Download PDF
Thromb Haemost 1996; 76(02): 166-170
DOI: 10.1055/s-0038-1650547
Original Article
Schattauer GmbH Stuttgart

Modulation of Plasma Fibrinogen Levels by Ticlopidine in Healthy Volunteers and Patients with Stable Angina Pectoris

Moniek P M de Maat
1   The Dept. Internal Medicine II, Erasmus University Rotterdam, The Netherlands
2   The Gaubius Laboratory TNO-PG, Leiden, The Netherlands
,
Alf E R Arnold
3   The Dept. Cardiology, Medical Center Alkmaar, The Netherlands
,
Stef van Buuren
2   The Gaubius Laboratory TNO-PG, Leiden, The Netherlands
,
J H Paul Wilson
1   The Dept. Internal Medicine II, Erasmus University Rotterdam, The Netherlands
,
Cornells Kluft
2   The Gaubius Laboratory TNO-PG, Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 01 March 1996

Accepted after resubmission 22 April 1996

Publication Date:
10 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Elevated plasma fibrinogen levels are associated with an increased risk for cardiac events. Ticlopidine is a drug that inhibits the ADP-induced aggregation of blood platelets and it also has been described that ticlopidine can decrease the plasma fibrinogen level in patients with vascular diseases. The mechanism of this decrease has not yet been elucidated and therefore mechanisms that are known to affect fibrinogen levels were studied, viz. the acute phase reaction, total fibrin plus fibrinogen degradation (TDP) levels and the polymorphisms of the fibrinogen β-gene.

The fibrinogen lowering effect of ticlopidine was studied in 26 healthy volunteers, selected on genotype of the BclI polymorphism of the fibrinogen β-gene, and in 26 patients with stable angina pectoris in a double blind, randomized cross-over study. Functional plasma fibrinogen levels were measured with the Clauss assay. Fibrinogen antigen, C-reactive protein (CRP) and TDP levels were measured using an enzyme immuno assay (EIA).

In the healthy volunteers the functional fibrinogen levels had decreased by 0.20 g/l (9%, p = 0.005 using the paired Student t-test) after 4 weeks of 250 mg bid ticlopidine administration, whereas fibrinogen antigen, CRP and TDP levels were not significantly changed. In the stable angina pectoris patients the pre-treatment fibrinogen, CRP and TDP levels were significantly higher than in the volunteer group. After four weeks 250 mg bid ticlopidine administration the functional fibrinogen levels had decreased by 0.38 g/l (11%, p < 0.005), whereas the fibrinogen antigen, CRP and TDP levels were not significantly changed. The levels of functional and antigen fibrinogen, CRP and TDP did not change significantly during the placebo period in the volunteers or the patients. Neither in the volunteers nor in the patients was the effect of ticlopidine on the fibrinogen levels associated with the fibrinogen β-gene polymorphisms.

Therefore, the fibrinogen lowering effect of ticlopidine is likely to be a modulation of the functionality of the molecule and unlikely to be modulated by the acute phase reaction, TDP-levels or the fibrinogen β-gene polymorphisms.

 

