Angiogenesis is a highly regulated process orchestrated by the vascular endothelial growth factor-A (VEGF-A) system of ligands and receptors. Heparin/heparan sulfate (HS) proteoglycans and neuropilin-1 (NRP-1) have been identified as co-receptors for VEGF-A, yet the mechanisms of action have not been fully defined. In the present study, we characterized molecular interactions between receptors and co-receptors and the two major VEGF-A isoforms, using surface plasmon resonance (SPR) and in vitro binding assays. We found that VEGF dissociated 25-times faster from its major signaling receptor, VEGF receptor-2 (VEGFR-2) than from its “decoy” receptor, VEGF receptor-1 (VEGFR-1). We identified a potential mechanism for co-receptors to decrease the dissociation rate and prolong the signaling complex lifetime. Using a systematic approach, we obtained kinetic parameters for each individual interaction in an intercomparable way to measure the effect NRP-1 and HS have on complex stability. Additionally, we demonstrated that these binding events influence VEGF activity within endothelial cells. These parameters can be used in mathematical models to predict therapy outcomes in defined cellular contexts. Furthermore, we optimized a competition-based technique using SPR and structurally defined HS oligosaccharides and demonstrated that it can be used to rapidly measure affinities to HS-binding proteins. We used this method to define interactions and structural and length requirements for heparin/HS interactions with VEGFR-1, NRP-1, and VEGF165, the most relevant VEGF-A isoform, in complex with VEGFR-2 and NRP-1. We show that the structural requirements were distinct for each interaction. We further found that VEGF165, VEGFR-2 and monomeric NRP-1 bound weakly to heparin alone, yet binding to heparin increased synergistically when presented together. This enhanced binding correlated with alterations in VEGF signaling in endothelial cells. We found that soluble NRP-1 increased VEGF binding and activated phosphorylation of VEGFR-2 and Erk1/2 in endothelial cells, and that these effects required sulfated HS. These data suggest that the presence of HS/heparin and NRP-1 may dictate the specific receptor type activated by VEGF and ultimately determine the biological output. The ability of co-receptors to fine-tune VEGF responsiveness suggests the possibility that VEGF-mediated angiogenesis can be selectively stimulated or inhibited by targeting HS/heparin and NRP-1.

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Objective: To determine whether dosage adjustment of enoxaparin during pregnancy, in order to maintain a peak anti-Xa of 1.0-1.2 U/ml, is safe for women with mechanical prosthetic heart valves (MPHV). Methods: This was a prospective observational study performed at Charlotte Maxeke Johannesburg Academic Hospital from 2007 to 2009. 15 women with MPHVs were treated with enoxaparin with dosage adjustment throughout pregnancy to achieve a peak anti-Xa of 1.0-1.2 U/ml. Main outcomes measured were prosthetic valve thrombosis, bleeding and maternal mortality. Results: There was no maternal mortality. None of the women developed valvular thrombosis during pregnancy. Two women developed epistaxis and another developed spotting per vagina. There was no foetal mortality. Conclusion: Our data show that enoxaparin may be administered safely during pregnancy to pregnant women with mechanical prosthetic heart valves when there is dosage adjustment throughout pregnancy in order to maintain an anti-Xa of 1.0-1.2 U/ml.

Respiratory disease represents an important component of small animal emergency medicine. The morbidity and mortality of respiratory disease and inflammation, although poorly defined, is considered to be significant. Much of the therapy used in the stabilization and management of respiratory disease in veterinary patients has been taken from human medicine, including inhalation therapy. Heparin has been shown to have substantial anticoagulant, anti-inflammatory, and antiibrotic effects within the lungs when administered via inhalation in human patients. To date, no studies have evaluated the use of nebulized heparin in dogs. This study is the first to attempt to generate pharmacokinetic data regarding nebulized unfractionated heparin in the dog.

No description available.

Zahlreiche Studien zeigten, dass perioperatives Bridging der oralen Antikoagulation zu einem erhöhten Blutungsrisiko führt. Ursache hierfür könnte eine zu aggressive Herangehensweise bezüglich der Dosierung des Bridgings sein. Daher war das Ziel dieser Arbeit herauszufinden, ob ein Risiko-adjustiertes Bridging-Schema in der elektiven Allgemein- und Viszeralchirurgie zu einem geringeren Auftreten von postoperativen Blutungsereignissen führt und ob trotzdem ein adäquater Schutz vor thromboembolischen Ereignissen gegeben ist. Hierfür wurde retrospektiv und monozentrisch das Auftreten der genannten postoperativen Ereignisse in zwei Zeiträumen untersucht. Das erste Studienintervall erstreckte sich von Januar 2011 bis Dezember 2014 und spiegelt die Ereignisraten vor der internen Leitlinienänderung wider. Es wurden 263 Personen eingeschlossen. Das zweite Intervall begann im Januar 2017 und endete im Dezember 2019, in diesem wurden 271 Personen untersucht. Zwischen diesen beiden Zeiträumen wurde eine überarbeitete klinikinterne Bridging-Leitlinie etabliert, welche an das individuelle thromboembolische Risiko, Alter, Gewicht und die Nierenfunktion der Patientinnen und Patienten angepasst war. Postoperative Major- (8.4% vs. 4.1%, p=0.039) und Minor-Blutungen (13.7% vs. 6.3%, p=0.004) nahmen im zweiten Intervall signifikant ab, während das thromboembolische Risiko weiterhin niedrig blieb (0.8% vs. 1.1%, p=1). Außerdem zeigte sich, dass es zu keiner signifikanten Zunahme der Mortalität, der Reoperationen, der Länge des postoperativen stationären Aufenthalts oder der Erythrozytenkonzentrat-Transfusionen kam. Die Ergebnisse dieser Arbeit zeigen, dass die differenzierte Bridging-Leitlinie für die Allgemein- und Viszeralchirurgie mit einer signifikant erniedrigten Blutungsrate assoziiert ist und eine Anpassung des Bridgings an die patientenspezifischen Risikofaktoren wichtig ist. / Multiple studies have shown that perioperative bridging of oral anticoagulation leads to an increased risk of bleeding. This could be due to an overly aggressive approach to bridging dosing. Therefore, the aim of this study was to find out whether a risk-adjusted bridging regimen in elective general and visceral surgery leads to a lower incidence of postoperative bleeding events and whether adequate protection against thromboembolic events is still provided. For this purpose, the occurrence of the aforementioned postoperative events was examined retrospectively and monocentrically in two time periods. The first study interval extended from January 2011 to December 2014 and reflects the event rates before the internal guideline change. 263 people were included. The second interval began in January 2017 and ended in December 2019, in which 271 people were examined. Between these two periods, a revised internal clinical bridging guideline was established, which was adapted to the individual thromboembolic risk, age, weight and renal function of the patients. Postoperative major (8.4% vs. 4.1%, p=0.039) and minor bleeding complications (13.7% vs. 6.3%, p=0.004) decreased significantly in the second interval, while the thromboembolic risk remained low (0.8% vs. 1.1%, p=1). In addition, there was no significant increase in mortality, reoperations, length of postoperative hospital stay or red blood cell transfusions. The results of this study show that the differentiated bridging guideline for general and visceral surgery is associated with a significantly lower bleeding rate and that it is important to adapt bridging to patient-specific risk factors.

Call number: LD2668 .T4 1961 R68

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

No description available.