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Johnson, Ben David. "Molecular genetic investigation into inherited thrombocytopenia." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7555/.
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Inherited thrombocytopenias are a heterogeneous group of disorders characterised by abnormally low platelet counts, often with secondary qualitative defects in platelet function, which can be associated with abnormal bleeding. Next generation sequencing has only previously been employed in small-scale studies and for the confirmation of suspected variants. This study presents the first large-scale approach to fully categorise inherited thrombocytopenia. Ninety-five patients were recruited to the UK-Genotyping and Phenotyping (GAPP) study with inherited thrombocytopenia of unknown genetic aetiology. An average platelet count of 88x109/L was observed across all individuals. Platelet function testing revealed a secondary phenotypic defect in addition to the reduction in platelet count in 71% (61/86). Of the 95 patients, 69 patients, encompassing 47 index cases, were analysed by whole exome sequencing. A variant with a positive prediction of pathogenicity was identified in 40% (19/47) of patients and overall plausible candidate variants of disease were identified in 69% of index cases. Subsequently an inherited thrombocytopenia specific gene panel was developed to serve as a pre-screen for patients prior to whole exome sequencing. In total, candidate variants in genes previously known to be implicated with disease were identified in 77% (20/26) of patients analysed. In conclusion, the application of a combined phenotyping and genotyping approach to patients with inherited thrombocytopenia is an effective and efficient means of complete diagnosis. It also has the added benefit of identifying novel candidate variants in genes not previously known to cause disease that may further our understanding of the processes surrounding haemostasis through subsequent functional studies.
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Ketchem, Shannon, Katie Prosser, Christine Colon, Diana Heiman, Kelly Covert, and David Stewart. "Thrombocytopenia Risk with Valproic Acid Therapy." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/47.
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Valproic acid (Depakote) is an antiepileptic drug approved for the treatment of bipolar disorder, migraine prophylaxis, and seizure disorders. While the exact mechanism is still unknown, thrombocytopenia, defined as platelet counts < 150,000/uL, has been reported secondary to Depakote treatment. The frequency of Depakote-induced thrombocytopenia varies greatly, with reported rates ranging from 5 to 54%. This adverse effect is dose-dependent and possible risk factors include lower baseline platelet counts, female gender, and high VPA serum concentrations.Our team came across two patient cases where thrombocytopenia during Depakote therapy was observed. Patient information was gathered through electronic medical records. The first patient was a 65-year-old male who was started on 500 mg Depakote ER three tablets at night for bipolar affective disorder. After several months on this dose, the patient’s platelets decreased to 59 X 103per microliter. One month after the drug was discontinued, the platelets recovered to 160 X 103per microliter. The second patient was a 57-year-old woman who had two occurrences of thrombocytopenia while on Depakote. The patient was started on Depakote for a seizure disorder. She was later admitted for symptomatic bradycardia, hypotension, and concern for thrombocytopenia. Her Depakote dose was decreased from 500 mg three times a day to twice a day. Approximately 5 weeks later, she presented to the emergency room for decreased arousal and hypotension. She was again found to have thrombocytopenia with a platelet count of 28 X 103per microliter with a Depakote level of 101 mcg/mL. The team discovered she had been receiving Depakote 500 mg three times a day following discharge from her last admission, not the reduced dose prescribed. On day four of admission, her platelets had not improved and the Depakote dose was decreased further to 250 mg twice daily. After Depakote was discontinued her platelets gradually improved and returned to normal after four days, the eighth day of admission. Utilizing the Naranjo adverse drug reaction probability scale, the first patient case had a probable reliability that this adverse reaction was due to Depakote, while the second patient case had a definite reliability.These cases illustrate the potential for thrombocytopenia secondary to Valproic acid use. Although this adverse event isn’t well understood, these cases add to the evidence that it can occur. Recognition of this reaction is important and clinicians should monitor hematologic labs, including platelets, for patients receiving Valproic acid.
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Joutsi-Korhonen, Lotta. "Autoimmune thrombocytopenia : detection of platelet-associated IgG, reticulated platelets and platelet Fcg[gamma] receptor polymorphism in thrombocytopenic patients." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/joutsi-korhonen/.
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Newman, Peter Michael Pathology UNSW. "Antibody and Antigen in Heparin-Induced Thrombocytopenia." Awarded by:University of New South Wales. Pathology, 2000. http://handle.unsw.edu.au/1959.4/17485.
