Risk Factors and Long-term Follow-up of Patients with the Immune Type of Heparin-Induced Thrombocytopenia

Abstract

Dispositional risk factors for developing the immune-type of heparin-induced thrombocytopenia (HIT) are yet unclear. This article presents a long-term follow-up of patients with HIT to define possible risk factors that may increase the risk of HIT. The clinical course of acute HIT was analyzed retrospectively in 52 patients with HIT. Thirteen patients died;8 due to HIT. A follow-up investigation was performed in 28 of the remaining 39 patients 29 ± 12 months after the onset of HIT, including genotyping for the factor V G1691A- and the prothrombin G20210A-mutation, measurement of antithrombin, protein C, protein S, factor VIII, and factor XII activity as well as the concentration of antiphospholipid antibodies. The results were compared to an age- and sex-matched control group. New thromboembolic events and re-exposure to heparin were also documented. No difference between patients and controls was observed concerning the factor V Leiden mutation, the prothrombin mutation, factor XII, antithrombin, protein S, or protein C deficiency and antiphospholipid antibodies. Increased factor VIII activity was found in 16 of 21 HIT patients compared to 4 of 21 controls (p=0.0005). New thromboembolic events developed in 5 patients within 9 months after HIT. One patient had been re-exposed to heparin 9 months after acute HIT without any complications. Increased factor VIII activity was frequently observed in patients in whom HIT developed. Thromboembolic complications within the first months after onset of HIT occurred often.

Keywords

Heparin-induced thrombocytopenia Elevated factor VIII Factor V Leiden mutation Prothrombin mutation Risk factors.

References

1. Chong BH , Berndt MC . Heparin-induced thrombocytopenia. Blood 1989;58:53-53.

2. Warkentin TE , Kelton JG . Heparin-induced thrombocytopenia. Progr Hemost Thromb 1991;10:1-1.

3. Warkentin TE , Kelton JG . A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502-502.

4. Warkentin TE , Sheppard JAI , Horsewood P , et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703-1703.

5. Dahlback B , Carlsson M , Svensson PJ . Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993;90:1004-1004.

6. Bertina RM , Koeleman BP , Koster T , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-64.

7. Poort SR , Rosendaal FR , Reitsma PH , et al. A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3698.

8. Gladson CL , Scharrer I , Hach V , et al. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988;59:18-18.

9. Melissari E , Monte G , Lindo VS , et al. Congenital thrombophilia among patients with venous thromboembolism. Blood Coag Fibrinol 1992;3:749-749.

10.

10. Kraaijenhagen RA , Anker PS , Koopman MMW , et al. High plasma concentration of factor VIlIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000;83:5-5.

11.

11. Folsom AR , Wu KK , Rosamond WD , et al. Prospective study of hemostatic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Circulation 1997;96:1102-1102.

12.

12. Folsom AR , Rosamond WD , Shahar E , et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. Circulation 1999;100:736-736.

13.

13. Seligsohn U , Lubetsky A . Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222-1222.

14.

14. Amiral J , Bridey F , Dreyfus M , Vissac AM , Fressinaud E , Wolf M , Meyer D . Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95-95.

15.

15. Greinacher A , Michels I , Kiefel V , et al. A rapid and sensitive test for diagnosing HAT. Thromb Haemost 1991;66:734-734.

16.

16. Boshkov LK , Warkentin TE , Hayward CPM , et al. Heparin-induced thrombocytopenia and thrombosis: Clinical and laboratory studies. Br J Haematol 1993;84:322-322.

17.

17. Lee DH , Warkentin TE , Denomme GA , et al. Factor V Leiden and thrombotic complications in heparin-induced thrombocytopenia. Thromb Haemost 1998;79:50-50.

18.

18. Rosendaal FR , Koster T , Vandenbroucke JP , et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85:1504-1504.

19.

19. Svensson PJ , Dahlback B . Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517-517.

20.

20. Kamphuisen PW , Eikenboom JCJ , Bertina RM . Elevated factor VIII levels and the risk of thrombosis. Arterioscl Thromb Vasc Biol 2001;21:731-731.

21.

21. Cushman M , Yanez D , Psaty BM , et al. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: The Cardiovascular Health Study: Cardiovascular Health Study Investigators. Am J Epidemiol 1996;143:665-665.

22.

22. Souto JC , Almasy L , Borrell M , et al. Genetic determinants of hemostasis phenotypes in spanish families. Circulation 2000;101:1546-1546.

23.

23. Gruel Y . Antiphospholipid syndrome and heparin-induced thrombocytopenia: Update on similarities and differences. J Autoimmunol 2000;15:265-265.

24.

24. Gruel Y , Rupin A , Watier H , et al. Anticardiolipin antibodies in heparin-associated thrombocytopenia. Thromb Res 1992;67:601-601.

25.

25. Warkentin TE , Kelton JG . Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286-1286.