Pathogenesis of heparin-induced thrombocytopenia

References

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6. Warkentin T.E., Greinacher A. So, does low-molecular-weight heparin cause less heparin-induced thrombocytopenia than unfractionated heparin or not? Chect. 2007; 132 (4): 1108–10. DOI: 10.1378/chest.07-1553
7. Linkins L.A., Dans A.L., Moores L.K., Bona R., Davidson B.L., Schulman S., Crowther M. 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 (2, Suppl.): e495S–e530S. DOI: 10.1378/ chest.11-2303
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10. Chong B.H., Ismail F. The mechanism of heparininduced platelet aggregation. Eur. J. Haematol. 1989; 43 (3): 245–51. DOI: 10.1111/j.1600-0609.1989.tb00290.x
11. Weismann R.E., Tobin R.W. Arterial embolism occurring during systemic heparin therapy. AMA Arch Surg. 1958; 76 (2): 219–27. DOI: 10.1001/archsurg.1958.01280200041005
12. Warkentin T.E., Sheppard J.A., Moore J.C., Cook R.J., Kelton J.G. Studies of the immune response in heparin-induced thrombocytopenia. Blood. 2009; 113 (20): 4963–9. DOI: 10.1182/blood-2008-10-186064
13. Amiral J., Bridey F., Dreyfus M., Vissoc A.M., Fressinaud E., Wolf M., Meyer D. Platelet factor 4 complexed 298 Reviews Clinical Physiology of Circulation. 2020; 17 (4). DOI: 10.24022/1814-6910-2020-17-4-294-298 to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost. 1992; 68 (1): 95–6. DOI: 10.1055/s-0038-1656329
14. Zucker M.B., Katz I.R. Platelet factor 4: production, structure, and physiologic and immunologic action. Proc. Soc. Exp. Biol. Med. 1991; 198 (2): 693–702. DOI: 10.3181/00379727-198-43309
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17. Marcum J.A., McKenney J.B., Rosenberg R.D. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J. Clin. Invest. 1984; 74 (2): 341–50. DOI: 10.1172/jci111429
18. Handin R.I., Cohen H.J. Purification and binding properties of human platelet factor four. J. Biol. Chem. 1976; 251 (14): 4273–82.
19. Bock P.E., Luscombe M., Marshall S.E., Pepper D.S., Holbrook J.J. The multiple complexes formed by the interaction of platelet factor 4 with heparin. Biochem. J. 1980; 191 (3): 769–76. DOI: 10.1042/bj1910769
20. Suvarna S., Espinasse B., Qi R., Lubica R., Poncz M., Cines D.B. et al. Determinants of PF4/heparin immunogeneicity. Blood. 2007; 110 (13): 4253–60. DOI: 10.1182/blood-2007-08-105098
21. Greinacher A., Alban S., Omer-Adam M.A., Weitschies W., Warkentin T.E. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb. Res. 2008; 122 (2): 211–20. DOI: 10.1016/j.thromres.2007.11.007
22. Brandt S., Krauel K., Gottschalk K.E., Renné T., Helm C.A., Greinacher A., Block S. Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity. Thromb. Haemost. 2014; 112 (1): 53–64. DOI: 10.1160/TH13-08-0634
23. Kreimann M., Brandt S., Krauel K., Block S., Helm C.A., Weitschies W. et al. Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4. Blood. 2014; 124 (15): 2442–9. DOI: 10.1182/blood2014-03-559518
24. Bauer T.L., Arepally G., Konkle B.A., Mestichelli B., Shapiro S.S., Cines D.B. et al. Prevalence of heparinassociated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation. 1997; 95 (5): 1242–6. DOI: 10.1161/01.cir.95.5.1242
25. Amiral J., Peynaud-Debayle E., Wolf M., Bridey F., Vissac A.M., Meyer D. Generation of antibodies to heparin-PF4 complexes without thrombocytopenia in patients treated with unfractionated or low-molecularweight heparin. Am. J. Hematol. 1996; 52 (2): 90–5. DOI: 10.1002/(sici)1096-8652(199606)52:2%3C90:: aid-ajh4%3E3.0.co;2-0
26. Warkentin T.E., Sheppard J.A., Horsewood P., Simpson P.J., Moore J.C., Kelton J.G. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000; 96 (5): 1703–8. DOI: 10.1182/blood.v96.5.1703.h8001703_1703_1708
27. Warkentin T.E., Cook R.J., Marder V.J., Sheppard J.I., Moore J.C., Eriksson B. et al. Antiplatelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood. 2005; 106 (12): 3791–6. DOI: 10.1182/blood-2005-05-1938
28. Visentin G.P., Malik M., Cyganiak K.A., Aster R.H. Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin: platelet factor 4 complexes. J. Lab. Clin. Med. 1996; 128 (4): 376–83. DOI: 10.1016/s0022-2143 (96)80009-6
29. Krauel K., Schulze A., Jouni R., Hackbarth C., Hietkamp B., Selleng S. et al. Further insights into the antiPF4/heparin IgM immune response. Thromb. Haemost. 2016; 115 (4): 752–61. DOI: 10.1160/TH15-08-0654
30. Khandelwal S., Lee G.M., Hester C.G., Poncz M., McKenzie S.E., Sachais B.S. et al. The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21). Blood. 2016; 128 (14): 1789–99. DOI: 10.1182/blood-2016-04-709634
31. Zheng Y., Wang A.W., Yu M., Padmanabhan A., Tourdot B., Newman D.K. et al. B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood. 2014; 123 (6): 931–4. DOI: 10.1182/blood-2013-11-540781
32. Reilly M.P., Taylor S.M., Hartman N.K., Arepally G.M., Sachais B.S., Cines D.B. et al. Heparininduced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgRIIA. Blood. 2001; 98 (8): 2442–7. DOI: 10.1182/blood.v98.8.2442
33. Warkentin T.E., Hayward C.P., Boshkov L.K., Santos A.V., Sheppard J.A., Bode A.P., Kelton J.G. 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 (11): 3691–9. DOI: 10.1182/blood.v84.11.3691.bloodjournal84113691
34. Arepally G.M., Mayer I.M. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood. 2001; 98 (4): 1252–4. DOI: 10.1182/blood.v98.4.1252

