Hakam, Sarah, B.S., Hughes, Rhome, M.D.

Background: Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated adverse drug reaction caused by the emergence of antibodies directed against immune complexes of heparin/anti-platelet factor 4. These antibodies activate FcγRIIa (CD32a), a low-affinity receptor for IgG expressed on platelets.^1,2 Activated platelets are then consumed within thrombi, resulting in thrombosis and thrombocytopenia. HIT is currently treated by ceasing Heparin and starting patients on direct thrombin inhibitors (Bivalirudin, Argatroban). However, these drugs often result in complications such as excessive bleeding and death.

Research Objective: The mechanism behind HIT is not fully understood. Therefore, more work is necessary to develop novel treatments for the disease. This work aims to compile and evaluate novel treatment strategies for HIT that have come about through recent research into the disease’s mechanism.

Methods: A thorough literature review was conducted using Google Scholar, Pub-Med, and Science Direct to find work published within the last five years. Keywords such as “HIT,” “Heparin Induced Thrombocytopenia,” and “HIT Mechanism” were used to locate mechanistic research regarding the subject.

Results: Five publications were chosen to be included in this work. The first highlights how IVIG treatment results in high plasma levels of IgG, which competes with HIT antibody Fc domains for binding to FcγRIIa.¹ As a result, patient platelet levels are dramatically increased, and further platelet activation is inhibited.¹ The second paper discovered that chemoattractant proteins released in post-operative inflammation might contribute to HIT thrombosis by priming platelets for FcγRIIa signaling.² Therefore, inhibiting platelet FcγRIIa results in a decrease in the procoagulant platelet population.² A third paper discovered a new bivalent binding mechanism between monoclonal PF4 antibody, 2E1, with PF4 via its antigen recognition site and charge-related interactions with Heparin.³ Targeting this interaction can inhibit platelet activation in HIT. The fourth publication found that Polyphosphate-PF4 complexes released by activated platelets can mediate HIT platelet aggregation.⁴ Therefore, degradation/inhibition of polyphosphate can inhibit platelet aggregation. The fifth and last publication used thrombi analysis to discover that reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) contribute to thrombus development in HIT through NETosis.⁵ Inhibition of NOX2 with diphenyleneiodonium-chloride can inhibit HIT-induced thrombosis.⁵

Conclusions: As the mechanism behind HIT is researched, more emphasis is put on treatments that target various steps in the disease pathway. Currently, different hospitals treat HIT differently, depending on what works best for them. However, there is a strong clinical need for a consensus on how to treat the drug reaction.

Work Cited:

1. Padmanabhan A, Jones CG, Pechauer SM, et al. IVIG for treatment of severe refractory heparin-induced thrombocytopenia. Chest. 2017;152(3):478-485. doi:10.1016/j.chest.2017.03.050
2. Lee CSM, Selvadurai MV, Pasalic L, et al. Measurement of procoagulant platelets provides mechanistic insight and diagnostic potential in heparin‐induced thrombocytopenia. Journal of Thrombosis and Haemostasis. 2022;20(4):975-988. doi:10.1111/jth.15650
3. Vayne C, Nguyen T-H, Rollin J, et al. Characterization of new monoclonal PF4-specific antibodies as useful tools for studies on typical and autoimmune heparin-induced thrombocytopenia. Thrombosis and Haemostasis. 2020;121(03):322-331. doi:10.1055/s-0040-1717078
4. Cines DB, Yarovoi SV, Zaitsev SV, et al. Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia. Blood Advances. 2016;1(1):62-74. doi:10.1182/bloodadvances.2016000877
5. Leung HH, Perdomo J, Ahmadi Z, Yan F, McKenzie SE, Chong BH. Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia. Blood Advances. 2021;5(23):5439-5451. doi:10.1182/bloodadvances.2020003093
6. Mordakhanova ER, Nevzorova TA, Synbulatova GE, Rauova L, Weisel JW, Litvinov RI. Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways. International Journal of Molecular Sciences. 2020; 21(7):2556. https://doi.org/10.3390/ijms21072556
7. Hassan Y, Awaisu A, Al-Meman AA, Aziz NA. The Pharmacotherapy of Heparin-Induced Thrombocytopenia (HIT) : A Review of Contemporary Therapeutic Challenges in Clinical Practice. Malays J Med Sci. 2008;15(2):3-13.
8. Chong, BH. Evolving concepts of pathogenesis of heparin-induced thrombocytopenia: Diagnostic and therapeutic implications. Int J Lab Hematol. 2020; 42(suppl. 1): 25– 32. https://doi.org/10.1111/ijlh.13223