyleserine (PS) [132], altered membrane fluidity [133], and increased expression of glycoproteins GPIb, IIbIIIa [134], P-selectin, and PLA [135].
Hyperglycemia induces secretion of TPO that potentiates agonist-induced activation of mature platelets. Levels positively correlate with blood glucose and level of control HbA1C [17].
6.3 Signal transduction mechanisms
Collagen at low dose selectively promotes granule secretions through GPVI receptors, a finding not found with high doses or thrombin [136].
DM platelets have upregulated protein C Kinase promoting aggregation [137], downregulation of cAMP, and subsequent increased expression of P2y12
6.4 Ca++signaling
Calcium fluxes are essential for platelet functions, and abnormalities in regulation contributed by prolonged exposure (24 hours) to high glucose are associated with platelet hyperactivity [138].
In T1DM, there is coexistence of insulin deficiency/absence and hypomagnesaemia [139]. Hypomagnesaemia is associated with oxidative stress [140] and increases in platelet baseline intracellular Ca++. The consequence of un-opposed intracellular calcium leads to signal transduction sequences that eventually promote membrane glycoprotein expression, adhesion, secretion, and aggregation [141, 142].
6.5 Lipids
DM subjects have hypertriglyceridaemia, apo E, and HDL receptors that modify cation transporters and nitric oxide synthase involved in platelet aggregation and activation [143, 144, 145].
6.6 Prostacyclin
Endothelium of individuals with diabetes mellitus is deficient in prostacyclin thought to contribute to enhanced platelet hyperactivity. However, in vitro testing found platelets from DM were less sensitive to PGI2 than normal controls [146].
6.7 Immune mechanisms
Inflammatory markers such as TNFα, cytokines, and immune complexes are abundant in diabetes, and these are thought to play a role in platelet activation. Cytokines contribute to platelet activation [147, 148, 149], and these are amplified by the presence of glucose and ADP [150].
6.8 Platelet-Neutrophil interaction
Animal studies have provided evidence for indirect platelet activation in DM that in the presence of hyperglycemia, neutrophils are stimulated to release S-100 calcium-binding proteins A8/A9 that lead to production of TPO from the liver. The released TPO consequently acts on bone marrow megakaryocytes to release reticulocytes [16]. Reticulocytes have high surface expression of GPIIbIIIa, P-selectin, and release cytokines [16]. The expressed P-selectin interacts with SGL-P on neutrophils to release neutrophil extracellular traps (NETs).
7. Clinical significance of platelet functions
Microangiopathy is common in T1DM and is associated with hyperactive platelets expressing agonist stimulated P-selectina and platelet-leucocyte aggregates [41]. A number of clinical trials have reported decreased efficacy of anti-platelets in DM subjects [152]. The reasons are multifactorial, but can be summarized as lack of effect in leukocyte-platelet interactions, chronic effects of hyperglycemia especially oxidative stress, insulin resistance, and inability of megakaryocytes to respond.
8. Conclusion
T1DM is associated with platelet hypersensitivity to stimulating agonists. Hyperglycemia, in a dose and duration-dependent manner, provides the substrates for energy generation that powers alpha granule translocation to the membrane surface. Enhanced expression of P-selectin and GPIIbIIIa contributes to increased platelet aggregation evident in T1DM. Platelet hyperactivity in T1DM represents a reversal of the attenuating effects of low dose or physiological insulin. This is augmented by the attendant hyperlipidemia. However, the paradoxical hyperactivity in the presence of hyperinsulinemia is due to counter-regulatory hormones and potentiation by insulin-like growth factor. Overall, platelet activation in T1DM occurs through multiple signal transduction pathways not targeted by currently available antiplatelet agents. These pathways offer avenues for the development of novel antiplatelet remedies with improved therapeutic efficacy.
References
- 1.
Salem MAEK, Adly AAM, Ismail EAR, Darwish YW, Kamel HA. Platelets microparticles as a link between micro- and macro-angiopathy in young patients with type 1 diabetes. Platelets. 2015; 26 (7):682-688 - 2.
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. I m p a i red glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999; 22 (6):920-924 - 3.
Vazzana N, Ranalli P, Cuccurullo C, Davì G. Diabetes mellitus and thrombosis. Thrombosis Research. 2012; 129 (3):371-377 - 4.
Shechter M, Bairey Merz CN, Paul-Labrador MJ, Kaul S. Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease. Journal of the American College of Cardiology. 2000; 35 (2):300-307 - 5.