  • References

  • 1 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thrompson SG. Haemostatic function and ischaemic heart disease: principle results of the Northwick Part heart study. Lancet 1986; ii: 533-537
    PubMedGoogle Scholar
  • 2 Wilhelmsen L, Svardsudd 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: 501-505
    CrossrefPubMedGoogle Scholar
  • 3 Stone MC, Thorpe JM. Plasma fibrinogen - a major coronary risk factor. J Roy Coll Gen Pract 1985; 35: 565-569
    PubMedGoogle Scholar
  • 4 Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insight from the Framingham study. Am Heart J 1987; 113: 1006-1010
    CrossrefPubMedGoogle Scholar
  • 5 Balleisen L, Schulte H, Assmann G, Epping PH, van de Loo J. Coagulation factors and the progress of coronary heart disease (Letter). Lancet 1987; i: 461
    PubMedGoogle Scholar
  • 6 Kostis JB, Baughman J, Kuo PT. Association of recurrent myocardial infarction with hemostatic factors: a prospective study. Chest 1982; 81: 571-575
    CrossrefPubMedGoogle Scholar
  • 7 Haverkate F. Thrombosis and disabilities. In: Advances in Medical Biology Baya C. ed. 1994. vol 3 IOS Press; Amsterdam: 81-103
  • 8 Baxter K, Wiseman S, Powell J, Greenhalgh R. Pilot study of a screening test for peripheral arterial disease in middle aged men: fibrinogen as a possible risk factor. Cardiovasc Res 1988; 22: 300-302
    CrossrefPubMedGoogle Scholar
  • 9 Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med 1988; 19: 634-636
    PubMedGoogle Scholar
  • 10 Small M, Lowe GDO, Beattie JM. Severity of coronary artery disease and basal fibrinolysis. Haemostasis 1987; 17: 305-311
    PubMedGoogle Scholar
  • 11 Lowe GDO, Drummond MM, Lorimer AR, Hutton I, Forbes CD, Prentice CRM, Barbenel JC. Relation between extent of coronary artery disease and blood viscosity. Br Med J 1980; 80: 673-677
    PubMedGoogle Scholar
  • 12 Handa K, Kono S, Saku K, Sasaki J, Kawano T, Sasaki Y, Hiroki T, Arakawa K. Plasma fibrinogen levels as an independent indicator of severity of coronary atherosclerosis. Atherosclerosis 1989; 77: 209-213
    CrossrefPubMedGoogle Scholar
  • 13 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809
    CrossrefPubMedGoogle Scholar
  • 14 Broadhurst P, Kelleher C, Hughes L, Imeson JD, Raftery EB. Fibrinogen, factor VII clotting activity and coronary artery disease severity. Atherosclerosis 1990; 85: 169-173
    CrossrefPubMedGoogle Scholar
  • 15 ECAT Angina Pectoris Study Group. ECAT Angina Pectoris Study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 8-17
    PubMedGoogle Scholar
  • 16 de Maat MPM, Pietersma A, Kofflard M, Sluiter W, Kluft C. Association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers. Atherosclerosis 1996; 121: 185-191
    CrossrefPubMedGoogle Scholar
  • 17 Neumann V, Cove DH, Shapiro LM, George AJ, Kenny MW, Meakin M, Stuart J. Effect of ticlopidine on platelet function and blood rheology in diabetes mellitus. Clin Hemorr 1983; 3: 13-21
    PubMedGoogle Scholar
  • 18 Conard J, Lecrubier C, Scarabin PY, Horellou MH, Samama M, Bousser MG. Effects of long term admininistration of ticlopidine on platelet function and hemostatic variables. Thromb Res 1980; 20: 143-148
    CrossrefPubMedGoogle Scholar
  • 19 Randi ML, Fabris F, Crociani ME, Battocchio F, Girolami A. Effects of ticlopidine on blood fibrinogen and blood viscosity in peripheral atherosclerotic disease. Drug Res 1985; 12: 1847-1849
    PubMedGoogle Scholar
  • 20 Randi ML, Mares M, Fabris F, Tison T, Barbbone E, Girolami A. Decrease of fibrinogen in patients with peripheral atherosclerotic disease by Ticlopidine. Arzneim-Forsch/Drug. Res 1991; 41: 414-416
    PubMedGoogle Scholar
