Heparininduced thrombocytopenia in patients with venous thromboembolic complications – clinical cases and review of the literature

Severe thrombocytopenia significantly (at times and dozens of times) increases in-hospital mortality, especially for General surgical, vascular, orthopedic and traumatological patients in comparison with cardiosurgery and interventional cardiac patients. Heparin-induced thrombocytopenia is immune-mediated complication, paradoxically accompanied by frequent thrombosis. The risk of thrombosis varies from 30–50% for moderate and up to 90% in severe thrombocytopenia. Venous thrombosis predominate over the arterial, especially thrombosis of deep veins of lower extremities and pulmonary thromboembolia. Strokes, acute myocardial infarction, thrombosis of the mesenteric, vertebral arteries, central catheters are also not rare. The delay in diagnosis and in cessation of the heparins, the use of tromboconcentrate, not appointment of alternative anticoagulants – all of it worsen prognosis and increase mortality. Currently, in order to assess the possibility of Heparin-induced thrombocytopenia «Scale 4 T» is often in usage. It contains inaccuracies and provides 4 criteria and 3 degrees, that to some extent complicates its use. In early 2014, on the basis of literature analysis and own experience, we have developed a simplified «Rule» for the rapid diagnosis of this condition. Key points are highlighted in review regarding the pathophysiology, epidemiology, diagnosis, aspects of modern management, as well as the economic impact of heparin-induced thrombocytopenia and clinical examples in surgical patients confirmed by immunoassay. The next message will show a 3-year analysis of the incidence, causes, dynamics of outcomes in a multidisciplinary hospital, and the results of the implementation of the original «Rule».

1. Barinov VYe, Lobastov KV, Boyarintsev VV, Schastlivtsev IV. Clinical evaluation of the CAPRINI scale for individual prediction of the post-operative venous thromboembolism risk in surgical patients. Fundamentalnyye Issledovaniya, 2013. 12, 1: 11–16.

2. Bokeria LA, Chicherin IN. Heparin-induced thrombocytopenia (status update on the problem). M.: Bakoulev SCCS, RAMS, 2007. 96 p.

3. Dutkevich IG, Sukhomlina EN, Selivanov EA. Fundamentals of clinical hemostasiology. SPb.: IPK Costa LLC, 2010. 144 p.

4. Russian clinical guidelines for diagnosis, treatment and prevention of venous thromboembolic complications (VTEO). Flebologiya, 2015, 4 (2): 2–52.

5. Poletaeva GS, Rogalskaya EA, Klimovich LG, et al. Evaluation of the incidence of heparin-induced thrombocytopenia in patients with thrombocytopenia. Based on the materials of 21st All-Russia Congress of Cardiovascular Surgeons, Bakoulev SCCS of the Ministry of Health of the Russian Federation, 22 November 25, 2015 [Electronic resource]. 2015. Access mode: http://racvs.com/ events / archive/xxi_vserossiyskiy_sezd serdechnososudistykh_khirurgov/otsenka _chastoty_ vstrechaemosti_git_u_patsientov_ s_ trombotsitopeniey/Accessed date: 11.10.2015).

6. Samsonova NN, Klimovich LG, Rogalskaya EA. The pathogenesis of post-operative coagulopathies. Klinicheskaya Fiziologiya Krovoobrashcheniya, 2014, 4: 17-24.

7. Amiral J., Bridey F., Dreyfus M., et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia (Letter). Thromb Haemost. 1992. 68. 95–96.

8. Arepally G.M., Maver I.M. Antibodies from patients with heparin-induced thrombocytopenia simulate monocytic cells to express tissue factor and secrete interleukin 8. Blood. 2001. 98. 1252–1254.

9. Arepally G.M., Ortel T.L. Clinical practice. Heparin-induced thrombocytopenia . N. Engl. J. Med. 2006. 355, 8. 809–817.

10. Bakchoul T., Zöllner H., Greinacher A. Current insights into the laboratory diagnosis of HIT. Int. J. Lab. Hematol. 2014. 36, 3. 296–305.

11. Barilla D., Martinelli G.L., Cotroneo A., Romano A., Iacopino Thrombosis due to Heparin-induced Thrombocytopenia in Cardiac Surgery: is Fondaparinux an Effective Treatment? J Cardiovasc Dis Diagn. 2016. 4, 3. 240–245.