Nusca A et al. Platelet effects of anti-diabetic therapies : New perspectives in the management of patients with diabetes and cardiovascular disease. Frontiers in Pharmacology. 2021; 12 :670155 - 6.
Ebeling P, Koistinen HA, Koivisto VA. Insulin-independent glucose transport regulates insulin sensitivity. FEBS Letters. 1998; 436 (3):301-303 - 7.
Malachowska B et al. Altered Platelets’ morphological parameters in children with type 1 diabetes – a case-control study. BMC Endocrinology Disorders. 1998; 15 (1):17 - 8.
Jindal S et al. Platelet indices in diabetes mellitus : Indicators of diabetic microvascular complications Platelet indices in diabetes mellitus : Indicators of diabetic microvascular complications. Hematology. 2011; 16 (2):86-89 - 9.
Findikli HA, Kirac CO. Evaluation of the relationship between blood glucose regulation and hematological indices in patients with diabetes mellitus. EJMI. 2022; 6 (2):240-244 - 10.
Manoj S, Swami YK, Meena SR. Study of impact of glycemic status (HbA1c) on platelet activity measured by mean platelet volume & vascular complications in. The Journal of the Association of Physicians of India. 2019; 67 :26-29 - 11.
Brown AS et al. Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997; 17 (4):802-807 - 12.
Tschoepe D et al. Large platelets circulate in an activated state in diabetes mellitus. Seminars in Thrombosis and Hemostasis. 1991; 17 (4):433-438 - 13.
Wisinski JA, Kimple ME. Platelet dysfunction in type 1 diabetes: Stressing the thromboxanes. Diabetes. 2016; 65 (2):349-351 - 14.
Fraser JK, Leahy MF, Berridge MV. Expression of antigens of the platelet glycoprotein IIb/IIIa complex on human hematopoietic stem cells. Blood. 1986; 68 (3):762-769 - 15.
Berridge MV, Ralph SJ, Tan AS. Cell-lineage antigens of the stem cell-megakaryocyte-platelet lineage are associated with the platelet IIb-IIIa glycoprotein complex. Blood. 1985; 66 (1):76-85 - 16.
Kraakman MJ et al. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. The Journal of Clinical Investigation. 2017; 127 (6):2133-2147 - 17.
Bosco O et al. Thrombopoietin contributes to enhanced platelet activation in patients with type 1 diabetes mellitus. International Journal of Molecular Sciences. 2021; 22 (13):1-12 - 18.
Mazzanti L et al. Altered platelet membrane dynamic properties in type 1 diabetes. Diabetes. 1997; 46 (12):2069-2074 - 19.
Bridges JM, Dalby AM, Millar JHD, Weaver JA. An effect of D-glucose on platelet stickiness. Lancet. 1965; 285 (7376):75-77 - 20.
Heath H, Gridgen WD, Canever JV, Pollock J, Kelsey J, Bloom A. Platelet adhesiveness and aggregation in relation to diabetic retinopathy. Diabetologia. 1971; 7 :308-315 - 21.
Colwell JA, Nair RMG, Halushka PV, Rogers C, Whetsell A, Sage J. Platelet adhesion and aggregation in diabetes mellitus. Metabolism. 2003; 28 (74):394-400 - 22.
Chan NN, Fuller JH, Rubens M, Colhoun HM. Von Willebrand factor in type 1 diabetes: Its relationship with endothelial nitric oxide production and coronary artery calcification. Medical Science Monitor. 2003; 9 (7):297-304 - 23.
Skeppholm M, Kallner A, Kalani M, Jörneskog G, Blombäck M, Wallén HN. ADAMTS13 and von willebrand factor concentrations in patients with diabetes mellitus. Blood Coagulation & Fibrinolysis. 2009; 20 (8):619-626 - 24.
Mohamed SM, El-kinany HA, Abdel-fattah MA. Platelet aggregation and von Willebrand factor in children with insulin dependent diabetes mellitus and their relation to glycemic control abstract : Introduction: Subjects and methods : Results and discussion. Alexander Journal of Pdiatrics. 1998; 12 (2):329-338 - 25.
Dittmar S, Polanowska-Grabowska R, Gear ARL. Platelet adhesion to collagen under flow conditions in diabetes mellitus. Thrombosis Research. 1994; 74 (3):273-283 - 26.
Sagel J, Ch B, Colwell JA, Ph D, Crook L, Ph D. Increased platelet aggregation in early diabetus mellitus. Annals of Internal Medicine. 1975; 82 (6):733-738 - 27.
