Reducing Venous Thrombosis with Antithrombin Supplementation in Patients Undergoing Treatment for ALL with Asparaginase Based Regimens

Introduction

The dramatic improvement in outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) has led to the incorporation of asparaginase into adult treatment protocols. However, increased thrombosis rates have been subsequently observed. In an effort to reduce venous thromboembolism (VTE) rates in this high-risk population and minimize the morbidity and cost associated with each event, Froedtert & the Medical College of Wisconsin implemented a practice of three-times weekly antithrombin (AT) activity monitoring with prophylactic AT supplementation (plasma derived antithrombin) for activity less than 50%. The type of AT used for supplementation was Thrombate III (human form) and dosing was weight-based (approximately 3000 units for patients < 70 kg, 4000 units for patients 70-100 kg, and 5000 units for patients > 100 kg) with a target AT activity level of 120%. Similarly, levels of fibrinogen were monitored three times weekly with cryoprecipitate supplementation provided for fibrinogen levels less than 100 if AT was also low. We retrospectively reviewed patient outcomes to determine impact of AT level monitoring with threshold-guided prophylactic AT infusions on VTE rates in patients undergoing asparaginase-based chemotherapy.

Methods

We conducted a single-center, retrospective, observational cohort study of ALL patients treated with asparaginase between 2009 and 2018. Patients were identified using our institution's hematological malignancy registry. The electronic medical record was reviewed for demographics, VTE events, AT activities, use of AT supplementation, and cryoprecipitate transfusion. Primary outcome was VTE events during treatment with asparaginase. We excluded catheter-related thrombosis from the outcomes. Secondary outcomes included: the number of patients receiving supplemental AT, the mean AT activity level (%) at the time of supplementation, number of asparaginase doses administered per patient, median number of days from asparaginase to VTE, median number of days from asparaginase administration to AT supplementation and the percentage of patients who received cryoprecipitate. The Fisher's exact test was used to compare categorical variables and Student's t-test compared continuous variables.

Results

A total of 65 patients were included: 20 patients were treated prior to protocol implementation (pre-intervention group), and 45 patients after implementation (post-intervention group). The median age of patients in the pre-intervention and post-intervention group was 35 and 38, respectively. The VTE rates were 50% (10 patients) in the pre-intervention group, and 25% (9 patients) in the post-intervention group (p = 0.02). The median number of days from asparaginase to VTE event was 15 in the pre-intervention group and 16 in the post intervention group. In the post-intervention group, 30 (46%) patients received AT and the mean AT activity level in supplemented patients was 46.7% (ranging from 32% to 64%). The median number of days from asparaginase administration to supplementation with AT concentrate was 8 days. A total of 28 patients (43%) received cryoprecipitate and the average fibrinogen level when patients were supplemented was 86.42 mg/dL. Fibrinogen levels were not monitored in the pre-intervention group.

Conclusion

Our results demonstrate that monitoring and replacing AT and fibrinogen in patients with ALL receiving asparaginase based regimens reduces the risk of VTE.