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Keywords:

  • coagulation;
  • diabetes;
  • fibrinolysis;
  • hyperglycemia and thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

Summary.  Diabetes mellitus is characterized by a high risk of atherothrombotic events. What is more, venous thrombosis has also been found to occur more frequently in this patient group. This prothrombotic condition in diabetes is underpinned by laboratory findings of elevated coagulation factors and impaired fibrinolysis. Hyperglycemia plays an important role in the development of these hemostatic abnormalities, as is illustrated by the association with glycemic control and the improvement upon treatment of hyperglycemia. Interestingly, stress induced hyperglycemia, which is often transient, has also been associated with poor outcome in thrombotic disease. Similar laboratory findings suggest a common effect of acute vs. chronic hyperglycemia on the coagulation system. Many mechanisms have been proposed to explain this prothrombotic shift in hyperglycemia, such as a direct effect on gene transcription of coagulation factors caused by hyperglycemia-induced oxidative stress, loss of the endothelial glycocalyx layer, which harbours coagulation factors, and direct glycation of coagulation factors, altering their activity. In addition, both chronic and acute hyperglycemia are often accompanied by hyperinsulinemia, which has been shown to have prothrombotic effects as well. In conclusion, the laboratory evidence of the effects of both chronic and acute hyperglycemia suggests a prothrombotic shift. Additionally, hyperglycemia is associated with poor clinical outcome of thrombotic events. Whether intensive treatment of hyperglycemia can prevent hypercoagulability and improve clinical outcome remains to be investigated.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

Patients with diabetes are notorious for their risk of vascular events. Apart from the effects of diabetes and its prerequisite hyperglycemia on the development of atherosclerosis, this high risk may also be caused by the procoagulant state found in diabetes [1,2].

In recent years hyperglycemia per se, even without overt diabetes, has gained interest as a potential target to improve clinical outcomes in hospitalized patients with acute illness [3]. In this setting the effects of hyperglycemia on the coagulation system may be of greater importance than previously considered. Here we discuss the current evidence regarding potentially harmful changes in the coagulation system and subsequent risk of thrombotic disease, not only caused by diabetes but also by acute hyperglycemia.

Chronic hyperglycemia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

Type 2 diabetes

Type 2 diabetes (DM2) is defined by hyperglycemia, but often accompanied by hyperinsulinemia, dyslipidemia, hypertension and obesity. Its effects on the coagulation system can therefore not easily be attributed to either one of these entities [4], but the impact of glucose on coagulation in diabetes has been studied quite extensively.

Markers of fibrinolysis and coagulation  Both parameters of increased coagulability as well as a fibrinolytic impairment have been found in DM2, although there are many different markers in the circulation to measure these abnormalities. Platelet-dependent thrombin generation, for instance, was measured in patients with poor glycemic control, patients with good glycemic control and healthy controls. In vitro induced thrombin generation was found to be increased in platelet-rich plasma from diabetes patients compared with that from healthy controls and a significant elevation of thrombin levels was also demonstrated in plasma from poorly controlled DM2 when compared with well-controlled patients [5]. In a placebo-controlled trial using diet modification and troglitazone, a peroxisome proliferator-activated receptor (PPAR) γ agonist, a significant association was shown between improved glycemic control and blood thrombogenicity, as reflected by a reduction in ex-vivo thrombus formation in a Badimon perfusion chamber. Improved glycemic control was the only significant predictor of a decrease in blood thrombogenicity irrespective of treatment allocation [6]. The contribution of hypercoagulability in DM2 to the development of cardiovascular disease was also illustrated by the increased levels of prothrombin fragment 1 + 2 (F1 + 2) found to be associated with the presence of proven cardiovascular disease in DM2 patients as compared with patients without cardiovascular disease [7].

In a group of poorly controlled DM2 patients (HbA1c 10%) extraordinarily high concentrations of plasminogen activator inhibitor-1 (PAI-1), indicating hypofibrinolysis, were detected, leading the authors to conclude that profound hyperglycemia is accompanied by profound increases in PAI-1. Subsequent treatment of hyperglycemia by either glipizide or metformine as monotherapy comparably decreased PAI-1, which argues for an effect of glucose lowering rather than a specific medication effect [8]. This state of hypofibrinolysis is well established in DM2 and characterized by elevated levels of PAI-1 as well as prolonged clot lysis time [7,9–11]. The impairment in the fibrinolytic system in DM2 is of interest because these impairments are independent primary risk factors for myocardial infarction [12,13].

