Impact of a Standardized Hydroxyurea Dose Regimen for Extreme Thrombocytosis in Children after Pancreatectomy with Islet Autotransplantation
Authors: Boucher Alexander A , Jenkins Todd M. , Luchtman-Jones Lori , Palumbo Joseph S. , Lin Tom K , Abu-El-Haija Maisam , Nathan Jaimie D 
Published: October 2019

Abstract
Total pancreatectomy with islet autotransplantation (TPIAT) is a therapeutic option for debilitating acute recurrent or chronic pancreatitis. While postoperative diabetes and pain outcomes are well-described in these patients, the hematologic outcomes have not been thoroughly examined. Specifically, the natural history and optimal management of the nearly universal post-IAT extreme thrombocytosis (platelets >1000 K/μL) beginning within days of surgery and often lasting for months remains enigmatic. Concern for thrombosis risk from the extreme thrombocytosis has prompted empiric, widely-employed pharmacologic alteration of platelet count (hydroxyurea) and function (aspirin, ASA); however, the optimal dosing strategy and efficacy of these therapies after IAT are poorly characterized.
Patients who underwent TPIAT (n=28) or subtotal pancreatectomy with islet autotransplantation (n=2), all with splenectomy, at Cincinnati Children's Hospital Medical Center between January 1, 2015 and April 30, 2018 were retrospectively reviewed. Hydroxyurea management strategies, hematologic trends, and hydroxyurea side effects were evaluated.
The mean age of the patients was 12.3 years (range 3-19 years). All started ASA on post-operative day (POD) 2-3 at a median daily dose of 2 mg/kg [Interquartile Range (IQR) 1.7-2.13). This was continued until hydroxyurea was discontinued and platelet count remained normal for 4 weeks. All received prophylactic heparin and later enoxaparin post-operatively per protocol until discharge. VerifyNow® ASA testing was performed after aspirin initiation, with dose increases as necessary to reach therapeutic result. Among the 30 patients evaluated, 26 developed extreme thrombocytosis (median maximum platelet count 1298 K/μL, IQR 1046-1563), peaking at a median of 16 days (IQR 14-20). Two patients developed portal vein thromboses (POD 4 in a 13 year old with platelets 321 K/μL at diagnosis, and POD 11 in a 15 year old with platelets 1458 K/μL at diagnosis, respectively). Both patients had clot resolution while on therapeutic enoxaparin for 3 months.
On July 1, 2016, a more standardized regimen for aspirin and hydroxyurea initiation, dose modification and weaning was implemented. These changes resulted in earlier hydroxyurea initiation [median 7 (IQR 6-8) versus 9 (IQR 8-10) days postoperatively, p=0.03] at lower platelet counts [median 529 (IQR 501-600) versus 938 (IQR 776-1085) K/μL, p<0.001] and potentially lower initial doses [15 (14-16) versus 20 (15-21) mg/kg/day, p=0.09]. Nine patients required hydroxyurea to be restarted after an initial wean (33% before protocol standardization, 29% afterwards). Four patients after protocol standardization never reached a platelet count >1000 K/μL, while all patients before standardization had extreme thrombocytosis. VerifyNow® ASA testing was performed earlier after standardization (POD 6 versus 7, p=0.01) with similar percentages of non-therapeutic ASA measurements in each group (22 versus 19%). The MCV rose a median 13 fL (IQR 8.75-20) while on hydroxyurea. With the current sample size, no statistically significant differences were detected between the two groups for maximum hydroxyurea dose, treatment duration, maximal platelet count, the number of patients with multiple episodes of extreme thrombocytosis, or number of days with extreme thrombocytosis. Of the 25 patients who were fully weaned off hydroxyurea as of July 31, 2018, the therapeutic course was a median 175 days (IQR 90-259). Median absolute neutrophil count (ANC) was 4140 K/μL (IQR 2700-7080). Neutropenia (ANC <1500 K/μL) was rare (24/678 measurements, 3.5%) over 5498 hydroxyurea treatment days, only necessitating hydroxyurea cessation on 4 occasions. Three patients had mild alopecia. No bleeding or gastritis occurred to necessitate ASA cessation, even while on prophylactic or therapeutic anticoagulation.
Hydroxyurea and ASA are well-tolerated and appear to favorably modulate post-IAT thrombocytosis and mitigate post-surgical thrombotic risks. Earlier hydroxyurea initiation with a standardized protocol may provide more predictable platelet count responses including decreasing the risk of extreme thrombocytosis. Future studies are needed to optimize hydroxyurea treatment in this setting.

Disclosures
Palumbo: Ionis Pharmaceuticals: Research Funding.