  • 21 Palareti G, Poggi M, Torricelli P, Balestra V, Coccheri S. Long-term effects of ticlopidine on fibrinogen and haemorheology in patients with peripheral arterial disease. Thromb Res 1988; 52: 621-629
    CrossrefPubMedGoogle Scholar
  • 22 Tekeres M, Sarosi I, Juricskay I, Losoncsy H, Nagy I. Effect of longterm ticlopidine therapy on the rheological properties of blood. Seventh International Congress on Thrombosis, Valencia, Spain, October 1982 (abstract 215).
    PubMedGoogle Scholar
  • 23 Vicari AM, Penasa L, Pozza G. Clinical effectiveness of ticlopidine in diabetic subjects: a double-blind study. Haemostasis 1982 12. 203 (Abstract).
    PubMedGoogle Scholar
  • 24 Aukland A, Hurlow RA, George AJ, Stuart J. Platelet inhibition with ticlopidine in atherosclerotic intermittent claudation. J Clin Pathol 1982; 35: 740-743
    CrossrefPubMedGoogle Scholar
  • 25 Drouet L, Mazoyer E, Ripoll L, Dosquet C, Tobelem G. Fibrinogen phenotype (plasma level and activity) and genotype in atherothrombotic patients. Evolution after ticlopidine treatment. Thromb Haemost 1995 76. 1379 (Abs 1834).
    PubMedGoogle Scholar
  • 26 Defreyn G, Bemat A, Delebassee D, Maffrand J. Pharmacology of Ticlopidine: A Review. Sem Thromb Hemost 1989; 15: 159-166
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 O’Brien JR. Ticlopidine - a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 1983; 13: 1-54
    PubMedGoogle Scholar
  • 28 O’Brien JR, Etherington MD, Shuttleworth RD. Ticlopidine- an antiplatelet drug: Effects in human volunteers. Thromb Res 1978; 13: 245-254
    CrossrefPubMedGoogle Scholar
  • 29 Hass WK, Easton JD, Adams Jr HP, Molony BA, Kamm B. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507
    CrossrefPubMedGoogle Scholar
  • 30 Stuart J. The acute-phase reaction and haematological stress syndrome in vascular disease. Int J Microcirc: Clin Exp 1984; 3: 115-129
    PubMedGoogle Scholar
  • 31 Clinton SK, Libby P. Cytokines and growth factors in atherogenesis. Arch Pathol Lab Med 1992; 116: 12292-3000
    PubMedGoogle Scholar
  • 32 Entman ML, Michael L, Rossen RD, Dreyer WJ, Anderson DC, Taylor AA, Smith CW. Inflammation in the course of early myocardial ischemia. FASEBJ 1991; 5: 2529-2537
    CrossrefPubMedGoogle Scholar
  • 33 La Duca FM, Tinsley LA, Dang CV, Bell WR. Stimulation of fibrinogen synthesis in cultured rat hepatocytes by fibrinogen degradation product fragment D. Proc Natl Acad Sci USA 1989; 86: 8788-8792
    CrossrefPubMedGoogle Scholar
  • 34 Peerschke EIB. The platelet fibrinogen receptor. Sem Haem 1985; 23: 241-259
    PubMedGoogle Scholar
  • 35 Kessler CM, Bell WR. The effect of homologous thrombin and fibrinogen degradation products on fibrinogen synthesis in rabbits. J Lab Clin Med 1979; 93: 768-782
    PubMedGoogle Scholar
  • 36 Princen HMG, Moshage HJ, Emeis JJ, de Haard HJW, Nieuwenhuizen W, Yap SH. Fibrinogen fragments X, Y, D and E increase levels of plasma fibrinogen and liver mRNA’s coding for fibrinogen polypeptides in rats. Thromb Haemost 1985; 53: 212-215
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Moshage HJ, Princen HMG, van Pelt J, Roelofs HMJ, Nieuwenhuizen W, Yap SH. Differential effects of endotoxin and fibrinogen degradation products (FDPS) on liver synthesis of fibrinogen and albumin: evidence for the involvement of a novel monokine in the stimulation of fibrinogen synthesis induced by FDPS. Int J Biochem 1990; 22: 1393-1400
    CrossrefPubMedGoogle Scholar
  • 38 Von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestim-mung des Fibrinogenes. Acta Haematol 1957; 17: 237-246
    CrossrefPubMedGoogle Scholar
  • 39 Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; 1: 1452-1455
    PubMedGoogle Scholar
  • 40 Cook M, Godiner N, Green F, Stirling Y, Meade TW, Humphries SE. Genetic control of plasma fibrinogen levels. In: Fibrinogen 3. Biochemistry, biological functions, gene regulation and expression. Mossewson MW.