Hyperinsulinemia  To disentangle the effects of glucose and insulin in type 2 diabetes, Boden et al. studied the effects of acute correction of hyperglycemia with insulin followed by either 24 h of experimentally induced normo-insulinemic euglycemia, 24 h of euglycemic hyperinsulinemia or 24 h of combined hyperinsulinemia and hyperglycemia, in DM2 patients as well as healthy controls. They found baseline elevations of tissue factor procoagulant activity (TF-PCA), monocyte TF mRNA and plasma factor (F) VII, FVIII and thrombin-antithrombin (TAT) complexes in patients with DM2 compared with healthy controls. Normalizing glucose significantly decreased TF-PCA. Increasing insulin levels raised TF-PCA and elevating glucose and insulin levels together resulted in a much larger rise of TF-PCA, which was associated with increases in TAT and F1 + 2 [14]. Thus glucose and insulin both seem to play a role in the pathogenesis of the prothrombotic state in type 2 diabetes.

Effect of glucose lowering therapies  The effects of improved glycemic control on PAI-1 levels in DM2 have been demonstrated for different oral antidiabetic therapies, such as metformin alone [15] or in combination with pioglitazone or rosiglitazone [16] and glimepiride in combination with pioglitazone or rosiglitazone [17]. Metformin, which already had proven beneficial cardiovascular effects in the United Kingdom Prospective Diabetes Study trial, also reduced FVII and fibrinogen levels and shortened clot lysis time [18]. When metformin was added to a sulphonylurea derivative in poorly controlled elderly DM2 patients, the resulting substantial improvement in glycemic control was accompanied by beneficial changes in markers of platelet function (platelet factor 4 and beta-thromboglobulin), thrombin generation (fibrinopeptide A, F1 + 2, and D-dimer) and fibrinolysis (PAI-1 activity and antigen) [19].

In the Diabetes Prevention Programme, which studied the stages preceding diabetes (i.e. impaired glucose tolerance), lifestyle interventions, even more than metformin treatment, showed a modest, but significant, amelioration in fibrinogen levels [20]. Data on the effects of insulin therapy on coagulation and fibrinolysis markers in DM2 are scarce, and more conflicting than for the oral antidiabetic treatments. Although some authors report beneficial effects of insulin [21], others were unable to find improvements with insulin therapy [22,23].

Type 1 diabetes

Markers of fibrinolysis and coagulation  In type 1 diabetes (DM1) patients the specific contribution of hyperglycemia to the prothrombotic state is clearer as they lack the other risk factors that confound the relationship in DM2 patients. In a long-term follow-up study, a highly significant correlation was found between mean HbA1c in DM1 patients over the course of 18 years and impaired fibrinolysis as represented by elevated PAI-1 and decreased tissue plasminogen activator (t-PA) [24]. In a smaller setting, eight DM1 patients on continuous subcutaneous insulin infusion therapy had treatment withheld for the duration of 4 h, which caused a rise of PAI-1 and plasma TF. Although the authors conclude that early ketogenesis causes a prothrombotic change in DM1 patients, the effects of acute hyperglycemia in this setting cannot be excluded [25]. Platelet function tests, including aggregation and platelet adhesion tests, did not improve with intensive glycemic control in DM1. However, platelet function tests are notoriously variable and the authors may not have included a sufficient number of patients to overcome this disadvantage [26]. Finally, despite the abundant evidence of fibrinolytic impairment in diabetes, not all markers of fibrinolysis are abnormal. Thrombin-activatable fibrinolysis inhibitor (TAFI) for instance, showed no difference between patients with DM1 and healthy controls [27], a finding that was recently confirmed in DM2 patients [7].

Diabetes and thrombosis

DM2 and, maybe to a lesser extent, DM1 are known for a high risk of developing atherothrombotic events. This is at least partly explained by hyperglycemia, given the continuous relationship between the development of cardiovascular disease and glycemic control, also seen in DM2 [28]. Moreover, intensive blood glucose control in the early stages of the disease proved effective in lowering the long-term incidence of cardiovascular disease in both disease entities [29,30].

