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Thromb Haemost 1997; 78(05): 1327-1331
DOI: 10.1055/s-0038-1665405
Review Article
Schattauer GmbH Stuttgart

Levels of Prothrombin Fragment F1+2 in Patients with Hyperhomocysteinemia and a History of Venous Thromboembolism

Paul A Kyrle
1   The Department of Internal Medicine I, University of Vienna, Austria
,
Andreas Stümpflen
2   The Department of Internal Medicine II, University of Vienna, Austria
,
Mirko Hirschl
3   The Department of Hanuschkrankenhaus, University of Vienna, Vienna, Austria
,
Christine Bialonczyk
4   The Department of Wilhelminenspital, University of Vienna, Vienna, Austria
,
Kurt Herkner
5   The Children's Hospital, University of Vienna, Vienna, Austria
,
Wolfgang Speiser
6   The Clinical Institute of Medical and Chemical Laboratory Diagnostic, University of Vienna, Austria
,
Ansgar Weltermann
1   The Department of Internal Medicine I, University of Vienna, Austria
,
Alexandra Kaider
7   The Department of Medical Computer Sciences, Section of Clinical Biometrics, University of Vienna, Austria
,
Ingrid Pabinger
1   The Department of Internal Medicine I, University of Vienna, Austria
,
Klaus Lechner
1   The Department of Internal Medicine I, University of Vienna, Austria
,
Sabine Eichinger
1   The Department of Internal Medicine I, University of Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received 18 1997

Accepted after resubmission 16 July 1997

Publication Date:
12 July 2018 (online)

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Summary

Increased thrombin generation occurs in many individuals with inherited defects in the antithrombin or protein C anticoagulant pathways and is also seen in patients with thrombosis without a defined clotting abnormality. Hyperhomocysteinemia (H-HC) is an important risk factor of venous thromboembolism (VTE). We prospectively followed 48 patients with H-HC (median age 62 years, range 26-83; 18 males) and 183 patients (median age 50 years, range 18-85; 83 males) without H-HC for a period of up to one year. Prothrombin fragment Fl+2 (Fl+2) was determined in the patient’s plasma as a measure of thrombin generation during and at several time points after discontinuation of secondary thromboprophylaxis with oral anticoagulants. While on anticoagulants, patients with H-HC had significantly higher Fl+2 levels than patients without H-HC (mean 0.52 ± 0.49 nmol/1, median 0.4, range 0.2-2.8, versus 0.36 ± 0.2 nmol/1, median 0.3, range 0.1-2.1; p = 0.02). Three weeks and 3,6,9 and 12 months after discontinuation of oral anticoagulants, up to 20% of the patients with H-HC and 5 to 6% without H-HC had higher Fl+2 levels than a corresponding age- and sex-matched control group. 16% of the patients with H-HC and 4% of the patients without H-HC had either Fl+2 levels above the upper limit of normal controls at least at 2 occasions or (an) elevated Fl+2 level(s) followed by recurrent VTE. No statistical significant difference in the Fl+2 levels was seen between patients with and without H-HC. We conclude that a permanent hemostatic system activation is detectable in a proportion of patients with H-HC after discontinuation of oral anticoagulant therapy following VTE. Furthermore, secondary thromboprophylaxis with conventional doses of oral anticoagulants may not be sufficient to suppress hemostatic system activation in patients with H-HC.

 