12. Battistelli S., Genovese A., Gori T. Heparin-induced thrombocytopenia in surgical patients. Am. J. Surg. 2010. 199, 1. 43–51.

13. Bito S., Miyata S., Migita K., et al. Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4/heparin antibody formation after orthopedic surgery. Blood. 2016. 127, 8. 1036–1043.

14. Bleasel J.F., Rasko J.E.J., Rickard K.A., Richards G. Acute adrenal insufficiency secondary to heparin-induced thrombocytopenia-thrombosis syndrome. Med J Aust. 1992. 157. 192–193.

15. Bozzato S., Galli L., Ageno W. Thromboprophylaxis in surgical and medical patients. Semin Respir Crit Care Med. 2012. 33, 2. 163–175.

16. Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005. 51. 70–78.

17. Creekmore F.M., Oderda G.M., Pendleton R.C., Brixner D.I. Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism. Pharmacotherapy. 2006. 10. 1438–1445.

18. Cuker A. Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost. 2011. 106. 6. 993–994.

19. Cuker A., Gimotty A., Crowther M.A., Warkentin T.E. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012. 120, 2. 4160–4167.20.Datta I., Ball C.G., Rudmik L., et al. Complications related to deep venous thrombosis prophylaxis in trauma: a systematic review of the literature. J Trauma Manag Outcomes. 2010. .4, 1 21.

20. Elalamy I., Le Gal G., Nachit-Ouinekh F., et al. Heparin-induced thrombocytopenia: an estimate of the average cost in the hospital setting in France. Clin Appl Thromb Hemost. 2009. 15, 4. 428–434.

21. Glance L.G., Blumberg N., Eaton M. et al. Preoperative Thrombocytopenia and Postoperative Outcomes after Noncardiac Surgery. Anesthesiology. 2014. 120, 1. 62–75.

22. Greinacher A., Warkentin T.E. Heparin-induced thrombocytopenia. New York, N.Y: Marcel Dekker. 2004. 106–107.

23. Greinacher A, Warkentin T.E. Recognition, treatment, and prevention of heparin-induced thrombocytopenia: review and update. Thromb Res. 2006. 118, 2. 165–176.

24. Gordois A., Posnett J., Borris L., et al. The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery. J Thromb Haemost 2003. 1, 10. 2167–2174.

25. Jaben E.A., Torloni A.S., Pruthi R.K., Winters J.L. Use of plasma exchange in patients with heparin-induced thrombocytopenia: a report of two cases and a review of the literature. J Clin Apher. 2011. 26, 4. 219–224.

26. Jang I.K., Hursting M.J. When heparins promote thrombosis: review of heparin-induced thrombocytopenia. Circulation. 2005. 111, 20. 2671–2683.

27. Jia Q., Brown M.J., Clifford L. et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulation tests: a single-institution propensity-adjusted cohort study. Lancet Haematology. 2016. 3, 3. e139 e148.

28. Kang M., Alahmadi M., Sawh S., Kovacs M.J., Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015. 125, 6. 924–929.

29. Kelton J.G., Sheridan D., Santos A., et al. Heparin-induced thrombocytopenia: laboratory studies. Blood. 1988. 72. 925–930.

30. LaMuraglia G.M., Houbballah R., Laposata M. The identification and management of heparin-induced thrombocytopenia in the vascular patient. J.Vasc.Surg. 2012. 55, 2. 562–570.

31. Lewis B.E., Wallis D.E., Berkowitz S.D., et al. Argatroban anticoagulant therapy in patients with heparin- induced thrombocytopenia. Circulation. 2001. 103. 1838–1843.

32. Linkins L.A., Dans A.L., Moores L.K. et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest. 2012. 141. e495S e530S.

33. Lo G.K., Juhl D., Warkentin T.E., et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006. 4, 4. 759–765.

34. Lo G.K., Sigouin C.S., Warkentin T.E. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol. 2007. 82, 12. 1037–1043.

35. Matthai W.H. Thrombocytopenia in Cardiovascular Patients. Diagnosis and Management. Chest. 2005. 127. 46S 52S.

36. Motokawa S., Torigoshi T., Maeda Y., et al. IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics. BMC Musculoskelet Disord. 2011. 12. 22–34.

