A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine Johannesburg, 2014 / Human immunodeficiency virus (HIV) associated thrombotic microangiopathy (TMA) is thought to be a common form of the disorder in South Africa with a severe clinical presentation and poor prognosis; it remains however poorly characterized. This study was undertaken to evaluate the presentation and prognosis of HIV-associated TMA through retrospective analysis of a cohort of HIV positive and negative subjects diagnosed with and treated for TMA at a single center (Helen Joseph Hospital) from 1/1/2001 to 31/12/2009. HIV-associated TMA was the dominant form of the disorder in this series and was associated with advanced HIV infection and a more severe presentation than TMA in HIV negative subjects. Although mortality was non-significantly more frequent, response to plasmapheresis was more rapid and recurrence less common in HIV positive subjects. This study adds to available literature on a rarely studied disorder. Despite its aggressive nature, timeous diagnosis and intervention facilitate satisfactory outcomes in HIV-associated TMA.

published_or_final_version / Pathology / Master / Master of Medical Sciences

Thrombotic microangiopathy is featured by microangiopathic haemolytic anaemia, thrombocytopenia and the presence of peripheral fragmented red cells. Thrombotic thrombocytopenic purpura (TTP) is the major disease entity of concern, which is caused by a congenital or acquired deficiency of a von Willebrand factor (vWF) cleaving protease known as ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 motif, member 13). Deficiency of this protease, leads to accumulation of uncleaved ultra-large hyperactive vWF multimers in peripheral circulation causing the extensive microvascular platelet aggregation in a TTP event. However, the differential diagnosis is sometimes difficult because symptoms and signs can be non-specific and the condition may resemble a number of disorders. Early recognition and definite diagnosis of TTP is critical to enable prompt plasma exchange therapy. Specific and sensitive ADAMTS13 assays will be potentially helpful. In this review, archive frozen plasma samples from six patients presented with prominent thrombotic microangiopathy were retrospectively analysed for ADAMTS13 by immunoassays. The relationship between ADAMTS13 antigen, activity and its autoantibodies and TTP was studied. Local reference ranges of these assays were also determined. The assay results were validated by identifying the clinically-confirmed cases of TTP, with also prospective serial measurements of ADAMTS13 in a few cases. Patients presented with acute TTP were characterized by a severely deficient ADAMTS13 antigen and activity level, as well as a positive autoantibody titre detected for its acquired immune aetiology ; while patients with non-TTP conditions only had mildly reduced ADAMTS13 antigen but variably decreased activity level and a negative autoantibody titre . A pooled analysis of patients and normal subjects also demonstrated a positive correlation between ADAMTS13 antigen and activity. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Healthcare costs continue to escalate and hospitals need to use programs that encourage cost effectiveness, reduce resources and staffing, and increase patient accountability for their own healthcare risk factors, comorbidities, and participation in their healthcare decisions. Post Thrombotic Syndrome (PTS) is a debilitating disease with few treatment options. Allowing patients to have shared decision making in a care plan for this disease process that involves an exercise program may be a significant factor in the success or failure of their own healthcare goals and outcomes. The development of a proposal for an exercise program for PTS should provide patients with input regarding their healthcare plan and participation needs, reduce healthcare risk factors, reduce comorbidities, and increase participation in their healthcare decisions. Seven stakeholders were presented with the proposal for the exercise program for PTS via PowerPoint presentation and a paper handout. Data collection was completed via a 7-question assessment tool designed to provide formative feedback on the refinement of the project and to establish whether the proposed study was a feasible option for the intended vascular population. The analysis consisted of a review and description of all stakeholder responses. Eighty-two percent of the stakeholders indicated that there is a sufficient population, a perception of potential benefit for patients, and that adequate resources are available for the proposed study. Implications for social change include the potential that, through the future implementation of this project, providers could reduce healthcare expenses by decreasing the amount of follow-up and re-hospitalization, thus leading to improved healthcare outcomes.

