Could Hemorrhagic and Thrombotic Risk Due to Peg-Asparaginase be Identified By Coagulative Tests Using Fibtem and Antithrombin Levels? A Single Centre Study

Introduction. Hypofibrinogenemia and its correlation with hemorrhagic risk is usually detected by serum fibrinogen level with Clauss test. Recently the role FIBTEM test of rotational thromboelastometry (ROTEM) has been evaluated for prevention and management of acute bleeding in intesive care and surgical settings. We applied it for monitoring fibrinogen deficiency for the first time in children affected by acute lymphoblastic leukemia (ALL) treated with Peg-asparaginase (PEG-Asp). Antithrombin levels (AT) were measured as parameter for thrombotic risk. This drug impairs protein synthesis and causes severe coagulative deficiencies, with both hemorrhagic and thrombotic complications. Guidelines for the management of coagulation abnormalities being missing, we tried to identify parameters for management and prevention.

Methods. Eightytwo children (age 1-17 years, mean 6 year) affected by ALL treated with AIEOP BFM ALL 2009 protocol at our Institution were studied. Platelet count and coagulation tests (protrombin time PT/INR, activated partial tromboplastin time aPTT, AT, serum fibrinogen level (SF) at Clauss test and fibrinogen function at MCF) were performed before and after each PEG-Asp administration. We previously found linear correlation with SF levels only for MCF > 9 mm. We then tried to identify clinically significant deficiency of SF. Severe hypofibrinogenemia was considered when Clauss test showed SF levels < 1g/L. MCF limit for severe fuctional hypofibrinogenemia was considered <= 5mm according to our experience in congenital and acquired hypofibrinogemia (cardiac surgery, liver transplant and intensive care settings). Severe AT deficiency was considered at <50%.

Results. Severe hypofibrinogenemia was found in 240 Clauss test (24.3%), but only in 44 (4.5%) of MCF at FIBTEM. Only 28% of SF at Clauss test < 1 g/L had an MCF value <= 4mm. Thirty-five percent of children presented MCF <=4mm with a prolonged alteration in 5.3% of them, mostly observed during Induction phase, when steroid therapy was concomitant. Prolonged administration of Peg-Asp (10 doses in 20 weeks) did not cause a prologed hypofribrinogenemia. Fibrinogen concentrates was supplemented only at MCF >= 2mm or at 3-4 mm in association with INR > 2.8. Fresh frozen plasma administration was avoided. No significant bleeding was observed. Severe AT deficiency was found in 287 measurements (23%) and in 57% of patients. AT deficiency was more frequent according to the number of PEG-Asp doses, in particular the percentage of affected patients increased in the different phases of chemotherapy (Table 1), being observed in all patients receiving prologed PEG-Asp therapy. AT was suggested at level of < 50%, but it was performed only in 54% of cases. Three thrombotic events were registered (3.6%) all in presence of AT levels <50%.

Conclusions. The frequency of fibrinogen functional deficiency as detected by MCF level at FIBTEM was inferior than hypofibrinogenemia at Clauss test. The MCF level chosen in our study to identify a parameter for hemorrhagic risk was helpful to select patients for coagulant therapy with fibrinogen concentrates. AT deficiency was more frequent than fibrinogen deficiency and was related to the numer of PEG-Asp doses. These tests can help in the management of patients with coagulative disturbancies in order to prevent seriuos adverse events.

Table 1: Frequency of MCF and AT deficiencies according to number of PEG-Asp doses

N° of doses	1	2	4	10
MCF <=4mm	25%	42%	43%	40%
AT < 50%	19%	65%	86%	100%
N° of patients	67	59	7	10