Relationship between Platelet Aggregatory and Heparin-Induced Thrombocytopenia Type II
Heparin-induced thrombocytopenia type II (HIT) is a significant adverse effect of heparin treatment in either therapeutic or prophylactic doses. HIT is an immune-mediated disorder caused by IgG antibodies that bind to platelet factor 4 (PF4), which becomes an antigenic target when bound to heparin. The possibility of HIT is suspected when patients show a reduction in the platelet count while receiving heparin. However, the diagnosis of HIT may be difficult on the basis of clinical symptoms alone, especially in patients with other diseases that may induce thrombocytopenia. Therefore, confirmation of HIT by using biologic or antigen assays is required. To analyze whether two patients in whom thrombocytopenia was induced after initiating administration of unfractionated heparin during percutaneous transluminal coronary angioplasty or coronary artery bypass grafting surgery had HIT, we measured levels of platelet aggregability, anti-heparin-PF4 complex antibody (anti-HIT antibody), tumor necrosis factor (TNF)-alpha, TNF-receptor 1 (TNF-R1), interleukin (IL)-6, and thrombin-antithrombin III complex (TAT). The two patients were judged to be HIT-positive from the results that platelet aggregation induced with induced by ADP 1 μM as well as collagen 0.2 μg/mL increased after addition of UFH. ELISA results of two patients showing optical density (OD) values greater than 0.40 were regarded as positive. Additionally, the levels of TNF-alpha and TAT in both patients were higher than in the control patients who underwent CABG without thrombocytopenia after heparin therapy initiation. The results suggest that blood coagulation is enhanced and an inflammatory reaction is induced in the endothelial cells of patients with HIT. In conclusion, the combined measurement of platelet aggregation and anti-HIT antibodies is crucial for defining HIT status, and measurement of TNF-alpha and TAT may play a significant role in the practice of anticoagulant therapy.
Relationship between Platelet Aggregatory and Heparin-Induced Thrombocytopenia Type II, Science Research.
Vol. 2, No. 4,
2014, pp. 78-86.
B. Girolami, P. Prandoni, P.M. Stefani, C. Tanduo, P. Sabbion, P. Eichler, R. Ramon, G. Baggio, F. Fabris, A. Girolami. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood, vol. 8, pp. 2955-2959, Apr 2003.
J. Hirsh, N. Heddle, J.G. Kelton. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med, vol. 8, pp. 361-369, Feb 2004.
E. Shantsila, G.Y. Lip, B.H. Chong. Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management. Chest, vol. 6, pp. 1651-1664, Jun 2009.
S. Battistelli, A. Genovese, T. Gori. Heparin-induced thrombocytopenia in surgical patients. Am J Surg, vol. 1, pp. 43-51, Jan 2010.
M. J. Zibaeenezhad, Y. Mazloum. Heparin infusion after successful percutaneous coronary intervention: a prospective, randomized trial. Acta Cardiol, vol. 1, pp. 65-70, Feb 2009.
G. Montalescot, V Polle, J.P. Collet, P. Leprince, A. Bellanger, I. Gandjbakhch, D. Thomas. Low molecular weight heparin after mechanical heart valve replacement. Circulation, vol. 10, pp. 1083-1086, Mar 2000.
B.H. Chong, J. Burgess, F. Ismail. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost, vol. 4, pp. 344-350, Apr 1993.
P. Fondu. Heparin-associated thrombocytopenia: an update. Acta Clin Belgica, vol. 6, pp. 343-357, 1995.
B.H. Chong. Heparin-induced thrombocytopenia. Br J Haematol, vol. 3, pp. 431-439, Mar 1995.
T.E. Warkentin, M.N. Levine, J. Hirsh, P. Horsewood, R.S. Roberts, M. Gent, J.G. Kelton. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med, vol. 20, pp. 1330-1335, May 1995.
B.H. Chong. Heparin-induced thrombocytopenia. Aust N Z J Med, vol. 2, pp. 145-152, Apr 1992.
T.E. Warkentin, J.G. Kelton. A 14-year study of heparin-induced thrombocytopenia. Am J Med, vol. 5, pp. 502-507, Nov 1996.
F. Fabris, G. Luzzatto, P.M. Stefani, B. Girolami, G. Cella, A. Girolami. Heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia. Haematologica, vol. 1, pp. 72-81, Jan 2000.