1. Bockeria L.A., Chicherin I.N. Нeparin-induced thrombocytopenia. Moscow; 2007 (in Russ.)
2. Pirogov A.L. Heparininduced thrombocytopenia in cardiovascular surgery. Pathogenesis, diagnostics and correction methods. Complex Issues of Cardiovascular Diseases. 2014; 4: 95–103 (in Russ.). DOI: 10.17802/ 2306-1278-2014-4-95-103
3. Petrova O.V., Egorova T.G., Murygina O.I., Vavilova T.V. New possibilities of diagnostics of heparin-induced thrombocytopenia in cardiosurgical patients. Medical Alphabet. 2013; 3 (16): 41–4 (in Russ.)
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5. Arepally G.M. Heparin-induced thrombocytopenia. Blood. 2017; 129: 2864–72. DOI: 10.1182/blood-2016- 11-709873 6. Warkentin Т.E. Нeparin-induced thrombocytopeniа and anaesthesiology. Can. J. Anesth. 2002; 49 (6): 36–49.
6. Warkentin T.E., Greinacher A. So, does low-molecular-weight heparin cause less heparin-induced thrombocytopenia than unfractionated heparin or not? Chect. 2007; 132 (4): 1108–10. DOI: 10.1378/chest.07-1553
7. Linkins L.A., Dans A.L., Moores L.K., Bona R., Davidson B.L., Schulman S., Crowther M. 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 (2, Suppl.): e495S–e530S. DOI: 10.1378/ chest.11-2303
8. Kosyrev A.B. A modern solution for diagnosing the syndrome of “heparin-induced thrombocytopenia”. Medical Alphabet. 2011; 1 (4): 44–6 (in Russ.)
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10. Chong B.H., Ismail F. The mechanism of heparininduced platelet aggregation. Eur. J. Haematol. 1989; 43 (3): 245–51. DOI: 10.1111/j.1600-0609.1989.tb00290.x
11. Weismann R.E., Tobin R.W. Arterial embolism occurring during systemic heparin therapy. AMA Arch Surg. 1958; 76 (2): 219–27. DOI: 10.1001/archsurg.1958.01280200041005
12. Warkentin T.E., Sheppard J.A., Moore J.C., Cook R.J., Kelton J.G. Studies of the immune response in heparin-induced thrombocytopenia. Blood. 2009; 113 (20): 4963–9. DOI: 10.1182/blood-2008-10-186064
13. Amiral J., Bridey F., Dreyfus M., Vissoc A.M., Fressinaud E., Wolf M., Meyer D. Platelet factor 4 complexed 298 Reviews Clinical Physiology of Circulation. 2020; 17 (4). DOI: 10.24022/1814-6910-2020-17-4-294-298 to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost. 1992; 68 (1): 95–6. DOI: 10.1055/s-0038-1656329
14. Zucker M.B., Katz I.R. Platelet factor 4: production, structure, and physiologic and immunologic action. Proc. Soc. Exp. Biol. Med. 1991; 198 (2): 693–702. DOI: 10.3181/00379727-198-43309
15. Klimovich L.G. Markers of hemostasis activation in antithrombotic therapy in patients with ischemic heart disease: Dr. Biol. Sc. Diss. Moscow; 2000 (in Russ.)
16. Bockeria L.A., Klimovich L.G., Potekhina A.V., Putyato N.A., Samsonova N.N. Mechanisms of the involvement of clotting inhibitors in the development of the inflammatory response and promising directions of anticoagulant therapy. Сlinical Physiology of Circulation. 2004; 1: 4–55 (in Russ.).]
17. Marcum J.A., McKenney J.B., Rosenberg R.D. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J. Clin. Invest. 1984; 74 (2): 341–50. DOI: 10.1172/jci111429
18. Handin R.I., Cohen H.J. Purification and binding properties of human platelet factor four. J. Biol. Chem. 1976; 251 (14): 4273–82.
19. Bock P.E., Luscombe M., Marshall S.E., Pepper D.S., Holbrook J.J. The multiple complexes formed by the interaction of platelet factor 4 with heparin. Biochem. J. 1980; 191 (3): 769–76. DOI: 10.1042/bj1910769
20. Suvarna S., Espinasse B., Qi R., Lubica R., Poncz M., Cines D.B. et al. Determinants of PF4/heparin immunogeneicity. Blood. 2007; 110 (13): 4253–60. DOI: 10.1182/blood-2007-08-105098
