Which Level of Emicizumab Is Necessary for a Good Hemostasis?

Introduction Emicizumab is a recombinant, humanized, bispecific antibody restoring the function of missing activated factor VIII (FVIII) by bridging activated FIX (FIXa) and zymogen factor X (FX), medicating the activation of FX. Emicizumab is approved in several countries, at the doses of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks, for the prophylaxis of bleeding episodes in patients with hemophilia A with and without inhibitors. The drug has shown a good efficacy either during registration studies as well as in real-world experiences and was well tolerated without significant side effects. The development of neutralizing anti-emicizumab antibodies has been reported in very few cases which frequently required the switch to other products due to inefficacy of the prophylaxis. Patients maintaining a plasma concentration range of the drug within 30-80 ug/ml did not show significant bleeds. However, real life experiences bring the need of personalization of the drug dose. A recent case series presented at ISTH 2021 from Malaysian authors evaluated the efficacy of a dose of emicizumab between 1.7 and 1.9 mg/kg every 4 weeks, showing that even at a lower dose than that approved could be effective for the prevention of bleeding events. Here we report the case of an adult patient with moderate hemophilia A with inhibitor who developed an anti-emicizumab antibody which reduced the concentration of the drug by 50%. Despite that the patient did not report bleeding events in a follow-up period of 18 weeks. Treatment with emicizumab requires further evaluation to understand the best dose for the prevention of bleeding. Case report A 74 years old patient with moderate hemophilia A (FVIII 1-3%) followed at our Center had history of high-titer inhibitor (maximum titer 20 BU). The patient was treated on-demand with plasma-derived FVIII concentrates, when, in Jul 2000, he developed a neutralizing anti-FVIII antibody requiring treatment with activated prothrombin complex concentrates (Feiba). In Nov 2020 the patient was hospitalized for traumatic brain hemorrhage treated with plasma-derived FVIII (inhibitor titer < 5 BU) and subsequently, for the recurrence of inhibitor, with activated prothrombin complex concentrates. In Feb 2021 the patient started prophylaxis with emicizumab at the initial dose of 3 mg/kg once weekly (loading dose), followed by a maintenance dose of 1.5 mg/kg. The patient underwent periodic blood withdrawal for monitoring drug plasma concentration. In Apr 2021 (week 10) drug concentration showed a slight decrease from initial levels, from 39.1 ug/ml (week 5) to 28.3 (week 10) and a weak positivity for an anti-emicizumab antibody was detected. At the following test (week 15) positivity for the anti-emicizumab antibody was confirmed, witnessed by the consistent reduction in drug plasma concentration up to 20.9 ug/ml. During the following weeks, until week 22, drug plasma concentrations were stable (range 17.0-19.4 ug/ml) and positivity for anti-emicizumab antibody remained, as shown in the table. The results of partial Thromboplastin Time (PTT) were consistent with the drug plasma concentrations during the observation period, in which the patient did not developed any bleeding event. Conclusion This case report may corroborate the hypothesis of the efficacy of a reduced dose of emicizumab in patients with hemophilia A. Close laboratory monitoring in patients in prophylaxis with emicizumab is warranted for the evaluation of drug plasma concentration and the prompt detection of anti-drug antibodies, particularly if patient show a reduced therapeutic efficacy. However, in the absence of bleeding events, positivity for anti-emicizumab antibodies should not bring to sudden drug discontinuation. Indeed, in the view of the above, a lower drug plasma concentration than standard might be effective in the prevention of bleeding. 1. Tang ASO et al. July 2021. Efficacy of Reduced-dose Emicizumab in Haemophilia A with Inhibitors: Real World Experience in East Malaysia. ISTH 2021. Figure 1 Figure 1. Disclosures Peyvandi: Takeda: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor–Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care

Background and Purpose: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor–related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor–related ICH. Methods: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. Results: Overall, 182 patients with factor-Xa inhibitor–related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20–0.78]; P =0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. Conclusions: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor–related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment.

