Aging Hemostasis: Changes to Laboratory Markers of Hemostasis As We Age—A Narrative Review

Emmanuel J. Favaloro; Massimo Franchini; Giuseppe Lippi

doi:10.1055/s-0034-1384631

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2014; 40(06): 621-633
DOI: 10.1055/s-0034-1384631

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Aging Hemostasis: Changes to Laboratory Markers of Hemostasis As We Age—A Narrative Review

Emmanuel J. Favaloro

¹Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, Westmead Hospital, Westmead, New South Wales, Australia

,

Massimo Franchini

²Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

,

Giuseppe Lippi

³Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy

› Institutsangaben

Abstract

The incidence of venous thromboembolism (VTE) is well recognized to increase with aging. Concurrently, the plasma concentrations of many coagulation factors (e.g., fibrinogen, factor [F] V, FVII, FVIII, and FIX) increase with aging, as does von Willebrand factor (VWF), thrombin generation, and platelet activation. Data are conflicting regarding age-related changes in the natural anticoagulants, including protein C, protein S, and antithrombin. Changes are also observed with components of the fibrinolytic pathway. All in all, aging is associated with a variety of hemostasis changes that on balance reflects a heightened procoagulant status compared with earlier age. It has to be recognized that as this occurs in the otherwise normal general population, this can also be considered a normal phenomenon of progressive life. An element of this heightened procoagulant status may reflect ongoing inflammatory processes, given some markers, notably FVIII and fibrinogen, are acute phase reactants. A variety of acquired prothrombotic risk factors (e.g., cancer, autoimmune disorders, and diabetes) also gradually develop with aging, some of which may induce profound abnormalities of hemostasis, and confound the age-related changes in hemostasis, as well as their influence on thrombotic risk. In this article, we review the changes in hemostasis markers measurable within many hemostasis laboratories, and consider many of the important implications for clinical and laboratory practice. Apart from representing an increased thrombotic risk, additional considerations entail the potential need (1) to utilize age-adjusted normal ranges (e.g., for D-dimer), (2) to consider the consequence on previous diagnoses (e.g., “mild type 1” von Willebrand disease [VWD], where VWF test results may “normalize” with aging), and (3) to consider the effect of these changes of risk factors on the (perceived) therapeutic efficacy of antithrombotic medications such as aspirin.

