Epistaxis in anticoagulated patients: Fewer hospital admissions and shorter hospital stays on rivaroxaban compared to phenprocoumon.

OBJECTIVES: Treatment of epistaxis in patients on anticoagulants is challenging and associated with higher admission rates and longer hospital stays compared with patients without anticoagulation. However, there is little information about epistaxis in patients taking new direct oral anticoagulants such as rivaroxaban compared with patients on traditional vitamin K antagonists such as phenprocoumon. DESIGN: Retrospective cohort study. SETTING: The study was conducted at the emergency department of the University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS: All admissions to the emergency department of the University Hospital Inselspital, Bern, Switzerland from 1st July 2012 to 30th June 2016 with non-traumatic epistaxis on anticoagulant therapy with phenprocoumon or rivaroxaban were included. MAIN OUTCOME MEASURES: We compared clinical outcome parameters (admission rates, length of hospital stay and mortality) for both anticoagulant groups. RESULTS: We included 440 patients with epistaxis, 123 (28%) on rivaroxaban and 317 (72%) on phenprocoumon. Fewer hospital admissions and shorter hospital stays were found in patients under rivaroxaban (12 (10.4%) vs 57 (18.0%) patients, P=.033; 0.7±2.2 vs 1.5±3.7 days, P=.011) compared with phenprocoumon. Anterior epistaxis was more common in the rivaroxaban group in contrast to posterior epistaxis in patients on phenprocoumon (74 (60.2%) vs 139 (43.8%) patients, P=.002; 7 (5.7%) vs 39 (12.3%) patients, P=.042). CONCLUSIONS: Our data suggests that epistaxis on direct oral anticoagulation with rivaroxaban is associated with shorter hospital stays and fewer hospital admissions than epistaxis on vitamin K antagonist phenprocoumon.

Local and controlled release of growth factors (combination of IGF-I and TGF-beta I, and BMP-2 alone) from a polylactide coating of titanium implants does not lead to ectopic bone formation in sheep muscle.

The osteoinductive potential of growth factors leads not only to a stimulated bone formation in bony tissue but also in extra skeletal tissue. This potential depends on the dosage and potentially on the application method and may limit the clinical use. The aim of the present study was to investigate the potential of IGF-I, TGF-beta1 and BMP-2 released from a newly developed application systems of orthopaedic implants to induce ectopic bone formation in muscles. This bioactive coating showed a stimulating effect on fracture healing in several experimental studies before. Titanium discs were coated on one side with the drug carrier poly(d,l-lactide) (PDLLA), with the carrier plus IGF-I and TGF-beta1 or with the carrier plus BMP-2. The discs were implanted in the Musculus cleidomastoideus of sheep and followed up for 3 months. X-rays were taken after the operation and the day of sacrifice. The muscles plus implant were harvested and prepared for histology. Neither the radiology nor the histology revealed any signs of ectopic ossification in the implant/muscle interface or in a distance to the plate in any group. An influence of the locally applied growth factor, however, was seen in the formation of a soft tissue capsule. Histomorphometric analysis revealed a significantly larger capsule area over the growth factor coated side in comparison to the uncoated side or the pure titanium plate, indicating an effect of the applied growth factors on cells, however, not resulting in osteoinduction in muscle. The result showed that the local and controlled release of growth factors from PDLLA coated implants does not induce ectopic bone formation in sheep muscle and could be used in orthopaedic surgery to increase healing without the risk of ectopic bone formation in the surrounding soft tissue.

Systemic application of growth hormone enhances the early healing phase of osteochondral defects--a preliminary study in micropigs.

Healing of osteochondral defects following trauma remains a significant clinical problem, often leading to osteoarthritis. Growth hormone (GH) has been shown to accelerate formation of bone and cartilage tissue in the growth plates and in cell cultures. To investigate the influence of systemically administered recombinant porcine growth hormone (r-pGH) on the healing of osteochondral defects we performed a histomorphometrical analysis of full-thickness cartilage defects in the femoral condyle of micropigs. Forty-eight mature female Yucatan micropigs were divided into two groups, one receiving a daily injection of r-pGH (100 microg/kg), the other receiving sodium chloride as placebo. A circular 6-mm-diameter full-thickness defect of the cartilage was created, extending 1.5 mm into the subchondral bone. The animals were sacrificed after 4 (n = 24) and 6 (n = 24) weeks. The von-Kossa stain was used to visualise the calcified structures; cartilage and the fibrous tissue were marked with a combined Safranin-O/light-green stain. The defect filling and the percentage of bone, cartilage, and fibrous tissue into the defect were evaluated using an image analysis system. Furthermore, histological grading was performed using the modified Wakitani score. After 4 weeks no differences were observed between both groups. The defect filling after 6 weeks with newly formed bone was significantly higher in the r-pGH-treated group. The formation of cartilage and fibrous tissue showed a trend towards better healing in the GH-treated group; however, there was no significant difference. In the r-pGH-treated group, the percentage of total defect filling was significantly higher. The evaluation of the vascularity showed a significantly lower number of vessels in the GH-treated group after 6 weeks. Histomorphological grading revealed a significantly lower total Wakitani score in the GH-treated group, which represents a better healing result compared to the controls. The results of the present study suggest that circulating r-pGH or one of its mediators may accelerate osteochondral defect healing by stimulating the formation of osseous and chondral tissue. The analysis of the vascularity leads to the assumption of an advanced maturation of the osteochondral defects under the influence of GH.