Colwell JA, Halushka PV, Sarji KE, Sagel J. Platelet function and diabetes mellitus. The Medical Clinics of North America. 1978; 62 (4):753-766 - 28.
Angiolillo DJ et al. Platelet dunction profiles in patients With type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 1978; 54 :2430-2435 - 29.
Angiolillo DJ et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. Journal of American College Cardiology. 1978; 48 (2):298-304 - 30.
Michno A, Bielarczyk H, Pawełczyk T, Jankowska-Kulawy A, Klimaszewska J, Szutowicz A. Alterations of adenine nucleotide metabolism and function of blood platelets in patients with diabetes. Diabetes. 2007; 56 (2):462-467 - 31.
Li Z, Zhang G, Le Breton GC, Gao X, Malik AB, Du X. Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. The Journal of Biological Chemistry. 2003; 278 (33):30725-30731 - 32.
Emery M, O’Dell BL. Biphasic platelet aggregation in rat plasma and the effect of calcium flux modulators. Thrombosis Research. 1987; 46 :617-623 - 33.
Fidler TP et al. Glucose transporter 3 potentiates degranulation and is required for platelet activation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37 (9):1628-1639 - 34.
Kutti J, Wadenvik H, Henestam B. Evaluation of platelet reactivity in diabetes mellitus. Acta Medica Scandinavica. 1986; 219 :195-199 - 35.
Al-sofiani ME et al. Diabetes and platelet response to low-dose aspirin. The Journal of Clinical Endocrinology and Metabolism. 2018; 103 :4599-4608 - 36.
Omoto S et al. Significance of platelet-derived microparticles and activated platelets in diabetic nephropathy. Nephron. 1999; 81 (3):271-277 - 37.
Sobczak AIS, Phoenix FA, Pitt SJ, Ajjan RA, Stewart AJ. Reduced plasma magnesium levels in type-1 diabetes associate with prothrombotic changes in fibrin clotting and fibrinolysis. Thrombosis and Haemostasis. 2020; 120 (2):243-252 - 38.
Trovati M, Anfossi G, Cavalot F, Massucco P, Mularoni E, Emanuelli G. Insulin directly reduces platelet sensitivity to aggregating agents. Studies in vitro and in vivo. Diabetes. 1988; 37 (6):780-786 - 39.
Etulain J et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thrombosis and Haemostasis. 2012; 107 :99-110 - 40.
Yngen M, Östenson CG, Hu H, Li N, Hjemdahl P, Wallén NH. Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: Evidence for platelet hyperactivity and chronic inflammation. Diabetologia. 2004; 47 (3):537-540 - 41.
Hu H, Li N, Yngen M. Enhanced leukocyte – platelet cross-talk in Type 1 diabetes mellitus: Relationship to microangiopathy. Journal of Thrombosis and Haemostasis. 2004; 2 :58-64 - 42.
Tschoepe D, Driesch E, Schwippert B, Lampeter EF. Activated platelets in subjects at increased risk of IDDM. Diabetologia. 1997; 40 (5):573-577 - 43.
Bergen K, Mobarrez F, Jörneskog G, Wallén H, Tehrani S. High levels of endothelial and platelet microvesicles in patients with type 1 diabetes irrespective of microvascular complications. Thrombosis Research. 1997; 196 :78-86 - 44.
Sabatier F et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes. 2002; 51 (9):2840-2845 - 45.
Popp SK, Vecchio F, Brown DJ, Fukuda R, Suzuki Y, Takeda Y, et al. Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice. JCI insight. 2022; 7 (2):e153993. DOI: 10.1172/jci.insight.153993 - 46.
Zahran AM, El-Badawy O, Mohamad IL, Tamer DM, Abdel-Aziz SM, Elsayh KI. Platelet activation and platelet–leukocyte aggregates in type I diabetes mellitus. Clinical Application in Thrombosis. 2002; 24 (9):230-239 - 47.
Chen Y, Zhong H, Zhao Y, Luo X, Gao W. Role of platelet biomarkers in inflammatory response. Biomark Research. 2020; 8 (1):28 - 48.
Haller MJ, Schatz DA. Cytokines and type 1 diabetes complications : Casual or causal association ? Pedriatric Diabetes. 2008; 9 (11):1-2 - 49.
Lumadue JA, Lanzkron SM, Kennedy SD, Kuhl DT, Mt BS, Kickler TS. Cytokine induction of platelet activation. American Journal of Clinical Pathology. 1996; 106 :795-798 - 50.