Recently it has become clear that not only atherothrombotic events are seen more often in patients with diabetes but that venous thromboembolism (VTE) may also be more frequent in this patient group. Movahed et al. [31] found an odds ratio (OR) of 1.27 (95% CI, 1.19–1.35) for the occurrence of pulmonary embolism in DM patients. A few years before, Tsai et al. [32] also found diabetes to be a risk factor for VTE with a hazard ratio (HR) of 1.46 (95% CI, 1.03–2.05), even after adjusting for BMI, a known predictor of VTE. However, in the earlier Nurses’ Health Study such an association could not be found [33], nor could Jones and Mitchell [34] find it in a smaller scale study in 1983. These apparently conflicting data on the effects of diabetes on the risk of venous thromboembolism have recently been subjected to meta-analysis, showing DM to be an independent risk factor for VTE with an OR of 1.41 (95% CI, 1.12–1.77) [35]. Although the effect of glucose lowering on VTE risk remains to be established, the over-representation of both venous thrombosis and atherothrombosis in diabetes is suggestive of a prothrombotic effect of its main component, hyperglycemia, in addition to its more established effects on atherosclerosis.

Acute hyperglycemia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

Apart from chronic hyperglycemia, it is important to consider the role of acute hyperglycemia. Frequently, this is transient hyperglycemia resulting from metabolic deterioration during (severe) illness [36]. Although this may result from pre-existing and undiagnosed diabetes, 30–40% of patients with ‘stress-hyperglycemia’ will revert to normoglycemia with follow-up [37,38]. Transient hyperglycemia will usually be accompanied by transient hyperinsulinemia.

Markers of fibrinolysis and coagulation

The effect of hyperglycemia and hyperinsulinemia on the coagulation system in subjects without diabetes has also been studied rather extensively. Already in 1988, Ceriello et al. [39] showed that experimentally increased glucose levels activated the coagulation system in non-diabetic subjects by increasing FVII clotting activity. Stegenga et al. [40] demonstrated in healthy volunteers that hyperglycemia (12 mmol L−1), irrespective of insulin levels, activates coagulation, marked by an increase in TAT complexes and soluble tissue factor (sTF). In contrast, hyperinsulinemia inhibited fibrinolysis by increasing PAI-1 levels. This was even more profound when systemic inflammation was induced [41]. In vitro studies with endothelial cells from pig aortas exposed to increasing glucose concentrations indicated that PAI-1 secretion and synthesis increased in parallel with glucose levels [42]. Activation of the tissue factor pathway following induction of hyperglycemia in healthy volunteers was also observed by Rao et al. [43]. In a subsequent study, 29 healthy volunteers were exposed to combinations of euglycemia or hyperglycemia with normoinsulinemia or hyperinsulinemia [44]. That study found that selective hyperglycemia and hyperinsulinemia activated the coagulation system, but the combination of both showed the largest increase in sTF procoagulant activity, TF expression on monocytes and TF mRNA in monocytes, TAT, FVII, FVIII and platelet activation, measured by platelet expression of soluble CD40 ligand. Finally, Nieuwdorp et al. [45] discovered that hyperglycemia in healthy volunteers concomitantly reduced the protective glycocalyx of the endothelium and the function of the endothelium itself and increased prothrombin fragment 1 + 2 and D-dimer levels.

Acute hyperglycemia and coagulation in the ICU

Two studies have attempted to elucidate the role of the coagulation system in relation to strict glycemic control. In the first Leuven trial, van den Berghe successfully implemented strict glycemic control in the ICU, showing a clear mortality benefit [3]. She published a sub-analysis, investigating the effect of strict glucose control on coagulation and fibrinolysis [46]. Although a variety of parameters was assessed, no differences were found between the intensively treated group and the control group. However, samples were obtained only at 5 and 10 days after admission and an acute effect within the first 5 days could have been missed. Savioli et al. [47] investigated the effect of strict glucose control on coagulation and fibrinolysis in patients with septic shock on admission and up to 28 days after admission. They found that strict glucose control reduced the impairment of the fibrinolytic system, as measured by PAI-1. However, strict glucose control in the ICU is now being heavily debated because of the recently published NICE-SUGAR trial, which showed increased mortality in the intervention group [48].

Acute hyperglycemia and thrombosis

Several thrombotic conditions have been described as being accompanied by acute hyperglycemia, most importantly myocardial infarction (MI), stroke and venous thromboembolism (VTE). What is more, clinical outcome may be influenced by hyperglycemia even in the absence of diabetes. During MI, for instance, hyperglycemia on admission predicts morbidity and mortality in patients without previously diagnosed diabetes [49–53]. Furthermore, elevated glucose levels on admission are directly related to the infarct size and reductions in coronary flow after stent implantation in non-diabetic patients [54,55].

