D-Dimers,Thrombin—Antithrombin Complexes,and Risk Factors for Thromboembolism in Hospitalized Patient

Abstract

Introduction There is lack of data about the correlation between hemostatic markers and the clinical and biological risk factors (RFs) for venous thromboembolism (VTE) in medical inpatients without suspicion of acute VTE. Material and methods To evaluate the coagulation activation status in patients with current known RFs for VTE, the authors measured 2 markers of hypercoagulability, thrombin antithrombin (TAT) complexes and D-dimers, at day 1 in 165 patients hospitalized in internal medicine wards without suspected acute VTE. All known RFs for VTE were systematically assessed at admission and classified in a chronological way as permanent or transient. Results Surprisingly, TAT values followed a multimodal distribution. D-dimers showed a normal distribution after a logarithmic transformation (P = .34, Shapiro—Wilk test). Interestingly, a significant progression in D-dimer levels was found according to the chronological classification of RFs. D-dimer variations on multivariate analysis (not applicable for TAT because of the multimodal distribution) correlated independently with a recent inability to walk and an increase in C reactive protein level more than 10 mg/L. Conclusions (a) this study is the first to describe the variations of hypercoagulability markers according to a systematic screening of RFs for VTE in inpatients without suspicion of acute VTE, (b) TAT appeared as a less relevant marker of hypercoagulability than D-dimers in internal medicine inpatients, (d) the chronological classification of RFs identified clearly groups at risk for the prethrombotic state, and (d) an increased hypercoagulability state was demonstrated in patients with an association between a recent immobility and increased inflammatory markers.

Keywords

thromboembolism risk factor hemostatic markers

References

Anderson DR , Kovacs MJ , Stiell I. , et al. Combined use of clinical assessment and D-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis. J Thromb Haemost. 2002 ;1:645-651.

Rosendaal FR Venous thrombosis: a multicausal disease. Lancet. 1999;353:1167-1173.

Cohen AT , Alikhan R. , Arcelus JI , et al. Assessment of venous thromboembolism risk and the benefits of thromboprophylaxis in medical patients. Thromb Haemost. 2005;94:750-759.

Wakefield TW , Henke PK The role of inflammation in early and late venous thrombosis: are there clinical implications? Semin Vasc Surg. 2005;18:118-129.

Chirinos JA , Heresi GA , Velasquez H. , et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism . J Am Coll Cardiol. 2005;45:1467-1471.

Collen D. , Hoylaerts MF Relationship between inflammation and venous thromboembolism as studied by microparticle assessment in plasma. J Am Coll Cardiol. 2005;45:1472-1473.

Esmon CT The impact of the inflammatory response on coagulation. Thromb Res. 2004;114:321-327.

Tsai AW , Cushman M. , Rosamond WD , et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med. 2002; 113:689-690.

Koster T. , Rosendaal FR , Reitsma PH , van der Velden PA , Briet E. , Vandenbroucke JP Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms-the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994;71:719-722.

10.

Bank I. , Libourel EJ , Middeldorp S. , et al. Elevated levels of FVIII:C within families associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost. 2005;3:79-84.

11.

Oger E. , Lacut K. , Van Dreden P. , et al. High plasma concentration of factor VIII coagulant is also a risk factor for venous thromboembolism in the elderly. Haematologica . 2003;88:465-469.

12.

Alikhan R. , Cohen AT , Combe S. , et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med. 2004;164:963-968.

13.

Yan SF , Mackman N. , Kisiel W. , Stern DM , Pinsky DJ Hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol. 1999;19:2029-2035.

14.

Ansari MT , Mahmood MT , Karlberg JP The association between seated immobility and local lower-limb venous coagulability in healthy adult volunteers: a simulation of prolonged travel immobility. Blood Coagul Fibrinolysis. 2006 ;17:335-341.

15.

Samama MM , Cohen AT , Darmon JY , et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341:793-800.

16.

Leizorovicz A. , Cohen AT , Turpie AG , Olsson CG , Vaitkus PT , Goldhaber SZ ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation . 2004;110:874-879.

17.

Cohen AT , Davidson BL , Gallus AS , et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ. 2006;332:325-329.

18.

