Egszsgtudomnyi Kzlemnyek, 3. ktet, 2. szm (2013), pp. 113118.

HAEMOCOAGULATION DISORDERS IN METABOLIC SYNDROME

VIOLA VARGOV1VIOLA MECHROV2,3G. TEFKOV3

LUCIA DIMUNOV3M. PYTLIAK3DENISA MACEKOV4
BERTALAN FODOR5OLIVR RCZ4,5
Introduction

Metabolic syndrome (MS) despite all controversies concerning its definition and
pathogenesis [14] is a serious problem of public health. Its prevalence in economically
developed countries is increasing (affecting around one third of the adult population) and
MS is associated with increased risk of cardiovascular morbidity and mortality [57].
Although not mentioned in any of the current definitions, it is clear that insulin
resistance (IR) alone and MS as a complex pathological condition is unambiguously
associated with hypercoagulation and trombophilic state. This is a result of endothel
dysfunction, increased activity of coagulation factors, hyperactivity of platelets and
decreased fibrinolysis [8].

Endothel dysfunction in MS

In physiological conditions endothel cells possess remarkable antithrombotic properties

dependent on many different factors as the negative charge of the glycocalyx, the secretion
of antithrombin III (ATIII) and of tissue activator of plasminogen (tPA) as well as a balance
between the production of prostacycline I2 (PGI2) and thromboxane A2 (TXA2) synthesis
and also a low level of von Willebrand factor (vWF) [9, 10].
In stress condtions endothel cells secrete more procoagulant and platelet activation
substances as the inhibtor of plasminogen activator, interleukin 1 (IL1), platelet activation
factor (PAF) tumor necrotizing factor alpha (TNF) and many others [11, 12].
Endothel dysfunction arising as a consequence of long-term mechanical and chemical
injury is characterized by inflammation, oxidative stress and by imbalance between
vasodilating and vasoconstricting equilibrium. These conditions can act both as etiological
factors and as consequences of clinically manifest cardiovascular disease.
MS is connected with oxidative stress [13] and the reactive forms of oxygen in addition
to other deleterious effects promote the formation and release of endothel-derived
microparticles (EMP). They activate both white blood cells and platelets and also induce
the release of tissue factor (TF) [14].

1
3rd Internal Department, Medical Faculty, Safarik University and Louis Pasteur University Hospital,
Koice, Slovakia
2 st
1 Internal Department, Medical Faculty, Safarik University and Louis Pasteur University Hospital,
Koice, Slovakia
3
Institute of Healthcare, Medical Faculty, Safarik University, Koice, Slovakia
4
Institute of Pathological Physiology, Medical Faculty, Safarik University, Koice, Slovakia
5
Institute of Nanobiotechnology and Regenerative Medicine, Faculty of Healthcare, Miskolc
University, Hungary
114 VargovMechrovtefkovDimunovPytliakMacekovFodorRcz

Another source of TF in MS is its release induced by oxidized LDL particles, another

substance formed in oxidative stress. A third possibility is TF release through C-reactive
protein, an acute phase protein. TF as the main initiator of the coagulation cascade is
causally connected to atherogenesis and thrombosis in MS, IR and also in diabetic patients
with micro- and macrovascular complications [15].

Hypercoagulation in MS

In addition to increased activation of TF patients with MS have increased concentration

of factors VII, VIII, IX, X, XIII, fibrinogen and vWF [1618]. The increased concentration
of fibrinogen is probably a caused by the direct effect of interleukin 6 (IL6) on its synthesis
in the liver. Hyperfibrinogenaemia is a well-known independent and strong risk factor of
coronary artery disease and ischaemic stroke [16]. According to [17] the increase of factors
VII, IX and X is associated with plasma triacylglycerol (TAG) concetration and the
increased activity of factor VII is associated with postprandial hyperlipidemia in general
[18]. The surface of triacylglycerol rich lipoproteins has marked procoagulant properties
wich can contribute to their activation.
In patients with manifest type 2 diabetes mellitus (T2DM) the increased level of fVII
correlated with the degree of their insulin resistance (measured as insulin concentration)
and with plasma cholesterol. Similar increase of fVII was detected also in first-grade
relatives of patients with T2DM [19]. Another factor associated with insulin resistance was
the increased concentration of prothrombin fragments F1 and F2, These fragments are
increased also in hypertension and are considered as an independent risk factor of acute
coronary events [18, 19]. The coagulation system is strictly controlled by anticoagulants as
ATIII, protein S and C. According to [20] the concentration of proteins S and C are
decreased in insulin resistance and the decrease is associated with elevated plasminogen
activator inhibitor 1 (PAI-1) concentration.