This might be related to intravascular thrombotic events. Patients with acute coronary syndrome and admission glucose > 7.0 mmol L−1 had elevated values of thrombin-antithrombin complexes and platelet activation, measured by soluble CD40 ligand levels, as compared with patients admitted with glucose < 7.0 mmol L−1 [56]. Also the fibrin clot lysis time was impaired in hyperglycemic subjects. In another study activation of platelets, as measured by beta-thromboglobulin, was associated with hyperglycemia after MI, independent of pre-existing diabetes [57]. In a rabbit model, reducing hyperglycemia using acarbose resulted in decreased infarct size [58].

In stroke patients, admission hyperglycemia was related to the infarct size [59–61] and a strong predictor of post-stroke morbidity and mortality [62,63]. Ribo et al. [64] showed that acute but not chronic hyperglycemia during stroke was associated with lower tissue-type plasminogen activator recanalization rates, suggesting an impairment of the fibrinolytic system by hyperglycemia.

A few studies investigated the relation between venous thromboembolism (VTE) and hyperglycemia. Presurgery hyperglycemia (> 11.1 mmol L−1) was associated with an OR of 3.2 for pulmonary embolism after orthopedic surgery [65]. However, this might reflect undiagnosed and uncontrolled diabetes. Recently, we published data on glucose levels at presentation for suspected VTE and showed that higher glucose levels at presentation are associated with actually having VTE, in a clear dose-response fashion [66]. During hip surgery, glucose levels rise in patients without diabetes and this precedes a rise in FVIII, vWF and F1 + 2 [67], but further investigation is needed to confirm that this is a causal relationship.

Whether intensive treatment of acute hyperglycemia improves clinical outcome in these thrombotic conditions remains unknown. Although the DIGAMI trial showed a beneficial clinical effect of intensive blood glucose control by glucose-insulin-potassium (GIK) infusion in MI patients with diabetes, these results could not be reproduced in patients without diabetes due to a lack of contrast in blood glucose values between intervention and control groups [68–71]. The GIST-UK trial randomized stroke patients to GIK infusion or saline infusion to investigate the effect of glucose modulation by GIK. In this trial no clinical benefit was observed either, but the trial was underpowered, the glucose lowering effect of GIK was small and patients were treated for only 24 h [72]. Clinical trials investigating the effect of glucose control on VTE development are yet to be performed.

Possible mechanisms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

Many theories on how hyperglycemia leads to hypercoagulability have already been proposed and studied [73]. First, on a cellular level, hyperglycemia and also hyperinsulinemia increases the expression of PAI-1 on vascular smooth muscle cells in vitro, thereby increasing its concentration and activity. As a result, the activity of t-PA is reduced, thereby decreasing the fibrinolytic potential [74]. The authors suggested that a direct effect of glucose and insulin on gene transcription could be responsible. Indeed, hyperglycemia in the presence of insulin increases the activity of transcription factor nuclear factor kappa-B (NF-kB) in human hepatocyte cells and the gene transcription of PAI-1 in vitro, which suggests that PAI-1 transcription is increased via NF-kB [75]. Because this effect disappeared when an antioxidant was added to the medium, hyperglycemia-induced oxidative stress was hypothesized to be the major activator of NF-kB. In line, Khechai et al. [76] studied the effect of advanced glycation end products (AGE) on TF expression in human monocytes and concluded that AGE induced TF expression at the mRNA level, which could be diminished by adding antioxidants. The effect of AGEs on coagulation activation was also seen when human umbilical vein endothelial cells were exposed to AGEs [77] and AGEs dose-dependently increased procoagulant activity and TF levels. In vivo, withholding insulin in patients with DM1 increased TF and PAI-1 levels, which was accompanied by a rise in malondialdehyde (MDA) and protein carbonyl groups (PCG), both markers of oxidative stress [25].

Next, hyperglycemia directly influences the vulnerability of the vascular endothelium by affecting the glycocalyx, a protective layer of proteoglycans covering the vessel wall. This results in enhanced platelet-endothelial cell adhesion and release of coagulation factors harboured within the endothelial glycocalyx [78]. What is more, hyperglycemia is known to cause increased glycation of proteins and this may also occur in proteins involved in coagulation and fibrinolysis. Verkleij et al. [7] showed that glycated TAFI loses its fibrinolytic properties in vitro, although this could not be reproduced in vivo. Fibrin clots from patients with diabetes type 2 are denser as compared with controls and displayed an altered structure, resulting in longer clot lysis time [79]. In vivo glycemic control was directly correlated to the clot density from the patients. A likely explanation for this is the possible non-enzymatic glycation of fibrin [80]. It is conceivable that other coagulation proteins are also glycated, altering their activity.

