Diurnal changes and levels of fibrin generation are not altered by continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA)

Bradley J. McEwen; Craig L. Phillips; Marie-Christine Morel-Kopp; Brendon J. Yee; David R. Sullivan; Christopher M. Ward; Geoffrey H. Tofler; Ronald R. Grunstein

doi:10.1160/TH12-04-0231

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(04): 701-709
DOI: 10.1160/TH12-04-0231

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Diurnal changes and levels of fibrin generation are not altered by continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA)

A randomised, placebo-controlled crossover study

Authors

Bradley J. McEwen^*

¹Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia

²Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Craig L. Phillips^*

³Department of Respiratory & Sleep Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia

⁴NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
Marie-Christine Morel-Kopp

¹Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia

²Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Brendon J. Yee

⁴NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia

⁵Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
David R. Sullivan

⁶Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
Christopher M. Ward

¹Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia

²Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, St Leonards, New South Wales, Australia
Geoffrey H. Tofler

⁷Department of Cardiology, Royal North Shore Hospital, New South Wales, Australia
Ronald R. Grunstein

⁴NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia

⁵Department of Respiratory & Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

Abstract

Summary

Obstructive sleep apnoea (OSA) is associated with increased cardiovascular disease (CVD) risk. In the general population, CVD events peak at 9:00–10:00 AM, associated with diurnal changes in thrombotic potential. However in OSA, these CVD events occur frequently at night. Measuring thrombotic potential across the sleep-wake cycle may provide insight into the temporal association of OSA with CVD. This study aimed to determine diurnal changes in fibrin generation in OSA and whether treatment of OSA with continuous positive airway pressure (CPAP) alters fibrin generation across the sleep-wake cycle. In a randomised placebo-controlled crossover trial, patients with OSA were assigned to two months each of therapeutic CPAP and placebo. After each treatment period, fibrin generation was determined by overall haemostatic potential assay at seven time points over 24 hours (h). Twenty-eight patients (25 men, 3 women) with severe OSA (Apnoea Hypopnoea Index = 37.9 ± 23.9/h, Oxygen Desaturation Index 31.3 ± 22.4/h) completed the study. All parameters, except lag time to fibrin generation, showed significant diurnal changes, both on CPAP and placebo. Compared to 9:00 AM, fibrin generation parameters were significantly lower at midnight and 3:00 AM for overall coagulation potential (OCP), overall haemostasis potential (OHP), maximum optical density, and maximum slope (all p≤0.001). CPAP produced no change in fibrin generation parameters compared to placebo. In severe OSA patients, fibrin generation peaked at 6:00 AM and 9:00 AM rather than during the sleep period (midnight and 3:00 AM). These findings suggest a prothrombotic shift in the morning similar to individuals without OSA. There was no difference between CPAP and placebo on fibrin generation.

Keywords

Fibrin generation - fibrinolysis - obstructive sleep apnoea - continuous positive airway pressure - cardiovascular risk

