Circadian Variation within Hemostasis: An Underrecognized Link between Biology and Disease?

ABSTRACT

Biological rhythms are a universal phenomenon in living organisms and serve to help organisms adapt within a circadian cycle to the 24-hour-oscillating environment. The rhythmic modulation of selective pathways thus enables organisms to optimize their ability to store and generate chemical energy, to minimize environmental stresses, and to reproduce by cycles of cell growth and division. Remarkably, the onset of both cardiovascular disorders and venous thromboembolism also undergoes circadian oscillations, which might be closely related to an internal biological clock. A highly repetitive rhythmic cycle seems to modulate platelet and endothelial functions, as well as the concentration and activity of several proteins of the coagulation and fibrinolytic systems. Although it is currently unknown how the global hemostatic efficiency might be affected by these circadian variations, understanding the nature, clinical significance, and pathophysiologic consequences of our hemostatic clock may be helpful for the prevention and treatment of a variety of conditions where either the severity of the illness or therapeutic efficacy exhibit circadian rhythmicity. In this review, clinical and laboratory data describing the effects of these cyclical rhythms on the hemostatic system are discussed.

Circadian variability - biological variability - hemostasis - coagulation - fibrinolysis

REFERENCES

• 1 Reilly D F, Westgate E J, FitzGerald G A. Peripheral circadian clocks in the vasculature.  Arterioscler Thromb Vasc Biol. 2007;  27 1694-1705
• 2 Lin J D, Liu C, Li S. Integration of energy metabolism and the mammalian clock.  Cell Cycle. 2008;  7 453-457
• 3 Barnard A R, Nolan P M. When clocks go bad: neurobehavioural consequences of disrupted circadian timing.  PLoS Genet. 2008;  4 e1000040
• 4 Harrisingh M C, Nitabach M N. Circadian rhythms. Integrating circadian timekeeping with cellular physiology.  Science. 2008;  320 879-880
• 5 Maemura K, Takeda N, Nagai R. Circadian rhythms in the CNS and peripheral clock disorders: role of the biological clock in cardiovascular diseases.  J Pharmacol Sci. 2007;  103 134-138
• 6 Guo Y F, Stein P K. Circadian rhythm in the cardiovascular system: chronocardiology.  Am Heart J. 2003;  145 779-786
• 7 Buijs R M, Kalsbeek A. Hypothalamic integration of central and peripheral clocks.  Nat Rev Neurosci. 2001;  2 521-526
• 8 Morse D, Sassone-Corsi P. Time after time: inputs to and outputs from the mammalian circadian oscillators.  Trends Neurosci. 2002;  25 632-637
• 9 Stephan F K, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions.  Proc Natl Acad Sci U S A. 1972;  69 1583-1586
• 10 Silver R, Lesauter J. Circadian and homeostatic factors in arousal.  Ann N Y Acad Sci. 2008;  1129 263-274
• 11 Hastings M, O'Neill J S, Maywood E S. Circadian clocks: regulators of endocrine and metabolic rhythms.  J Endocrinol. 2007;  195 187-198
• 12 Portaluppi F, Lemmer B. Chronobiology and chronotherapy of ischemic heart disease.  Adv Drug Deliv Rev. 2007;  59 952-965
• 13 Tofler G H, Muller J E. Triggering of acute cardiovascular disease and potential preventive strategies.  Circulation. 2006;  114 1863-1872
• 14 Muller J E, Stone P H, Turi Z G et al.. Circadian variation in the frequency of onset of acute myocardial infarction.  N Engl J Med. 1985;  313 1315-1322