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Immune heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin therapy and is associated with antibodies directed against a complex of platelet factor 4 (PF4) and heparin. Early diagnosis of HIT is important to reduce morbidity and mortality. I developed an enzyme immunoassay that detects the binding of HIT IgG to PF4-heparin in the fluid phase. This required techniques to purify and biotinylate PF4. The fluid phase assay produces consistently low background and can detect low levels of anti-PF4-heparin. It is suited to testing alternative anticoagulants because, unlike in an ELISA, a clearly defined amount of antigen is available for antibody binding. I was able to detect anti-PF4-heparin IgG in 93% of HIT patients. I also investigated cross-reactivity of anti-PF4-heparin antibodies with PF4 complexed to alternative heparin-like anticoagulants. Low molecular weight heparins cross-reacted with 88% of the sera from HIT patients while half of the HIT sera weakly cross-reacted with PF4-danaparoid (Orgaran). The thrombocytopenia and thrombosis of most of these patients resolved during danaparoid therapy, indicating that detection of low affinity antibodies to PF4-danaparoid by immunoassay may not be an absolute contraindication for danaparoid administration. While HIT patients possess antibodies to PF4-heparin, I observed that HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells but not to soluble PF4 in the absence of heparin. Having developed a technique to affinity-purify anti-PF4-heparin HIT IgG, I provide the first estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional affinity for both PF4-heparin (Kd=7-30nM) and polystyrene adsorbed PF4 alone (Kd=20-70nM). Furthermore, agarose beads coated with PF4 alone were almost as effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti-PF4-heparin antibodies. I conclude that the HIT antibodies which bind to polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that bind PF4-heparin and thus most HIT antibodies bind epitope(s) on PF4 and not epitope(s) formed by part of a PF4 molecule and part of a heparin molecule. Binding of PF4 to heparin (optimal) or polystyrene/agarose (sub-optimal) promotes recognition of this epitope. Under conditions that are more physiological and sensitive than previous studies, I observed that affinity-purified HIT IgG will cause platelet aggregation upon the addition of heparin. Platelets activated with HIT IgG increased their release and surface expression of PF4. I quantitated the binding of affinity-purified HIT 125I-IgG to platelets as they activate in a plasma milieu. Binding of the HIT IgG was dependent upon heparin and some degree of platelet activation. Blocking the platelet Fc??? receptor-II with the monoclonal antibody IV.3 did not prevent HIT IgG binding to activated platelets. I conclude that anti-PF4-heparin IgG is the only component specific to HIT plasma that is required to induce platelet aggregation. The Fab region of HIT IgG binds to PF4-heparin that is on the surface of activated platelets. I propose that only then does the Fc portion of the bound IgG activate other platelets via the Fc receptor. My data support a dynamic model of platelet activation where released PF4 enhances further antibody binding and more release.
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Tytgat, Godelieve Andrea Maria. "[131I]Meta-iodobenzylguanidine ([131I]MIBG) related thrombocytopenia." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/57592.
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Apostu, Raluca. "Understanding cyclical thrombocytopenia : a mathematical modeling approach." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101834.
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Cyclical thrombocytopenia (CT) is a rare hematological disease characterized by periodic oscillations in the platelet count. Although first reported in 1936, the pathogenesis and an effective therapy remain to be identified. Since besides fluctuations in platelet levels the patients hematological profile have been consistently normal, a destabilization of a peripheral control mechanism might play an important role in the genesis of this disorder. In this thesis, we investigate through computer simulations the mechanisms underlying the platelet oscillations observed in CT. First, we collected the data published in the last 40 years and quantified the significance of the platelet fluctuations using Lomb-Scargle periodograms. Our analysis reveals that the incidence of the statistically significant periodic data is equally distributed in men and women. The mathematical model proposed in this thesis captures the essential features of hematopoiesis and successfully duplicates the characteristics of CT. With the same parameter changes, the model is able to fit the platelet counts and to qualitatively reproduce the TPO oscillations (when data is available). Our results indicate that a variation in the megakaryocyte maturity, a slower relative growth rate of megakaryocytes, as well as an increased random destruction of platelets are the critical elements generating the platelet oscillations in CT.La thrombocytopénie cyclique (TC) est une rare maladie hématologique caracteriséepar des oscillations périodiques dans les plaquettes sanguines. Bien qu'elle fût évoquéepour la première fois en 1936, la maladie et une thérapie efficace restent à trouver.Puisque malgré les fluctuations au niveau des plaquettes, les profiles hématologiquesdes patients restent toujour normaux, une destabilisation du méchanisme de contrôlepériphérique peut jouer un rôle important dans la formation de ce maladie. Dans cettethèse, nous recherchons à travers des simulations informatiques les mechanismes sousjacentaux oscillations des plaquettes observées dans TC. En premier lieu, nous avonscollecté les données publiées ces 40 dernière années et quantifié l'importance des fluctuationsdes plaquettes en utilisant les périodograms Lomb-Scargle. Notre analysestatistique révèle que les données périodiques sont équitablement distribuée chez leshommes et les femmes. Le modèle mathématique proposé dans cette thèse prenden compte les caractéristiques essentielles de la production des cellules sanguineset reproduit avec succès les charactéristiques de TC. Avec les même changementde parametèrs, le modèle reproduit bien le comportement des plaquettes sanguineset donne qualitativement les même oscillations que TPO (quand les données sontdisponibles). Nos résultats indiquent que les éléments critiques générant les oscillationsdes plaquettes dans TC sont une variation dans la maturité du mégakaryocytes,un taux de croissance relativement lent des mégakaryo cytes , ainsi que une augmentationaléatoire de destruction des plaquettes.
