Impaired Activity of Blood Coagulant Factor XIII in Patients with Necrotizing Enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) medical/surgical emergency of the newborn and a leading cause of preterm neonate morbidity and mortality. NEC is a challenge to diagnose since it often shares similar clinical features with neonatal sepsis. In the present study, plasma protein profiling was compared among NEC, sepsis and control cohorts using gel electrophoresis, immunoblot and mass spectrometry. We observed significant impairment in the formation of fibrinogen-γ dimers (FGG-dimer) in the plasma of newborns with NEC that could efficiently differentiate NEC and sepsis with a high level of sensitivity and specificity. Interestingly, the impaired FGG-dimer formation could be restored in NEC plasma by the addition of exogenous active factor XIII (FXIII). Enzymatic activity of FXIII was determined to be significantly lower in NEC subject plasma for crosslinking FGG when compared to sepsis. These findings demonstrate a potential novel biomarker and related biologic mechanism for diagnosing NEC, as well as suggest a possible therapeutic strategy.

The Microbiome and Biomarkers for Necrotizing Enterocolitis: Are We Any Closer to Prediction?

“…Furthermore, they recently identified fibrinogen-γ dimers in plasma discriminated NEC (N=40) from sepsis (N=20), with an AUC 0.95. Factor XIII, responsible for fibrin cross-linking, was also significantly lower in NEC versus sepsis (66). The presence of fibrinogen-γ dimers in the urine and serum of infants with NEC is consistent with the prothrombotic coagulation processes that occur as NEC evolves, identifying both a novel potential biomarker and a therapeutic target.…”

“…To date, six studies on NEC have used proteomic techniques on blood, urine or buccal samples (61–66). Sampling was typically done at the time of diagnosis (62, 64–66), mainly for differentiation of NEC from sepsis (63, 64, 66) with two studies looking for identification of predictive biomarkers prior to onset (61, 63).…”

“…Sampling was typically done at the time of diagnosis (62, 64–66), mainly for differentiation of NEC from sepsis (63, 64, 66) with two studies looking for identification of predictive biomarkers prior to onset (61, 63). Ng et al combined Proapolipoprotein CII and a des-arginine variant of serum amyloid A (SAA) to identify sepsis/NEC cases (62), but the ApoSAA score was a combination marker used only on suspected cases and did not differentiate between the two diseases.…”

“…The ability to differentiate NEC from sepsis has had moderate success, most notably in the proteomic studies described above (64, 66). Kim et al developed a new approach to distinguish NEC (N=10) from sepsis (N=5) and controls (N=5), by designing a magnetic multiplexed biosensor system to analyze serum C-reactive protein (CRP), matrix metalloproteinase-7 (MMp7), and epithelial cell adhesion molecule (EpCAM) (78).…”

New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment

“…Much attention has been given to C-reactive protein [56] and serum amyloid protein A [57,58], two separate acute phase reactive proteins which are increased in response to injury and inflammation, and are each expected to be elevated in inflammatory diseases like NEC [59]. Excitingly, Sylvester and colleagues recently described the impaired activity of blood coagulant factor XIII in patients with NEC [60], and this group has also performed an extensive proteomic approach in order to search for novel biomarkers in the urine or blood to distinguish NEC from other non-NEC causes of sepsis [61][62][63]. Other groups have focused on assessing the microbiota in the stool of patients with NEC [11], in a search for signature bacterial changes that can be readily assessed and which may provide clues to the onset of NEC development [64,65].…”