D.E. Wallis, D.L. Workman, B.E. Lewis, L. Steen, R. Pifarre, J.F. Moran. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med, vol. 6, pp. 629-635, Jun 1999.
J.G. Kelton. Heparin-induced thrombocytopenia: an overview. Blood Rev, vol. 1, pp. 77-80, Mar 2002.
T.P. Baglin. Heparin induced thrombocytopenia thrombosis (HIT/T) syndrome: diagnosis and treatment. J Clin Pathol, vol. 4, pp. 272-274, Apr 2001.
J. Amiral, F. Bridey, M. Dreyfus, A.M. Vissoc, E. Fressinaud, M. Wolf, D. Meyer. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost, vol. 1, pp. 95-96, Jul 1992.
J.G. Kelton, J.W. Smith, T.E. Warkentin, C.P. Hayward, G.A. Denomme, P. Horsewood. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood, vol. 11, pp. 3232-3239, Jun 1994.
A. Greinacher, B. Pötzsch, J. Amiral, V. Dummel, A. Eichner, C. Mueller-Eckhardt. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost, vol. 2, pp. 247-251, Feb 1994.
B.H. Chong, C.S. Grace, M.C. Rozenberg. Heparin-induced thrombocytopenia: effect of heparin platelet antibody on platelets. Br J Haematol, vol. 4, pp. 531-540, Dec 1981.
B.H. Chong, I. Fawaz, C.N. Chesterman, M.C. Berndt. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol, vol. 2, pp. 235-240, Oct 1989.
T.E. Warkentin, J.G. Kelton. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med, vol. 17, pp. 1286-1292, Apr 2001.
T.E. Warkentin, J.I. Sheppard. Generation of platelet-derived microparticles and procoagulation activity by heparin-induced thrombocytopenia IgG/serum and other IgG platelet agonists: a comparison with standard platelet agonists. Platelets, vol. 5, pp. 319-326, 1999.
G.M. Arepally, I.M. Mayer. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood, vol. 4, pp. 1252-1254, Aug 2001.
C. Pouplard, S. Iochmann, B. Renard, O. Herault, P. Colombat, J. Amiral, Y. Gruel. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia. Blood, vol. 10, pp. 3300-3302, May 2001.
Lee D.H, Warkentin T.E. Frequency of heparin-induced thrombocytopenia. In: Warkentin T.E, Greinacher A editors. Heparin-induced thrombocytopenia, 3rd ed. NY: Marcel Dekker press, 2004, pp. 107-48.
T.E. Warkentin, A. Greinacher. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. The seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 3 Suppl, pp. 311S-337S, Sep 2004.
N. Martel, J. Lee, P.S. Wells. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood, vol. 8, pp. 2710-2715, Oct 2005.
J.L. Francis, G.J. 3rd. Palmer, R. Moroose, A. Drexler. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg, vol. 1, pp. 17-22, Jan 2003.
T.E. Warkentin. Clinical picture of heparin-induced thrombocytopenia. In: T.E. Warkentin, A. Greinacher editors. Heparin-induced thrombocytopenia. 3rd ed. NY: Marcel Dekker press, 2004, pp. 53-106.
T.E. Warkentin, N.M. Heddle. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep, vol. 2, pp. 148-157, Mar 2003.
A. Lillo-Le Louët, P. Boutouyrie, M. Alhenc-Gelas, C. Le Beller, I. Gautier, M. Aiach , D. Lasne. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost, vol. 11, pp. 1882-1888, Nov 2004.
Y. Gruel, S. Régina, C. Pouplard. Usefulness of pretest clinical score (4Ts) combined with immunoassay for the diagnosis of heparin-induced thrombocytopenia. Curr Opin Pulm Med, vol. 5, pp. 397-402, Sep 2008.
B. Denys, V. Stove, J. Philippé, K. Devreese. A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia. Thromb Res, vol. 1, pp. 137-145, 2008.
K. Nakamura. Heparin-induced thrombocytopenia. In: Charles H. Lawrie, ed. Hematology- Science and Practice. Croatia: In Tech, 2012, pp 517-540.
H. Toyohira, K. Nakamura, H. Kariyazono, K. Yamada, Y. Moriyama, S. Shimokawa, H. Saigenji, A. Taira. Significance of combined use of anticoagulants and antiplatelet agents in the early stage after prosthetic valve replacement. Kyobu Geka, vol. 9, pp. 749-55, Aug 1995.