• 15 Kapiotis S, Jilma B, Quehenberger P, Ruzicka K, Handler S, Speiser W. Morning hypercoagulability and hypofibrinolysis. Diurnal variations in circulating activated factor VII, prothrombin fragment F1+2, and plasmin-plasmin inhibitor complex.  Circulation. 1997;  96 19-21
• 16 Feng D L, Tofler G H. Diurnal physiologic processes and circadian variation of acute myocardial infarction.  J Cardiovasc Risk. 1995;  2 494-498
• 17 Weitzman E D, Fukushima D, Nogeire C, Roffwarg H, Gallagher T F, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects.  J Clin Endocrinol Metab. 1971;  33 14-22
• 18 Muller J E. Circadian variation and triggering of acute coronary events.  Am Heart J. 1999;  137 S1-S8
• 19 Fujita M, Franklin D. Diurnal changes in coronary blood flow in conscious dogs.  Circulation. 1987;  76 488-491
• 20 Turton M B, Deegan T. Circadian variations of plasma catecholamine, cortisol, and immunoreactive insulin concentrations in supine subjects.  Clin Chim Acta. 1974;  55 389-397
• 21 Decousus H A, Croze M, Levi F A et al.. Circadian changes in anticoagulant effect of heparin infused at a constant rate.  Br Med J (Clin Res Ed). 1985;  290 341-344
• 22 Pinotti M, Bertolucci C, Portaluppi F et al.. Daily and circadian rhythms of tissue factor pathway inhibitor and factor VII activity.  Arterioscler Thromb Vasc Biol. 2005;  25 646-649
• 23 Bilora F, Manfredini R, Petrobelli F, Vettore G, Boccioletti V, Pomerri F. Chronobiology of non fatal pulmonary thromboembolism.  Panminerva Med. 2001;  43 7-10
• 24 Manfredini R, Boari B, Smolensky M H et al.. Circadian variation in stroke onset: identical temporal pattern in ischemic and hemorrhagic events.  Chronobiol Int. 2005;  22 417-453
• 25 Casetta I, Granieri E, Portaluppi F, Manfredini R. Circadian variability in hemorrhagic stroke.  JAMA. 2002;  287 1266-1267
• 26 Gallerani M, Portaluppi F, Maida G et al.. Circadian and circannual rhythmicity in the occurrence of subarachnoid hemorrhage.  Stroke. 1996;  27 1793-1797
• 27 Manfredini R, Portaluppi F, Zamboni P, Salmi R, Gallerani M. Circadian variation in spontaneous rupture of abdominal aorta.  Lancet. 1999;  353 643-644
• 28 Arntz H R, Willich S N, Schreiber C, Brüggemann T, Stern R, Schultheiss H P. Diurnal, weekly and seasonal variation of sudden death. Population-based analysis of 24,061 consecutive cases.  Eur Heart J. 2000;  21 315-320
• 29 Entrican J H, Douglas A S. Circannual rhythm of arterial and venous thromboembolic disease.  Scott Med J. 1979;  24 273-278
• 30 Lemmer B. Circadian rhythm regulations of the cardiovascular system. Studies in rats and mice.  IEEE Eng Med Biol Mag. 2007;  26 30-32
• 31 Hjalmarson A, Gilpin E, Nicod P et al.. Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction.  Circulation. 1989;  80 267-275
• 32 Ridker P M, Manson J AE, Buring J E, Muller J E, Hennekens C H. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians.  Circulation. 1990;  82 897-902
• 33 Willich S N, Linderer T, Wegscheider K, Leizorovicz A, Alamercery I, Schroder R. ISAM Study Group . Increased morning incidence of myocardial infarction in the ISAM study: absence with prior β-adrenergic blockade.  Circulation. 1989;  80 853-858
• 34 Haus E. Chronobiology of hemostasis and inferences for the chronotherapy of coagulation disorders and thrombosis prevention.  Adv Drug Deliv Rev. 2007;  59 966-984
• 35 Kornmann B, Schaad O, Reinke H, Saini C, Schibler U. Regulation of circadian gene expression in liver by systemic signals and hepatocyte oscillators.  Cold Spring Harb Symp Quant Biol. 2007;  72 319-330