  • References

  • 1 Bauer KA. Laboratory markers of coagulation activation. Arch Pathol Lab Med 1993; 117: 71-77
    PubMedSearch in Google Scholar
  • 2 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-353
    PubMedSearch in Google Scholar
  • 3 Boneu B, Bes G, Pelzer H, Sie P, Boccalon H. D-dimers, thrombin antithrombin ID complexes and prothrombin fragments 1+2: diagnostic value in clinically suspected deep vein thrombosis. Thromb Haemost 1991; 65: 28-31
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Elias A, Bonfils S, Daoud-Elias M, Gauthier B, Sie P, Boccalon H, Boneu B. Influence of long term oral anticoagulants upon Fl+2, thrombin-anti- thrombin III complex and D-dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69: 302-305
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68
    CrossrefPubMedSearch in Google Scholar
  • 6 de StefanoV, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87: 3531-3544
    PubMedSearch in Google Scholar
  • 7 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlback B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 2. Thromb Haemost 1996; 76: 824-834
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Conard J, Bauer KA, Gruber A, Griffin JH, Schwarz HP, Horellou MH, Samama MM, Rosenberg RD. Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency. Blood 1993; 82: 1159-1164
    PubMedSearch in Google Scholar
  • 9 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Bood 1988; 71: 1418-1426
    PubMedSearch in Google Scholar
  • 10 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De StefanoV, Palareti G, Manotti C, Nazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. Thromb Haemost 1992; 67: 200-202
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Zoeller B, Holm J, Svensson P, Dahlbäck B. Elevated levels of prothrombin activation fragment 1+2 in plasma from patients with heterozygous Arg506to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost 1996; 75: 270-274
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost 1996; 75: 703-705
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Kyrle PA, Eichinger S, Pabinger I, Stümpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Melichart M, Traxler G, Weltermann A, Speiser W, Lechner K. Prothrombin fragment Fl+2 is not predictive for recurrent venous thromboembolism. Thromb Haemost. 1997 in press.
    PubMedSearch in Google Scholar
  • 14 Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocysteinemia in patients with juvenile venous thrombosis. Arterioscl Thromb 1994; 14: 1080-1083
    CrossrefPubMedSearch in Google Scholar
  • 15 Fermo I, D’Angelo SV, Paroni R, Mazzola G, Calori G, D’Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med 1995; 123: 747-753
    CrossrefPubMedSearch in Google Scholar
  • 16 den HeijerM, Koster T, Blom HJ, Bos GMJ, Briet E, Reitsma PH, Vanden- broucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-762
    CrossrefPubMedSearch in Google Scholar
  • 17 Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Bene-detti L, Girolami A. Hyperhomocysteinemia and deep-vein thrombosis: a case control study. Thromb Haemost 1996; 76: 883-886
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Eichinger S, Pabinger I, Stiimpflen A, Hirschl M, Bialonczyk C, Schneider B, Mann C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thron****mbolism in patients with and without factor V Leiden. Thromb Haemost 1997; 77: 624-628
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Fiskerstrand T, Refsum H, Kvalheim G, Ueland PM. Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem 1993; 39: 263-271
    PubMedSearch in Google Scholar
  • 20 Pabinger I, Briicker S, Kyrle PA, Schneider B, Kominger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C, and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagulation Fibrinolysis 1992; 3: 547-553
    CrossrefPubMedSearch in Google Scholar
  • 21 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde, van dervelden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
    CrossrefPubMedSearch in Google Scholar
  • 22 Anderson A, Brattstrom L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender and menopausal status. Eur J Clin Invest 1992; 22: 79-87
    CrossrefPubMedSearch in Google Scholar
  • 23 Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270: 2693-2698
    CrossrefPubMedSearch in Google Scholar
  • 24 Nilsson K, Gustafson L, Faldt R, Andersson A, Hultberg P. Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriat- ric population. Eur J Clin Invest 1994; 24: 600-606
    CrossrefPubMedSearch in Google Scholar
  • 25 Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995; 274: 1526-1533
    CrossrefPubMedSearch in Google Scholar
  • 26 Malinow MR, Kang SS, Taylor LM, Wong PWK, Coull B, Inahara T, Mukeijee D, Sexton G, Upson B. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989; 79: 1180-1188
    CrossrefPubMedSearch in Google Scholar
  • 27 Genest JJ, McNamara JR, Salem DN, Wilson PWF, Schaefer EJ, Malinow MR. Plasma homocyst(e)ine in men with premature coronary artery disease. J Am Coll Cardiol 1990; 16: 1114-1119
    CrossrefPubMedSearch in Google Scholar
  • 28 Brattstrom L, Lindgren A, Isrealsson B, Malinow MR, Norving B, Upson HamfeltA. Hyperhomocysteinemia in stroke - prevalence, cause and relationships to type of stroke and stroke risk factors. Eur J Clin Invest 1992; 22: 214-221
    CrossrefPubMedSearch in Google Scholar
  • 29 Dalery K, Lussier-Cacan S, Selhub J, Davignon J, Latour Y, Genest JJ. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate and folate. Am J Card 1995; 75: 1107-1111
    CrossrefPubMedSearch in Google Scholar
  • 30 den HeijerM, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-885
    CrossrefPubMedSearch in Google Scholar