Keywords

hemostasis - coagulation factors - laboratory testing - thrombosis - aging

Volltext

Referenzen

References
1 Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 2011; 86 (2) 217-220
2 Access Economics. The burden of venous thromboembolism in Australia. Report for the Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism. 2008; Available at: https://www.deloitteaccesseconomics.com.au/uploads/File/The%20burden%20of%20VTE%20in%20Australia.pdf. Accessed August 5, 2014
3 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34 (8) 747-761
4 Favaloro EJ, Lippi G. Coagulation update: what's new in hemostasis testing?. Thromb Res 2011; 127 (2) (Suppl. 02) S13-S16
5 Lippi G, Franchini M, Favaloro EJ. Unsuspected triggers of venous thromboembolism—trivial or not so trivial?. Semin Thromb Hemost 2009; 35 (7) 597-604
6 Lippi G, Franchini M, Favaloro EJ. Holiday thrombosis. Semin Thromb Hemost 2011; 37 (8) 869-874
7 Favaloro EJ, Franchini M, Lippi G. Coagulopathies and thrombosis: usual and unusual causes and associations. Part V. Semin Thromb Hemost 2011; 37 (8) 859-862
8 Silverstein RL, Bauer KA, Cushman M, Esmon CT, Ershler WB, Tracy RP. Venous thrombosis in the elderly: more questions than answers. Blood 2007; 110 (9) 3097-3101
9 Lippi G, Favaloro EJ, Cervellin G. A review of the value of D-dimer testing for prediction of recurrent venous thromboembolism with increasing age. 2014; 40 (6) 634-639
10 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (8) 709-733
11 Bouma BN, Meijers JC. New insights into factors affecting clot stability: A role for thrombin activatable fibrinolysis inhibitor (TAFI; plasma procarboxypeptidase B, plasma procarboxypeptidase U, procarboxypeptidase R). Semin Hematol 2004; 41 (1) (Suppl. 01) 13-19
12 Du VX, Huskens D, Maas C, Al Dieri R, de Groot PG, de Laat B. New insights into the role of erythrocytes in thrombus formation. Semin Thromb Hemost 2014; 40 (1) 72-80
13 Franchini M. Hemostasis and aging. Crit Rev Oncol Hematol 2006; 60 (2) 144-151
14 Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Exp Gerontol 2008; 43 (2) 66-73
15 Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258 (9) 1183-1186
16 Stone MC, Thorp JM. Plasma fibrinogen—a major coronary risk factor. J R Coll Gen Pract 1985; 35 (281) 565-569
17 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311 (8) 501-505
18 Meade TW, North WR, Chakrabarti R, Haines AP, Stirling Y. Population-based distributions of haemostatic variables. Br Med Bull 1977; 33 (3) 283-288
19 Tracy RP, Bovill EG, Fried LP , et al. The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study. Ann Epidemiol 1992; 2 (4) 509-519
20 Tofler HT, Massaro J, Levy D , et al. Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study). Am J Cardiol 2005; 96 (9) 1280-1283
21 Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med 1992; 116 (12) 1307-1312
22 Tracy RP. Hemostatic and inflammatory markers as risk factors for coronary disease in the elderly. Am J Geriatr Cardiol 2002; 11 (2) 93-100 , 107
23 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345 (8943) 152-155
24 Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population: I. Baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using, and menopause. Thromb Haemost 1985; 54 (2) 475-479
25 Lowe GD, Rumley A, Woodward M , et al. Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97 (4) 775-784
26 Conlan MG, Folsom AR, Finch A , et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70 (3) 380-385
27 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L. Cross-laboratory audit of normal reference ranges and assessment of ABO blood group, gender and age on detected levels of plasma coagulation factors. Blood Coagul Fibrinolysis 2005; 16 (8) 597-605
28 Lippi G, Meschi T, Borghi L. Variation of activated partial thromboplastin time according to age and sex in a large population study: analytical and clinical implications. Blood Coagul Fibrinolysis 2012; 23 (2) 177-178
