In 2013 around 289,000 women died from what was categorised as maternal complications. This figure is likely to be higher as only 40% of the world has an adequately function health reporting system (WHO et al 2014, p.1). Severe bleeding causes around 27% of all maternal deaths; this is the single biggest threat to pregnancy and childbirth. Moreover, maternal complications are the second biggest cause of death for women of reproductive age globally. The risks women and girls face through pregnancy and childbirth are the outcome of socio-cultural structures and norms, which increase the inequalities in many societies. The decisions we make, the choices we have, and the actions we carry out are a product of our social system’s structures and norms. Humanitarian crises painfully display the divisiveness and destruction that these structures and norms can have on the members of that system. But, crises also offer an opportunity to either, rebuild structures and norms in a way that reduces inequality and protects the vulnerable, or a regression to more traditional, more patriarchal and more hierarchical structures and norms which will ultimately disadvantage women and girls further in their plight for equality. There is a vicious circle of poverty and mortality that can be triggered by maternal death. In order to prevent these cycles from continuing, creative, simple and appropriate strategies need to be developed for humanitarian response that build on the knowledge systems and capacities of those affected, as well as the experience and expertise of practitioners. Instead of a discussion between development or humanitarian, the conversation should try to find ways for all interventions to be more homophilious with those affected and ensure that they do not worsen the structures protecting the most vulnerable. Innovation has long since been seen as a process for those who ‘have’, and not for those who ‘have not’. Criticisms of increasing inequality through a division based on socio-economic markers have only led to self-fulfilling stereotypes of who is innovative and who is not. This research is trying to shift the focus from one that is divisive to a more inclusionary approach. To address maternal mortality caused by severe bleeding, it is imperative to understand the context in which it is happening. Who is affected? Why? What do they think and believe? What happens to the family, the community? How are the structures and norms of the society affecting it? What solutions have been offered? In answering these questions it is clear how far the impact of maternal mortality can reach. It is the hope of this research, that its can be used to reduce and lessen this impact through better-targeted and tailored responses using appropriate tools – such as the non-pneumatic anti-shock garment, implemented in a mind frame of sustainability and resilience in an environment receptive to innovation. There is a need for fresh ideas and approaches to reduce a burden that does not exist in resource stable parts of the world, and a burden that has come to be seen as a problem of the poor. The non-pneumatic anti-shock garment is a game changer. It has the potential to inspire interest and access health systems, yet implementation thus far has been limited in humanitarian response. This research investigates maternal mortality caused by postpartum haemorrhage in humanitarian crises, in an endeavour to improve the discussion on including the NASG into the MISP as an appropriate tool to fight maternal mortality and the inequality that is found at its root.

Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC. Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment. Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year). Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.

Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.

Haemorrhage is a leading cause of trauma morbidity and mortality, with many deaths potentially preventable. Hyperfibrinolysis is a central characteristic of trauma-induced coagulopathy (TIC) which develops rapidly and is associated with poor outcomes. Tranexamic acid (TXA) improves survival in trauma haemorrhage but its uptake worldwide remains variable, in part because its effects on the coagulation system during trauma haemorrhage have not been described. Further uncertainty regarding patient selection for TXA therapy has emerged following the description of an early viscoelastic haemostatic assay (VHA) diagnosed hypofibrinolytic phenotype in whom TXA may potentiate thrombotic complications. The patient characteristics and mechanisms leading to this apparent hypofibrinolytic phenotype are poorly understood. Over 900 trauma patients prospectively recruited to a multicentre observational cohort study had blood drawn within 2-hours of injury for VHA and fibrinolysis plasma protein analysis. Patients were categorised according to VHA maximum lysis (ML) and D-dimer (DD) levels. Patients with MLLOW exhibited heterogeneity in clinical and injury characteristics and outcomes. Those who died were severely injured, with a high incidence of traumatic brain injury and a 7-fold higher D-dimer. Patients with MLLOW+DDHIGH had a hyperfibrinolytic biomarker profile, with the fibrinolytic mediator S100A10 identified as a potential driver of fibrinolysis, which can ex-vivo artificially reduce ML. Empiric TXA could benefit this occult hyperfibrinolytic phenotype. Over two subsequent observational studies, the effects of TXA on the coagulation system during trauma haemorrhage and the effect of TXA infusion and timing of treatment on thrombotic events were investigated. Early empiric TXA avoided VHA-hyperfibrinolysis and provided a degree of protection from TIC. Whilst univariate analysis suggested increased thromboses with later TXA treatment in patients receiving TXA bolus+infusion, neither the TXA infusion nor time to bolus were associated with thrombotic events after multivariate analysis. A single TXA bolus may provide a lower effective therapeutic dose with reduced complications.

