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Vol. 33, No. 4, 2003
Issue release date: July–August 2003
Pathophysiol Haemost Thromb 2003;33:192–196
(DOI:10.1159/000081507)

Acquired and Inherited Thrombophilic Factors and the Risk for Residual Venous Thrombosis

Bank I.a · Tick L.W.c · Hutten B.A.b · Kramer M.H.H.c · Middeldorp S.a · Büller H.R.a
Departments of aVascular Medicine and bClinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam and cDepartment of Internal Medicine, Eemland Hospital, Amersfoort, The Netherlands
email Corresponding Author

Abstract

Acquired and inherited thrombophilic factors increase the risk for (recurrent) venous thrombotic disease. However, little is known about the pathophysiological mechanisms causing these recurrences, or the persistence of thrombosis despite adequate treatment. Because residual thrombosis has been associated with a worse prognostic outcome, we performed an explorative study in order to investigate the prevalence of residual thrombotic lesions after anticoagulant treatment in patients with deep venous thrombosis. Thrombotic parameters as assessed by ultrasonography after a 12-week course of anticoagulants were used. Both thrombophilia in general and acquired thrombophilia in particular were found to be associated with the extent of residual thrombosis. Of the individual thrombophilic factors, protein C deficiency, prothrombin 20210A mutation, active malignant disease and lupus anticoagulant were associated with an increased risk of residual thrombotic mass. Patients with inherited thrombophilia did not differ from patients without any thrombophilic abnormality with regard to residual thrombotic mass [relative risk (RR) 1.3, 95% confidence interval (CI) 0.9–1.8], while acquired thrombophilic disorders increased the risk for residual thrombotic mass as compared to patients without any defect (RR 1.7, 95% CI 1.2–2.2). Although these results should be confirmed in a larger study, they might help us form hypotheses concerning why patients with thrombophilia are more prone to recurrent venous thromboembolic disease.


 goto top of outline Key Words

  • Residual thrombosis
  • Location of thrombotic lesions
  • Deep venous thrombosis
  • Inherited thrombophilia
  • Acquired thrombophilia

 goto top of outline Abstract

Acquired and inherited thrombophilic factors increase the risk for (recurrent) venous thrombotic disease. However, little is known about the pathophysiological mechanisms causing these recurrences, or the persistence of thrombosis despite adequate treatment. Because residual thrombosis has been associated with a worse prognostic outcome, we performed an explorative study in order to investigate the prevalence of residual thrombotic lesions after anticoagulant treatment in patients with deep venous thrombosis. Thrombotic parameters as assessed by ultrasonography after a 12-week course of anticoagulants were used. Both thrombophilia in general and acquired thrombophilia in particular were found to be associated with the extent of residual thrombosis. Of the individual thrombophilic factors, protein C deficiency, prothrombin 20210A mutation, active malignant disease and lupus anticoagulant were associated with an increased risk of residual thrombotic mass. Patients with inherited thrombophilia did not differ from patients without any thrombophilic abnormality with regard to residual thrombotic mass [relative risk (RR) 1.3, 95% confidence interval (CI) 0.9–1.8], while acquired thrombophilic disorders increased the risk for residual thrombotic mass as compared to patients without any defect (RR 1.7, 95% CI 1.2–2.2). Although these results should be confirmed in a larger study, they might help us form hypotheses concerning why patients with thrombophilia are more prone to recurrent venous thromboembolic disease.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Schulman S, Svenungsson E, Granqvist S: Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998;104:332–338.
  2. Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, Weltermann A, Speiser W, Lechner K, Eichinger S: High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457–462.
  3. Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999;78:285–291.
  4. Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P: Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002;137:955–960.
  5. The Persist investigators: A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemost 2004;2:47–53.
  6. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, Villalta S, Buller HR, Turpie AG, Prandoni P: Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: Prospective cohort study. BMJ 1998;316:17–20.
  7. Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, ten Cate JW, Huisman MV, Buller HR: Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342–345.
  8. Michiels JJ, Hamulyak K: Laboratory diagnosis of hereditary thrombophilia. Semin Thromb Hemost 1998;24:309–320.
  9. Sturk A, Morrien-Salomons WM, Huisman MV, Borm JJ, Buller HR, ten Cate JW: Analytical and clinical evaluation of commercial protein C assays. Clin Chim Acta 1987;165:263–270.
  10. Deutz-Terlouw PP, Ballering L, van Wijngaarden A, Bertina RM: Two ELISA’s for measurement of protein S, and their use in the laboratory diagnosis of protein S deficiency. Clin Chim Acta 1990;186:321–334.
  11. Guidelines on testing for the lupus anticoagulant. Lupus Anticoagulant Working Party on behalf of the BCSH Haemostasis and Thrombosis Task Force. J Clin Pathol 1991;44:885–889.
  12. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–67.
  13. Danneberg J, Abbes AP, Bruggeman BM, Engel H, Gerrits J, Martens A: Reliable genotyping of the G-20210-A mutation of coagulation factor II (prothrombin). Clin Chem 1998;44:349–351.
  14. Ubbink JB, Hayward VW, Bissbort S: Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991;565:441–446.
  15. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR: Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995;345:152–155.
  16. Middeldorp S, Buller HR, Prins MH: Approach to the thrombophilic patient; in Colman RW, Hirsch JL, Marder VJ, Clowes AW, George JN (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, ed 4. Philadelphia, Lippincott-Raven, 2000, pp 1085–1100.