It is not entirely clear how hyperinsulinemia adds to the prothrombotic effects of hyperglycemia. However, several studies have shown an independent effect of both hyperinsulinemia and hyperglycemia on thrombotic markers and an additive effect when simultaneously present, as in DM2 or acute hyperglycemia [14,44,74]. What is more, the insulin-resistant state that underlies these metabolic conditions has been described to extend to blood platelet activity as well. Whereas insulin has an inhibiting effect on platelet activation and aggregation in healthy individuals, there are several studies that show platelets of DM2 patients to be resistant to this inhibitory effect of insulin, making them more susceptible to activation [81–83].

Thus, multiple complex pathways are likely to be involved in the induction of hypercoagulability by hyperglycemia, and its effect is more profound in combination with hyperinsulinemia. Although we separately discussed the effects of chronic and acute hyperglycemia on coagulation and fibrinolysis, the current evidence gives no reason to assume that the underlying mechanisms differ. Nevertheless, the models used to study the effects of chronic and acute hyperglycemia are quite different and not easily comparable.

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References

In summary, laboratory evidence is suggestive of a contribution of both chronic and acute hyperglycemia to coagulation activation and hypofibrinolysis, resulting in a procoagulant state (Fig. 1). What is more, hyperglycemia is often accompanied by hyperinsulinemia and their combined effects may result in an even stronger hypercoagulable state.

image

Figure 1.  A simplified impression of the relationship between hyperglycemia, hyperinsulinemia and coagulation, leading to clinical outcome.