Bern MM. Platelet functions in diabetes mellitus. Diabetes. 1978; 2 (3):342-350 - 51.
BETTERIDGE DJ, TAHIR KEHE, RECKLESS JPD, WILLIAMS KI. Platelets from diabetic subjects show diminished sensitivity to prostacyclin. European Journal of Clinical Investigation. 1982; 12 (5):395-398 - 52.
Kim JH, Bae HY, Kim SY. Clinical marker of platelet hyperreactivity in diabetes mellitus. Diabetes and Metabolism Journal. 2013; 37 (6):423-428 - 53.
Cesur M, Sayin I. Diabetic Ketoacidosis, In: Type 1 Diabetes. London, United Kingdom: IntechOpen; 2013. DOI: 10.5772/53199 Available from: https://www.intechopen.com/chapters 10/pp 251-291/43299 - 54.
Campbell RR, Foster KJ, Stirling C, Mundy D, Reckless JPD. Paradoxical platelet behaviour in diabetic ketoacidosis. Diabetic Medicine. 1986; 3 (2):161-164 - 55.
Janka HU, Mehmet H. No rationale for antiplatelet drug treatment in diabetic ketoacidosis. Diabetologia. 1982; 23 :1982 - 56.
Ileri NŞ et al. Evaluation of the haemostatic system during ketoacidotic deterioration of diabetes mellitus. Haemostasis. 1999; 29 (6):318-325 - 57.
Goldschmidt B. Effect of lactic acid on the aggregation of human platelets induced by ADP, adrenaline and collagen. Specialia. 1973; 15 (11):1399-1401 - 58.
Foley ME, Mcnicol GP. An in-vitro study of acidosis, platelet function, and perinatal cerebral intraventricular haemorrhage. Lancet. 1977; 11 :1230-1232 - 59.
Lanier CJ, Taintor JS, Christopherson PW, Spangler EA. Effect of lactic acid addition to equine whole blood on platelet aggregation measured by impedance aggregometry. Veterinary Clinical Pathology. 2022; 51 (1):65-69 - 60.
Lawson CA, Spangler EA. The effect of adding lactic acid to canine whole blood on platelet aggregation as measured by impedance aggregometry. Veterinary Clinical Pathology. 2020; 49 (2):217-221 - 61.
Marumo M, Suehiro A, Kakishita E, Groschner K, Wakabayashi I. Extracellular pH affects platelet aggregation associated with modulation of store-operated Ca2+ entry. Thrombosis Research. 2001; 104 (5):353-360 - 62.
Laskay G, Kálmán K, Van Kerkhove E, Steels P, Ameloot M. Store-operated Ca2+-channels are sensitive to changes in extracellular pH. Biochemical and Biophysical Research Communications. 2005; 337 (2):571-579 - 63.
Nachmias VT, Yoshida K, Glennon MC. Lowering pH in blood platelets dissociates myosin phosphorylation from shape change and myosin association with the cytoskeleton. The Journal of Cell Biology. 1987; 105 (4):1761-1769 - 64.
Djaldetti M, Fishman P, Bessler H, Chaimoff C. Platelet ultrastructural alterations. A possible mechanism for impaired platelet aggregation. Archives of Surgery. 1979; 114 :707-710 - 65.
Bertolini F, Porretti L, Lauri E, Rebulla P, Sirchia G. Role of lactate in platelet storage lesion. Vox Sanguinis. 1993; 65 (3):194-198 - 66.
Kobzar G, Mardla V, Samel N. Short-term exposure of platelets to glucose impairs inhibition of platelet aggregation by cyclooxygenase inhibitors. Platelets. 2011; 22 (5):338-344 - 67.
Kobzar G, Mardla V, Samel N. Lactate is a possible mediator of the glucose effect on platelet inhibition. Platelets. 2014; 25 (4):239-245 - 68.
Przygodzki T, Luzak B, Kassassir H, Mnich E, Boncler M, Siewiera K, et al. Diabetes and Hyperglycemia Affect Platelet GPIIIa Expression. Effects on Adhesion Potential of Blood Platelets from Diabetic Patients under In Vitro Flow Conditions. International journal of molecular sciences. 2020; 21 (9):3222. DOI: 10.3390/ijms21093222 - 69.
Gresele P et al. Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide – donating agent. Diabetes Care. 2010; 33 (6):1262-1268 - 70.