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Desborough, Michael J. R. "Desmopressin for treatment of thrombocytopenia or platelet dysfunction." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:4de19720-328a-4d01-9153-02dec6202aff.
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The objective of the work presented in this thesis was to explore the role of potential alternatives to platelet transfusions and specifically to investigate whether desmopressin could be used for treatment of thrombocytopenia or platelet dysfunction. Patients with thrombocytopenia or platelet dysfunction are often treated with platelet transfusions to treat or prevent bleeding. However the evidence for the efficacy of platelet transfusion is limited and there is some evidence of harm. I have focused on thrombocytopenic patients with haematological malignancies or critically ill patients, who are amongst the groups most commonly treated with platelet transfusions. The aims of this research were to determine: 1. If levels of Von Willebrand factor (VWF) or other measures of haemostasis are predictive of bleeding in severe thrombocytopenia; 2. Whether VWF compensates for thrombocytopenia in vitro; 3. The evidence for the efficacy of desmopressin in all patients undergoing surgery or invasive procedures; 4. The evidence for desmopressin for platelet dysfunction or thrombocytopenia; 5. If it is feasible to use desmopressin to treat critically ill thrombocytopenic patients in a clinical trial. To identify derangements of haemostasis that may signify candidates for alternatives to platelet transfusions, I analysed blood samples from an observational trial of fifty patients with haematological malignancies and profound thrombocytopenia due to intensive chemotherapy. I used a panel of tests to investigate measures of primary haemostasis, thrombin generation, cross-linked fibrin formation and fibrinolysis. Using multivariable logistic regression, I found no consistent correlation between any measures of haemostasis and the risk of clinically significant bleeding. VWF antigen levels were the best predictor of clinically significant bleeding on the same day (odds ratio 0.31, 95% confidence interval 0.10 to 0.98, p=0.047) but were not predictive of severe bleeding over the 24 hours after the test (odds ratio 0.48, 95% confidence interval 0.10 to 2.34, p=0.36). In a separate set of experiments, I evaluated thrombus formation under flow in thrombocytopenia. This technique was sensitive to the platelet count . Addition of exogenous VWF to thrombocytopenic blood resulted in improvement in thrombus formation, suggesting that agents that affect or influence VWF pathways might have a role. Desmopressin can be used to increase VWF levels, so leading on from my laboratory experiments; I used systematic reviews and meta-analyses to assess whether desmopressin could be used in unselected patients to reduce bleeding peri-operatively. I identified 62 randomised controlled trials. Overall there was no evidence of benefit for administering desmopressin to unselected patients. However further analysis of eleven randomised controlled trials that focused on patients with platelet dysfunction found that desmopressin resulted in transfusion of fewer units of red cells (equivalent to a 25% reduction compared to control), less blood loss (equivalent to a 23% reduction compared to control) and a lower risk of requiring a re-operation due to bleeding (Peto odds ratio 0.39, 95% confidence interval 0.18 to 0.84). There was no evidence for an increase in thrombotic events. There was no randomised controlled trial evidence for perioperative desmopressin for patients with thrombocytopenia. These specific research gaps were addressed by designing new clinical trials. I have commenced a randomised controlled feasibility trial of desmopressin versus placebo for critically ill patients with thrombocytopenia undergoing invasive procedures. This trial is ongoing and is the first randomised trial evaluating peri-procedural desmopressin in thrombocytopenia. The programme of work arising from this research has the potential to benefit a large number of patients by preventing bleeding and reducing exposure to allogeneic blood components such as platelets. The results presented in this thesis are exploratory but are an important step on a path towards larger trials using desmopressin as an alternative, or adjunct to platelet transfusion.