Background: Cerebral small vessel disease (SVD) causes substantial cognitive, psychiatric and physical disabilities. Despite its common nature, SVD pathogenesis and molecular mechanisms remain poorly understood, and prevention and treatment are probably suboptimal. Identifying the genetic determinants of SVD will improve understanding and may help identify novel treatment targets. The aim of this thesis is to better understand genetic associations with SVD through investigating its pathological, radiological and clinical phenotypes. Methods: To unravel the genetic associations with SVD, I used three complementary approaches. First, I performed a systematic review looking at existing intracerebral haemorrhage (ICH) classification systems and their reliability, to help inform future studies of ICH genetics. Second, I performed a series of systematic reviews and meta-analyses, investigating associations between genetic polymorphisms and histopathologically confirmed cerebral amyloid angiopathy (CAA). Third, I performed meta-analyses of existing genome-wide datasets to determine associations of >1000 common single nucleotide polymorphisms (SNP) in the COL4A1/COL4A2 genomic region with clinico-radiological SVD phenotypes: ICH and its subtypes, ischaemic stroke and its subtypes, and white matter hyperintensities. Results: The reliability of existing ICH classification systems appeared excellent in eight studies conducted in specialist centres with experienced raters, although these existing systems have several limitations. In my systematic evaluation of CAA genetics, meta-analyses of 24 studies including 3520 participants showed robust evidence for a dose-dependent association between APOE ɛ4 and histopathological CAA. There was, however, no convincing association between APOE ɛ2 and presence of CAA in a meta-analysis of 11 studies including 1640 participants. Meta-analyses of five studies including 497 participants showed, contrary to an existing popular hypothesis, that while APOE 4 may increase the risk of developing severe CAA vasculopathy, there is no clear evidence to support a role of ɛ2. There were few data about the role of APOE in hereditary CAA, but in the three studies that had looked at this, there was no evidence for an association between APOE ɛ4 and CAA severity. There were too few studies and participants to draw firm conclusions about the effect of non-APOE ε2/ε3/ε4 genetic polymorphisms on CAA, but there were positive associations with TGF-β1, TOMM40 and CR1 genes in four studies. Finally, in my meta-analyses of the COL4A1/COL4A2 genomic region, three intronic SNPs in COL4A2 were associated with SVD phenotypes: significantly with deep ICH, and suggestively with lacunar ischaemic stroke and WMH. Conclusions: I have shown that while existing ICH classification systems appear to have very good reliability, further research is needed to determine their performance in different settings. For large population-based prospective studies of ICH genetics, anatomical systems are likely to be more feasible, scalable and appropriate, although they have limitations and will need to be further developed. Using systematic reviews and meta-analyses, I have confirmed a dose-related association between APOE ɛ4 and histopathological CAA, but also demonstrated that, despite popular acceptance, there is insufficient data to draw firm conclusions about the association with APOE ɛ2. I found some positive associations with CAA in other genes, which merit replication in further larger studies, and showed that there is currently insufficient data about the role of APOE in hereditary CAA. Finally, I identified a novel association between a locus in a known hereditary SVD gene – COL4A2 – and sporadic SVD. This highlights a new and successful approach for selecting candidate genes and can be expanded in future studies to include other known hereditary SVD genes.

[Truncated abstract] Cardiac surgery involving cardiopulmonary bypass is a complex procedure that results in significant changes to blood coagulation, fibrinolytic biochemistry, platelet number and function, and the vasculature. These are due to pharmacological agents which are administered, haemodilution and contact of the blood with artificial surfaces. Consequently there are significant risks of thrombosis and haemorrhage associated with this procedure. The research presented in this thesis utilises in vitro, in vivo, and a novel ex vivo model to investigate the nature of the haemostatic defect induced by cardiopulmonary bypass. The components studied include the drugs heparin, protamine sulphate, and aprotinin, different types of bypass circuitry (including heparin bonded circuits) and procedures such as acute normovolaemic haemodilution. Patient variables, such as Factor V Leiden, are also studied. Each of these components is assessed for the effects on a number of laboratory measures of haemostasis including activated partial thromboplastin time, prothrombin time, activated protein C ratio, antithrombin concentration, heparin concentration, thrombin-antithrombin complex formation, prothrombin fragment 1+2 formation, markers of platelet surface activation and secretion, activated clotting time, haemoglobin concentration and coagulation factor assays.

Today around 28 000 women originally from countries where FGM is practised, are living in Sweden. Many of them are at childbearing age which means that knowledge about FGM and its consequences is of outmost importance during delivery. The aim of this study is to describe current research on how to manage the delivery, regarding deinfibulation and the following stitching as well as the risk of complications when the labouring woman is mutilated. This review of literature is based on 12 scientific articles published between years 1989 – 2005. Five different databases have been searched with use of a large number of keywords.The review found that no scientific research has been carried out that describes how deinfibulation and following stitching should be managed when the woman is mutilated. All available articles within this area are referring to best practice only. The review also found that the conclusions of the studies are contradictory. The majority, however, show an increased frequency for prolonged labour that could be related to FGM. The three largest studies also show an increased rate of caesarean section among mutilated women. In the few studies that examine haemorrhage, the majorities show an increased tendency to bleed, that could be related to FGM. Several articles emphasize the importance of good routines for deinfibulation to reduce the risk for complications.In summary it can be established that due to methodological problems in many studies, no reliable conclusion can be made that the researched complications exists to a greater extent when the woman is mutilated