Peripheral artery disease (PAD) is associated with increased risk for arterial thromboembolic events, and antithrombotic therapy is fundamental to its treatment. Females with PAD have unique characteristics that impact their disease experience, but data is lacking on the differential effects of antithrombotic regimens in females with PAD. We developed a protocol and conducted two systematic reviews and meta-analyses to 1) assess the impact of female sex on cardiovascular, limb, and bleeding events in antithrombotic trials enrolling PAD patients, and 2) evaluate the representation of female PAD patients in antithrombotic trials, as well as trial generalizability. Females did not confer any benefit from dual antiplatelet therapy, dual pathway inhibition, or therapeutic oral anticoagulation over mono-antiplatelet therapy alone, however trial generalizability was limited by poor female enrolment and insufficient sex-based analyses. A more tailored approach to secondary prevention in females with PAD (beginning with improved study design) may yield better outcomes.

We report on 2 cases of chronic relapsing thrombotic thrombocytopenic purpura, in which anti-phospholipid antibodies were also found. The first patient was felt to have the antiphospholipid antibody syndrome, while the second patient had anti-phospholipid antibodies without clinical manifestations of the anti-phospholipid antibody syndrome. We discuss chronic relapsing thrombotic thrombocytopenic purpura and the anti-phospholipid antibody syndrome. Furthermore, we introduce the possibility of an association between chronic relapsing thrombotic thrombocytopenic purpura and the presence of anti-phospholipid antibodies.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted. Includes bibliographical references.

No description available.

Pendant plus de six décennies, les antivitamines K (AVK) ont été la seule classe d’anticoagulants oraux disponibles sur le marché. L’arrivée des Anticoagulants Oraux Directs (AOD) en 2008 a marqué un réel tournant dans l’anticoagulation par voie orale. La première partie de ce travail s’est intéressée aux caractéristiques des patients traités par anticoagulants, et les conséquences en termes d’hospitalisations pour évènement hémorragique ou ischémique. Au sein d’une cohorte de patients hospitalisés pour AVC (cohorte BIOSTROKE, Lille), aucun facteur d’influence particulier, intervenant sur la survenue et l’évolution (mortalité, de déclin cognitif, et de handicap à 3 mois) de l’AVC n’était mis en évidence. En parallèle, une étude menée dans le service d’urgences du Centre Hospitalier de Béthune sur 3 années (2012, 2014, 2016) pour suivre l’évolution des prescriptions d’anticoagulants oraux et observer l’impact de la mise sur le marché des AOD, montrait une population dont certaines caractéristiques semblaient être associées à une utilisation plus volontiers des AOD ou des AVK. Le nombre d’évènements hémorragiques et thrombotiques sous AVK restait cependant stable sur les trois périodes d’étude (770 patients inclus au total). Forts de ces données rassurantes, la deuxième partie de ce travail s’est intéressée aux pratiques de prescription et au bon usage des anticoagulants, avec un focus particulier sur les AOD, à travers trois études : la première réalisée auprès des médecins généralistes du Nord et du Pas de Calais qui montrait une population de prescripteurs plutôt méfiants envers les AOD et ayant une préférence pour les anti-Xa. Les deux autres études portaient sur le bon usage des AOD, à partir de prescriptions à l’officine (grâce à la participation des étudiants en pharmacie de la faculté de Lille en stage d’officine) et à l’hôpital (Centre Hospitalier Régional de Lille). Ces études retrouvaient globalement des chiffres de prescriptions d’AOD transposables aux données françaises, avec cependant des disparités ville/hôpital. En termes de bon usage, les prescriptions étaient pour moins d’un tiers d’entre elles non-conformes aux recommandations en vigueur, avec une forte proportion de situations de sous-dosages. En conclusion, ce travail de thèse a permis de mettre à jour des pistes de formation/information des professionnels de santé sur ces nouvelles molécules anticoagulantes qui vont participer à une prise en charge avisée et optimale des patients. / For over six decades, vitamin K antagonists (VKAs) were the only class of oral anticoagulants available on the market. The arrival of Direct Oral Anticoagulants (DOAs) in 2008 marked a real turning point in the oral anticoagulation. The first part of this work was interested in the characteristics of patients treated with anticoagulants and the consequences in terms of hospitalizations for ischemic or hemorrhagic events. In a cohort of patients hospitalized for stroke (cohort BIOSTROKE Lille), no particular influencer, on the onset and course (mortality, cognitive decline, and disability at 3 months) of stroke was highlighted. In parallel, a study conducted in the emergency department of the Hospital of Bethune on three years (2012, 2014, 2016) to observe oral anticoagulants prescriptions and the impact of DOAs arriving, showed a population where many characteristics appear to be associated with a more readily using DOAs or VKAs. The number of bleeding and thrombotic events with VKAs remained stable during the three study periods (in total 770 patients were included). With these reassuring data, the second part of this work has focused on prescribing practices and the appropriate use of anticoagulants, with a particular focus on DOAs, through three studies: one conducted among general practitioners of Nord and Pas de Calais departments, which showed a rather wary about DOAs but with a preference for anti-Xa. The other two studies focused on the appropriate use of DOAs, estimated from pharmacy (with the participation of pharmacy students of the Faculty of Lille) and hospital (Lille Regional Hospital Center) prescriptions. Data about DOAs prescriptions were transposable to French data, albeit with city / hospital disparities. Non-appropriate prescriptions were observed in less than one-third file, with a high proportion of under dosing situations. In conclusion, this work has allowed updating training tracks / information for health care professionals on these new anticoagulant molecules to improve information and optimal patients’ care.