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Antel, Katherine. "Splenectomy for immune thrombocytopenia : our 11-year experience." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/14134.
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Splenectomy has been practiced for the treatment of ITP for the past few decades. Currently it is utilised when a patient is either dependent or resistant to steroid treatment and the platelet count remains less than 30×109/L. Recently new agents have been added to the armamentarium used to treat ITP, including immune-suppressants such as rituximab and the new thrombopoetin-receptor agonists. This has brought into question the role of surgery for the treatment of ITP, and the need to compare the response and complication rates of splenectomy to these newer agents. Historic studies done on splenectomy for the treatment of ITP have been performed in the setting of low HIV prevalence. There is a relative paucity of data on the response rate in HIV-associated thrombocytopenia to splenectomy and the durability of response to splenectomy is unclear in this patient population. We retrospectively analysed 73 consecutive patients who underwent splenectomy for ITP from 2001 to 2011. The primary objective was to determine the rate of complete response, this was defined as a platelet count greater than 100×109/L at one year post splenectomy. Results were compared between HIV positive and HIV negative patients. The secondary objectives were: to evaluate the intra-operative and post†operative complications and mortality in the HIV positive and HIV negative groups, and to investigate for associations between co-morbidities, pre-operative treatment and response to splenectomy.
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Chan, Ernest Ricky. "Genetic Analysis of Novel Models of Thrombocytopenia and Leucopenia." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1248212698.
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Lundin, Ann-Sofie. "QUALITY OF TACSI PLATELETS AND THEIR EFFECT ON THROMBOCYTOPENIA PATIENTS." Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-126714.
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Conclusion:Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.
Methods: A new approach that pools 8 buffy coats (TACSI platelets) that were separated into 2 units instead of 4-6 buffy coats pooled to 1 unit was investigated in this study. After the platelets were extracted from the buffy coats their quality was controlled and subsequently the platelet product was evaluated in 96 patients.
Results: The results showed that 80 % of the platelet units passed the European quality requirements. Further, the platelet count was increased in most patients that received TACSI platelets.
Conclusion: Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.
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Watts, Timothy Lloyd. "The role of impaired megakaryocytopoiesis in thrombocytopenia in preterm babies." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270477.
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Hirata, Shinji. "Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling." Kyoto University, 2018. http://hdl.handle.net/2433/232073.
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Дудченко, Ірина Олександрівна, Ирина Александровна Дудченко, and Iryna Oleksandrivna Dudchenko. "Treatment of arterial hypertension on patients with thrombocytopenia: literature review." Thesis, Sumy State University, 2017. http://essuir.sumdu.edu.ua/handle/123456789/64798.
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Background. Thrombocytopenia is a common hematological problem. If a patient with thrombocytopenia has high level of blood pressure, this increases the risk of a hemorrhagic stroke or other life-treating bleeding. Literature sources also indicate that thrombocytopenia in some cases may be an adverse effect of antihypertensive treatment. Thus, it is very complicated to prescribe correct antihypertensive drug in patients with thrombocytopenia.
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Matsuoka, Hideaki. "Molecular Characterization of Histone Deacetylase Inhibitor-mediated Immunosuppression and Thrombocytopenia." Kyoto University, 2008. http://hdl.handle.net/2433/124015.
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Hickman, DaShawn Antwane. "Platelet-inspired Nanomedicine for the Hemostatic Management of Bleeding Complications in Thrombocytopenia and Trauma." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1537017099431262.
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Westbury, Sarah Kate. "Mechanisms in heamopietic differentiation : insights from novel loci in genetic thrombocytopenia." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752731.
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Ali, Ashfaq. "The mechanism of thrombocytopenia induced by a pan histone deacetylase inhibitor." Paris 7, 2014. http://www.theses.fr/2014PA077069.
