Thrombin Generation Test Can Predict Bleeding Tendency In Patients With Severe Factor XI Deficiency
Authors: Livnat Tami , Martinowitz Uriel , Mansharov Rachel , Ariella Zivelin , Salomon Ophira 
Published: October 2019

Abstract

Introduction
Factor XI (FXI) is a rare bleeding disorder defined as severe deficiency when FXI activity level is less than 20IU/dL. Unlike hemophilia A or B, patients with severe FXI deficiency do not bleed spontaneously and their bleeding tendency is unpredictable and poorly correlated with FXI level. Therefore, almost all patients with severe FXI deficiency are being treated similarly unrelated to their inert bleeding tendency. Lately there is a growing interest in introducing global coagulation tests to assess the risk of bleeding in trauma patients as well as in patients with congenital bleeding disorders. Thrombin generation (TG) test is a global assay that can provide information regarding hemostasis in healthy individuals or in patients with congenital and acquired bleeding disorders. Our group had previously shown that recalcification induced TG is a useful tool to determine the optimal dose of recombinant factor VIIa for patients with severe FXI deficiency and inhibitors going through major surgery (Livnat et al. Thromb Haemost 2009).

Aim
In the present study we aimed to characterize the capability of TG to serve as an ideal tool to define upfront bleeders and non-bleeders among FXI deficient patients and find the optimal conditions of TG that could distinguish between bleeders and non-bleeders thus eventually leading to efficient personalized treatment.

Methods
Case control study composed of 16 unrelated patients with FXI levels range >1-8dL-1and 14 healthy controls. For TG assay blood was taken from all participants simultaneously in both buffered citrate and corn trypsin inhibitor (CTI) tubes after obtaining informed consent. TG was performed in platelet poor plasma (PPP) in the presence of 4 µM phospholipids and initiated by recalcification in the presence and absence of 1pM tissue factor (TF). Three TG parameters were analyzed: lag time, thrombin peak and endogenous thrombin potential (ETP).

Results
Table 1 summarizes FXI activity, FXI genotype, thrombin peak height and bleeding status (i.e, bleeding following challenges when prophylactic treatment was not given) of patients in the study group. As expected, FXI levels poorly correlated with bleeding tendency. Good correlation between FXI levels, bleeding tendency and TG peak height was found when blood was taken in citrated tubes and not in CTI containing tubes. While the normal range of peak height in recalcification-induced TG (without TF) was 421±161 nM, no TG was initiated with recalcification in PPP of FXI patients with less than 1%. FXI levels 2-4% were sufficient to induce TG with recalcification but thrombin peak height was remarkable lower in comparison to controls. In FXI levels above 5%, the thrombin peak height induced by recalcification varied between low to normal range. Interestingly, when TG was initiated by 1pM TF the TG peak of non-bleeders reached normal values (normal peak height in the presence of 1pM TF=411±121), while in the bleeders the peak was reduced unrelated to FXI levels (range 74-205).

Conclusions
In summary TG induced by recalcification in the presence of low TF but not when performed in CTI tubes may efficiently distinguish between bleeders and non-bleeders in FXI deficient patients going through major trauma unrelated to patients' FXI level. This observation permits to consider less aggressive prophylactic treatment to patients with reduced risk for bleeding thus lowering the risk of thrombosis due to over treatment.

Disclosures:
No relevant conflicts of interest to declare.