Download figure to PowerPoint

Evidence for the clinical consequences of these prothrombotic alterations during hyperglycemia is still circumstantial. However, intensive glycemic control in patients with diabetes reduced the incidence of thrombotic diseases such as myocardial infarction and stroke in the long run. Whether intensive glucose control during acute hyperglycemia, acute MI, stroke and VTE could prevent hypercoagulability and thereby improve outcome awaits further investigation in randomized controlled trials.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chronic hyperglycemia
  5. Acute hyperglycemia
  6. Possible mechanisms
  7. Summary
  8. Disclosure of Conflict of Interests
  9. References
  • 1
    Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 4454.
  • 2
    Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 15772.
  • 3
    van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 135967.
  • 4
    Nieuwdorp M, Stroes ES, Meijers JC, Buller H. Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol 2005; 5: 1559.
  • 5
    Aoki I, Shimoyama K, Aoki N, Homori M, Yanagisawa A, Nakahara K, Kawai Y, Kitamura SI, Ishikawa K. Platelet-dependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes. J Am Coll Cardiol 1996; 27: 5606.
  • 6
    Osende JI, Badimon JJ, Fuster V, Herson P, Rabito P, Vidhun R, Zaman A, Rodriguez OJ, Lev EI, Rauch U, Heflt G, Fallon JT, Crandall JP. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control. J Am Coll Cardiol 2001; 38: 130712.
  • 7
    Verkleij CJN, Gerdes VEA, de Bruijn R, Meijers JCM, Marx PF. The hemostatic system in patients with type 2 diabetes with and without cardiovascular disease. J Thromb Haemost 2009; 7(Suppl. 2): PP-WE-336.
  • 8
    Cefalu WT, Schneider DJ, Carlson HE, Migdal P, Gan LL, Izon MP, Kapoor A, Bell-Farrow A, Terry JG, Sobel BE. Effect of combination glipizide GITS/metformin on fibrinolytic and metabolic parameters in poorly controlled type 2 diabetic subjects. Diabetes Care 2002; 25: 21238.
  • 9
    Mansfield MW, Grant PJ. Fibrinolysis and diabetic retinopathy in NIDDM. Diabetes Care 1995; 18: 157781.
  • 10
    Opatrny K Jr, Zemanova P, Mares J, Vit L, Opatrna S, Sefrna F, Hejda V, Tomsu M, Eiselt J, Massry SG. Fibrinolysis defect in long-term hemodialysis patients with type 2 diabetes mellitus and its relation to metabolic disorders. Am J Nephrol 2002; 22: 42936.
  • 11
    Takada Y, Urano T, Watanabe I, Taminato A, Yoshimi T, Takada A. Changes in fibrinolytic parameters in male patients with type 2 (non-insulin-dependent) diabetes mellitus. Thromb Res 1993; 71: 40515.
  • 12
    Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Reduced plasma fibrinolytic capacity as a potential risk factor for a first myocardial infarction in young men. Br J Haematol 2009; 145: 1217.
  • 13
    Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 22417.
  • 14
    Boden G, Vaidyula VR, Homko C, Cheung P, Rao AK. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose. J Clin Endocrinol Metab 2007; 92: 43528.
  • 15
    Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, Andre P, Isnard F, Cohen JM, Grandmottet P, Vague P, Safar ME, Eschwege E. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care 1996; 19: 9206.
  • 16
    Derosa G, Dangelo A, Ragonesi PD, Ciccarelli L, Piccinni MN, Pricolo F, Salvadeo S, Montagna L, Gravina A, Ferrari I, Galli S, Paniga S, Cicero AF. Effects of rosiglitazone and pioglitazone combined with metformin on the prothrombotic state of patients with type 2 diabetes mellitus and metabolic syndrome. J Int Med Res 2006; 34: 54555.
  • 17
    Derosa G, Cicero AF, Gaddi A, Ragonesi PD, Piccinni MN, Fogari E, Salvadeo S, Ciccarelli L, Fogari R. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome. Diabetes Res Clin Pract 2005; 69: 513.
  • 18
    Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab 2003; 29: 6S4-52.
  • 19
    Gregorio F, Ambrosi F, Manfrini S, Velussi M, Carle F, Testa R, Merante D, Filipponi P. Poorly controlled elderly Type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabet Med 1999; 16: 101624.
  • 20
    Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, Marcovina S, Mather K, Orchard T, Ratner R, Barrett-Connor E. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 2005; 54: 156672.
  • 21
    Aso Y, Okumura KI, Yoshida N, Tayama K, Takemura Y, Inukai T. Enhancement of fibrinolysis in poorly controlled, hospitalized type 2 diabetic patients by short-term metabolic control: association with a decrease in plasminogen activator inhibitor 1. Exp Clin Endocrinol Diabetes 2004; 112: 17580.
  • 22
    Fonseca VA, Reynolds T, Hemphill D, Randolph C, Wall J, Valiquet TR, Graveline J, Fink LM. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998; 12: 1816.
  • 23
    Knobl P, Schernthaner G, Schnack C, Pietschmann P, Proidl S, Prager R, Vukovich T. Haemostatic abnormalities persist despite glycaemic improvement by insulin therapy in lean type 2 diabetic patients. Thromb Haemost 1994; 71: 6927.
  • 24
    Seljeflot I, Larsen JR, hl-Jorgensen K, Hanssen KF, Arnesen H. Fibrinolytic activity is highly influenced by long-term glycemic control in Type 1 diabetic patients. J Thromb Haemost 2006; 4: 6868.