In der vorliegenden Arbeit wurde das Outcome von 112 Patienten mit intrakranieller Blutung analysiert, um das Blutungsvolumen und die unterschiedliche Dynamik der Blutungen als Einfluss- und prädiktive Faktoren zu korrelieren. 21.4% der 112 eingeschlossenen Patienten hatten ein EDH, 38.4 % ein SDH- bzw. 40.2% ein Intrazerebralhämatom. Die Sub- und Epiduralhämatome waren mehrheitlich traumatische Läsionen, die intrazerebralen Blutungen vorwiegend spontane. Im Gesamtkollektiv hatten 28.6% ein funktionelles, respektive 71.4% ein nicht funktionelles Outcome. Das Ergebnis der 71 traumatischen Blutungen war signifikant besser (38.0% funktionell) als das der 41 spontanen (12.2% funktionell, p=0.004). Bei gleichem Hämatomvolumen haben operativ versorgte spontane Blutungen eine 88% geringere Chance für ein funktionelles Ergebnis als operierte traumatische Blutungen. Im Untersuchungskollektiv wurde der reziproke Zusammenhang von Volumen und GOS sowohl für spontane und traumatische, als auch für akute und subakute Blutungen demonstriert. Nicht signifikant verschieden waren akut und subakut verlaufende Blutungen bezüglich ihres Outcomes (32.8% vs. 23.5% funktionelles Outcome, p= 0.302), und der Volumina (47.5ml vs. 52.8ml, p=0.102)). Der vermutete Zusammenhang zwischen Hämatomgröße und zeitlichem Verlauf konnte damit nicht gezeigt werden. Wir fanden auch keinen signifikanten Unterschied des klinischen Ergebnisses in Bezug auf den chirurgischen Interventionszeitpunkt (< 6h vs. > 6h). Bei den traumatischen Hämorrhagien wurde ein Modell mit 3 unabhängigen Faktoren (Alter, initaler GCS und Volumen) zur Prädiktion des Outcomes entwickelt. Kleine Volumina, ein niedriges Alter und ein initial hoher GCS lassen ein funktionelles Outcome vorhersagen. Weitere Faktoren, die jedoch nicht unabhängig mit dem Outcome assoziiert waren, sind Mittellinienverlagerung, initiale Blutglukose, Vorliegen eines Hirnödems und arterielle Hypertonie. Die initiale Glukosekonzentration kann zur Vorhersage des Outcomes nach traumatischen Blutungen beitragen, Als einziger unabhängiger Prädiktor wurde bei den spontanen Raumforderungen die Mittellinienverlagerung ermittelt. Volumen und initiale GCS waren nicht unabhängige Prädiktoren. Das schlechte Outcome nach spontaner Blutung, unabhängig vom Versorgungszeitpunkt, unterstreicht die kontroverse Datenlage bezüglich operativer Therapie dieser Raumforderungen. Traumatische Hämorrhagien in temporaler Lokalisation zeigen ein besseres Ergebnis als vergleichbare lokalisierte spontane Blutungen.

Maternal mortality in Kyrgyzstan is a discrimination of women not only based on sex, but also on rural/urban setting. Rural women are most likely to die of haemorrhage than urban women in Kyrgyzstan. Postpartum haemorrhage constitutes 45 per cent of all maternal deaths in Kyrgyzstan. This work concentrates on the obligations of Kyrgyzstan under articles 12 and 14.b of the Convention on Elimination of all Forms of Discrimination against Women (CEDAW). The work analyses the nature and scope of state obligations under respective articles. Kyrgyzstan has obligations to respect, protect and fulfill rural women’s human rights to address discriminations against rural women, provide appropriate health services and ensure availability and accessibility of misoprostol to rural women. Misoprostol is more suitable to the conditions of rural area than traditionally used oxytocin. Therefore, the availability and accessibility of rural women to misoprostol will prevent avoidable maternal deaths in haemorrhage.

Maternal mortality in Kyrgyzstan is a discrimination of women not only based on sex, but also on rural/urban setting. Rural women are most likely to die of haemorrhage than urban women in Kyrgyzstan. Postpartum haemorrhage constitutes 45 per cent of all maternal deaths in Kyrgyzstan. This work concentrates on the obligations of Kyrgyzstan under articles 12 and 14.b of the Convention on Elimination of all Forms of Discrimination against Women (CEDAW). The work analyses the nature and scope of state obligations under respective articles. Kyrgyzstan has obligations to respect, protect and fulfill rural women’s human rights to address discriminations against rural women, provide appropriate health services and ensure availability and accessibility of misoprostol to rural women. Misoprostol is more suitable to the conditions of rural area than traditionally used oxytocin. Therefore, the availability and accessibility of rural women to misoprostol will prevent avoidable maternal deaths in haemorrhage.