Proceduralists are likely familiar with the routine treatment options for patients with hemophilia A who present for surgical interventions. These include factor VIII (FVIII) concentrates and bypassing agents in those with significant FVIII inhibitors. A novel therapy for hemophilia A has been recently introduced that will have perioperative implications. After caring for a patient undergoing a major procedure (revision knee arthroplasty) who was receiving emicizumab, we wish to inform proceduralists about this new prophylactic treatment option and possible clinical and monitoring implications.
Emicizumab (Hemlibra®, Roche, Basel, Switzerland) is a US Food and Drug Administration–approved monoclonal antibody that mimics the function of FVIIIa by bridging factor IXa and X through two separate binding regions to restore effective hemostasis and does not require activation or is inactivated itself.1 The limiting step for factor Xa generation thus becomes factor IXa rather than VIIIa. It is used for prophylaxis of bleeding events and is not a replacement therapy for hemophilia A. Initial reports showed decreased spontaneous bleeding rates in hemophilia A patients along with improved quality of life.2 Emicizumab has a good safety record, with subcutaneous injection site reaction as the most common event. Thrombotic events are very uncommon, usually described in patients with inhibitors and associated with simultaneous bypassing agent administration.1
Review of the few patients in the original study cohorts who required emergency procedures revealed an infrequent need for bypassing agent use (31%), although most procedures were minor, such as tooth extractions or central venous catheter placement.2 There have been only isolated case reports in patients undergoing more invasive surgical procedures.3,4 These have affirmed the need for continued appropriate perioperative FVIII replacement or bypassing agents, possible challenges in coagulation monitoring in patients receiving emicizumab, and perioperative considerations.5,6
Emicizumab is used for prophylaxis for hemophilia A patients with and without inhibitors. Although the half-life is prolonged (up to 30 days), effects of interruption of therapy are yet to be determined, so administration should be continued. Of note, the effect of emicizumab on activated partial thromboplastin time (aPTT)–based assays persists for a variable period after discontinuation of treatment.
Routine coagulation tests based on the aPTT for assessment of hemophilia patients (PTT, one-stage FVIII, and Bethesda inhibitor assay) will be affected by emicizumab, giving the appearance of full coagulation restoration, and should not be used to guide management during surgical procedures.5,6 A chromogenic FVIII assay with bovine substrate is the best option to monitor FVIII activity for patients on emicizumab therapy. This assay measures endogenous or infused FVIII independent of emicizumab concentration. The same principle can be used to measure inhibitor levels.
Emicizumab does not interfere with coagulation tests such as thrombin time, fibrinogen assays, and prothrombin time. Although viscoelastic tests and a thrombin generation assay may be theoretically useful, data remain limited to date with small patient numbers.7 In our patient, baseline kaolin-activated thrombelastography was reassuring, with intact indices of fibrin formation and clot strength.
For major surgery or bleeding hemophilia A patients receiving emicizumab, principles for use of FVIII or a bypassing agent remain similar to current practice. However, concomitant use of emicizumab and high-dose activated prothrombin complex (>200 IU/kg/day) should be avoided due to the potential risk of thrombosis and/or thrombotic microangiopathy.1
Coordination of perioperative replacement therapy with a hematologist who has experience with hemophilia patients is strongly recommended until further data on monitoring and treatment strategies in surgical patients become more available.
CONFLICTS OF INTEREST
Dr. Pivalizza has no conflicts of interested to declare. Dr. Escobar has participated in advisory committees and/or consultancy for: Genentech, National Hemophilia Foundation, Novo Nordisk, Pfizer, Sanofi, Takeda, Biomarin, CSL Behring, Kedrion, and the US Food and Drug Administration, none of which are relevant for this submission.
References
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