    PubMedGoogle Scholar
  • 41 Berg K, Kierulf P. DNA polymorphisms at fibrinogen loci and plasma fibrinogen concentration. Clin Gen 1989; 36: 229-235
    PubMedGoogle Scholar
  • 42 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the β fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-490
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Green F, Hamsten A, Blombäck M, Humphries S. The role of β-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Haemostasis 1993; 70: 915-920
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Sherman LA. Catabolism of fibrinogen and its derivatives. Thromb Haemost 1977; 38: 809-822
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Hoegee-de Nobel E, Voskuilen M, Briet E, Brommer EJP, Nieuwenhuizen W. A monoclonal antibody-based quantitative enzyme immuoassay for the determination of plasma fibrinogen concentrations. Thromb Haemost 1988; 60: 415-418
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Koopman J, Haverkate F, Koppert P, Nieuwenhuizen W, Brommer EJP, van der Werf WGC. New enzyme immuno assay of fibrin-fibrinogen degradation products in plasma using a monoclonal antibody. J Lab Clin Med 1987; 109: 75-84
    PubMedGoogle Scholar
  • 47 Koppert PW, Hoegee-De Nobel E, Nieuwenhuizen W. A monoclonal antibody-based immunoassay for fibrin degradation products in plasma. Thromb Haemost 1988; 59: 310-315
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Koopman J, Haverkate F, Koppert P, Nieuwenhuizen W, Brommer EJP, van der Werf WGC. New enzyme immuno assay of fibrin-fibrinogen degradation products in plasma using a monoclonal antibody. J Lab Clin Med 1987; 109: 75-84
    PubMedGoogle Scholar
  • 49 Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A−455 (UaeIII), C/T−148 (HindIII/Alul), T/G+1689 (AvaII), and BclI (β-fibrinogen) and TaqI (aα-fibrinogen), and their detection by PCR. Human Mutation 1994; 3: 79-81
    CrossrefPubMedGoogle Scholar
  • 50 Senn S. Cross-over trials in clinical research. Barnet V (Ed), 1993 John Wiley, Sons Chichester, Amram DL, Siebenlist KR, DiOrio JP. (eds) 1988. Elsevier Science Publishers BV; Amsterdam: 1 1-15
  • 51 Harbison JW. For the Ticlopidine Aspirin Stroke Study Group. Ticlopidine versus aspirin for the prevention of recurrent stroke. Stroke 1992; 23: 1723-1727
    CrossrefPubMedGoogle Scholar
  • 52 Krusius T, Hirvonen M, Vahtera E, Kala R. Short-term aspirin treatment does not reduce plasma fibrinogen concentration in young healthy adults. Thromb Res 1994; 75: 653-656
    CrossrefPubMedGoogle Scholar
  • 53 Hampton KK, Cerletti C, Louizou LA, Bucchi F, Donati MB, Davies JA, de Gaetano G, Prentice CRM. Coagulation, fibrinolytic and platelet function in patients on long-term therapy with aspirin 300 mg or 1,200 mg daily compaired with placebo. Thromb Haemost 1990; 64: 17-20
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Eritsland J, Seljeflot I, Amesen H, Smith P, Westvik A. Effects of longterm treatment with warfarin on fibrinogen, FPA, TAT, and D-Dimer in patients with coronary artery disease. Thromb Res 1992; 66: 55-60
    CrossrefPubMedGoogle Scholar
  • 55 de Bart ACW, Hennis BC, Havelaar AC, Kluft C. Variability in information from a single venapuncture in healthy volunteers: analysis of the haemostatic variables fibrinogen, plasminogen activator inhibitor (PAI) activity and histidine-rich glycoprotein (HRG). Fibrinolysis 1992; 6 (Suppl. 03) 81-82
    PubMedGoogle Scholar
  • 56 Scarabin P, Plu-Bureau G, Bara L, Bonithon-Kopp C, Guize L, Samama MM. Haemostatic variables and menopausal status: influence of hormone replacement therapy. Thromb Haemost 1993; 70: 584-587
    Article in Thieme ConnectPubMedGoogle Scholar