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Effect of heparin administration on heparin-induced thrombocytopenia (HIT) in atherosclerotic New Zealand Rabbit (Oryctolagus cuniculus)

  • Victor Jesron Nababan ,
  • Agung Prasmono ,
  • Endang Retnowati ,
  • Djoko Legowo ,
  • Sofna Banjarnahor ,


Background: Platelets have been associated with the pathogenesis of atherosclerosis by excreting various chemokines (i.e. PF4), which systematically interact with multiple molecules. The formation of circulating heparin-platelet factor-4 (PF4) complexes have been observed in heparin-induced thrombocytopenia (HIT) cases, raising questions about the role of PF4-derived atherosclerosis in the predisposition of HIT.  

Methods: An in vivo model of atherosclerosis was generated by feeding rabbits with a high-cholesterol diet for six weeks and a normal rabbit as a control group. HIT was induced by injecting heparin subcutaneously for ten days twice daily. Platelets count before and after heparinization was performed by hemocytometer, PF4 measurement was determined by ELISA assay. Histopathology examinations for artery thickness, foam cell, and endothelial denudation were conducted by Hematoxylin and Eosin (H&E) staining.

Results: There was no significant difference in the IgG PF4/heparin complex between the atherosclerotic and the normal groups (43.84±2.07 ng/mL vs. 41.87±3.44 ng/mL), platelet count was significantly reduced only in the atherosclerotic group (p=0.01; mean differences 7162.00±57311.02/mm3), endothelial denudation and foam cell formation were observed in the atherosclerotic group. Also, a significant difference observed in endothelial thickness between the atherosclerotic group compared to the normal group (470.32 ± 131.15 µm vs. 332.05±50.82 µm; p=0.032).

Conclusion: Our results suggest that atherosclerosis was significantly associated with the development of heparin-induced thrombocytopenia. However, atherosclerosis is not a risk factor for the formation of PF4-heparin complex in HIT.


  1. World Health Organization. Cardiovascular diseases (CVDs). 2013
  2. Huo Y, Ley KF. Role of platelets in the development of atherosclerosis. Trends in cardiovascular medicine. 2004;14(1):18-22. PubMed PMID: 14720470.
  3. Linden MD, Jackson DE. Platelets: pleiotropic roles in atherogenesis and
  4. atherothrombosis. The international journal of biochemistry & cell biology. 2010;42(11):1762-6. PubMed PMID: 20673808
  5. Karshovska E, Weber C, von Hundelshausen P. Platelet chemokines in health and disease. Thrombosis and haemostasis. 2013;110(5):894-902. PubMed PMID: 23783401.
  6. Kannan M, Saxena R, Adiguzel C, Fareed J. An update on the prevalence and characterization of H-PF4 antibodies in Asian-Indian patients. Seminars in thrombosis and hemostasis. 2009;35(3):337-43. PubMed PMID: 19452409.
  7. Prechel MM, Walenga JM. Emphasis on the Role of PF4 in the Incidence,
  8. Pathophysiology and Treatment of Heparin Induced Thrombocytopenia. Thrombosis journal. 2013;11(1):7. PubMed PMID: 23561460. Pubmed Central PMCID: 3627638
  9. Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest. 2007;131(6):1644-9. PubMed PMID: 17400685.
  10. Tervaert JW. Translational mini-review series on immunology of vascular disease: accelerated atherosclerosis in vasculitis. Clinical and experimental immunology. 2009;156(3):377-85. PubMed PMID: 19309350. Pubmed Central PMCID: 2691964.
  11. Kim DN, Scott RF, Schmee J, Thomas WA. Endothelial cell denudation,
  12. labelling indices and monocyte attachment in advanced swine coronary artery lesions. Atherosclerosis. 1988;73(2-3):247-57. PubMed PMID: 3190822.
  13. Aliev G, Burnstock G. Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis. Histology and histopathology. 1998;13(3):797-817. PubMed PMID: 9690137.
  14. Qian Y, Pan J, Zhou X, Weiser P, Lu H, Zhang L. Molecular mechanism
  15. underlines heparin-induced thrombocytopenia and thrombosis. Progress in molecular biology and translational science. 2010; 93:395-421. PubMed PMID: 20807654.
  16. Sandset PM. CXCL4-platelet factor 4, heparin-induced thrombocytopenia and cancer. Thrombosis research. 2012;129 Suppl 1: S97-100. PubMed PMID: 22682144.
  17. Nakamoto H, Shimada Y, Kanno T, Wanaka K, Matsuo T, Suzuki H. Role of platelet factor 4-heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis. Hemodialysis international International Symposium on Home Hemodialysis. 2005;9 Suppl 1:S2-7. PubMed PMID: 16223438.
  18. Selleng K, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Critical care medicine. 2007;35(4):1165-76. PubMed PMID: 17334253.
  19. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. British journal of haematology. 2003;121(4):535-55. PubMed PMID: 12752095.
  20. Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Critical care. 2011;15(2):211. PubMed PMID: 21457505. Pubmed Central PMCID: 3219407.
  21. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a metaanalysis. Blood. 2005;15;106(8):2710-5. PubMed PMID: 15985543
  22. Lubenow N, Hinz P, Thomaschewski S, Lietz T, Vogler M, Ladwig A, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood. 2010;4;115(9):1797- 803. PubMed PMID: 19965682.
  23. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. The Annals of thoracic surgery. 2003;76(2):638-48. PubMed PMID: 12902132.
  24. Seigerman M, Cavallaro P, Itagaki S, Chung I, Chikwe J. Incidence and
  25. outcomes of heparin-induced thrombocytopenia in patients undergoing cardiac surgery in North America: an analysis of the nationwide inpatient sample. Journal of cardiothoracic and vascular anesthesia. 2014;28(1):98-102. PubMed PMID: 24295719.
  26. Sakr Y, Haetscher F, Gonsalves MD, Hoffman M, Theis B, Barz D, et al. Heparin-induced thrombocytopenia type II in a surgical intensive care unit. Journal of critical care. 2012;27(3):232-41. PubMed PMID: 21855286.

How to Cite

Nababan, V. J., Prasmono, A., Retnowati, E., Legowo, D., & Banjarnahor, S. (2020). Effect of heparin administration on heparin-induced thrombocytopenia (HIT) in atherosclerotic New Zealand Rabbit (Oryctolagus cuniculus). Bali Medical Journal, 9(3), 737–744.




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