  • 25
    Iorio A, Federici MO, Mourvaki E, Ferolla P, Piroddi M, Stabile A, Timi A, Celleno R, Benedetti MM. Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type 1 diabetic patients. Thromb Haemost 2007; 98: 63541.
  • 26
    Roshan B, Tofler GH, Weinrauch LA, Gleason RE, Keough JA, Lipinska I, Lee AT, DElia JA. Improved glycemic control and platelet function abnormalities in diabetic patients with microvascular disease. Metabolism 2000; 49: 8891.
  • 27
    Harmanci A, Kandemir N, Dagdelen S, Gonc N, Buyukasik Y, Alikasifoglu A, Kirazli S, Ozon A, Gurlek A. Thrombin-activatable fibrinolysis inhibitor activity and global fibrinolytic capacity in Type 1 diabetes: evidence for normal fibrinolytic state. J Diabetes Complications 2006; 20: 404.
  • 28
    Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med 2004; 141: 41320.
  • 29
    Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 157789.
  • 30
    Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 264353.
  • 31
    Movahed MR, Hashemzadeh M, Jamal MM. The prevalence of pulmonary embolism and pulmonary hypertension in patients with type II diabetes mellitus. Chest 2005; 128: 356871.
  • 32
    Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162: 11829.
  • 33
    Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 6425.
  • 34
    Jones EW, Mitchell JR. Venous thrombosis in diabetes mellitus. Diabetologia 1983; 25: 5025.
  • 35
    Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93102.
  • 36
    Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet 2009; 373: 1798807.
  • 37
    Greci LS, Kailasam M, Malkani S, Katz DL, Hulinsky I, Ahmadi R, Nawaz H. Utility of HbA(1c) levels for diabetes case finding in hospitalized patients with hyperglycemia. Diabetes Care 2003; 26: 10648.
  • 38
    Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Hata T, Nakama Y, Kijima Y, Kagawa E. Is admission hyperglycaemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance? Eur Heart J 2006; 27: 24139.
  • 39
    Ceriello A, Giugliano D, Quatraro A, Dello RP, Torella R. Blood glucose may condition factor VII levels in diabetic and normal subjects. Diabetologia 1988; 31: 88991.
  • 40
    Stegenga ME, van der Crabben SN, Blumer RM, Levi M, Meijers JC, Serlie MJ, Tanck MW, Sauerwein HP, van der Poll T. Hyperglycemia enhances coagulation and reduces neutrophil degranulation, whereas hyperinsulinemia inhibits fibrinolysis during human endotoxemia. Blood 2008; 112: 829.
  • 41
    Stegenga ME, van der Crabben SN, Dessing MC, Pater JM, van den Pangaart PS, de Vos AF, Tanck MW, Roos D, Sauerwein HP, van der Poll T. Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans. Diabet Med 2008; 25: 15764.
  • 42
    Nordt TK, Klassen KJ, Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb 1993; 13: 18228.
  • 43
    Rao AK, Chouhan V, Chen X, Sun L, Boden G. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 1999; 48: 115661.
  • 44
    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: 2028.
  • 45
    Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, Meijers JC, Holleman F, Hoekstra JB, Vink H, Kastelein JJ, Stroes ES. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 2006; 55: 4806.
  • 46
    Langouche L, Meersseman W, Vander Perre S, Milants I, Wouters PJ, Hermans G, Gjedsted J, Hansen TK, Arnout J, Wilmer A, Schetz M, Van den Berghe G. Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients. Crit Care Med 2008; 36: 147580.
  • 47
    Savioli M, Cugno M, Polli F, Taccone P, Bellani G, Spanu P, Pesenti A, Iapichino G, Gattinoni L. Tight glycemic control may favor fibrinolysis in patients with sepsis. Crit Care Med 2009; 37: 42431.
  • 48
    Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360: 128397.
  • 49
    Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000; 355: 7738.
  • 50
    Ishihara M, Kojima S, Sakamoto T, Asada Y, Tei C, Kimura K, Miyazaki S, Sonoda M, Tsuchihashi K, Yamagishi M, Ikeda Y, Shirai M, Hiraoka H, Inoue T, Saito F, Ogawa H. Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era. Am Heart J 2005; 150: 81420.
  • 51
    Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 21404.
  • 52
    Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek EP, Krumholz HM. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 2005; 111: 307886.
  • 53
    Kosiborod M, Inzucchi SE, Krumholz HM, Masoudi FA, Goyal A, Xiao L, Jones PG, Fiske S, Spertus JA. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch Intern Med 2009; 169: 43846.
  • 54
    Nakamura T, Ako J, Kadowaki T, Funayama H, Sugawara Y, Kubo N, Momomura S. Impact of acute hyperglycemia during primary stent implantation in patients with ST-elevation myocardial infarction. J Cardiol 2009; 53: 2727.
  • 55
    Timmer JR, van der Horst ICC, Ottervanger JP, Henriques JPS, Hoorntje JCA, de Boer MJ, Suryapranata H, Zijlstra F. Prognostic value of admission glucose in non-diabetic patients with myocardial infarction. Am Heart J 2004; 148: 399404.
  • 56
    Undas A, Wiek I, Stepien E, Zmudka K, Tracz W. Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care 2008; 31: 15905.
  • 57