• 36 Westgate E J, Cheng Y, Reilly D F et al.. Genetic components of the circadian clock regulate thrombogenesis in vivo.  Circulation. 2008;  117 2087-2095
• 37 Hartley P S, John Sheward W, French K, Horn J M, Holmes M C, Harmar A J. Food-entrained rhythmic expression of PER2 and BMAL1 in murine megakaryocytes does not correlate with circadian rhythms in megakaryopoiesis.  J Thromb Haemost. 2008;  6 1144-1152
• 38 Muller J E, Tofler G H, Stone P H. Circadian variation and triggers of onset of acute cardiovascular disease.  Circulation. 1989;  79 733-743
• 39 Braunwald E. Morning resistance to thrombolytic therapy.  Circulation. 1995;  91 1604-1606
• 40 Undar L, Ertuğrul C, Altunbaş H, Akça S. Circadian variations in natural coagulation inhibitors protein C, protein S and antithrombin in healthy men: a possible association with interleukin-6.  Thromb Haemost. 1999;  81 571-575
• 41 Jafri S M, VanRollins M, Ozawa T, Mammen E F, Goldberg A D, Goldstein S. Circadian variation in platelet function in healthy volunteers.  Am J Cardiol. 1992;  69 951-954
• 42 Numminen H, Syrjälä M, Benthin G, Kaste M, Hillbom M. The effect of acute ingestion of a large dose of alcohol on the hemostatic system and its circadian variation.  Stroke. 2000;  31 1269-1273
• 43 Bremner W F, Sothern R B, Kanabrocki E L et al.. Relation between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men.  Am Heart J. 2000;  139 164-173
• 44 Jones A R, Twedt D, Swaim W, Gottfried E. Diurnal change of blood count analytes in normal subjects.  Am J Clin Pathol. 1996;  106 723-727
• 45 Guagnano M T, Davi G, Sensi S. Morning sudden cardiac death.  Int J Immunopathol Pharmacol. 2000;  13 55-60
• 46 Tofler G H, Brezinski D, Schafer A I et al.. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death.  N Engl J Med. 1987;  316 1514-1518
• 47 Willich S N, Goldberg R J, Maclure M, Perriello L, Muller J E. Increased onset of sudden cardiac death in the first three hours after awakening.  Am J Cardiol. 1992;  70 65-68
• 48 Willich S N, Maclure M, Mittelmann M, Arntz H R, Muller J E. Sudden cardiac death: support for a role of triggering in causation.  Circulation. 1993;  87 1442-1450
• 49 Undar L, Akkoc N, Alakavuklar M N, Cehreli C, Undar L. Flow cytometric analysis of circadian changes in platelet activation using anti-GMP-140 monoclonal antibody.  Chronobiol Int. 1999;  16 335-342
• 50 Osmancik P, Kvasnicka J, Widimsky P, Tarnok A. Diurnal variation of soluble E- and P-selectin, and intercellular adhesion molecule-1 in patients with and without coronary artery disease.  Cardiology. 2004;  102 194-199
• 51 Opper C, Weiner N, Xü F, Adam W, Fruhstorfer H, Wesemann W. Daily variations of functional parameters and density distribution in human blood platelets.  Chronobiol Int. 1994;  11 309-319
• 52 Wiens L, Lutze G, Luley C, Westphal S. Platelet count and platelet activation: impact of a fat meal and day time.  Platelets. 2007;  18 171-173
• 53 Dalby M C, Davidson S J, Burman J F, Davies S W. Diurnal variation in platelet aggregation with the PFA-100 platelet function analyser.  Platelets. 2000;  11 320-324
• 54 Tengattini S, Reiter R J, Tan D X, Terron M P, Rodella L F, Rezzani R. Cardiovascular diseases: protective effects of melatonin.  J Pineal Res. 2008;  44 16-25
• 55 Vacas M I, Del Zar M M, Martinuzzo M, Cardinali D P. Binding sites for [3H]-melatonin in human platelets.  J Pineal Res. 1992;  13 60-65
• 56 Champier J, Claustrat B, Besancon R et al.. Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets.  Life Sci. 1997;  60 2191-2197
