Enhanced platelet activation by prolactin in patients with ischemic stroke

Henri Wallaschofski; Tobias Lohmann; Eva Hild; Anna Kobsar; Annelie Siegemund; E. Spilcke-Liss; Betina Hentschel; Christian Stumpf; Werner G. Daniel; Christian D. Garlichs; Martin Eigenthaler

doi:10.1160/TH05-09-0634

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(01): 38-44
DOI: 10.1160/TH05-09-0634

Platelets and Blood Cells

Schattauer GmbH

Enhanced platelet activation by prolactin in patients with ischemic stroke

Henri Wallaschofski

¹Department of Gastroenterology, Endocrinology and Nutrition, University of Greifswald

,

Tobias Lohmann

²City Hospital Dresden-Neustadt

,

Eva Hild

³Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg

,

Anna Kobsar

³Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg

,

Annelie Siegemund

⁴Laborgemeinschaft Reisig Ackermann Leipzig

,

E. Spilcke-Liss

¹Department of Gastroenterology, Endocrinology and Nutrition, University of Greifswald

,

Betina Hentschel

⁵Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

,

Christian Stumpf

⁶Department of Internal Medicine II, University of Erlangen, Germany

,

Werner G. Daniel

⁶Department of Internal Medicine II, University of Erlangen, Germany

,

Christian D. Garlichs

⁶Department of Internal Medicine II, University of Erlangen, Germany

,

Martin Eigenthaler

³Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg

› Author Affiliations

Abstract

Summary

Prolactin and leptin are newly recognised platelet co-stimulators due to potentiation of ADP-induced platelet aggregation. Elevated leptin levels have recently been found to be a risk factor for ischemic stroke in both men and women, and especially in combination with increased blood pressure for hemorrhagic stroke in men. Until now an association between hyperprolactinemia and ischemic stroke has not been investigated systematically.We determined plasma prolactin and leptin levels as well as platelet P-selectin expression in 36 patients with ischemic stroke or transient ischemic attack and detecteda significant correlation between increased prolactin values and enhanced ADP stimulated P-selectin expression on platelets. In contrast, no correlation of leptin values with platelet P-selectin expression was found. Next we determined plasma prolactin and leptin as well as acquired and congenital risk factors of thrombophilia in patients with first-ever non-hemorrhagic stroke with or without atrial fibrillation. Excluding patients with such preexisting risk factors,21 patients with and 59 patients without atrial fibrillation were identified. Patients without atrial fibrillation revealed significantly higher plasma prolactin levels than patients with atrial fibrillation. Furthermore, the influence of aspirin or clopidogrel on prolactin stimulated P-selectin expression in vitro was tested, showing that aspirin was without effect,whereas clopidogrel significantly inhibited platelet P-selectin expression. In conclusion, hyperprolactinemia might be a novel risk factor for stroke mediating its thrombogenic effect through enhanced platelet reactivity, and this might correspond to a higher efficacy of antiplatelet combination therapy with clopidogrel compared to aspirin therapy alone.