H. Kariyazono, K. Nakamura, T. Shinkawa, Y. Moriyama, H. Toyohira, A. Taira, K. Yamada. Inhibitory effects of antibiotics on platelet aggregation in vitro. Hum Exp Toxicol, vol 11, pp. 662-666, Nov 1997.
K. Nakamura, H. Kariyazono, M. Masuda, R. Sakata, Y. Yamada. Effects of sarpogrelate hydrochloride onadenosine diphosphate- or collagen-induced platelet response in arteriosclerosis obliterans. Blood Coagul Fibrinolysis, vol. 5, pp. 391-397, Jul 2001.
A. Greinacher, J. Amiral, V. Dummel, A. Vissac, V. C. Mueller-Eckhardt. Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion, vol. 5, pp. 381-385, May 1994.
Y. Ozaki, T. Matuo, S. Okamoto, Y. Ikeda. Heparin-induced thrombocytopenia, HIT information center Press, Japan, 2004, pp. 1-22.
N.L. Whitlatch, S.L. Perry, T.L. Ortel. Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost, vol. 4, pp. 678-684, Oct 2008.
T.E. Warkentin. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost, vol. 2, pp. 439-447, Aug 1999.
G.K. Lo, D. Juhl, T.E. Warkentin, C.S. Sigouin, P. Eichler, A. Greinacher. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost, vol. 4, pp. 759-765, Apr 2006.
T.E. Warkentin. Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transfus Med Rev, vol. 4, pp. 249-258, Oct 1996.
A.P. Betrosian, G. Theodossiades, G. Lambroulis, D. Kostantonis, M. Balla, M. Papanikolaou, G. Georgiades. Heparin-induced thrombocytopenia with pulmonary embolism and disseminated intravascular coagulation associated with low-molecular-weight heparin. Am J Med Sci, vol. 1, pp. 45-47, Jan 2003.
K. Althaus, G. Hron, U. Strobel, R. Abbate, A. Rogolino, S. Davidson, A. Greinacher, T. Bakchoul. Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. Thromb Res, vol. 3, pp. 85-90, Mar 2013.
J. Amiral, A. Marfaing-Koka, M. Poncz, D. Meyer. The biological basis of immune heparin-induced thrombocytopenia. Platelets, vol. 2, pp. 77-91, 1998.
T.E. Warkentin, J.A. Sheppard, P. Horsewood, P.J. Simpson, J.C. Moore, J.G. Kelton. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood, vol. 5, pp. 1703-1708, Sep 2000.
A. Greinacher, I. Michels, C. Mueller-Eckhardt. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost, vol. 5, pp. 545-549, May 1992.
A. Greinacher, I. Michels, U. Liebenhoff, P. Presek, C. Mueller-Eckhardt. Heparin-associated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulphated oligosaccharides. Br J Haematol, vol. 4, pp. 711-716, Aug 1993.
Y. Gruel, B. Boizard-Boval, J.L. Wautier. Further evidence that alpha-granule components such as platelet factor 4 are involved in platelet-IgG-heparin interactions during heparin-associated thrombocytopenia. Thromb Haemost, vol. 2, pp. 374-375, Aug 1993.
G. Gentilini, N.E. Kirschbaum, J.A. Augustine, R.H. AsterH, G.P. Visentin. Inhibition of human umbilical vein endothelial cell proliferation by the CXC chemokine, platelet factor 4 (PF4), is associated with impaired downregulation of p21(Cip1/WAF1). Blood, vol. 1, pp 25-33, Jan 1999.
G.P. Visentin, S.E. Ford, J.P. Scott, R.H. Aster. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. Clin Invest, vol. 1, pp. 81-88, Jan 1994.
S. Pillarisetti, L. Paka, A. Sasaki, T. Vanni-Reyes, B. Yin, N. Parthasarathy, W.D. Wagner, I.J. Goldberg. Endothelial cell heparanase modulation of lipoprotein lipase activity. Evidence that heparan sulfate oligosaccharide is an extracellular chaperone. J Biol Chem, vol. 25, pp. 15753-15759, Jun 1997.
J.S. Suh, R.H. Aster, G.P. Visentin. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin: platelet factor 4. Blood, vol. 3, pp. 916-922, Feb 1998.
