Snake envenomation globally is attributed to an ever-increasing human population encroaching into snake territories. Responsible for many bites in Asia is the widespread genus Trimeresurus. While... Show moreSnake envenomation globally is attributed to an ever-increasing human population encroaching into snake territories. Responsible for many bites in Asia is the widespread genus Trimeresurus. While bites lead to haemorrhage, only a few species have had their venoms examined in detail. We found that Trimeresurus venom causes haemorrhaging by cleaving fibrinogen in a pseudo-procoagulation manner to produce weak, unstable, short-lived fibrin clots ultimately resulting in an overall anticoagulant effect due to fibrinogen depletion. The monovalent antivenom `Thai Red Cross Green Pit Viper antivenin', varied in efficacy ranging from excellent neutralisation of T. albolabris venom through to T. gumprechti and T. mcgregori being poorly neutralised and T. hageni being unrecognised by the antivenom. While the results showing excellent neutralisation of some non-T. albolabris venoms (such as T. flavomaculaturs, T. fucatus, and T. macrops) needs to be confirmed with in vivo tests, conversely the antivenom failure T. hageni, and the very poor results against T. gumprechti and T. mcgregori, despite being conducted in the ideal scenario of preincubation of antivenom:venom, indicates that the likelihood of clinically relevant cross-reactivity for these species is low (T. gumprechti and T. mcgregori) to non-existent (T. hageni). These same latter three species were also not inhibited by the serine protease inhibitor AEBSF, suggesting that the toxins leading to a coagulotoxic effect in these species are non-serine proteases while in contrast T. albolabris coagulotoxicity was completely impeded by AEBSF, and thus driven by kallikrein-type serine proteases. There was a conspicuous lack of phylogenetic pattern in venom variation, with the most potent venoms (T. albolabris and T. hageni) being distant to each other on the organismal tree, and with the three most divergent and poorly neutralised venoms (T. gumprechti, T. hageni, and T. mcgregori) were also not each others closest relatives. This reinforces the paradigm that the fundamental dynamic evolution of venom results in organismal phylogeny being a poor predictor of venom potency or antivenom efficacy. This study provides a robust investigation on the differential venom effects from a wide range of Trimeresurus species on coagulation, highlighting differential fibrinogenolytic effects, while also investigating the relative antivenom neutralisation capabilities of the widely available Thai Red Cross Green Pit Viper antivenom. These results therefore have immediate, real-world implications for patients envenomed by Trimeresurus species. Show less
Postpartum haemorrhage, in this thesis defined as blood loss above 1000mL within the first 24 hours after birth, remains a major cause of maternal morbidity and mortality with an incidence that... Show morePostpartum haemorrhage, in this thesis defined as blood loss above 1000mL within the first 24 hours after birth, remains a major cause of maternal morbidity and mortality with an incidence that seems to be increasing over the last decade. In this thesis we focussed on improvement of prognostic and diagnostic strategies for major obstetric haemorrhage, which may subsequently lead to a reduction of severe maternal morbidity, mortality and need for surgical interventions. In pursuit of this aim, research questions were posed corresponding to all three phases leading up to adverse outcome due to postpartum haemorrhage: pregnancy (prior to childbirth), early postpartum haemorrhage and persistent postpartum haemorrhage. In the first part of this thesis we focused on prediction of postpartum haemorrhage.Bleeding assessment tools were found to have no predictive value for postpartum haemorrhage. The change of coagulation parameters during the course of postpartum haemorrhage was described, and fibrinogen was found to be an early predictor of a worse outcome of postpartum haemorrhage. The association between fibrinogen measured by the Clauss method and ROTEM Fibtem was described in this thesis. Show less