21. Greinacher A., Alban S., Omer-Adam M.A., Weitschies W., Warkentin T.E. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb. Res. 2008; 122 (2): 211–20. DOI: 10.1016/j.thromres.2007.11.007
22. Brandt S., Krauel K., Gottschalk K.E., Renné T., Helm C.A., Greinacher A., Block S. Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity. Thromb. Haemost. 2014; 112 (1): 53–64. DOI: 10.1160/TH13-08-0634
23. Kreimann M., Brandt S., Krauel K., Block S., Helm C.A., Weitschies W. et al. Binding of anti-platelet factor 4/heparin antibodies depends on the thermodynamics of conformational changes in platelet factor 4. Blood. 2014; 124 (15): 2442–9. DOI: 10.1182/blood2014-03-559518
24. Bauer T.L., Arepally G., Konkle B.A., Mestichelli B., Shapiro S.S., Cines D.B. et al. Prevalence of heparinassociated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation. 1997; 95 (5): 1242–6. DOI: 10.1161/01.cir.95.5.1242
25. Amiral J., Peynaud-Debayle E., Wolf M., Bridey F., Vissac A.M., Meyer D. Generation of antibodies to heparin-PF4 complexes without thrombocytopenia in patients treated with unfractionated or low-molecularweight heparin. Am. J. Hematol. 1996; 52 (2): 90–5. DOI: 10.1002/(sici)1096-8652(199606)52:2%3C90:: aid-ajh4%3E3.0.co;2-0
26. Warkentin T.E., Sheppard J.A., Horsewood P., Simpson P.J., Moore J.C., Kelton J.G. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000; 96 (5): 1703–8. DOI: 10.1182/blood.v96.5.1703.h8001703_1703_1708
27. Warkentin T.E., Cook R.J., Marder V.J., Sheppard J.I., Moore J.C., Eriksson B. et al. Antiplatelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood. 2005; 106 (12): 3791–6. DOI: 10.1182/blood-2005-05-1938
28. Visentin G.P., Malik M., Cyganiak K.A., Aster R.H. Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin: platelet factor 4 complexes. J. Lab. Clin. Med. 1996; 128 (4): 376–83. DOI: 10.1016/s0022-2143 (96)80009-6
29. Krauel K., Schulze A., Jouni R., Hackbarth C., Hietkamp B., Selleng S. et al. Further insights into the antiPF4/heparin IgM immune response. Thromb. Haemost. 2016; 115 (4): 752–61. DOI: 10.1160/TH15-08-0654
30. Khandelwal S., Lee G.M., Hester C.G., Poncz M., McKenzie S.E., Sachais B.S. et al. The antigenic complex in HIT binds to B cells via complement and complement receptor 2 (CD21). Blood. 2016; 128 (14): 1789–99. DOI: 10.1182/blood-2016-04-709634
31. Zheng Y., Wang A.W., Yu M., Padmanabhan A., Tourdot B., Newman D.K. et al. B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia. Blood. 2014; 123 (6): 931–4. DOI: 10.1182/blood-2013-11-540781
32. Reilly M.P., Taylor S.M., Hartman N.K., Arepally G.M., Sachais B.S., Cines D.B. et al. Heparininduced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgRIIA. Blood. 2001; 98 (8): 2442–7. DOI: 10.1182/blood.v98.8.2442
33. Warkentin T.E., Hayward C.P., Boshkov L.K., Santos A.V., Sheppard J.A., Bode A.P., Kelton J.G. 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 (11): 3691–9. DOI: 10.1182/blood.v84.11.3691.bloodjournal84113691
34. Arepally G.M., Mayer I.M. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood. 2001; 98 (4): 1252–4. DOI: 10.1182/blood.v98.4.1252

About Authors

• Natal'ya N. Samsonova, Dr. Med. Sc., Professor, Chief Researcher; ORCID
• Galina S. Esayan, Junior Researcher; ORCID
• Ekaterina A. Rogal'skaya, Cand. Med. Sc., Head of Clinical Laboratory Diagnostics Division; ORCID
• Mikhail B. Yaroustovsky, Dr. Med. Sc., Professor, Corresponding Member of RAS, Head of Department of Gravitational Blood Surgery and Endoscopy, Deputy Director of the Burakovsky Institute of Cardiac Surgery; ORCID