• 57 Di Bella L, Gualano L. Key aspects of melatonin physiology: thirty years of research.  Neuroendocrinol Lett. 2006;  27 425-432
• 58 Vacas M I, Del Zar M M, Martinuzzo M, Falcon C, Carreras L O, Cardinali D P. Inhibition of human platelet aggregation and thromboxane B2 production by melatonin. Correlation with plasma melatonin levels.  J Pineal Res. 1991;  11 135-139
• 59 Cardinali D P, Del Zar M M, Vacas M I. The effects of melatonin in human platelets.  Acta Physiol Pharmacol Ther Latinoam. 1993;  43 1-13
• 60 Jones S B, Bylund D B, Rieser C A, Shekim W O, Byer J A, Carr G W. Alpha 2-adrenergic receptor binding in human platelets: alterations during the menstrual cycle.  Clin Pharmacol Ther. 1983;  34 90-96
• 61 Jespersen J, Ingeberg S, Bach E. Antithrombin III and platelets during the normal menstrual cycle and in women receiving oral contraceptives low in oestrogen.  Gynecol Obstet Invest. 1983;  15 153-162
• 62 Madden L A, Vince R V, Sandström M E, Taylor L, McNaughton L, Laden G. Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects.  Thromb Haemost. 2008;  99 909-915
• 63 Morel O, Toti F, Hugel B et al.. Procoagulant microparticles – disrupting the vascular homeostasis equation?.  Arterioscler Thromb Vasc Biol. 2006;  26 2594-2604
• 64 Wolf P. The nature and significance of platelet products in human plasma.  Br J Haematol. 1967;  13 269-288
• 65 Combes V, Simon A C, Grau G E et al.. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant.  J Clin Invest. 1999;  104 93-102
• 66 Omoto S, Nomura S, Shouzu A, Nishikawa M, Fukuhara S, Iwasaka T. Detection of monocyte-derived microparticles in patients with type II diabetes mellitus.  Diabetologia. 2002;  45 550-555
• 67 Pattanapanyasat K, Noulsri E, Fucharoen S et al.. Flow cytometric quantitation of red blood cell vesicles in thalassemia.  Cytometry B Clin Cytom. 2004;  57B 23-31
• 68 Etsuda H, Takase B, Uehata A et al.. Morning attenuation of endothelium-dependent, flow-mediated dilation in healthy young men: possible connection to morning peak of cardiac events?.  Clin Cardiol. 1999;  22 417-421
• 69 Gaenzer H, Sturm W, Kirchmair R, Neumayr G, Ritsch A, Patsch J. Circadian variation of endothelium-dependent vasodilatation of the brachial artery as a confounding factor in the evaluation of endothelial function.  Atherosclerosis. 2000;  149 227-228
• 70 Ringqvist A, Caidahl K, Petersson A S, Wennmalm A. Diurnal variation of flow-mediated vasodilation in healthy premenopausal women.  Am J Physiol Heart Circ Physiol. 2000;  279 H2720-H2725
• 71 Otto M E, Svatikova A, Barretto R B et al.. Early morning attenuation of endothelial function in healthy humans.  Circulation. 2004;  109 2507-2510
• 72 Tamura E K, Silva C L, Markus R P. Melatonin inhibits endothelial nitric oxide production in vitro.  J Pineal Res. 2006;  41 267-274
• 73 Parra D A, Lim D S, Buller C L, Charpie J R. Endothelial dysfunction and circadian blood pressure rhythmicity in young heart transplant recipients.  Pediatr Cardiol. 2007;  28 1-7
• 74 Müller-Schweinitzer E, Gilles H, Grapow M, Kern T, Reineke D, Zerkowski H R. Attenuation of lipopolysaccharide-induced hyperreactivity of human internal mammary arteries by melatonin.  J Pineal Res. 2004;  37 92-97
• 75 Järvisalo M J, Jartti L, Marniemi J et al.. Determinants of short-term variation in arterial flow-mediated dilatation in healthy young men.  Clin Sci (Lond). 2006;  110 475-482
• 76 Hijmering M L, Stroes E S, Olijhoek J, Hutten B A, Blankestijn P J, Rabelink T J. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation.  J Am Coll Cardiol. 2002;  39 683-688