29 Mina A, Favaloro EJ, Mohammed S, Koutts J. A laboratory evaluation into the short activated partial thromboplastin time. Blood Coagul Fibrinolysis 2010; 21 (2) 152-157
30 Lippi G, Salvagno GL, Ippolito L, Franchini M, Favaloro EJ. Shortened activated partial thromboplastin time: causes and management. Blood Coagul Fibrinolysis 2010; 21 (5) 459-463
31 Korte W, Clarke S, Lefkowitz JB. Short activated partial thromboplastin times are related to increased thrombin generation and an increased risk for thromboembolism. Am J Clin Pathol 2000; 113 (1) 123-127
32 Howard PR, Bovill EG, Pike J, Church WR, Tracy RP. Factor VII antigen levels in a healthy blood donor population. Thromb Haemost 1994; 72 (1) 21-27
33 Scarabin PY, Vissac AM, Kirzin JM , et al. Population correlates of coagulation factor VII. Importance of age, sex, and menopausal status as determinants of activated factor VII. Arterioscler Thromb Vasc Biol 1996; 16 (9) 1170-1176
34 Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17 (8) 1539-1544
35 Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19 (7) 1776-1783
36 Mennen LI, Witteman JC, den Breeijen JH , et al. The association of dietary fat and fiber with coagulation factor VII in the elderly: the Rotterdam Study. Am J Clin Nutr 1997; 65 (3) 732-736
37 Allman-Farinelli MA, Dawson B. Diet and aging: bearing on thrombosis and hemostasis. Semin Thromb Hemost 2005; 31 (1) 111-117
38 Miller GJ, Martin JC, Webster J , et al. Association between dietary fat intake and plasma factor VII coagulant activity—a predictor of cardiovascular mortality. Atherosclerosis 1986; 60 (3) 269-277
39 Ofosu FA, Craven S, Dewar L, Anvari N, Andrew M, Blajchman MA. Age-related changes in factor VII proteolysis in vivo. Br J Haematol 1996; 94 (2) 407-412
40 Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study. J Clin Invest 1987; 80 (6) 1527-1534
41 Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ, Rosenberg RD. Detection of factor X activation in humans. Blood 1989; 74 (6) 2007-2015
42 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76 (4) 731-736
43 Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85 (11) 3144-3149
44 Cadroy Y, Pierrejean D, Fontan B, Sié P, Boneu B. Influence of aging on the activity of the hemostatic system: prothrombin fragment 1+2, thrombin-antithrombin III complexes and D-dimers in 80 healthy subjects with age ranging from 20 to 94 years. Nouv Rev Fr Hematol 1992; 34 (1) 43-46
45 Coppola R, Cristilli P, Cugno M, Ariëns RA, Mari D, Mannucci PM. Measurement of activated factor XII in health and disease. Blood Coagul Fibrinolysis 1996; 7 (5) 530-535
46 Sweeney JD, Hoernig LA. Age-dependent effect on the level of factor IX. Am J Clin Pathol 1993; 99 (6) 687-688
47 Ariëns RA, Kohler HP, Mansfield MW, Grant PJ. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension. Arterioscler Thromb Vasc Biol 1999; 19 (8) 2012-2016
48 Sugawara J, Hayashi K, Kurachi S, Tanaka T, Yokoi T, Kurachi K. Age-related effects of regular physical activity on hemostatic factors in men. J Thromb Thrombolysis 2008; 26 (3) 203-210
49 Kurachi K, Kurachi S. Genetic mechanisms of age regulation of blood coagulation: factor IX model. Arterioscler Thromb Vasc Biol 2000; 20 (4) 902-906
50 Coppola R, Mari D, Lattuada A, Franceschi C. Von Willebrand factor in Italian centenarians. Haematologica 2003; 88 (1) 39-43
51 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L, Favaloro JW. Reassessment of ABO blood group, sex, and age on laboratory parameters used to diagnose von Willebrand disorder: potential influence on the diagnosis vs the potential association with risk of thrombosis. Am J Clin Pathol 2005; 124 (6) 910-917
52 Kokame K, Sakata T, Kokubo Y, Miyata T. von Willebrand factor-to-ADAMTS13 ratio increases with age in a Japanese population. J Thromb Haemost 2011; 9 (7) 1426-1428
53 Hjelmborg JV, Nzietchueng R, Kimura M , et al. Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor. Thromb Res 2010; 125 (6) e339-e342