Tan KK , Koh WP , Chao AKH Risk factors and presentation of deep venous thrombosis among Asian patients: a hospital-based case-control study in Singapore. Ann Vasc Surg. 2007;2:490-495.

19.

Chen JY , Chao TH , Guo YL , et al. A simplified clinical model to predict pulmonary embolism in patients with acute dyspnea. Int Heart J. 2006;47:259-271.

20.

Ravanat C. , Freund M. , Schuhler S. , Grunert P. , Meyer L. , Cazenave JP Species specific immunoassays to measure blood platelet and coagulation activation in the rat. Thromb Haemost. 1996 ;76:1090-1095.

21.

Pottier P. , Planchon B. , Truchaud F. , et al. Development of an experimental model of pre-thrombosis in rats based on Wessler’s principle using a calibrated venous stasis. Blood Coagul Fibrinolysis. 2003;14:3-9.

22.

Pottier P. , Planchon B. , Truchaud F. , et al. Efficacy of pentasaccharide on a prethrombosis model based on a calibrated stasis by the increase in up-stream venous pressure. Blood Coagul Fibrinolysis. 2003;14:587-591.

23.

Bounameaux H. , Slosman S. , de Moerloose P. , Reber G. Laboratory diagnosis of pulmonary embolism: value of increased levels of plasma D-dimers and thrombin-antithrombin III complexes. Biomed Pharmacother. 1989;43:385-388.

24.

Desjardins L. , Bara L. , Boutitie F. , et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Arch Pathol Lab Med. 2004 ;128: 519-526.

25.

Kakkar VV , Hoppenstead DA , Fareed J. , et al. Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis. Blood. 2002;99:1965-1970.

26.

Lopez Y. , Palmoma MJ , Rifon J. , Cuesta B. , Paramo JA Measurement of prethrombotic markers in the assessment of acquired hypercoagulable state. Thromb Res. 1999;93:71.

27.

Pottier P. , Planchon B. , Pistorius MA , Grolleau JY Risk factors and incidence of venous thromboembolic disease in internal medicine: prospective descriptive study on 947 hospitalized patients. Rev Med Interne. 2000; 22:348-359.

28.

Spyropoulos AC Emerging strategies in the prevention of venous thromboembolism in hospitalized medical patients. Chest. 2005;128:958-969.

29.

Lewis MR , Callas PW , Jenny NS , Tracy RP Longitudinal stability of coagulation, fibrinolysis and inflammation factors in stored plasma samples. Thromb Haemost. 2001;86:1495-1500.

30.

Miller DM Reducing transformation bias in curve fitting. Am Stat. 1984;38:124-126.

31.

Duan N. Smearing estimate: a non parametric retransformation method. J Am Stat Assoc. 1983;78:605-610.

32.

Bounameaux H. , Perrier A. Diagnostic approaches to suspected deep vein thrombosis and pulmonary embolism. Hematol J. 2003;4:97-103.

33.

Andreescu AC , Cushman M. , Rosendaal FR D-dimer as a risk factor for deep vein thrombosis: the Leiden Thrombophilia Study. Thromb Haemost. 2002;87:47-51.

34.

So AK , Varisco PA , Kemkes-Matthes B. , et al. Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. J Thromb Haemost. 2003;1:2510-2515.

35.

Psuja P. , Zozulinska M. , Turowiecka Z. , Cieslikowski W. , Vinazzer H. , Zawilska K. Plasma markers of hypercoagulability in patients with serious infections and risk of septic shock. Clin Appl Thromb Haemost. 2002;8:225-230.

36.

Francis CW Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med. 2007;356:1438-1444.

37.

Unlu Y. , Karapolat S. , Karaca Y. , Kiziltunc A. Comparison of levels of inflammatory markers and hemostatic factors in the patients with and without peripheral arterial disease. Thromb Res. 2006;117:357-364.

38.

Morange PE , Bickel C. , Nicaud V. , et al. Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: The Athero Gene Study. Arterioscler Thromb Vasc Biol. 2006;26:2793-2799.

39.

Mezzano D. , Pais EO , Aranda E. , et al. Inflammation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia. Kidney Int. 2001;60:1844-1850.

40.

Anzej S. , Bozic M. , Antovic A. , et al. Evidence of hypercoagulability and inflammation in young patients long after acute cerebral ischaemia. Thromb Res. 2007;120: 39-46.