[Experimental fusion of the sheep cervical spine. Part II: Effect of growth factors and carrier systems on interbody fusion]. / Experimentelle Spondylodese der Schafshalswirbelsäule Teil 2: Der Effekt von Wachstumsfaktoren und Carrier-Systemen auf die intervertebrale Fusion.

INTRODUCTION: A sheep cervical spine interbody fusion model was used to determine the effect of different carriers and growth factors on interbody bone matrix formation. The purpose of this study was to compare the efficacy and safety of combined IGF-I and TGF-beta1 application with BMP-2 application in spinal fusion. Additionally, a new poly (D, L-lactide) carrier system was compared to a collagen sponge carrier. METHOD: Forty sheep underwent C3/4 discectomy and fusion: group 1: titanium cage ( n=8), group 2: titanium cage coated with a PDLLA carrier (n=8), group 3: titanium cage coated with a PDLLA carrier including BMP-2 ( n=8), group 4: titanium cage with a collagen carrier including BMP-2 ( n=8), and group 5: titanium cage coated with a PDLLA carrier including IGF-I and TGF-beta1 ( n=8). Blood samples, body weight, and temperature were analyzed. Radiographic scans were performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks, respectively. At the same time points, disc space height (DSH) and intervertebral angle (IVA) were measured. After 12 weeks the animals were killed and fusion sites were evaluated using functional radiographic views in flexion and extension. Quantitative computed tomographic scans (QCT) were performed to assess bone mineral density (BMD), bone mineral content (BMC), and bony callus volume (BCV). Biomechanical testing was carried out in flexion, extension, axial rotation, and lateral bending. Range of motion (ROM), neutral zone (NZ), and elastic zone (EZ) were determined. Histomorphological and histomorphometrical analyses were performed and polychrome sequential labeling was used to determine the time frame of new bone formation. RESULTS: In comparison to the non-coated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus and bone volume/total volume ratio. In comparison to the cage groups (groups 1 and 2), the cage plus BMP-2 (groups 3 and 4) and the cage plus IGF-I and TGF-beta1 group (group 5) demonstrated a significantly higher fusion rate in radiographic findings, a higher biomechanical stability, an advanced interbody fusion in histomorphometric analysis, and an accelerated interbody fusion on fluorochrome sequence labeling. BMP-2 application by the PDLLA carrier system (group 3) demonstrated significantly higher bony callus volume than BMP-2 application by a collagen sponge carrier (group 4). The BMP-2 group (group 3) showed significantly lower residual motion on functional radiographic evaluation and higher intervertebral bone matrix formation on fluorochrome sequence labeling at 9 weeks in comparison to the IGF-I/TGF-beta1 group (group 5). In contrast, the IGF-I/TGF-beta1 group (group 5) showed a significantly higher bone mineral density of the callus than the BMP-2 group (group 3). CONCLUSION: PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective and safe. In comparison to the collagen sponge carrier, the new PDLLA carrier system was able to improve results of interbody bone matrix formation. Both growth factors (BMP-2 and combined IGF-I and TGF-beta1) significantly accelerated results of interbody fusion. Based on these preliminary results, the combined IGF-I/TGF-beta1 application yields results equivalent to BMP-2 application at an early time in anterior sheep cervical spine fusion.

Recombinant species-specific growth hormone increases hard callus formation in distraction osteogenesis.

The effect of growth hormone (GH) on secondary fracture healing and callus formation has been demonstrated in several previously investigated animal models. The aim of this study was to investigate and quantify the effects of GH on bone regenerates in a distraction osteogenesis model. In 20 mature female Yucatan micropigs, the tibia and fibula were osteotomized, stabilized with an external fixator, and distracted at 2 mm/day for 10 days after a 4 day latency period. The regenerates were allowed to consolidate for 10 days. Micropigs in the study group (ten animals) received a daily injection of 100 microg per kilogram body weight of recombinant porcine growth hormone (r-pGH). Micropigs in the control group (ten animals) received sodium chloride as placebo. After killing on day 25, a quantitative histomorphometrical analysis of the formed callus and the adjacent cortical bone was performed and the results of polychrome in vivo labeling were assessed. The regenerates of the r-pGH-treated animals showed a significantly larger callus area but no change in callus structure. We found islands of cartilage tissue in the regenerates of both groups; the calli from the control group exhibited a higher fraction of cartilage compared with the r-pGH group, but this was not significant. Quantification of the fluorescent in vivo labeling revealed that the distraction gap in GH-treated group showed significant ossification even during distraction. These results demonstrate that growth hormone can accelerate the maturation of the regenerate in distraction osteogenesis without changing the callus microstructure. This may prove to be a useful clinical tool for shortening the healing time in limb lengthening and bone segment transport.