54 Chen SF, Xia ZL, Han JJ , et al. Increased active von Willebrand factor during disease development in the aging diabetic patient population. Age (Dordr) 2013; 35 (1) 171-177
55 Dolan G, Neal K, Cooper P, Brown P, Preston FE, Protein C. antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol 1994; 86 (4) 798-803
56 Tait RC, Walker ID, Islam SI , et al. Influence of demographic factors on antithrombin III activity in a healthy population. Br J Haematol 1993; 84 (3) 476-480
57 Stout RW, Crawford VL, McDermott MJ, Rocks MJ, Morris TC. Seasonal changes in haemostatic factors in young and elderly subjects. Age Ageing 1996; 25 (3) 256-258
58 Cadroy Y, Daviaud P, Saivin S, Sie P, Boneu B. Distribution of 16 hemostatic laboratory variables assayed in 100 blood donors. Nouv Rev Fr Hematol 1990; 32 (4) 259-264
59 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L. Laboratory identification of familial thrombophilia: do the pitfalls exceed the benefits? A reassessment of ABO-blood group, gender, age, and other laboratory parameters on the potential influence on a diagnosis of protein C, protein S, and antithrombin deficiency and the potential high risk of a false positive diagnosis. Lab Hematol 2005; 11 (3) 174-184
60 Mannucci PM, Vigano S. Deficiencies of protein C, an inhibitor of blood coagulation. Lancet 1982; 2 (8296) 463-467
61 Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001; 113 (3) 636-641
62 Starr ME, Ueda J, Takahashi H , et al. Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood 2010; 115 (23) 4886-4893
63 Sakkinen PA, Cushman M, Psaty BM , et al. Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. Thromb Haemost 1998; 80 (1) 134-139
64 Ariëns RA, Coppola R, Potenza I, Mannucci PM. The increase with age of the components of the tissue factor coagulation pathway is gender-dependent. Blood Coagul Fibrinolysis 1995; 6 (5) 433-437
65 Kario K, Matsuo T, Kobayashi H. Heparin cofactor II deficiency in the elderly: comparison with antithrombin III. Thromb Res 1992; 66 (5) 489-498
66 Hamilton PJ, Dawson AA, Ogston D, Douglas AS. The effect of age on the fibrinolytic enzyme system. J Clin Pathol 1974; 27 (4) 326-329
67 Gleerup G, Winther K. The effect of ageing on platelet function and fibrinolytic activity. Angiology 1995; 46 (8) 715-718
68 Abbate R, Prisco D, Rostagno C, Boddi M, Gensini GF. Age-related changes in the hemostatic system. Int J Clin Lab Res 1993; 23 (1) 1-3
69 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28 (6) 555-568
70 Mehta J, Mehta P, Lawson D, Saldeen T. Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations. J Am Coll Cardiol 1987; 9 (2) 263-268
71 Eren M, Painter CA, Atkinson JB, Declerck PJ, Vaughan DE. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation 2002; 106 (4) 491-496
72 Yamamoto K, Shimokawa T, Yi H , et al. Aging accelerates endotoxin-induced thrombosis: increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging. Am J Pathol 2002; 161 (5) 1805-1814
73 Cushman M, Lemaitre RN, Kuller LH , et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19 (3) 493-498
74 Yamamoto K, Takeshita K, Shimokawa T , et al. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 2002; 99 (2) 890-895
75 Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005; 66 (2) 276-285
76 Sakkinen PA, Cushman M, Psaty BM , et al. Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. Arterioscler Thromb Vasc Biol 1999; 19 (3) 499-504
77 Schatteman KA, Goossens FJ, Scharpé SS, Neels HM, Hendriks DF. Assay of procarboxypeptidase U, a novel determinant of the fibrinolytic cascade, in human plasma. Clin Chem 1999; 45 (6 Pt 1) 807-813
78 Favaloro EJ, McDonald D. Futility of testing for factor V Leiden. Blood Transfus 2012; 10 (3) 260-263
79 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L. Activated protein C resistance: the influence of ABO-blood group, gender and age. Thromb Res 2006; 117 (6) 665-670
80 Oger E, Lacut K, Le Gal G , et al. Is APC resistance a risk factor for venous thromboembolism in patients over 70 years?. Thromb Haemost 2002; 88 (4) 587-591