Atypical hemolytic uremic syndrome (aHUS) is a rare renal disorder characterized by thrombotic microangiopathy, thrombocytopenia, and acute kidney injury. Its pathogenesis has been attributed to a ‘triggering' event that leads to dysregulation of the complement cascade at the level of the endothelial cell surface. Consistent with this understanding of the disease, mutations in complement genes have been definitively implicated in aHUS. However, the existence of other genetic contributors is supported by two observations. First, in ~50% of cases, disease-causing variants are not identified in complement genes, and second, disease penetrance is typically incomplete and highly variable. To test this hypothesis, we identified pathways established to have crosstalk with the complement cascade, focusing initially on the coagulation pathway. Using targeted genomic enrichment and massively parallel sequencing we screened 36 European-American patients with sporadic aHUS patients for genetic variants in 85 complement and coagulation genes, identifying deleterious rare variants in several coagulation genes. The most frequently mutated coagulation gene in our study cohort was PLG, which encodes a zymogen of plasmin and plays key role in fibrinolysis. These results implicate the coagulation pathway in the pathogenesis of aHUS. Based on this outcome, we developed a clinical genetic testing panel to screen disease-related genes in a group of ultra-rare complement-mediated diseases that includes, in addition to aHUS, thrombotic thrombocytopenic purpura (TTP), C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) patients. Data from 193 patients validate the usage of this panel in clinical practice and also provide confirmatory insight into the pathogeneses of these diseases. Specifically, we found that in aHUS and TTP patients, variants were frequently identified in complement regulator genes, while in C3GN and DDD patients, variants were additionally found in C3 convertase genes. To understand variability in disease penetrance, we completed targeted genetic screening in two aHUS families grossly discordant for disease penetrance, identifying in one family a co-segregating Factor X-deficiency variant (F10 p.Glu142Lys) that abrogated the effect of the complement mutation. Functional studies of the F10 p.Glu142Lys variant show that it decreases Factor X activity predicting to a hypo-coagulable state and further illustrating the importance of complement-coagulation crosstalk in exacerbating, but also mitigating the aHUS phenotype. In our final studies, we have sought to complete a comprehensive analysis for other potentially related pathways by using bioinformatics to identify candidate pathways coupled with whole exome sequencing. Preliminary data from 43 aHUS patients and 300 controls suggest that pathways for dermatan and heparan sulfate synthesis, which are relevant to the formation of the extra-cellular matrix and cell surface adhesion, may be implicated in the aHUS.