    Oswald GA, Smith CC, Delamothe AP, Betteridge DJ, Yudkin JS. Raised concentrations of glucose and adrenaline and increased in vivo platelet activation after myocardial infarction. Br Heart J 1988; 59: 66371.
  • 58
    Minatoguchi SM, Zhang ZM, Bao NM, Kobayashi HM, Yasuda SM, Iwasa MM, Sumi SM, Kawamura IM, Yamada YM, Nishigaki KM, Takemura GM, Fujiwara TM, Fujiwara HM. Acarbose reduces myocardial infarct size by preventing postprandial hyperglycemia and hydroxyl radical production and opening mitochondrial KATP channels in rabbits. [article]. J Cardiovasc Pharmacol 2009; 54: 2530.
  • 59
    Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking CH. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis 2002; 13: 8994.
  • 60
    Fuentes B, Castillo J, San JB, Leira R, Serena J, Vivancos J, Davalos A, Nunez AG, Egido J, ez-Tejedor E. The prognostic value of capillary glucose levels in acute stroke: the GLycemia in Acute Stroke (GLIAS) study. Stroke 2009; 40: 5628.
  • 61
    Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, Tress BM, Davis SM. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol 2002; 52: 208.
  • 62
    Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick JP, Kwiatkowski TG, Fineberg SE. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002; 59: 66974.
  • 63
    Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care 2009; 32: 61722.
  • 64
    Ribo M, Molina C, Montaner J, Rubiera M, gado-Mederos R, Arenillas JF, Quintana M, varez-Sabin J. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke 2005; 36: 17059.
  • 65
    Mraovic B, Hipszer BR, Epstein RH, Pequignot EC, Parvizi J, Joseph JI. Preadmission hyperglycemia is an independent risk factor for in-hospital symptomatic pulmonary embolism after major orthopedic surgery. J Arthroplasty 2010; 25: 6470.
  • 66
    Hermanides J, Cohn DM, DeVries JH, Kamphuisen PW, Huijgen R, Meijers JC, Hoekstra JB, Buller HR. Venous thrombosis is associated with hyperglycemia at diagnosis: a case-control study. J Thromb Haemost 2009; 7: 9459.
  • 67
    Hermanides J, Huijgen R, Henny CP, Mohammad NH, Hoekstra JB, Levi MM, DeVries JH. Hip surgery sequentially induces stress hyperglycaemia and activates coagulation. Neth J Med 2009; 67: 2269.
  • 68
    Ceremuzynski L, Budaj A, Czepiel A, Burzykowski T, Achremczyk P, Smielak-Korombel W, Maciejewicz J, Dziubinska J, Nartowicz E, Kawka-Urbanek T, Piotrowski W, Hanzlik J, Cieslinski A, Kawecka-Jaszcz K, Gessek J, Wrabec K. Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther 1999; 13: 191200.
  • 69
    Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E, Ahmed R, Xie C, Kazmi K, Tai J, Orlandini A, Pogue J, Liu L. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA 2005; 293: 43746.
  • 70
    van der Horst I, Zijlstra F, van‘t Hof AW, Doggen CJ, de Boer MJ, Suryapranata H, Hoorntje JC, Dambrink JH, Gans RO, Bilo HJ. Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003; 42: 78491.
  • 71
    Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995; 26: 5765.
  • 72
    Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE, Cartlidge NE, Bamford JM, James OF, Alberti KG. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol 2007; 6: 397406.
  • 73
    Ceriello A. Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia 1993; 36: 111925.
  • 74
    Pandolfi A, Iacoviello L, Capani F, Vitacolonna E, Donati MB, Consoli A. Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. Diabetologia 1996; 39: 142531.
  • 75
    Iwasaki Y, Kambayashi M, Asai M, Yoshida M, Nigawara T, Hashimoto K. High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro. J Diabetes Complications 2007; 21: 5662.
  • 76
    Khechai F, Ollivier V, Bridey F, Amar M, Hakim J, de Prost D. Effect of advanced glycation end product-modified albumin on tissue factor expression by monocytes. Role of oxidant stress and protein tyrosine kinase activation. Arterioscler Thromb Vasc Biol 1997; 17: 288590.
  • 77
    Min C, Kang E, Yu SH, Shinn SH, Kim YS. Advanced glycation end products induce apoptosis and procoagulant activity in cultured human umbilical vein endothelial cells. Diabetes Res Clin Pract 1999; 46: 197202.
  • 78
    Vink H, Constantinescu AA, Spaan JA. Oxidized lipoproteins degrade the endothelial surface layer : implications for platelet-endothelial cell adhesion. Circulation 2000; 101: 15002.
  • 79
    Dunn EJ, Philippou H, Ariens RA, Grant PJ. Molecular mechanisms involved in the resistance of fibrin to clot lysis by plasmin in subjects with type 2 diabetes mellitus. Diabetologia 2006; 49: 107180.
  • 80
    Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation reduces the susceptibility of fibrin to degradation by plasmin. Diabetes 1983; 32: 6804.
  • 81
    Anfossi G, Mularoni EM, Burzacca S, Ponziani MC, Massucco P, Mattiello L, Cavalot F, Trovati M. Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care 1998; 21: 1216.
  • 82
    Trovati M, Mularoni EM, Burzacca S, Ponziani MC, Massucco P, Mattiello L, Piretto V, Cavalot F, Anfossi G. Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. Diabetes 1995; 44: 131822.
  • 83
    Westerbacka J, Yki-Jarvinen H, Turpeinen A, Rissanen A, Vehkavaara S, Syrjala M, Lassila R. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 16772.