• 77 Celermajer D S, Sorensen K E, Gooch V M et al.. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.  Lancet. 1992;  340 1111-1115
• 78 Maruo T, Nakatani S, Kanzaki H et al.. Circadian variation of endothelial function in idiopathic dilated cardiomyopathy.  Am J Cardiol. 2006;  97 699-702
• 79 Walters J F, Hampton S M, Deanfield J E, Donald A E, Skene D J, Ferns G A. Circadian variation in endothelial function is attenuated in postmenopausal women.  Maturitas. 2006;  54 294-303
• 80 el-Tamimi H, Mansour M, Pepine C J, Wargovich T J, Chen H. Circadian variation in coronary tone in patients with stable angina. Protective role of the endothelium.  Circulation. 1995;  92 3201-3205
• 81 Dart A M, Chin-Dusting J P. Lipids and the endothelium.  Cardiovasc Res. 1999;  43 308-322
• 82 Lewis T V, Dart A M, Chin-Dusting J P. Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol.  J Am Coll Cardiol. 1999;  33 805-812
• 83 Mayer G A. Diurnal, postural and postprandial variations of hematocrit.  Can Med Assoc J. 1965;  93 1006-1008
• 84 Maemura K, de la Monte S M, Chin M T et al.. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.  J Biol Chem. 2000;  275 36847-36851
• 85 Maemura K, Layne M D, Watanabe M, Perrell M A, Nagai R, Lee M E. Molecular mechanisms of morning onset of myocardial infarction.  Ann N Y Acad Sci. 2001;  947 398-402
• 86 Viswambharan H, Carvas J M, Antic V et al.. Mutation of the circadian clock gene Per2 alters vascular endothelial function.  Circulation. 2007;  115 2188-2195
• 87 Haus E, Cusulos M, Sackett-Lundeen L, Swoyer J. Circadian variations in blood coagulation parameters, alpha-antitrypsin antigen and platelet aggregation and retention in clinically healthy subjects.  Chronobiol Int. 1990;  7 203-216
• 88 Bertolucci C, Pinotti M, Colognesi I, Foà A, Bernardi F, Portaluppi F. Circadian rhythms in mouse blood coagulation.  J Biol Rhythms. 2005;  20 219-224
• 89 Bertolucci C, Cavallari N, Colognesi I et al.. Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators.  Mol Cell Biol. 2008;  28 3070-3075
• 90 Kapur R, Hoffman C J, Bhushan V, Haltin M B. Postprandial elevation of activated factor VII in young adults.  Arterioscler Thromb Vasc Biol. 1996;  16 1327-1332
• 91 Tracy R P. Diet and hemostatic factors.  Curr Atheroscler Rep. 1999;  1 243-248
• 92 Kobayashi H, Oishi K, Hanai S, Ishida N. Effect of feeding on peripheral circadian rhythms and behaviour in mammals.  Genes Cells. 2004;  9 857-864
• 93 Cooper D N, Millar D S, Wacey A, Banner D W, Tuddenham E G. Inherited factor VII deficiency: molecular genetics and pathophysiology.  Thromb Haemost. 1997;  78 151-160
• 94 Iversen P O, Groot P D, Hjeltnes N, Andersen T O, Mowinckel M C, Sandset P M. Impaired circadian variations of haemostatic and fibrinolytic parameters in tetraplegia.  Br J Haematol. 2002;  119 1011-1016
• 95 Bridges A B, McLaren M, Scott N A, Pringle T H, McNeill G P, Belch J J. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease.  Br Heart J. 1993;  69 121-124
• 96 Bridges A B, McLaren M, Saniabadi A, Fisher T C, Belch J J. Circadian variation of endothelial cell function, red blood cell deformability and dehydro-thromboxane B2 in healthy volunteers.  Blood Coagul Fibrinolysis. 1991;  2 447-452
• 97 Blombäck M, Konkle B A, Manco-Johnson M J, Bremme K, Hellgren M, Kaaja R. ISTH SSC Subcommittee on Women's Health Issues . Preanalytical conditions that affect coagulation testing, including hormonal status and therapy.  J Thromb Haemost. 2007;  5 855-858
