Aim: Insulin resistance has effects on the coagulation system, which is important in the acute phase of infarct. We examined the relationships between insulin resistance, hemostatic markers and stroke severity in acute ischemic stroke patients. Methods: Protein C (PC), protein S (PS), fibrinogen, von Willebrand factor and antithrombin III (AT III) were studied in 75 acute ischemic stroke patients with and without insulin resistance. Results: The PC and PS levels of insulin-resistant patients were significantly lower than those of non-insulin-resistant patients (PC: 87 ± 19.23 vs. 97.89 ± 13.3%, p = 0.007; PS: 84.75 ± 15.72 vs. 93.21 ± 15.02%, p = 0.02), and both of the anticoagulants were correlated with the homeostasis model assessment (HOMA; r = –0.339, p = 0.003 and r = –0.481, p = 0.000, respectively). Additionally, the NIH Stroke Scale (NIHSS) score correlated negatively with PS (r = –0.329, p = 0.004) and AT III levels (r = –0.235, p = 0.04). The parameters with positive correlations with NIHSS were fibrinogen (r = 0.270, p = 0.019), fasting glucose (r = 0.358, p = 0.008) and HOMA (r = 0.286, p = 0.013). Conclusions: The significant associations between insulin resistance and hemostatic markers may be relevant to stroke severity by causing a procoagulant tendency in acute ischemic stroke.

Keywords:
Insulin resistance, Hypercoagulability, Natural anticoagulants, Stroke severity
1.
Moller DE, Flier JS: Insulin resistance – mechanisms, syndromes, and implications. N Engl J Med 1991;325:938–948.
2.
Robinson LE, van Soeren MH: Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control. AACN Clin Issues 2004;15:45–62.
3.
Melamed E: Reactive hyperglycemia in patients with acute stroke. J Neurol Sci 1976;29:267–275.
4.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426–2432.
5.
Yudkin JS: Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? Diabetes Care 1999;22(Suppl 3):C25–C30.
6.
Kohler HP: Insulin resistance syndrome: interaction with coagulation and fibrinolysis. Swiss Med Wkly 2002;132:241–252.
7.
Mertens I, Gaal FV: Obesity, haemostasis and the fibrinolytic system. Obes Rev 2002;3:85–101.
8.
Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D’Agostino RB, Wilson PW: Hyperinsulinemia, hyperglycemia, and impaired hemostasis. JAMA 2000;283:221–228.
9.
Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP: Clustering of procoagulation, inflammation and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000;152:897–907.
10.
Marques-Vidal P, Mazoyer E, Bongard V, Gourdy P, Ruidavets JB, Drouet L, Ferrières J: Prevalence of insulin resistance syndrome in Southwestern France and its relationship with inflammatory and hemostatic markers. Diabetes Care 2003;25:1371–1377.
11.
Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC: Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002;105:576–582.
12.
Imperatore G, Riccardi G, Iovine C, Rivellese AA, Vaccaro O: Plasma fibrinogen: a new factor of the metabolic syndrome. A population based study. Diabetes Care 1998;21:649–654.
13.
Haapaniemi E, Soinne L, Syrjälä M, Kaste M, Tatlisumak T: Serial changes in fibrinolysis and coagulation activation markers in acute and convalescent phase of ischemic stroke. Acta Neurol Scand 2004;110:242–247.
14.
Anzola GP, Magoni M, Ascari E, Maffi V: Early prognostic factors in ischemic stroke. The role of protein C and protein S. Stroke 1993;24:1496–1500.
15.
Berge E, Friis P, Sandset PM: Hemostatic activation in acute ischemic stroke. Thromb Res 2001;101:13–21.
16.
Rewers M, Zaccaro D, D’Agostino R, Haffner S, Saad MF, Selby JV, Bergman R, Savage P; Insulin Resistance Atherosclerosis Study Investigators: Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study. Diabetes Care 2004;27:781–787.
17.
Kip KE, Marroquin OC, Kelley DE, Johnson BD, Kelsey SF, Shaw LJ, Rogers WJ, Reis SE: Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women’s Ischemia Syndrome Evaluation (WISE) Study. Circulation 2004;109:706–713.
18.
Orlov SV, Domashenko MA, Kostyreva MV, Shabalina AA, Ionova VG, Tanashian MM: Hemorheology and hemostasis in patients suffering from ischemic cerebral stroke and metabolic syndrome. Klin Med (Mosk) 2007;85:40–44.
19.
Landi G, D’Angelo A, Boccardi E, Candelise L, Mannucci PM, Nobile Orazio E, Morabito A: Hypercoagulability in acute stroke: prognostic significance. Neurology 1987;37:1667–1671.
20.
Takano K, Yamaguchi T, Okada Y, Kagehiro U, Kisiel W, Kato H: Hypercoagulability in acute ischemic stroke: analysis of the extrinsic coagulation reactions in plasma by a highly sensitive automated method. Thromb Res 1990;58:481–491.
21.
Takano K, Yamaguchi T, Kato H, Omae T: Activation of coagulation in acute cardioembolic stroke. Stroke 1991;22:12–16.
22.
Takano K, Yamaguchi T, Uchida K: Markers of hypercoaguble state following acute ischemic stroke. Stroke 1992;23:194–198.