Worthley MI et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes. Mediation by superoxide production, resolution with intensive insulin administration. Journal of the American College of Cardiology. 2007; 49 (3):304-310 - 71.
Li N, Sudic D, Forslund M, Razmara M. Acute hyperglycaemia enhances platelet activation: Involvement of multiple mechanisms. Blood. 2004; 104 (11):3884-3884 - 72.
Yngen M, Ostenson C-G, Li N, Hjemdahl P, Wallen NH. Acute hyperglycemia increases soluble P- selectin in male patients with mild diabetes mellitus. Blood Coagulation & Fibrinolysis. 2001; 12 (2):109-116 - 73.
Santilli F et al. Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus. Journal of Thrombosis and Haemostasis. 2010; 8 (4):828-837 - 74.
Spectre G et al. Meal intake increases circulating procoagulant microparticles in patients with type 1 and type 2 diabetes mellitus. Platelets. 2019; 30 (3):348-355 - 75.
Vaidyula VR, Rao AK, Mozzoli M, Homko C, Cheung P, Boden G. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes. 2006; 55 (1):202-208 - 76.
Spectre G, Stålesen R, Östenson C, Hjemdahl P. Meal-induced platelet activation in diabetes mellitus type 1 or type 2 is related to postprandial insulin rather than glucose levels ☆. Thrombosis Research. 2016; 141 :93-97 - 77.
Knobler H, Savion N, Shenkman B, Kotev-Emeth S, Varon D. Shear-induced platelet adhesion and aggregation on subendothelium are increased in diabetic patients. Thrombosis Research. 1998; 90 (4):181-190 - 78.
Pawelczyk M, Kaczorowska B, Baj Z. The impact of hyperglycemia and hyperlipidemia on plasma P-selectin and platelet markers after ischemic stroke. Archives of Medical Science. 2017; 13 (5):1049-1056 - 79.
Best L, Jones PBB, Preston FE. Effect of glucose on platelet thromboxane biosynthesis. Lancet. 1979; 314 (8146):790 - 80.
Ogweno GO. The Effects of Crystalloid Solutions on the Human Blood Coagulation System. Kenyatta University; 2016. dc.identifier.uri. Available from: http://ir-library.ku.ac.ke/handle/123456789/14948 - 81.
Wilder DM, Reid T, Bakaltcheva IB. Hypertonic resuscitation and blood coagulation: In vitro comparison of several hypertonic solutions for their action on platelets and plasma coagulation. Thrombosis Research. 2002; 107 (5):255-261 - 82.
Tang WH et al. Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane. The Journal of Clinical Investigation. 2011; 121 (11):4462-4476 - 83.
De La Cruz JP et al. Influence of glucose concentration on the effects of aspirin, ticlopidine and clopidogrel on platelet function and platelet-subendothelium interaction. European Journal of Pharmacology. 2004; 484 (1):19-27 - 84.
Sudic D, Razmara M, Forslund M, Ji Q , Hjemdahl P, Li N. High glucose levels enhance platelet activation: Involvement of multiple mechanisms. British Journal of Haematology. 2006; 133 (3):315-322 - 85.
Keating FK, Sobel BE, Schneider DJ. Effects of increased concentrations of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes mellitus. The American Journal of Cardiology. 2003; 92 (11):1362-1365 - 86.
Jones DB, Davis TME, Bown E, Carter RD, Infirmary R, Unit S. Determinants of ADP-induced platelet aggregation in diabetes mellitus. Diabetologia. 1986; 29 :291-294 - 87.
Mürer EH, Hellem AJ, Rozenberg MC. Energy metabolism and platelet function. Scandinavian Journal of Clinical and Laboratory Investigation. 1967; 19 (3):280-282 - 88.
Chaudhry AA, Sagone AL, Metz EN, Balcerzak SP. Relationship of glucose oxidation to aggregation of human platelets. Blood. 1973; 41 (2):249-258 - 89.
Fidler TP et al. Glucose metabolism is required for platelet hyperactivation in a murine model of type 1 diabetes. Diabetes. 2019; 68 (5):932-938 - 90.
Whiteheart SW. Fueling platelets: Where does the glucose come from? Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37 (9):1592-1594 - 91.
Heijnen HFG, Oorschot V, Sixma JJ, Slot JW, James DE. Thrombin stimulates glucose transport in human platelets via the translocation of the glucose transporter GLUT-3 from α-granules to the cell surface. The Journal of Cell Biology. 1997; 138 (2):323-330 - 92.