Keywords

Platelets - CD62p - stroke - prolactin - leptin

Full Text

References

References
1 Ross R. Atherosclerosis– an inflammatory disease. N Engl J Med 1999; 340: 115-26.
2 Fisher M, Levine P, Fullerto A. et al. Marker proteins of platelet activation in patients with cerebrovascular disease. Arch Neurol 1982; 39: 692-5.
3 Fisher M, Francis R. Altered coagulation in cerebral ischemia: platelet, thrombin, and plasmin activity. Arch Neurol 1990; 47: 1075-9.
4 Joseph R, D’Andrea G, Oster S. et al. Whole blood platelet function in acute ischemic stroke: importance of dense body secretion and effects of antithrombotic agents. Stroke 1989; 20: 38-44.
5 Toghi H, Suzuki H, Tamura K. et al. Platelet volume, aggregation, and adenosine triphosphate release in cerebral thrombosis. Stroke 1991; 22: 17-22.
6 Grau A, Ruf A, Vogt A. et al. Increased fraction of circulating activated platelets in acute and previous cerebrovascular ischemia. Thromb Haemost 1998; 80: 298-301.
7 Zeller JA, Tschoepe D, Kessler C. Circulating platelets show increased activation in patients with acute cerebral ischemia. Thromb Haemost 1999; 81: 373-7.
8 Marquardt L, Ruf A, Mansmann U. et al. Course of platelet activation markers after ischemic stroke. Stroke 2002; 33: 2570-4.
9 Beamer NB, Coull BM, Clark WM. et al. Persistent inflammatory response in stroke survivors. Neurology 1998; 50: 1722-8.
10 Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 2001; 32: 133-8.
11 Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001; 32: 917-24.
12 Grau A, Buggle F, Becher H. et al. The association of leucocyte count, fibrinogen and C-reactive protein with vascular risk factors and ischemic vascular diseases. Thromb Res 1996; 82: 245-55.
13 Ridker PM, Cushman M, Stampfer MJ. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.
14 Wallaschofski H, Donne M, Eigenthaler M. et al. Prolactinas a novel potent cofactor for platelet aggregation. J Clin Endocrinol Metab 2001; 86: 5912-9.
15 Wallaschofski H, Kobsar A, Koksch M. et al. Prolactin receptor signaling during platelet activation. Horm Metab Res 2003; 35: 228-35.
16 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-9.
17 Konstantinidis S, Schäfer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggesta mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-40.
18 Soderberg S, Ahren B, Stegmayr B. et al. Leptin is a risk marker for first-ever hemorrhagic stroke in a population-based cohort. Stroke 1999; 30: 328-37.
19 Soderberg S, Stegmayr B, Ahlbeck-Glader C. et al. High leptin levels are associated with stroke. Cerebrovasc Dis 2003; 15: 63-9.
20 Kolominsky-Rabas PL, Weber M, Gefeller O. et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and longterm survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32: 2735-40.
21 Adams HP, Bendixen BH, Kappelle LJ. et al. for the TOAST Investigators. Classification of subtype of acute stroke: definitions for use in a multicenter clinical trial. Stroke 1993; 24: 35-41.
22 Wallaschofski H, Kobsar A, Sokolova O. et al. Differences in platelet activation by prolactin and leptin. Horm Metab Res 2004; 36: 453-7.
23 Kittner SJ, Stern BJ, Feeser BR. et al. Pregnancy and the risk of stroke. N Engl J Med 1996; 335: 768-74.
24 Biswas S, Rodeck CH. Plasma prolactin levels during pregnancy. Br J Obstet Gynaecol 1976; 83: 683-7.
25 Boyar RM, Finkelstein JW, Kapen S. et al. Twentyfour hour prolactin (PRL) secretory patterns during pregnancy. J Clin Endocrinol Metab 1975; 40: 1117-20.
26 Rolih CA, Ober KP. Pituitary apoplexy. Endocrinol Metab Clin North Am 1993; 22: 291-302.
27 Masago A, Ueda Y, Kanai H, Nagai H, Umemura S. Pituitary apoplexy after pituitary function test: a report of two cases and review of the literature. Surg Neurol 1995; 43: 158-64.
28 Prandoni P, Bilora F, Marchiori A. et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348: 1435-41.
29 Foley PW, Irvine CD, Standen GR. et al. Activated protein C resistance, factor V Leiden and peripheral vascular disease. Cardiovasc Surg 1997; 05: 157-60.
30 Gaustadnes M, Rudiger N, Moller J. et al. Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients. Blood Coagul Fibrinolysis 1999; 10: 251-9.
31 Marder VJ, Matei DE. Hereditary and acquired thrombophilic syndromes. In: Hemostasis and thrombosis: basic principles and clinical practice. 4th ed.. Philadelphia: Lippincott Williams & Wilkins; 2000: 1243-76.
32 Libby P, Simon DI. Thrombosis and atherosclerosis. In: Hemostasis and thrombosis: basic principles and clinical practice. 4th ed.. Philadelphia: Lippincott Williams & Wilkins; 2000: 743-52.
33 Libby P. Multiple mechanisms of thrombosis complicating atherosclerotic plaques. Clin Cardiol 2000; 23 (Suppl. 06) VI-3.
34 Sueishi K, Ichikawa K, Kato K. et al. Atherosclerosis: coagulation and fibrinolysis. Semin Thromb Hemost 1998; 24: 255-60.
35 Holvoet P, Collen D. Thrombosis and atherosclerosis. Curr Opin Lipidol 1997; 08: 320-8.
36 FitzGerald GA, Tigges J, Barry P. et al. Markers of platelet activation and oxidant stress in atherothrombotic disease. Thromb Haemost 1997; 78: 280-4.
37 Drouet L, Mazoyer E, Bal dit, Sollier C. et al. Participation des mécanismes de la thrombose et de l'hémostase aux étapes initiales de l'athérosclérose. Arch Mal Coeur Vaiss 1998; 91: 41-51.
38 Koenig W, Rothenbacher D, Hoffmeister A. et al. Plasma fibrin D-dimer levels and risk of stable coronary artery disease: results of a large case-control study. Arterioscler Thromb Vasc Biol 2001; 21: 1701-5.
39 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-34.
40 Celi A, Lorenzet R, Furie B. et al. Platelet-leukocyte-endothelial cell interaction on the blood vessel wall. Semin Hematol 1997; 34: 327-35.
41 Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 2000; 102: 1931-6.
42 Pulmonary Embolism Prevention trial. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295-302.
43 Collins R, Baigent C, Sandercock P, Peto R. Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists' Collaboration. BMJ 1994; 309: 1215-7.
44 Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration. BMJ 1994; 308: 235-46.
45 Lande K, Os I, Kjeldsen SE. et al. Effect of dopamine and dopamine-antagonist infusion on blood platelet count, size and release reaction in hypertensive and normotensive subjects. Scand J Clin Lab Invest 1989; 49: 307-15.
46 Abbott RD, Curb JD, Rodriguez BL. et al. Age-related changes in risk factor effects on the incidence of thromboembolic and hemorrhagic stroke. J Clin Epidemiol 2003; 56: 479-86.
47 Clevenger CV, Freier DO, Kline JB. Prolactin receptor signal transduction in cells of the immune system. J Endocrinol 1998; 157: 187-97.
48 Morales T, Sawchenko PE. Brainstem prolactin-releasing peptide neurons are sensitive to stress and lactation. Neuroscience 2003; 121: 771-8.
49 Culebras A, Miller M. Dissociated patterns of nocturnal prolactin, cortisol, and growth hormone secretion after stroke. Neurology 1984; 34: 631-6.
50 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
51 Albers GW, Amarenco P. Combination therapy with clopidogrel and aspirin: can the CURE results be extrapolated to cerebrovascula patients?. Stroke 2001; 32: 2948-9.
52 Caplan LR. Thoughts evoked by MATCH and other trials. Stroke 2004; 35: 2604-5.
53 Holmes MB, Sobel BE, Howard DB. et al. Differences between activation thresholds for platelet P-selectin glycoprotein IIb-IIIa expression and their clinical implications. Thromb Res 1999; 95: 75-82.
54 Klinkhardt U, Graff J, Harder S. Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model. Clin Pharmacol Ther 2002; 71: 176-85.