23.
Yamazaki M, Uchiyama S, Maruyama S: Alterations of haemostatic markers in various subtypes and phases of stroke. Blood Coagul Fibrinolysis 1993;4:707–712.
24.
Mayer SA, Sacco RL, Hurle-Jensen A, Shi T, Mohr JP: Free protein S deficiency in acute ischemic stroke. Stroke 1993;24:224–227.
25.
Akyol A, Ozkul A, Yenisey C, Kiylioglu N: The relationship between protein C, protein S and cytokines in acute ischemic stroke. Neuroimmunomodulation 2006;13:187–193.
26.
Haapaniemi E, Tatlisumak T, Soinne L, Syrjälä M, Kaste M: Natural anticoagulants (antithrombin III, protein C, and protein S) in patients with mild to moderate ischemic stroke. Acta Neurol Scand 2002;105:107–114.
27.
Rallidis LS, Vikelis M, Panagiotakos DB, Liakos GK, Krania E, Kremastinos DT: Usefulness of inflammatory and haemostatic markers to predict short-term risk for death in middle-aged ischaemic stroke patients. Acta Neurol Scand 2008;117:415–420.
28.
Turaj W, Slowik A, Dziedzic T, Pulyk R, Adamski M, Strojny J, Szczudlik A: Increased plasma fibrinogen predicts one-year mortality in patients with acute ischemic stroke. J Neurol Sci 2006;246:13–19.
29.
Di Napoli M, Papa F, Bocola V: Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 2001;32:133–138.
30.
Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng K, Futrell N, Hsu CY, Levy DE: Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 2000;283:2395–2403.
31.
Hennerici MG, Kay R, Bogousslavsky J, Lenzi GL, Verstraete M, Orgogozo JM; ESTAT investigators: Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet 2006;368:1871–1878.
32.
Oláh L, Csépány T, Bereczky Z, Kerényi A, Misz M, Kappelmayer J, Csiba L: Activity of natural coagulation inhibitor proteins in the acute phase of ischaemic stroke. Ideggyogy Sz 2005;58:33–39.
33.
Bernard TJ, Fenton LZ, Apkon SD, Boada R, Wilkening GN, Wilkinson CC, Soep JB, Miyamoto SD, Tripputi M, Armstrong-Wells J, Benke TA, Manco-Johnson MJ, Goldenberg NA: Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke. J Pediatr 2010;156:651–656.
34.
Vila N, Reverter JC, Yague J, Charmorro A: Interaction between IL-6 and the natural anticoagulant system in acute stroke. J Interferon Cytokine Res 2000;20:325–329.
35.
Sato M, Suzuki A, Nagata K, Uchiyama S: Increased von Willebrand factor in acute stroke patients with atrial fibrillation. J Stroke Cerebrovasc Dis 2006;15:1–7.
36.
Melamed E: Reactive hyperglycemia in patients with acute stroke. J Neurol Sci 1976;29:267–275.
37.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426–2432.
38.
Garg R, Chaudhuri A, Munschauer F, Dandona P: Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke 2006;37:267–273.
39.
Chmielewska B, Hasiec T, Belniak-Legieć E, Stelmasiak Z: Usefulness of current and retrospective markers of glycemia for early prognostication of ischemic stroke in diabetics and non-diabetics. Ann Univ Mariae Curie Sklodowska Med 1999;54:261–267.
40.
Murros K, Fogelholm R, Kettunen S, Vuorela AL, Valve J: Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction. J Neurol Sci 1992;111:59–64.
41.
Christensen H, Boysen G: Blood glucose increases early after stroke onset: a study on serial measurements of blood glucose in acute stroke. Eur J Neurol 2002;9:297–301.
42.
Gray CS, Hildreth AJ, Alberti GK, O’Connell JE: Poststroke hyperglycemia: natural history and immediate management. Stroke 2004;35:122–126.
43.
Allport L, Baird T, Butcher K, Macgregor L, Prosser J, Colman P, Davis S: Frequency and temporal profile of poststroke hyperglycemia using continuous glucose monitoring. Diabetes Care 2006;29:1839–1844.
44.
Agewall S, Bokemark L, Wikstrand J, Lindahl A, Fagerberg B: Insulin sensitivity and hemostatic factors in clinically healthy 58-year-old men. Thromb Haemost 2000;84:571–575.
45.
De Pergola G, De Mitrio V, Sciaraffia M, Pannacciulli N, Minenna A, Giorgino F, Petronelli M, Laudadio E, Giorgino R: Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism 1997;46:1287–1293.
46.
De Pergola G, De Mitrio V, Giorgino F, Sciaraffia M, Minenna A, Di Bari L, Pannacciulli N, Giorgino R: Increase in both pro-thrombotic and anti-thrombotic factors in obese premenopausal women: relationship with body fat distribution. Int J Obes Relat Metab Disord 1997;21:527–535.
47.
Agewall S: Insulin sensitivity and haemostatic factors in men at high and low cardiovascular risk. The Risk Factor Intervention Study Group. J Intern Med 1999;246:489–495.
48.
Schneider DJ: Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance. Coron Artery Dis 2005;16:473–476.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.