37. Newman M., Chong B.H. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood. 2000. 96. 182–187.

38. Pannucci C.J., Bailey S.H., Dreszer G., et al. Validation of the Caprini Risk Assessment Model in Plastic and Reconstructive Surgery Patients. J Am Coll Surg. 2011. 212, 1. 105– 112.

39. Pearson M., Nadeau Ch., Blais N. Correlation of ELISA Optical Density With Clinical Diagnosis of Heparin-Induced Thrombocytopenia. A Retrospective Study of 104 Patients With Positive Anti-PF4/Heparin ELISA. Clin Appl Thromb Hemost. 2014. 20, 4. 349–354.

40. Pouplard C., May M-A., Iochmann S., et al. Antibodies to Platelet Factor 4-Heparin After Cardiopulmonary Bypass in Patients Anticoagulated With Unfractionated Heparin or a Low-Molecular-Weight Heparin: Clinical Implications for Heparin-Induced Thrombocytopenia. Circulation. 1999. 99. 2530– 2536.

41. Potzsch B., Klovekorn W. , Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia (Letter). N Engl J Med. 2000. 343. 515–522.

42. Smythe MA, Koerber JM, Fitzgerald M, Mattson JC. The financial impact of heparin-induced thrombocytopenia. Chest. 2008. 134, 3. 568–573

43. Schindewolf M., Steindl J., Beyer-Westendorf J., et al. Frequent of-label use of fondaparinux in patients with suspected acute heparin-induced thrombocytopenia (HIT) – findings from the GerHIT multi-centre registry study. Thrombosis research. 2014. 134. 29–35.

44. Sullivan S.D., Kwong L. Cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against venous thromboembolism in patients undergoing hip fracture surgery. Value Health. 2006. 9, 2. 68–76.

45. Topol E.J., Moliterno D.J., Herrmann H.C., et al. Comparison of two platelet glycoprotein IIb/ IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N. Engl. J. Med. 2001. 344. 1888–1894.

46. Visentin G., Ford S.E., Scott J., Aster R.H. Antibodies from patients with heparin-induced thrombocytope nia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest. 1994. 93. 81–88.

47. Wallis D.E., Workman D.L., Lewis B.E., et al. Failure of early heparin cessation as treat ment fogy heparin-induced thrombocytopenia. Am J Med. 1999. 106. 629–635.

48. Warkentin T.Е., Hayward C. M., Boshkov U.K., et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood. 1994. 84. 3691–3699.

49. Warkentin T.E., Levine M.N., Hirsh J., et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995. 332. 1330–1335.

50. Warkentin T.E., Kelton J.G. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996. 101. 502–507.

51. Warkentin T.E., Elavathil L.J., Hayward C. M., et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997. 127. 804–812.

52. Warkentin T.E. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin T.E., Greinacher A. (Eds.). Heparin-Induced Thrombocytopenia, 2nd ed. New York: Marcel Dekker Inc. 2001. 43–86.

53. Warkentin T.E., Kelton J.G. Temporal aspects of heparin-induced thrombocytopenia. N. Engl. J. Med. 2001. 344. 1286–1292.

54. Warkentin T.E., Heddle N.M. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr. Hematol. Re 2003. 2, 2. 148–157.

55. Warkentin T.E. Heparin-induced thrombocytopenia: pathogenesis and management. Br. J. Haematol. 2003. 121. 4. 535–555.

56. Warkentin T.E. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest. 2005. 127. 35–45.

57. Warkentin T.E., Greinacher A. So, does low-molecular-weight heparin cause less heparin-induced thrombocytopenia than unfractionated heparin or not?. Chest. 2007. 132, 4. 1108–1110.

58. Warkentin T.E., Sheppard J.A., Heels-Ansdell D., et al. Heparin-induced thrombocytopenia in medical surgical critical illness. Chest. 2013. 144, 3. 848–858.

59. Warkentin T.E., Greinacher A. Management of heparin-induced thrombocytopenia. Curr Opin Hematol. 2016. 5. 462–470.

60. Watson H, Davidson S, Keeling D. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br. J. Haematol. 2012. 159. 5. 528–540.

61. Wilke T, Tesch S, Scholz A, Kohlmann T, Greina -cher A. The costs of heparin-induced thrombocytopenia: a patient-based cost of illness analysis. J Thromb Haemost. 2009. 7. 5. 766–773.