Risk of Thrombosis with Different Approaches to Central Venous Access During Acquired Asparaginase Related Antithrombin Deficiency in Children with Leukemia.
Authors: Ranta Susanna , Heyman Mats , Jahnukainen Kirsi , Taskinen Mervi , Saarinen-Pihkala Ulla M. , Frisk Tony , Söderhäll Stefan , Petrini Pia , Mäkipernaa Anne 
Published: October 2019

Abstract
Abstract 2241

Background
Children with acute lymphoblastic leukemia (ALL) have several risk factors for thrombosis including asparaginase related acquired antithrombin (AT) deficiency and central venous catheters (CVCs). Both external tunneled and internal CVCs (tunneled, fully implantable devices known as ports) are used to provide reliable venous access. After introduction of a new ALL protocol with prolonged continuous asparaginase treatment aiming at approximately 30 weeks depletion of asparagine more symptomatic thromboses than expected were observed at the Children's Hospital, Helsinki University Central Hospital, Finland. To ensure asparaginase treatment and prevent thromboses an on-demand AT substitution regimen was adopted. Previous studies have described AT substitution during ALL induction; this is the first description and evaluation of on-demand AT substitution over a longer period of time in children.

Aim
The aim of this study is to describe the prolonged on-demand AT substitution practice in Helsinki during depletion of asparagine from the blood with PEG-ASP and to compare experiences from two Nordic pediatric oncology centers (Children's Hospital in Helsinki and the Astrid Lindgren Children's Hospital Karolinska University Hospital, in Stockholm, Sweden) with the same leukemia protocol but different approaches to central venous access.

Procedure
All Finnish children with ALL and external tunneled CVCs diagnosed at Children's Hospital in Helsinki between May 2008 and November 2011 (n=38) were compared with Swedish children with ALL and internal CVCs treated concurrently with the same ALL protocol (n=39). Children treated in Helsinki according to the standard or intermediate risk NOPHO-ALL 2008 protocol after initiation of the AT substitution regiment received AT concentrate when their AT level decreased below 55% (the intervention group, n=25). The thrombosis rate and laboratory parameters were compared with children treated earlier in the same unit (the control group, n=10).

Results
In Helsinki, 2/10 (20%) children in the control group had 3 symptomatic thromboses and 2/25 (8%) children in the intervention group with on-demand AT substitution had one symptomatic thrombotic event each. Both thromboses in the intervention group were associated with concomitant steroid treatment. In the intervention group 14/25 (56%) received AT concentrate (median number of infusions 3, range 1–17).
Altogether, 4/38 Finnish patients with external CVCs and 0/39 Swedish patients with internal CVCs had thromboses (Mann Whitney U test, p=0.039) in spite of similar exposure to asparaginase and low antithrombin. A significant difference was also observed in the use of tissue plasminogen activator (tPA): 28/38 Swedish patients had received tPA at least once to restore dysfunctional CVCs (usually loss of the ability to withdraw blood) compared to 2/38 Finnish patients (Mann Whitney U test, p≤0.001).

Conclusions
Most children are exposed to low AT levels during ASP treatment predisposing to thrombosis especially with concomitant steroids. Larger studies are needed to evaluate the benefit of prophylactic antithrombin treatment. Internal CVCs and tPA may be beneficial in preventing symptomatic thrombosis during leukemia treatment.

Disclosures:
No relevant conflicts of interest to declare.