• 98 Rudnicka A R, Rumley A, Lowe G D, Strachan D P. Diurnal, seasonal, and blood-processing patterns in levels of circulating fibrinogen, fibrin D-dimer, C-reactive protein, tissue plasminogen activator, and von Willebrand factor in a 45-year-old population.  Circulation. 2007;  115 996-1003
• 99 Favaloro E J. The utility of the PFA-100 in the identification of von Willebrand disease: a concise review.  Semin Thromb Hemost. 2006;  32 537-545
• 100 Ohkura N, Oishi K, Fukushima N et al.. Circadian clock molecules CLOCK and CRYs modulate fibrinolytic activity by regulating the PAI-1 gene expression.  J Thromb Haemost. 2006;  4 2478-2485
• 101 Akiyama Y, Kazama M, Tahara C et al.. Reference values of hemostasis related factors of healthy Japanese adults. I: circadian fluctuation.  Thromb Res. 1990;  60 281-289
• 102 Hermida R C, Calvo C, Ayala D E et al.. Seasonal variation of fibrinogen in dipper and nondipper hypertensive patients.  Circulation. 2003;  108 1101-1106
• 103 Crawford V L, McNerlan S E, Stout R W. Seasonal changes in platelets, fibrinogen and factor VII in elderly people.  Age Ageing. 2003;  32 661-665
• 104 Folsom A R, Wu K K, Conlan M G et al.. Distributions of hemostatic variables in blacks and whites: population reference values from the Atherosclerosis Risk in Communities (ARIC) Study.  Ethn Dis. 1992;  2 35-46
• 105 Kouides P A. Current understanding of von Willebrand's disease in women - some answers, more questions.  Haemophilia. 2006;  12(Suppl 3) 143-151
• 106 Kouides P A. Aspects of the laboratory identification of von Willebrand disease in women.  Semin Thromb Hemost. 2006;  32 480-484
• 107 Lethagen S, Hillarp A, Ekholm C, Mattson E, Halldén C, Friberg B. Distribution of von Willebrand factor levels in young women with and without bleeding symptoms: influence of ABO blood group and promoter haplotypes.  Thromb Haemost. 2008;  99 1013-1038
• 108 Pasqualetti P, Festuccia V, Acitelli P, Natali L, Collacciani A, Casale R. Circadian rhythms of fibrinogen antithrombin III and plasminogen in chronic liver diseases of increasing severity.  Haemostasis. 1997;  27 140-148
• 109 Chong N W, Codd V, Chan D, Samani N J. Circadian clock genes cause activation of the human PAI-1 gene promoter with 4G/5G allelic preference.  FEBS Lett. 2006;  580 4469-4472
• 110 Fearnley G R, Balmforth G, Fearnley E. Evidence of a diurnal fibrinolytic rhythm; with a simple method of measuring natural fibrinolysis.  Clin Sci. 1957;  16 645-650
• 111 Rosing D R, Brakman P, Redwood D R et al.. Blood fibrinolytic activity in man. Diurnal variation and the response to varying intensities of exercise.  Circ Res. 1970;  27 171-184
• 112 Angleton P, Chandler W L, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1).  Circulation. 1989;  79 101-106
• 113 Kurnik P B. Circadian variation in the efficacy of tissue-type plasminogen activator.  Circulation. 1995;  91 1341-1346
• 114 Ogawa H, Yasue H, Oshima S, Okumura K, Matsuyama K, Obata K. Circadian variation of plasma fibrinopeptide A level in patients with variant angina.  Circulation. 1989;  80 1617-1626
• 115 Del Zar M M, Martinuzzo M, Falcón C, Cardinali D P, Carreras L O, Vacas M I. Inhibition of human platelet aggregation and thromboxane-B2 production by melatonin: evidence for a diurnal variation.  J Clin Endocrinol Metab. 1990;  70 246-251
• 116 Trifiletti A, Bartolone S, Scamardi R et al.. Evaluation of haemostatic parameters and circadian variations of the haemostatic system in patients with systemic sclerosis and Raynaud's phenomenon.  Panminerva Med. 2000;  42 7-9