Ferreira IA, Mocking AIM, Urbanus RT, Varlack S, Wnuk M, Akkerman JWN. Glucose uptake via glucose transporter 3 by human platelets is regulated by protein kinase B. The Journal of Biological Chemistry. 2005; 280 (38):32625-32633 - 93.
Spectre G, Östenson CG, Li N, Hjemdahl P. Postprandial platelet activation is related to postprandial plasma insulin rather than glucose in patients with type 2 diabetes. Diabetes. 2012; 61 (9):2380-2384 - 94.
Jarek-Martynowa IR et al. Influence of hyperinsulinemic - hypoglycemic clamp on induced platelet aggregation, activity of physiological anticoagulants and von willebrand factor in patients with type I diabetes. Diabetes Mellitus. 2018; 21 (2):84-91 - 95.
Bulut T, Demirel F, Metin A. The prevalence of dyslipidemia and associated factors in children and adolescents with type 1 diabetes. Journal of Pediatric Endocrinology & Metabolism. 2017; 30 (2):181-187 - 96.
Mona HM, Sahar SA, Hend SM, Nanees A-WA. Dyslipidemia in type 1 diabetes mellitus: Relation to diabetes duration, glycemic control, body habitus, dietary intake and other epidemiological risk factors. Egyptian Pediatric Associated Gazette. 2015; 63 (2):63-68 - 97.
Alrasheed AA. Dyslipidemia among patients with type 1 diabetes and its associated factors in Saudi Arabia: An analytical cross-sectional study. Cureus Journal of Medical Science. 2022; 14 (2):e1923 - 98.
Ewald U, Kobbah M, Vessby B, Tevemo T. Increased platelet aggregability in diabetic children: Relation to serum lipid and fatty acid composition. Diabetologia. 1983; 25 :382-385 - 99.
Betteridge DJ, Zahavi J, Jones NAG, Shine B, Kakkar VV, Galton DJ. Platelet function in diabetes mellitus in relationship to complications, glycosylated haemoglobin and serum lipoproteins. European Journal of Clinical Investigation. 1981; 11 (4):273-277 - 100.
Fuhrman B, Brook JG, Aviram M. Increased platelet aggregation during alimentary hyperlipemia in normal and hypertriglyceridemic subjects. Annals of Nutrition & Metabolism. 1986; 30 (4):250-260 - 101.
Kobbah AM, Ewald U, Tuvemo T, Hospital A. Platelet aggregability during the first two years of type 1 (insulin-deependent) diabetes mellitus in children. Diabetologia. 1989; 32 :729-735 - 102.
Hiramatsu K, Nozaki H, Arimori S. Reduction of platelet aggregation induced by euglycaemic insulin clamp. Diabetologia. 1987; 30 (5):310-313 - 103.
Ferroni P, Basili S, Falco A, Davì G. Platelet activation in type 2 diabetes mellitus. Journal of Thrombosis and Haemostasis. 2004; 2 (8):1282-1291 - 104.
Roshan B et al. Improved glycemic control and platelet function abnormalities in diabetic patients with microvascular disease. Metabolism. 2000; 49 (1):88-91 - 105.
Singer J, Weissler Snir A, Leshem-Lev D, Rigler M, Kornowski R, Lev EI. Effect of intensive glycemic control on platelet reactivity in patients with long-standing uncontrolled diabetes. Thrombosis Research. 2014; 134 (1):121-124 - 106.
Westerbacka J, Turpeinen A, Rissanen A, Vehkavaara S, Lassila R. Inhibition of platelet-collagen interaction. An in vivo action of insulin abolished by insulin resistance in obesity. An in vivo action of insulin abolished by insulin resistance in obesity. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002; 22 :167-172 - 107.
Ferreira IA, Eybrechts KL, Mocking AIM, Kroner C, Akkerman JWN. IRS-1 mediates inhibition of Ca2+ mobilization by insulin via the inhibitory G-protein Gi. The Journal of Biological Chemistry. 2004; 279 (5):3254-3264 - 108.
Hwang DL, Yen CF, Nadler JL. Insulin increases intracellular magnesium transport in human platelets. The Journal of Clinical Endocrinology and Metabolism. 1993; 76 (3):549-553 - 109.
Kahn NN, Bauman WA, Hatcher VB, Sinha AK. Inhibition of platelet aggregation and the stimulation of prostacyclin synthesis by insulin in humans. American Journal of Physiology. 1993; 265 :H2160 - 110.