Full Text

References

References
1 Wolk R, Kara T, Somers VK. Sleep-disordered breathing and cardiovascular disease. Circulation 2003; 108: 9-12.
2 Marin JM, Carrizo SJ, Vicente E. et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046-1053.
3 Peker Y, Hedner J, Norum J. et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 2002; 166: 159-165.
4 Nobili L, Schiavi G, Bozano E. et al. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000; 22: 21-27.
5 Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. J Am Med Assoc 2003; 290: 1906-1914.
6 Lattimore JD, Celermajer DS, Wilcox I. Obstructive sleep apnea and cardiovascular disease. J Am Coll Cardiol 2003; 41: 1429-1437.
7 Tofler GH, Brezinski D, Schafer AI. et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 3164: 1514-1518.
8 Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989; 79: 733-743.
9 Martino TA, Sole MJ. Molecular time: an often overlooked dimension to cardiovascular disease. Circ Res 2009; 105: 1047-1061.
10 Kario K. Morning surge in blood pressure and cardiovascular risk: evidence and perspectives. Hypertension 2010; 56: 765-773.
11 Eisensehr I, Ehrenberg BL, Noachtar S. et al. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome. Neurology 1998; 51: 188-195.
12 Geiser T, Buck F, Meyer BJ. et al. In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome. Respiration 2002; 69: 229-234.
13 Bokinsky G, Miller M, Ault K. et al. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995; 108: 625-630.
14 Kuniyoshi FH, Garcia-Touchard A, Gami AS. et al. Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 2008; 52: 343-346.
15 Gami AS, Howard DE, Olson EJ. et al. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005; 352: 1206-1214.
16 Dempsey JA, Veasey SC, Morgan BJ. et al. Pathophysiology of sleep apnea. Physiol Rev 2010; 90: 47-112.
17 Caples SM, Gami AS, Somers VK. Obstructive sleep apnea. Ann Intern Med 2005; 142: 187-197.
18 Sobel BE. Coronary artery disease and fibrinolysis: from the blood to the vessel wall. Thromb Haemost 1999; 82 (Suppl. 01) 8-13.
19 Tofler GH, Muller JE. Triggering of acute cardiovascular disease and potential preventive strategies. Circulation 2006; 114: 1863-1872.
20 Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 07: 260-273.
21 Weisel JW. Structure of fibrin: impact on clot stability. J Thromb Haemost 2007; 05 (Suppl. 01) 116-24.
22 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
23 Fatah K, Silveira A, Tornvall P. et al. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76: 535-540.
24 He S, Antovic A, Blomback M. A simple and rapid laboratory method for determination of haemostasis potential in plasma. II. Modifications for use in routine laboratories and research work. Thromb Res 2001; 103: 355-361.
25 Curnow JL, Morel-Kopp MC, Roddie C. et al. Reduced fibrinolysis and increased fibrin generation can be detected in hypercoagulable patients using the overall hemostatic potential assay. J Thromb Haemost 2007; 05: 528-534.
26 Antovic A. Screening haemostasis--looking for global assays: the Overall Haemostasis Potential (OHP) method--a possible tool for laboratory investigation of global haemostasis in both hypo- and hypercoagulable conditions. Curr Vasc Pharmacol 2008; 06: 173-185.
27 Antovic A. The overall hemostasis potential: a laboratory tool for the investigation of global hemostasis. Semin Thromb Hemost 2010; 36: 772-779.
28 Mansfield DR, Gollogly NC, Kaye DM. et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004; 169: 361-366.
29 Kaneko Y, Floras JS, Usui K. et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003; 348: 1233-1241.
30 Doherty LS, Kiely JL, Swan V. et al. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005; 127: 2076-2084.
31 Phillips CL, McEwen BJ, Morel-Kopp MC. et al. Effects of continuous positive airway pressure on coagulability in obstructive sleep apnoea: a randomised, placebo-controlled crossover study. Thorax 2012; 67: 639-644.
32 Chin K, Ohi M, Kita H. et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996; 153: 1972-1976.
33 von Kanel R, Loredo JS, Ancoli-Israel S. et al. Association between sleep apnea severity and blood coagulability: Treatment effects of nasal continuous positive airway pressure. Sleep Breath 2006; 10: 139-146.
34 Phillips CL, Yee BJ, Marshall NS. et al. Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial. Am J Respir Crit Care Med 2011; 184: 355-361.
35 American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999 22. 667-689.
36 He S, Bremme K, Blomback M. A laboratory method for determination of overall haemostatic potential in plasma. I. Method design and preliminary results. Thromb Res 1999; 96: 145-156.
37 Muller JE, Stone PH, Turi ZG. et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985; 313: 1315-1322.
38 Antovic A, Blomback M, Bremme K. et al. The assay of overall haemostasis potential used to monitor the low molecular mass (weight) heparin, dalteparin, treatment in pregnant women with previous thromboembolism. Blood Coagul Fibrinolysis 2002; 13: 181-186.
39 Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults. Mayo Clin Proc 2007; 82: 864-873.
40 Baglin T. The measurement and application of thrombin generation. Br J Haematol 2005; 130: 653-661.
41 Sanner BM, Konermann M, Tepel M. et al. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000; 16: 648-652.
42 von Kanel R, Dimsdale JE. Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease. Chest 2003; 124: 1956-1967.
43 Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost 2001; 85: 584-595.
44 Wessendorf TE, Thilmann AF, Wang YM. et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000; 162: 2039-2042.
45 Reinhart WH, Oswald J, Walter R. et al. Blood viscosity and platelet function in patients with obstructive sleep apnea syndrome treated with nasal continuous positive airway pressure. Clin Hemorheol Microcirc 2002; 27: 201-207.
46 von Kanel R, Loredo JS, Ancoli-Israel S. et al. Elevated plasminogen activator inhibitor 1 in sleep apnea and its relation to the metabolic syndrome: an investigation in 2 different study samples. Metabolism 2007; 56: 969-976.
47 Rangemark C, Hedner JA, Carlson JT. et al. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep 1995; 18: 188-194.
48 Hui DS, Ko FW, Fok JP. et al. The effects of nasal continuous positive airway pressure on platelet activation in obstructive sleep apnea syndrome. Chest 2004; 125: 1768-1775.
49 Cross MD, Mills NL, Al-Abri M. et al. Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial. Thorax 2008; 63: 578-583.
50 Willich SN, Levy D, Rocco MB. et al. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol 1987; 60: 801-806.
51 Gottlieb DJ, Yenokyan G, Newman AB. et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010; 122: 352-360.
52 Redline S, Yenokyan G, Gottlieb DJ. et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010; 182: 269-277.