 goto top of outline Author Contacts

I. Bank
Department of Vascular Medicine, Academic Medical Center
F4-277, Meibergdreef 9
NL–1105 AZ, Amsterdam (The Netherlands)
Tel. +31 20 5665976, Fax +31 20 6968833, E-Mail I.Bank@amc.uva.nl


 goto top of outline Article Information

Received: February 25, 2004
Accepted after revision: June 22, 2004
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 2, Number of References : 16


 goto top of outline Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 33, No. 4, Year 2003 (Cover Date: July-August 2003)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/pht


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Acquired and inherited thrombophilic factors increase the risk for (recurrent) venous thrombotic disease. However, little is known about the pathophysiological mechanisms causing these recurrences, or the persistence of thrombosis despite adequate treatment. Because residual thrombosis has been associated with a worse prognostic outcome, we performed an explorative study in order to investigate the prevalence of residual thrombotic lesions after anticoagulant treatment in patients with deep venous thrombosis. Thrombotic parameters as assessed by ultrasonography after a 12-week course of anticoagulants were used. Both thrombophilia in general and acquired thrombophilia in particular were found to be associated with the extent of residual thrombosis. Of the individual thrombophilic factors, protein C deficiency, prothrombin 20210A mutation, active malignant disease and lupus anticoagulant were associated with an increased risk of residual thrombotic mass. Patients with inherited thrombophilia did not differ from patients without any thrombophilic abnormality with regard to residual thrombotic mass [relative risk (RR) 1.3, 95% confidence interval (CI) 0.9–1.8], while acquired thrombophilic disorders increased the risk for residual thrombotic mass as compared to patients without any defect (RR 1.7, 95% CI 1.2–2.2). Although these results should be confirmed in a larger study, they might help us form hypotheses concerning why patients with thrombophilia are more prone to recurrent venous thromboembolic disease.



 goto top of outline Author Contacts

I. Bank
Department of Vascular Medicine, Academic Medical Center
F4-277, Meibergdreef 9
NL–1105 AZ, Amsterdam (The Netherlands)
Tel. +31 20 5665976, Fax +31 20 6968833, E-Mail I.Bank@amc.uva.nl


 goto top of outline Article Information

Received: February 25, 2004
Accepted after revision: June 22, 2004
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 2, Number of References : 16


 goto top of outline Publication Details

Pathophysiology of Haemostasis and Thrombosis

Vol. 33, No. 4, Year 2003 (Cover Date: July-August 2003)

Journal Editor: Rosing, J. (Maastricht)
ISSN: 1424–8832 (print), 1424–8840 (Online)

For additional information: http://www.karger.com/pht


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Schulman S, Svenungsson E, Granqvist S: Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med 1998;104:332–338.
  2. Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, Weltermann A, Speiser W, Lechner K, Eichinger S: High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457–462.
  3. Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth R, Rimm AA: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999;78:285–291.
  4. Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P: Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002;137:955–960.
  5. The Persist investigators: A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemost 2004;2:47–53.
  6. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, Villalta S, Buller HR, Turpie AG, Prandoni P: Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: Prospective cohort study. BMJ 1998;316:17–20.
  7. Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, ten Cate JW, Huisman MV, Buller HR: Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342–345.
  8. Michiels JJ, Hamulyak K: Laboratory diagnosis of hereditary thrombophilia. Semin Thromb Hemost 1998;24:309–320.
  9. Sturk A, Morrien-Salomons WM, Huisman MV, Borm JJ, Buller HR, ten Cate JW: Analytical and clinical evaluation of commercial protein C assays. Clin Chim Acta 1987;165:263–270.
  10. Deutz-Terlouw PP, Ballering L, van Wijngaarden A, Bertina RM: Two ELISA’s for measurement of protein S, and their use in the laboratory diagnosis of protein S deficiency. Clin Chim Acta 1990;186:321–334.
  11. Guidelines on testing for the lupus anticoagulant. Lupus Anticoagulant Working Party on behalf of the BCSH Haemostasis and Thrombosis Task Force. J Clin Pathol 1991;44:885–889.
  12. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–67.
  13. Danneberg J, Abbes AP, Bruggeman BM, Engel H, Gerrits J, Martens A: Reliable genotyping of the G-20210-A mutation of coagulation factor II (prothrombin). Clin Chem 1998;44:349–351.
  14. Ubbink JB, Hayward VW, Bissbort S: Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991;565:441–446.
  15. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR: Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995;345:152–155.
  16. Middeldorp S, Buller HR, Prins MH: Approach to the thrombophilic patient; in Colman RW, Hirsch JL, Marder VJ, Clowes AW, George JN (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, ed 4. Philadelphia, Lippincott-Raven, 2000, pp 1085–1100.