Unfractionated heparin dosing requirements in the presence of inflammation during the first six months of life.

BACKGROUND: Critically ill neonates with inflammation secondary to SIRS or sepsis often develop an acquired pro-thrombotic state. Unfractionated heparin (UFH) is commonly prescribed in this population, but these subjects often remain sub-therapeutic or require very high doses of UFH to achieve and sustain therapeutic anti-Xa activity. This is due, in part, to the unique pharmacokinetics/dynamics of this population but may also be influenced by the degree of inflammation. OBJECTIVE: To evaluate UFH dosing requirements in neonates and infants <6 months of age with variable degrees of systemic inflammation. Clinical outcomes of bleeding and clotting will also be examined. SUBJECTS/METHODS: A retrospective chart review was performed in infants <6 months of age treated with intravenous UFH for at least 24 h with intent to reach a goal anti-Xa of 0.3-0.7 U/mL at Children's Hospital Colorado between October 2008 and August 2014. Subjects were divided into two groups, based on their ability to achieve and maintain anti-Xa concentrations between 0.3 and 0.7 U/mL. The relationship between UFH dose (U/kg/h) and inflammatory status (using pediatric age-specific definitions for SIRS, sepsis, severe sepsis, or septic shock) was examined. RESULTS: Seventy-three subjects were included in the analysis. Twenty-three subjects (mean age = 41.2 days ±â€¯standard deviation [SD] 52.3) achieved therapeutic anti-Xa concentrations while fifty subjects (mean age = 43.4 days ±â€¯SD 53) did not. The median UFH dose needed in subjects who achieved goal anti-Xa concentrations in the absence of SIRS or sepsis criteria was 24.5 U/kg/h (interquartile range [IQR] = 23.6-25.9) while the median dose of UFH in subjects who achieved goal anti-Xa level in the setting of infection, SIRS, or sepsis of any type was 36.1 U/kg/h (IQR = 34-43.5) (p < 0.0001). In subjects who maintained therapeutic anticoagulation, there was a direct relationship between UFH dose and the severity of inflammation as determined by pediatric SIRS/sepsis criteria. CONCLUSIONS: Maintenance of therapeutic UFH levels remains a challenge in infants, especially in those with concomitant inflammatory processes. Infection, SIRS, and sepsis of any type were collectively associated with a 32% increase in unfractionated heparin dose required to achieve and maintain therapeutic anti-Xa serum concentrations.

The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis.

Essentials Signaling by Gas6 through Tyro3/Axl/Mer receptors is essential for stable platelet aggregation. UNC2025 is a small molecule inhibitor of the Mer tyrosine kinase. UNC2025 decreases platelet activation in vitro and thrombus formation in vivo. UNC2025's anti-platelet effect is synergistic with inhibition of the ADP receptor, P2Y12 . SUMMARY: Background Growth arrest-specific protein 6 signals through the TAM (TYRO-3-AXL-MERTK) receptor family, mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb ß3 integrin. Objective To describe the antithrombotic effects mediated by UNC2025, a small-molecule MERTK tyrosine kinase inhibitor. Methods MERTK phosphorylation and downstream signaling were assessed by immunoblotting. Light transmission aggregometry, flow cytometry and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregates in vitro. The effects of MERTK inhibition on arterial and venous thrombosis, platelet accumulation at microvascular injury sites and tail bleeding times were determined with murine models. The effects of combined treatment with ADP-P2Y1&12 pathway antagonists and UNC2025 were also evaluated. Results and Conclusions Treatment with UNC2025 inhibited MERTK phosphorylation and downstream activation of AKT and SRC, decreased platelet activation, and protected animals from pulmonary embolism and arterial thrombosis without increasing bleeding times. The antiplatelet effect of UNC2025 was enhanced in combination with ADP-P2Y1&12 pathway antagonists, and a greater than additive effect was observed when these two agents with different mechanisms of inhibition were coadministered. TAM kinase signaling represents a potential therapeutic target, as inhibition of this axis, especially in combination with ADP-P2Y pathway antagonism, mediates decreased platelet activation, aggregate stability, and thrombus formation, with less hemorrhagic potential than current treatment strategies. The data presented here also demonstrate antithrombotic activity mediated by UNC2025, a novel translational agent, and support the development of TAM kinase inhibitors for clinical applications.