Lee YS, Hahm K-S, Lee SY. Effects of calcium channel blockers and insulin on the platelet function in patients with diabetes mellitus. Yonsei Medical Journal. 1993; 27 (2):132 - 111.
Hutton RA, Mikhailidis D, Dormandy KM, Ginsburg J. Platelet aggregation studies during transient hypoglycaemia. A potential method for evaluating platelet function. Journal of Clinical Pathology. 1979; 32 (5):434-438 - 112.
Trovati M et al. Studies on mechanisms involved in hypoglycemia-lnduced platelet activation. Diabetes. 1986; 35 :818-825 - 113.
Kahal H et al. Platelet function following induced hypoglycaemia in type 2 diabetes. Diabetes & Metabolism. 2018; 44 (5):431-436 - 114.
Anfossi G et al. Insulin exerts opposite effects on platelet function at physiological and supraphysiological concentrations. Thrombosis Research. 1996; 82 (1):57-68 - 115.
Yngen M, Li N, Hjemdahl P, HWallen NH. Insulin enhances platelet activation in vitro. Thrombosis Research. 2001; 104 :85-91 - 116.
Hu H, Hjemdahl P, Li N. Effects of insulin on platelet and leukocyte activity in whole blood. Thrombosis Research. 2002; 107 (5):209-215 - 117.
Murer EH, Gyda MA, Martinez NJ. Insulin increases the aggregation response of human platelets to ADP. Thrombosis Research. 1994; 73 :69-74 - 118.
Hunter RW, Hers I. Insulin/IGF-1 hybrid receptor expression on human platelets: Consequences for the effect of insulin on platelet function. Journal of Thrombosis and Haemostasis. 2009; 7 (12):2123-2130 - 119.
Motani AS, Angard EE, Ferns GAA. Recombinant Insulin-like growth factor-1 modulates aggregation in human platelets via extracellular calcium. Life Sciences. 1996; 58 (15):269-274 - 120.
Hers I. Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway. Blood. 2007; 110 (13):4243-4252 - 121.
Stolla MC, Li D, Lu L, Woulfe DS. Enhanced platelet activity and thrombosis in a murine model of type I diabetes are partially insulin-like growth factor 1-dependent and phosphoinositide 3-kinase-dependent. Journal of Thrombosis and Haemostasis. 2013; 11 (5):919-929 - 122.
Westerbacka J, Turpeinen A, Rissanen A, Vehkavaara S, Lassila R. An in vivo action of insulin abolished by insulin resistance in obesity. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002; 22 :167-172 - 123.
Gaborit B, FrèRe C, Cuisset T, Alessi MC, Dutour A. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. Journal of Thrombosis and Haemostasis. 2009; 7 (11):1939-1941 - 124.
Russo I et al. High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin-induced inhibition of thromboxane synthesis in human platelets. Diabetes. 2012; 61 (11):2913-2921 - 125.
Sikora J, Kostka B, Marczyk I, Krajewska U, Chałubiński M, Broncel M. Effect of statins on platelet function in patients with hyperlipidemia. Archives of Medical Science. 2013; 9 (4):622-628 - 126.
De Man FH et al. Activated platelets in patients with severe hypertriglyceridemia: Effects of triglyceride-lowering therapy. Atherosclerosis. 2000; 152 (2):407-414 - 127.
Bending D, Zaccone P, Cooke A. Inflammation and type one diabetes. International Immunology. 2012; 24 (6):339-346 - 128.
Triolo G et al. Circulating immune complexes and platelet thromboxane synthesis in patients with insulin-dependent (type I) diabetes mellitus. Diabetes. 1984; 33 (8):728-731 - 129.
Dominguez C, Ruiz E, Gussinye M, Carrascosa A. Oxidative stress at onset and in early stages of type 1 diabetes in children and adolescents. Diabetes Care. 1998; 21 :1736-1742 - 130.
Chen J, Stimpson SE, Fernandez-bueno GA, Mathews CE, Al CET. Mitochondrial reactive oxygen species and type 1 diabetes. Antioxidants & Redox Signaling. 2018; 29 (14):1361-1372 - 131.
Malladi N et al. Understanding the activation of platelets in diabetes and its modulation by allyl methyl sulfide, an active metabolite of garlic. Hindawi. 2021; 2021 :12 - 132.
Wang Y et al. Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT 2A / 2C receptors. American Journal of Physiology. Cell Physiology. 2007; 293 :C328-C336 - 133.
