HEMOSTATIC ALTERATIONS DURING BRUTON KINASE INHIBITORS TREATMENT

Patients with chronic lymphocytic leukemia (CLL) are at increased risk for major bleeding compared with the general population. The hazard ratio (HR) for major bleeding among 6,717 treated CLL/SLL patients compared with 14816 matched noncancer patients was 8.3 (95% confidence interval [CI]: 7.5-9.2).1 Moreover, up to 25% of patients are on anticoagulant or antiplatelet treatment at the time of CLL diagnosis, due to advanced age and the associated comorbidities,2 thus increasing the risk for bleeding complication. Patients with CLL might experience immune thrombocytopenia (5%)2 or even a more rare bleeding condition such as acquired von Willebrand disease,3 both condition allowing for severe hemorrhagic complications. Since the introduction of Bruton Tyrosine Kinase inhibitors (BTKi) the anti-aggregating effect on platelets appeared as a typical off-target effect. BTKi are known to affect not only BTK but also other kinases, particularly those from the Tec and Src family of kinases. Inhibition of these kinases that are expressed by platelets and involved in GPVI activation by collagen and GPIb activation by von Willebrand factor increases the bleeding risk of BTKi-treated patients.4-7 Moreover in vitro experiments have suggested that ibrutinib also inhibits platelet adhesion to fibrinogen. Good clinical practices about the management of anticoagulant and antiplatelet drugs use in CLL patients treated with BTKi include: - In patient with atrial fibrillatione and indication to anticoagulant treatment, DOACs are recommended over warfarin - BTKi and full-dose DOACs can be administered together, however an alternative anti-CLL treatment should be considered if deemed equally effective8 - In acute phase of Venous Thromboembolic Event and long-term phase, if the patient is under covalent BTKi, LMWH should be preferred. If LMWH is not indicated/not tolerated, apixaban and rivaroxaban can be considered, because of their potentially weaker pharmacokinetic interaction with respect to other DOACs9 - Concomitant treatment with BTKi and antiplatelet agents increases the risk of bleeding in patients with CLL, so the physician should assess properly the antiplatelet treatment indication. If the antiplatelet agent is indicated, CLL per se does not require specific monitoring besides the standard blood cell count. The management of patients treated with BTKi requiring surgery, invasive procedure, or having a bleeding event are described in Table 1 and Table 2. Table 1. Management of patients taking BTKi and candidate to invasive procedure. *Ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib Table 2. Management of bleeding events during BTKi therapy. ISTH: International Society of Thrombosis and Haemostasis, BTKi: Bruton Tyosine Kinase, DOAC: Direct Oral Anticoagulant, 4 factor PCC: prothombin complex concentrate with 4 factors, VKA: vitamin k antagonist. References 1. Gifkins D, Matcho A, Yang A, Xu Y, Gooden MA, Wildgust M. Incidence of major hemorrhage among CLL and MCL patients compared to the general elderly population: an analysis of the US SEER‐Medicare linked database. Blood. 2015;126:3268. 2. Visco C, Ruggeri M, Laura Evangelista M, Stasi R, Zanotti R, Giaretta I, Ambrosetti A, Madeo D, Pizzolo G, Rodeghiero F. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood. 2008 1;111(3):1110-6. 3. Franchini M, Mannucci PM. Acquired von Willebrand syndrome: focused for hematologists. Haematologica. 2020;105(8):2032-2037. 4. Nicolson PLR, Nock SH, Hinds J, et al. Low-dose Btk inhibitors selectively block platelet activation by CLEC-2. Haematologica. 2021;106(1):208-219. 5. Busygina K, Denzinger V, Bernlochner I, Weber C, Lorenz R, Siess W. Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs? Thromb Haemost. 2019;119(8):1212-1221. 6. Goldmann L, Duan R, Kragh T, et al. Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT? Blood Adv. 2019;3(23):4021-4033. 7. Shatzel, J.J., Olson, S.R., Tao, D.L., Mc Carty,O.J.T., Danilov, A.V. & DeLoughery, T.G. (2017) Ibrutinib associated bleeding: pathogenesis, management and risk reduction strategies. Journal of Thrombosis and Haemostasis, 15, 835–847. 8. Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019 21;133(12):1298-1307. 9. Aghel N, Baro Vila RC, Lui M, Hillis C, Leong DP. Diagnosis and Management of Cardiovascular Effects of Bruton's Tyrosine Kinase Inhibitors. Curr Cardiol Rep. 2023;25(9):941-958.