Timing of Venous Thromboembolism Prophylaxis Initiation and Complications in Polytrauma Patients with High-Risk Bleeding Orthopedic Interventions: A Nationwide Analysis.

INTRODUCTION: There are no clear recommendations for the perioperative timing and initiation of venous thromboembolism pharmacologic prophylaxis (VTEp) among polytrauma patients undergoing high-risk bleeding orthopedic operative intervention, leading to variations in VTEp administration. Our study examined the association between the timing of VTEp and VTE complications in polytrauma patients undergoing high-risk operative orthopedic interventions nationwide. METHODS: A retrospective cohort study of trauma patients ≥18 years who underwent high-risk bleeding operative orthopedic interventions for pelvic, hip, and femur fractures within 24 hours of admission at American College of Surgeons (ACS) verified trauma centers using the 2019-2020 ACS-TQIP databank. We excluded patients with a competing risk of non-orthopedic surgical bleeding. We assessed operative orthopedic polytrauma patients who received VTEp within 12 hours of orthopedic surgical intervention compared to VTEp received beyond 12 hours of intervention. The primary outcome assessed was overall VTE events. Secondary outcomes were orthopedic reinterventions within 72 hours after primary orthopedic surgery, DVT, and PE rates. RESULTS: The study included 2,229 patients who underwent high-risk orthopedic operative intervention. The median time to VTEp initiation was 30 hours (IQR 18, 44). After adjustment for baseline patient, injury, and hospital characteristics, VTEp initiated more than 12 hours from primary orthopedic surgery was associated with increased odds of VTE (aOR 2.02; 95% CI 1.08-3.77). Earlier initiation of prophylaxis was not associated with an increased risk for surgical reintervention (HR 0.90; 95% CI 0.62-1.34). CONCLUSIONS: Administering VTEp within 24 hours of admission and within 12 hours of major orthopedic surgery involving the femur, pelvis, or hip demonstrated an associated decreased risk of in-hospital VTE without an accompanying elevated risk of bleeding-related orthopedic re-intervention. Clinicians should reconsider delays in initiating or withholding perioperative VTEp for stable polytrauma patients needing major orthopedic intervention. LEVEL OF EVIDENCE: Level III, Therapeutic.

Vascular Endothelial Cells Produce Coagulation Factors That Control Their Growth via Joint Protease-Activated Receptor and C5a Receptor 1 (CD88) Signaling.

As per the classical view of the coagulation system, it functions solely in plasma to maintain hemostasis. An experimental approach modeling vascular reconstitution was used to show that vascular endothelial cells (ECs) endogenously synthesize coagulation factors during angiogenesis. Intracellular thrombin generated from this synthesis promotes the mitotic function of vascular endothelial cell growth factor A (VEGF-A). The thrombin concurrently cleaves C5a from EC-synthesized complement component C5 and unmasks the tethered ligand for EC-expressed protease-activated receptor 4 (PAR4). The two ligands jointly trigger EC C5a receptor-1 (C5ar1) and PAR4 signaling, which together promote VEGF receptor 2 growth signaling. C5ar1 is functionally associated with PAR4, enabling C5a or thrombin to elicit Gαi and/or Gαq signaling. EC coagulation factor and EC complement component synthesis concurrently down-regulate with contact inhibition. The connection of these processes with VEGF receptor 2 signaling provides new insights into mechanisms underlying angiogenesis. Knowledge of endogenous coagulation factor/complement component synthesis and joint PAR4/C5ar1 signaling could be applied to other cell types.

Neurological Chimeras and the Moral Staircase.

The possibility of human/nonhuman acute neurological chimeras stirs much controversy. There is concern that neurologically humanizing a research animal could grant it protected moral status, making the performance of invasive experiments on the resulting chimera unethical. However, the real ethical problems may involve smaller increases in moral status along what may be termed the "moral staircase" of research subjects, both animal and human. Through appropriate recognition of incremental increases in moral status along the moral staircase, acute neurological chimera experiments may be permitted to ethically proceed. The real ethical issues around human/nonhuman acute neurological chimeras lie in the realm of animal welfare.

Macrophages with a deletion of the phosphoenolpyruvate carboxykinase 1 (Pck1) gene have a more proinflammatory phenotype.

Phosphoenolpyruvate carboxykinase (Pck1) is a metabolic enzyme that is integral to the gluconeogenic and glyceroneogenic pathways. However, Pck1's role in macrophage metabolism and function is unknown. Using stable isotopomer MS analysis in a mouse model with a myeloid cell-specific Pck1 deletion, we show here that this deletion increases the proinflammatory phenotype in macrophages. Incubation of LPS-stimulated bone marrow-derived macrophages (BMDM) with [U-13C]glucose revealed reduced 13C labeling of citrate and malate and increased 13C labeling of lactate in Pck1-deleted bone marrow-derived macrophages. We also found that the Pck1 deletion in the myeloid cells increases reactive oxygen species (ROS). Of note, this altered macrophage metabolism increased expression of the M1 cytokines TNFα, IL-1ß, and IL-6. We therefore conclude that Pck1 contributes to M1 polarization in macrophages. Our findings provide important insights into the factors determining the macrophage inflammatory response and indicate that Pck1 activity contributes to metabolic reprogramming and polarization in macrophages.

Using Stable Isotopes in Bone Marrow Derived Macrophage to Analyze Metabolism.

Using gas chromatography mass spectrometry (GC-MS) to analyze the citric acid cycle (CAC) and related intermediates (such as glutamate, glutamine, GABA, and aspartate) is an analytical approach to identify unexpected correlations between apparently related and unrelated pathways of energy metabolism. Intermediates can be as expressed as their absolute concentrations or relative ratios by using known amounts of added reference standards to the sample. GC-MS can also distinguish between heavy labeled molecules (2H- or 13C-labeled) and the naturally occurring most abundant molecules. Applications using tracers can also assess the turnover of specific metabolic pools under various physiological and pathological conditions as well as for pathway discovery. The following protocol is a relatively simple method that is not only sensitive for small concentrations of metabolic intermediates but can also be used in vivo or in vitro to determine the integrity of various metabolic pathways, such as flux changes within specific metabolite pools. We used this protocol to determine the role of phosphoenolpyruvate carboxykinase 1 (Pck1) gene in mouse macrophage cells to determine the percent contribution from a precursor of 13C labeled glucose into specific CAC metabolite pools.