Increased activity of platelets in MS

The increased adhesivity and aggregability of platelets in patients with MS (as well as
those with IR and impaired glucose tolerance) is a complex process. The causes of this
complex condition are listed in Table 1. Endothel dysfunction and changes in the
coagulation system described above are also connected with platelet dysfunction in MS
[21]. The key factor of platelet hyperactivity is probably the altered biophysical state of
their plasma membrane which can lead to calcium release and increased synthesis and
secretion of thromboxane A2 (TXA2). This was demonstrated in patients with T2DM. On
the other side increased TXA2 is also associated with increased triacylglycerol, VLDL and
chylomicron remnant concentration as well and all these conditions are present in MS [22].
The lectin-like receptors LOX-1 present on the surface of platelets bind oxidized LDL
particles and subsequently activate them through proteinkinase p38. This probably the
explanation of the association between oxidative stress and thrombophilic state in MS
[23, 24].
Last but not least insulin itself can play role in platelet function. Insulin application in
healthy subjects decreases their aggregability but this is not case in obese subjects with
IR [25].
 Haemocoagulation Disorders in Metabolic Syndrome 115

Table 1
Possible causes of thrombocyte hypersensitivity and hyperactivity in MS
Abundance or overexpression of glycoprotein receptors for adhesion molecules
Increased binding of fibrinogen to platelets
Decreased fluidity of thrombocyte plasma membrane
Altered metabolism of thrombocytes
Changes in intrathrombocyte signal pathways

Decreased fibrinolysis in MS

In MS thrombosis is a menacing situation but one should keep in mind that common
gene polymorphisms are influencing the coagulation-fibrinolysis system and can contribute
to clinical manifestation of both venous and arterial thrombosis in patients wit MS and IR.
Patients with MS have an unfavorable ratio between tissue plasminogen activator (t-PA)
and its inhibitor PAI-1 [26, 27]. PAI-1 is elevated already in patients with isolated
components of MS as in abdominal obesity, hypertension, hypertriacylglycerolaemia and
nonalcoholic fatty liver disease (NAFLD) [28]. NAFLD itself is associated with
hypercoagulation and inflammation independently on other cardiovascular risk factors
[29]. In IR and MS also the concentration of tPA/PAI-1complex is also increased [26]. The
source of increased PAI-1 synthesis in MS is not fully clear. In addition to liver and
visceral fat in metabolic disturbance associated with MS also other tissues can produce
PAI-I [30]. Probably also the inflammatory cytokines (TNF, IL6) overexpressed in MS can
stimulate PAI-1 synthesis. PAI-1 through its influence on vitronectin is also associated with
vessel wall remodelation and contributes to the pathogenesis of angiopathy already before
manifestation of diabetes. Another inhibitor of fibrinolysis balthough with weaker effect as
PAI-1 of produced solely in liver is the thrombin-activable fibrinolysis inhibitor (TAFI) Its
concentration is increased in T2DM but its role in MS is also probable
Weight loss, physical activity and some pharmacological approaches (Table 2) decrease
PAI-1 concentration and the risk of thrombotic and cardiovascular events in MS patients
[3136].
Table 2
Favourable effects of some drugs on PAI-1 concentration in MS and T2DM
Insulin sensitisers as metformin and rosiglitasone
ACE inhibitors (also attenuating endothel dysfuction and platelet hyperactivity)*
Blockers of angiotensin II receptors.
Second generation imidazole receptor inhibitors.
*In contrast to blockers of angiotensin II (sartans).

Abbreviations

ATIII Antithrombin III

EMP Endothel-derived microparticles
fVII Proconvertin
fVIII Antihaemophilic globulin
116 VargovMechrovtefkovDimunovPytliakMacekovFodorRcz

fIX Christmas factor

fX Stuart factor
fXIII Fibrin stabilising factor
IL1, IL6 Interleukin 1, 6
IR Insulin resistance
LDL, VLDL Low density, very low density lipoprotein
LOX1 Lectin-like oxidized lipoprotein receptor 1
MS Metabolic syndrome
NAFLD Non-alcholic fatty liver disease
PAF Platelet activation factor
PAI-1 Plasminogen activator inhibitor 1
PGI2 Prostacyclin 2
TAFI Thrombin-activable fibrinolysis inhibitor
TAG Triacylglycerol
TF Thromboplastin, (fIII and CD142)
TNF Tumor necrosis factor alpha
tPA Tissue plasminogen activator
TXA2 Thromboxane A2
T2DM Type 2 diabetes mellitus
vWf Von Willebrand factor

Acknowledgement

This research was partially carried out with the contribution of the Workgroup for Health Sciences,
Center of Excellence of Applied Materials Science and Nano-Technology at the University of
Miskolc.