81 Zunker P, Hohenstein C, Plendl HJ , et al. Activated protein C resistance and acute ischaemic stroke: relation to stroke causation and age. J Neurol 2001; 248 (8) 701-704
82 Adams M. Assessment of thrombin generation: useful or hype?. Semin Thromb Hemost 2009; 35 (1) 104-110
83 Lippi G. Thrombophilia testing. Useful or hype?. Clin Chem Lab Med 2014; 52 (4) 467-469
84 Franchini M. The utility of thrombophilia testing. Clin Chem Lab Med 2014; 52 (4) 495-497
85 Favaloro EJ. The futility of thrombophilia testing. Clin Chem Lab Med 2014; 52 (4) 499-503
86 Berntorp E, Salvagno GL. Standardization and clinical utility of thrombin-generation assays. Semin Thromb Hemost 2008; 34 (7) 670-682
87 Hemker HC, Al Dieri R. Age-dependency of thrombin generation. Thromb Haemost 2006; 95 (5) 756-757
88 Mina A, Favaloro EJ, Koutts J. Relationship between short activated partial thromboplastin times, thrombin generation, procoagulant factors and procoagulant phospholipid activity. Blood Coagul Fibrinolysis 2012; 23 (3) 203-207
89 Tripodi A, Martinelli I, Chantarangkul V, Battaglioli T, Clerici M, Mannucci PM. The endogenous thrombin potential and the risk of venous thromboembolism. Thromb Res 2007; 121 (3) 353-359
90 Kaibara M, Iwata H, Ujiie H, Himeno R, Kaibara M. Rheological analyses of coagulation of blood from different individuals with special reference to procoagulant activity of erythrocytes. Blood Coagul Fibrinolysis 2005; 16 (5) 355-363
91 Haidl H, Cimenti C, Leschnik B, Zach D, Muntean W. Age-dependency of thrombin generation measured by means of calibrated automated thrombography (CAT). Thromb Haemost 2006; 95 (5) 772-775
92 Devreese K, Wijns W, Combes I, Van kerckhoven S, Hoylaerts MF. Thrombin generation in plasma of healthy adults and children: chromogenic versus fluorogenic thrombogram analysis. Thromb Haemost 2007; 98 (3) 600-613
93 Filippin L, Debaugnies F, Noubouossié D, Lê PQ, Ferster A, Demulder A. Thrombin generation test: establishment of reference values according to age and tissue factor concentration is essential before implementation into the laboratory [in French]. Rev Med Brux 2011; 32 (2) 69-73
94 Brummel-Ziedins K, Vossen CY, Rosendaal FR, Umezaki K, Mann KG. The plasma hemostatic proteome: thrombin generation in healthy individuals. J Thromb Haemost 2005; 3 (7) 1472-1481
95 Ninivaggi M, Kelchtermans H, Kuipers M , et al. Increased Thrombin Generation and Fibrin Formation In Premature Aging BMAL1 Deficient Mice. [Abstract] Blood 2013; 122 (21) 3575
96 Hézard N, Bouaziz-Borgi L, Remy MG, Nguyen P. Utility of thrombin-generation assay in the screening of factor V G1691A (Leiden) and prothrombin G20210A mutations and protein S deficiency. Clin Chem 2006; 52 (4) 665-670
97 Lippi G, Sanchis-Gomar F, Montagnana M. Biological markers in older people at risk of mobility limitations. Curr Pharm Des 2014; 20 (19) 3222-3244
98 Maggio M, Lauretani F, De Vita F , et al. Multiple hormonal dysregulation as determinant of low physical performance and mobility in older persons. Curr Pharm Des 2014; 20 (19) 3119-48
99 Agledahl I, Brodin E, Svartberg J, Hansen JB. Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels. Thromb Haemost 2009; 101 (3) 471-477
100 Brodin E, Vikan T, Hansen JB, Svartberg J. Testosterone, hemostasis, and cardiovascular diseases in men. Semin Thromb Hemost 2011; 37 (1) 87-94
101 Cesari M, Kritchevsky SB, Leeuwenburgh C, Pahor M. Oxidative damage and platelet activation as new predictors of mobility disability and mortality in elders. Antioxid Redox Signal 2006; 8 (3-4) 609-619
102 Dayal S, Wilson KM, Motto DG, Miller Jr FJ, Chauhan AK, Lentz SR. Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation 2013; 127 (12) 1308-1316
103 Jørgensen KA, Dyerberg J, Olesen AS, Stoffersen E. Acetylsalicylic acid, bleeding time and age. Thromb Res 1980; 19 (6) 799-805
104 Reilly IA, FitzGerald GA. Eicosenoid biosynthesis and platelet function with advancing age. Thromb Res 1986; 41 (4) 545-554