Direct (new) oral anticoagulants (DOACs): Drawbacks, bleeding and reversal

Background and Objective: Direct (new) Oral Anticoagulants (DOACs) have emerged as a contemporary and promising option in the treatment of thromboses and VTE, while protecting the coagulation cascade against untoward bleeding events. They are used in the management and prophylaxis of Venous Thromboembolism (VTE) and other thrombotic diseases. The most prominent complication of these agents is bleeding. These agents have similar or lower rates of major intracranial hemorrhages, while they had a higher risk of major gastrointestinal bleeding when compared to warfarin. This manuscript is aimed to revise and update the literature findings to outline the side effects of DOACs in various clinical scenarios. Methods: A narrative review of currently published studies was performed. Online database searches were performed for clinical trials published before July 2021, on the efficacy and adverse effects attributed to the anticoagulant treatment, especially DOACs. A literature search via electronic databases was carried out, beginning with the usage of the agents in the Western Languages papers. The search terms initially included direct (new) oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, idarucizumab, andexanet, prothrombin complex concentrates, and fresh frozen plasma. Papers were examined for methodological soundness before being included. Results: Severe bleeding episodes require aggressive interventions for successful management. Therefore, bleeding should be evaluated in special regard to the location and rate of hemorrhage, and total volume of blood loss. Patient's age, weight and organ dysfunctions (e.g., kidney/liver failure or chronic respiratory diseases) directly affect the clinical course of overdose. Conclusion: Management recommendations for hemorrhage associated with DOAC use vary, depending on the class of the culprit agent (direct thrombin inhibitor vs. FXa inhibitor), the clinical status of the patient (mild/ moderate vs. severe/life-threatening), and capabilities of the institution. Specific reversal agents (i.e., idarucizumab and andexanet alfa) can be used if available, while prothrombin complex concentrates, fresh frozen plasma and/ or tranexamic acid can also be employed as nonspecific replacement agents in the management of DOAC-related bleeding diathesis.

Utilization of anti–factor Xa levels to guide reversal of oral factor Xa inhibitors in the emergency department

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Oral factor Xa inhibitors (FXaIs) are increasingly utilized for outpatient anticoagulation therapy; however, laboratory monitoring is not routinely used to assess the safety and efficacy of these agents. We aimed to evaluate the role of chromogenic anti–factor Xa (anti-Xa) assays in the emergency department (ED) in the setting of patients with an acute bleed or requiring emergent procedures. Methods A retrospective review was completed of anti-Xa levels obtained in the ED between June 1, 2019, and April 30, 2020. Data were collected to describe the clinical setting of anti-Xa level collection, oral FXaIs used before admission, administration of reversal agents, and patient disposition to further characterize the role of anti-Xa levels in the management of rivaroxaban and apixaban reversal. Results Thirty anti-Xa levels were included in the final analysis. The median time from sample collection to anti-Xa assay result was 45.9 minutes (interquartile range, 35.3-54.7 minutes). Eleven patients (37%) received anticoagulation reversal after their anti-Xa levels were determined. Anticoagulation reversal agents included either activated prothrombin complex concentrates (aPCCs) or prothrombin complex concentrates (PCCs). Anti-Xa levels were collected in 2 patients who had received PCCs before arrival at our ED. Of the patients with anti-Xa levels below 30 ng/mL, none received aPCCs or PCCs after their anti-Xa levels were determined. Anti-Xa assays were used to rule out the presence of FXaIs in 3 patients. Conclusion This study illustrates the novel role of anti-Xa levels in managing patients with an emergent need for reversal in the ED. The assay may be used to rule out the presence of oral FXaIs and avoid unnecessary administrations of anticoagulation reversal agents.

Review of Prothrombin Complex Concentrates Use in Apixaban and Rivaroxaban Associated Intracranial Hemorrhages

Study Objective: Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages. Methods: A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*. Results: Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent. Conclusion: Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.