Impaired bone healing in multitrauma patients is associated with altered leukocyte kinetics after major trauma

Abstract

Animal studies have shown that the systemic inflammatory response to major injury impairs bone regeneration. It remains unclear whether the systemic immune response contributes to impairment of fracture healing in multitrauma patients. It is well known that systemic inflammatory changes after major trauma affect leukocyte kinetics. We therefore retrospectively compared the cellular composition of peripheral blood during the first 2 weeks after injury between multitrauma patients with normal (n=48) and impaired (n=32) fracture healing of the tibia. The peripheral blood-count curves of leukocytes, neutrophils, monocytes, and thrombocytes differed significantly between patients with normal and impaired fracture healing during the first 2 weeks after trauma (P-values were 0.0122, 0.0083, 0.0204, and <0.0001, respectively). Mean myeloid cell counts were above reference values during the second week after injury. Our data indicate that leukocyte kinetics differ significantly between patients with normal and impaired fracture healing during the first 2 weeks after major injury. This finding suggests that the systemic immune response to major trauma can disturb tissue regeneration.

Enhancement of fracture healing after citrulline supplementation in mice

“…An adequate inflammatory response and fracture haematoma formation are necessary during the fracture healing process, with recruitment and activation of macrophages and, subsequently, neutrophils as well as production of pro-inflammatory cytokines, chemokines and growth factors. Disturbances to these inflammatory signalling processes often lead to development of delayed union and non-union later in the healing process (Bastian et al, 2016). Deletion of Nos2 results in prolonged inflammation and higher degrees of neutrophil influx in and around the fracture callus (Meesters et al, 2016) and, subsequently, in delayed union.…”

“…Every year, about 1 % of the population sustains a fracture (Mills et al, 2017;van Staa et al, 2001). Generally, fractures heal without any complication, however, in around 10 % of all long-bone fractures, difficulties occur during the healing process resulting in delayed union or non-union formation (Bastian et al, 2016;Court-Brown and McQueen, 2008). Next to the fracture location, the degree of (soft) tissue injury, the type and quality of (surgical) treatment as well as several patient-dependent risk factors are known to contribute to non-union development.…”

Neutrophil phenotypes in health and disease

“…53 Intriguingly, normal uneventful fracture healing of large bones, such as tibia and femur, is associated with a clear neutrophilia 10-12 days after the fracture. 54 This neutrophilia is not associated with a detectable infection and/or sterile pathological inflammation. In fact, data in small cohorts of trauma patients with fractures of larger bones imply that this neutrophilia is important, as the absence of such neutrophilia is associated with poor bone formation and non-union of the bone (pseudoarthrosis).…”

“…Intriguingly, normal uneventful fracture healing of large bones, such as tibia and femur, is associated with a clear neutrophilia 10‐12 days after the fracture . This neutrophilia is not associated with a detectable infection and/or sterile pathological inflammation.…”

Innate immune responses to trauma

“…The inflammatory response can alter its kinetics 34 and lose compartmentalization and diversity and thus become overwhelming. This ‘cytokine storm’ can lead to alterations in Na + -K + ATPases and thereby result in electrophysiological membrane dysfunction 35 .…”