105 Bastyr III EJ, Kadrofske MM, Vinik AI. Platelet activity and phosphoinositide turnover increase with advancing age. Am J Med 1990; 88 (6) 601-606
106 Zahavi J, Jones NA, Leyton J, Dubiel M, Kakkar VV. Enhanced in vivo platelet “release reaction” in old healthy individuals. Thromb Res 1980; 17 (3-4) 329-336
107 Kasjanovová D, Baláz V. Age-related changes in human platelet function in vitro. Mech Ageing Dev 1986; 37 (2) 175-182
108 Mohebali D, Kaplan D, Carlisle M, Supiano MA, Rondina MT. Alterations in platelet function during aging: clinical correlations with thromboinflammatory disease in older adults. J Am Geriatr Soc 2014; 62 (3) 529-535
109 Oleksowicz L, Mrowiec Z, Zuckerman D, Isaacs R, Dutcher J, Puszkin E. Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism. Thromb Haemost 1994; 72 (2) 302-308
110 Roshan TM, Normah J, Rehman A, Naing L. Effect of menopause on platelet activation markers determined by flow cytometry. Am J Hematol 2005; 80 (4) 257-261
111 Bucciarelli P, Mannucci PM. The hemostatic system through aging and menopause. Climacteric 2009; 12 (Suppl. 01) 47-51
112 Miller VM, Jayachandran M, Owen WG. Ageing, oestrogen, platelets and thrombotic risk. Clin Exp Pharmacol Physiol 2007; 34 (8) 814-821
113 Carubbi C, Masselli E, Nouvenne A , et al. Laboratory diagnostics of inherited platelet disorders. Clin Chem Lab Med 2014; ; doi: 10.1515/cclm-2014-0131
114 Sestito A, Sciahbasi A, Landolfi R, Maseri A, Lanza GA, Andreotti F. A simple assay for platelet-mediated hemostasis in flowing whole blood (PFA-100): reproducibility and effects of sex and age. Cardiologia 1999; 44 (7) 661-665
115 Lippi G, Manzato F, Franchini M, Brocco G, Florenziani G, Guidi G. Establishment of reference values for the PFA-100 platelet function analyzer in pediatrics. Clin Exp Med 2001; 1 (1) 69-70
116 Cho YU, Chi HS, Jang S, Park CJ. Reconfirmation of preanalytical variables and establishment of reference intervals of platelet function analyzer-100 closure times in Korean adults [in Korean]. Korean J Lab Med 2007; 27 (5) 318-323
117 Kilanowska J, Favaloro EJ, Lippi G. Aspirin ‘responsiveness’, ‘nonresponsiveness’ or ‘resistance’: a putative role for von Willebrand factor?. Blood Coagul Fibrinolysis 2008; 19 (8) 823-824
118 Franchini M, Montagnana M, Targher G, Manzato F, Lippi G. Pathogenesis, clinical and laboratory aspects of thrombosis in cancer. J Thromb Thrombolysis 2007; 24 (1) 29-38
119 Lippi G, Maffulli N. Biological influence of physical exercise on hemostasis. Semin Thromb Hemost 2009; 35 (3) 269-276
120 Franchini M, Coppola A, Levi M, Favaloro EJ. Thrombotic and hemorrhagic syndromes associated with autoimmunity and infection. Semin Thromb Hemost 2012; 38 (5) 421-424
121 Morel O, Jesel L, Abbas M, Morel N. Prothrombotic changes in diabetes mellitus. Semin Thromb Hemost 2013; 39 (5) 477-488
122 Plebani M, Lippi G. Reference values and the journal: why the past is now present. Clin Chem Lab Med 2012; 50 (5) 761-763
123 Lippi G, Franchini M, Montagnana M, Guidi GC. Coagulation testing in pediatric patients: the young are not just miniature adults. Semin Thromb Hemost 2007; 33 (8) 816-820
124 Attard C, van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V. Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 2013; 11 (10) 1850-1854
125 Linden MD, Tran H, Woods R, Tonkin A. High platelet reactivity and antiplatelet therapy resistance. Semin Thromb Hemost 2012; 38 (2) 200-212
126 Frelinger AL, Li Y, Linden MD , et al. Aspirin ‘resistance’: role of pre-existent platelet reactivity and correlation between tests. J Thromb Haemost 2008; 6 (12) 2035-2044
127 Frelinger III AL, Li Y, Linden MD , et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009; 120 (25) 2586-2596
128 Gonzales JU, Thistlethwaite JR, Thompson BC, Scheuermann BW. Exercise-induced shear stress is associated with changes in plasma von Willebrand factor in older humans. Eur J Appl Physiol 2009; 106 (5) 779-784
129 Adams M, Williams A, Fell J. Exercise in the fight against thrombosis: friend or foe?. Semin Thromb Hemost 2009; 35 (3) 261-268