Winocour PD, Watala C, Perry DW, Kinlough-rathbone RL. Decreased platelet membrane fluidity due to glycation or acetylatîon of membrane proteins. Thrombosis and Haemostasis. 1992; 68 (5):577-582 - 134.
Gawlowski T et al. Advanced glycation end products strongly activate platelets. European Journal of Nutrition. 2009; 48 (8):475-481 - 135.
Gawlowski T, Stratmann B, Stirban AO, Negrean M, Tschoepe D. AGEs and methylglyoxal induce apoptosis and expression of Mac-1 on neutrophils resulting in platelet-neutrophil aggregation. Thrombosis Research. 2007; 121 (1):117-126 - 136.
Ollivier V et al. Collagen can selectively trigger a platelet secretory phenotype via glycoprotein VI. PLoS One. 2007; 9 (8):e104712 - 137.
Assert R, Scherk G, Bumbure A, Pirags V, Schatz H, Pfeiffer AFH. Regulation of protein kinase C by short term hyperglycaemia in human platelets in vivo and in vitro. Diabetologia. 2001; 44 :188-195 - 138.
Li Y, Woo V, Bose R. Platelet hyperactivity and abnormal CA2+ homeostasis in diabetes mellitus. American Journaal of Physiology. 2001; 280 (4):1480-1489 - 139.
Andac B, Bulbul BY, Durak DM. Relationship of magnesium level with glycemic control and lipid profile in adult patients with TYPE 1 diabetes mellitus. Journal of Elementology. 2021; 26 (2):307-317 - 140.
Van Dijk PR, Waanders F, Qiu J, De Boer HHR, Van Goor H, Bilo HJG. Hypomagnesemia in persons with type 1 diabetes : Associations with clinical parameters and oxidative stress. Therapeutic Advances in Endocrinology and Metabolism. 2020; 11 :1-9 - 141.
Hwang DL, Yen CF, Nadler JL. Effect of extracellular magnesium on platelet activation and intracellular calcium mobilization. American Journal of Hypertension. 1992; 5 :700-706 - 142.
Sheu J, Hsiao G, Shen M, Fong T, Chen Y. Mechanisms involved in the antiplatelet activity of magnesium in human platelets. British Journal of Haematology. 2002; 119 :1033-1041 - 143.
Rabini RA et al. Influence of low density lipoprotein from insulin- dependent diabetic patients on platelet functions. The Journal of Clinical Endocrinology and Metabolism. 1999; 84 (10):3770-3774 - 144.
Ferretti G et al. Glycated low density lipoproteins modify platelt properties : A compositional and functional study. The Journal of Clinical Endocrinology and Metabolism. 2002; 87 (5):2180-2184 - 145.
Pedren J, Hurt-camejo E, Wiklund O, Badimo L. Platelet function in patients with familial hypertriglyceridemia: Evidence that platelet reactivity is modulated by apolipoprotein E content of very–low-density lipoprotein particles. Metabolism. 2000; 49 (7):942-949 - 146.
Akai T, Naka K, Okuda K, Takemura T, Fujii S. Decreased sensistivity of platelets to prostacyclin in patients with diabetes mellitus. Hormone and Metabolic Research. 1983; 15 :523-526 - 147.
Lumadue JA, Lanzkron SM, Kennedy SD, Kuhl DT, Mt BS, Kickler TS. Cytokine-induced alteration of platelet and hemostatic function. American Journal of Clinical Pathology. 1996; 106 :795-798 - 148.
Kim SW, Lim YA. Effects of cytokines on platelet activation. Journal of Korean Society. 2002; 1 (13):1-9 - 149.
Maione F, Cicala C, Liverani E, Mascolo N, Perretti M, D’Acquisto F. IL-17A Increases ADP-induced platelet aggregation. Biochemical and Biophysical Research Communication. 2011; 408 (4):658-662. DOI: 10.1016/j.bbrc.2011.04.080. Epub 2011 Apr 22. PMID: 21530487; PMCID: PMC3182527 - 150.
Davizon-Castillo P et al. TNF-a–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging. Blood. 2019; 134 (9):727-740 - 151.
Guthikonda S et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. Journal of Thrombosis and Haemostasis. 2007; 5 :490-496 - 152.
Kakouros N, Rade JJ, Kourliouros A, Resar JR. Platelet function in patients with diabetes mellitus: From a theoretical to a practical perspective. International Journal of Endocrinology. 2007; 2011 :74219