References

[1] Yudkin, J. S.: Insulin resistance and the metabolic syndrome or the pitfalls of epidemiology.
Diabetologia, 2007; 50: 15761586.
[2] Rybka, J.: Metabolick syndrom realita, nikoli fikce. In: Kvapil M (Ed.) Diabetologie 2011,
Triton Praha 2011, 1931.
[3] Borch-Johnsen, K.Wareham, N.: The rise and fall of the metabolic syndrome. Diabetologia,
2010; 53: 597599.
[4] Halmos, T.: A 2-es tpus diabetes etiopatogenzise. In: Diabetes mellitus. Elmlet s klinikum.
Halmos T., Jermendy G. (Eds.) Medicina, Budapest, 2002, 237255.
[5] Kimkov, T. et al.: Metabolick syndrm a vysokokolsk mlde. Med Monitor, 2012: 2226.
[6] Babk, M.Meriakov, M.: Prevalencia diabetes mellitus 2. typ a jeho komplikci na
internej klinike I. Zdravotnctvo a socilna prca, 2006; 1: 712.
[7] Galajda, P.: Metabolick syndrm. In: Mok, M., Martinka, E., Galajda, P. (Eds) Diabetes
mellitus a vybran metabolick ochorenia. P+M Turany a Martin 2008, 685698.
[8] Juhan-Vague, I.Morange, P. E.Alessi, M. C.: The insulin resistance syndrome: implications
for thrombosis and cardiovascular disease. Pathophysiol Haemost Thromb, 2002; 32: 269273.
[9] Vaughan, D. E.: Endothelial function, fibrinolysis and angiotensin-converting enzyme
inhibition. Clin Cardiol 1997; 20 (suppl. II): 3437.
[10] Dellipizzi, A.Pucci, M. L.Mosny, A. I. et al.: Contribution of constrictor prostanoids to the
calcium dependent basal tone in the aorta from rats with aortic coarctation-induced
hypertension. Relationship to nitric oxide. J Pharm Exp Ther, 1997; 238: 7581.
 Haemocoagulation Disorders in Metabolic Syndrome 117

[11] Ridker, P. M.Gaboury, C. L.Conlin, P. R. et al.: Stimulation of plasminogen activator