L. Ziporen, Z.Q. Li, K.S. Park, P. Sabnekar, W.Y. Liu, G. Arepally, Y. Shoenfeld, T. Kieber-Emmons, D.B. Cines, M. Poncz. Defining an antigenic epitope on platelet factor 4 associated with heparin-induced thrombocytopenia. Blood, vol. 9, pp 3250–3259, Nov 1998.
J. Amiral, F. Bridey, M. Wolf, C. Boyer-Neumann, E. Fressinaud, A.M. Vissac, E. Peynaud-Debayle, M. Dreyfus, D. Meyer. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost, vol. 1, pp. 21-28, Jan 1995.
L.K. Boshkov, T.E. Warkentin, C.P. Hayward, M. Andrew, J.G. Kelton. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol, vol. 2, pp. 322-328, Jun 1993.
T.E. Warkentin. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med, vol. 11, pp. 1415-1423, Nov 2002.
R.A. Saad. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol, vol. 2, pp. 373-374, Oct 2003.
J.G. Kelton, D. Sheridan, A. Santos, J. Smith, K. Steeves, C. Smith, C. Brown, W.G. Murphy. Heparin-induced thrombocytopenia: laboratory studies. Blood, vol. 3, pp. 925-930, Sep 1988.
C. Bachelot-Loza, R. Saffroy, D. Lasne, G. Chatellier, M. Aiach, F. Rendu. Importance of the FcgammaRIIa-Arg/His-131 polymorphism in heparin-induced thrombocytopenia diagnosis. Thromb Haemost, vol. 3, pp. 523-528, Mar 1998.
C. Pouplard, M.A. May, S. Iochmann, J. Amiral, A.M. Vissac, M. Marchand, Y. Gruel. 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, vol. 19, pp. 2530-2536, May 1999.
M.A. Orchard, K.A. Waddell, P.J. Lewis, I.A. Blair IA. Thromboxane synthase inhibition causes re-direction of prostaglandin endoperoxides to prostaglandin D2 during collagen stimulated aggregation of human platelet rich plasma. Thromb Res, vol. 6, pp. 701-710, Sep 1985.
B.W. Böttiger, H. Böhrer, T. Böker, J. Motsch, M. Aulmann, E. Martin. Platelet factor 4 release in patients undergoing cardiopulmonary resuscitation--can reperfusion be impaired by platelet activation? Acta Anaesthesiol Scand, vol. 5, pp. 631-635, May 1996.
J.N. Zhang, A.L. Bergeron, Q. Yu, C. Sun, L. McBride, P.F. Bray, J.F. Dong. Duration of exposure to high fluid shear stress is critical in shear-induced platelet activation-aggregation. Thromb Haemost, vol. 4, pp. 672-678, Oct 2003.
G.K. Lo, C.S. Sigouin, T.E. Warkentin. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol, vol. 12, pp. 1037-1043, Dec 2007.
T.E. Warkentin, J.I. Sheppard, J.C. Moore, C.S. Sigouin, J.G. Kelton. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost, vol. 8, pp. 1304-1312, Aug 2008.
V. Nellen, I. Sulzer, G. Barizzi, B. Lämmle, L. Alberio. Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a single-center experience with 1,291 patients. Haematologica, vol. 1, pp. 89-97, Jan 2012.
S. Schenk, A. El-Banayosy, M. Morshuis, L. Arusoglu, P. Eichler, N. Lubenow, G. Tenderich, R. Koerfer, A. Greinacher, W. Prohaska. IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support. J Thromb Haemost, vol. 2, pp. 235-241, Feb 2007.
T.E. Warkentin, J.A. Sheppard, J.C. Moore, K.M. Moore, C.S. Sigouin, J.G. Kelton. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med, vol. 6, pp. 341-346, Dec 2005.
J.M. Walenga, W.P. Jeske, M.M. Prechel, M. Bakhos. Newer insights on the mechanism of heparin-induced thrombocytopenia. Semin Thromb Hemost, vol. Suppl 1, pp. 57-67, Feb 2004.
T.E. Warkentin , L.J. Elavathil, C.P. Hayward, M.A. Johnston, J.I. Russett, J.G. Kelton. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med, vol. 9, pp. 804-812, Nov 1997.
L. Chilver-Stainer, B. Lämmle, L. Alberio. Titre of anti-heparin/PF4-antibodies and extent of in vivo activation of the coagulation and fibrinolytic systems. Thromb Haemost, vol. 2, pp. 276-282, Feb 2004.