inhibitor in vivo by infusion of angiotensin II; Evidence of potential interaction between the
renin-angiotensin system and fibrinolytic function. Ciculation 1993; 87: 19691967.
[12] Thompson, S. G.Kienast, J.Pyke, S. D. M. et al.: Hemostatic factors and the risk of
myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med, 1995;
332: 635641.
[13] Lastra, G.Manrique, C.: The expanding role of oxidative stress RAAS, beta cell dysfunction in
the cardiometabolic syndrome and type 2 diabetes mellitus. Antiox Redox Sign, 2007; 9:
943954.
[14] Aizawa, K.Shoemaker, J. K.Overend, T. J. et al.: Metabolic syndrome, endothelial function
and lifestyle modification. Diabetes and Vascular Disease Research 2009; 6: 181189.
[15] Radomski, M. W.Palmer, R. M.Moncada, S.: The anti-aggregating properties of vascular
endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol, 1987; 92:
639646.
[16] Nieuwdorp, M.Stroes, E. S.Meijers, J. C. et al.: Hypercoagulability in the metabolic
syndrome. Curr Opin Pharmacol, 2005; 5: 155159.
[17] Sakkinen, P. A.Wahl, P.Cushman, M. et al.: Clustering of procoagulation, inflammation, and
fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol,
2000; 152: 897907.
[18] Agewall, S.Wikstrand, J.Fagerberg, B.: Prothrombin fragment 1+2 is a risk factor for
myocardial infarction in treated hypertensive men. J Hypertens, 1998; 16: 537554.
[19] Galajda, P.Mok, M.: Poruchy hemostzy pri diabetes mellitus. Prokonzult Martin 2001, 255.
[20] Agewall, S.Bokemark, L.Wikstrand, J. et al.: Insulin sensitivity and hemostatic factors in
clinically healthy 58-year-old men. Thromb Haemost, 2000; 84: 571575.
[21] Alessi, M. C.Juhan-Vague, I.: Metabolic syndrome, haemostasis and thrombosis. Thromb
Haemostas, 2008; 99: 9951000.
[22] Olufadi, R.Byrne, C. D.: Effects of VLDL and remnant particles on platelets. Pathophysiol
Haemostas Thromb, 2006; 35: 281291.
[23] Sakurai, K.Sawamura, T.: Stress and vascular responses: endothelial dysfunction via lectin-
like oxidized low-density lipoprotein receptor-1: close relationships with oxidative stress.
J Pharmacol Sci, 2003; 91: 182186.
[24] Dandona, P.Ghanim, H.Mohanty, P. et al.: The metabolic syndrome: linking oxidative stress
and inflammation to obesity, type 2 diabetes, and the syndrome. Drug Dev Res, 2006; 67:
619626.
[25] Anfossi, G.Russo, I.Trovati, M.: Platelet dysfunction in central obesity. Nutr Metab
Cardiovasc Dis, 2009; 19: 440419.
[26] Meigs, J. B.Mittleman, M. A.Nathan, D. et al.: Hyperinsulinemia, hyperglycemia, and
impaired hemostasis. The Framingham Offspring Study. JAMA, 2000; 283: 221228
[27] Aso, Y.Matsumoto, S.Fujiwara, Y. et al.: Impaired fibrinolytic compensation for
hypercoagulability n obese patients with type 2 diabetes: Association with increased
plasminogen activator inhibitor-1. Metab Clin Exp, 2002; 51: 471476.
[28] Remkov, A.: Protrombotick stav ako sas metabolickho syndrmu. Vnit Lk, 2005; 51:
11201125.
[29] Targher, G.Bertolini, L.Scala, L. et al.: Non-alcoholic hepatic steatosis and its relation to
increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men.
Role of visceral adipose tissue. Diabet Med, 2005; 22: 13541358.
[30] Skurk, T.Hauner, H.: Obesity and impaired fibrinolysis: role of adipose production of
plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord, 2004; 28: 13571364.
[31] Mal, J.Mal, H.Pecka, M. a spol.: Zmny hemostzy u obznch pi redukci hmotnosti. Vnit
Lk, 2001, 47: 203209.
118 VargovMechrovtefkovDimunovPytliakMacekovFodorRcz

[32] Hadigan, C.Meigs, J. B.Rabe, J.DAgostino R. B. et al.: Increased PAI-1 and tPA antigen
levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and
insulin resistance. J Clin Endocrinol Metab, 2001; 86: 939943.
[33] Ferrari, R.Arbustini, E.Blann, A. et al.: PERTINENT PERindopril-Thrombosis, Inflam-
matio N, ENDothelial dysfunction and Neurohormonal activation Trial: a substudy of the
EUROPA study. Cardiovasc Drugs Ther, 2003; 17: 8391.
[34] Brown, N. J.Agirbasli, M.Vaughan, D. E.: Comparative effect of angiotensin-converting
enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance
in humans. Hypertension, 1999; 34: 285290.
[35] Remkov, A.Kratochvov, H.: Effect of the new centrally acting antihypertensive agent
rilmenidine on endothelial and platelet function in essential hypertension. J Hum Hypertens,
2002; 16: 549555.
[36] Krespi, P. G.Makris, T. K.Hatzizacharias, A. N. et al.: Moxonidine effect on micro-
albuminuria, thrombomodulin, and plasminogen activator inhibitor-1 levels in patients with
essential hypertension. Cardiovasc Drugs Ther, 1998; 12: 463467.
115 Haemocoagulation Disorders in Metabolic Syndrome

Kiadja a Miskolci Egyetem Tudomnyszervezsi s Nemzetkzi Osztlya

A kiadsrt felels: Prof. Dr. Kkesi Tams rektorhelyettes
Mszaki szerkeszt: Balatoni Enik
A kziratot gondozta a Miskolci Egyetemi Kiad
A kiad felels vezetje: Burmeister Erzsbet
Kszlt a Miskolci Egyetem Sokszorost zemben, Miskolcon
A sokszorostsrt felels: Psztor Erzsbet
Pldnyszm:
TNO 2014 80 ME ISSN 2063-2142