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Les histones déacétylases (HDAC) jouent un rôle important dans l'acétylation des histones et d'autres protéines. Les HDACi ciblent pour la plupart d'entre eux l'ensemble des HDAC (pan-HDACi) et entraînent de nombreux effets secondaires, en particulier une thrombopénie, constamment observée, et facteur limitant dans l'association avec d'autres médicaments. L'objectif de cette thèse a été de comprendre par quels mécanismes ces médicaments pouvaient induire des thrombopénies, en étudiant in vitro les effet d'un pan HDACi, l'abexinostat utilisé actuellement en phase I/II d'essais cliniques sur le compartiment des progéniteurs mégacaryocytaires (CFU-MK), la prolifération des MK et la formation des proplaquettes (FPPs). Nos résultats montrent que l'abexinostat entraine une diminution : 1) de la pousse des CFU-MK, 2) de la prolifération des MK, 3) de la FPPs) et 4) de la ploïdie. La diminution de la prolifération des MKs est essentiellement due à une augmentation de l'apoptose qui n'est pas liée à une dérégulation de la voie de signalisation TPO/MPL/JAK2, mais à une augmentation des cassures double brins de l'ADN. Elles sont mises en évidence par la formation de foyers 7H2AX associée à une diminution de l'expression Rad51, médiateur majeur de la recombinaison homologue. Ces résultats sont associés à l'activation de la p53, et l'induction de ces gènes cibles. L'utilisation d'un shRNA p53 diminue l'apoptose des cellules traitées par le pan HDAC inhibiteur et restore partiellement la FPPs. Au total, ces résultats montrent que l'abexinostat, inhibe la mégacaryopoïèse par deux mécanismes : - l'un, p53 dépendant, lié à des cassures doubles brins, mécanisme proche de ce qui a été décrit dans les modèles de souris KO conditionnel pour hdac 1 et hdac 2. La double invalidation conduit à l'apoptose des MK et à une thrombopénie. - l'autre, p53 indépendant. Il affecte essentiellement la FPPs et pourrait être lié à une désorganisation du cytosquelette. La suite du travail va consister à comprendre quels spécifiques HDACs sont responsables de ces effets sur la mégacaryopoïèse en espérant trouver des inhibiteurs spécifiques d'HDAC qui resteraient efficaces sur les cellules cancéreuses sans entraîner de thrombopénieThe histone-deacetylases (HDACs) play an important role in the regulation of acetylation of histones and other proteins. HDAC inhibitors (HDACi) are the new emerging class of the anticancer drug. Abexinostat which targets all the HDACs (like pan-HDACi) results in many side effects, particularly a thrombocytopenia is constantly observed side effect, and is a limiting factor when used alone or even in combination therapies. The aim of this study was to understand the mechanism by which HDACi induces thrombocytopenia. In this study to understand in vitro effects of abexinostat, a pan HDACi, which is currently in phase I / II clinical trials, is used on the megakaryocyte progenitor (CFU-MK), MK proliferation and proplatelet formation (PPF). Our results have shown that abexinostat induces a decrease in i) CFU-MK growth; ii) a MK proliferation, iii) proplatelet formation (PPF) and iv) MK ploidy. The decrease in the MK proliferation is mostly related to increase apoptosis. This increase in apoptosis is not related to a deregulation of the TPO/MPL/JAK2 signaling pathway, but to an increase in DNA damage attested by yH2AX foci formation and a decreased expression of RAD51, a key mediator of homologous recombination. This induced ATM phosphorylation leading to p53 stabilization and expression of target genes such as p21 and BAX. The use of p53 shRNA rescued apoptosis, but partially rescued the defect in proplatelet formation. Altogether, these results show that abexinostat inhibits megakaryopoiesis by two mechanisms: - One, dependent of p53 activation by double strand breaks. This mechanism is close to what has been described in models of hdac 1 and hdac 2 conditional knockout mice, the double knockout inducing MK apoptosis and thrombocytopenia. - Another independent of p53. It mainly affects the formation of proplatelets and may be related to disruption of the cytoskeleton. It remains to determine which HDACs are involved in these two different processes to develop HDACi, which may have low toxic effects on the platelet count while conserving their effects on cancer cells
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Simões, Cátia Isabel da Cruz Pires Martins. "Trombocitopénia imuno-mediada na clínica de animais de companhia." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2008. http://hdl.handle.net/10400.5/1493.
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Dissertação de Mestrado Integrado em Medicina VeterináriaNa clínica veterinária onde decorreu o estágio, a trombocitopénia é um sinal laboratorial encontrado com alguma frequência em cães e gatos apresentados para consulta veterinária devido a alguma alteração do estado hígido. A trombocitopénia pode ser secundária a diversos mecanismos, embora nesta dissertação se realcem os fenómenos de diminuição da contagem de plaquetas devidos a destruição imuno-mediada. Esta última caracteriza-se pela redução da contagem de plaquetas por unidade de volume de sangue acompanhada pela redução do volume médio destas células (diminuição do Volume Plaquetário Médio ou MPV). Entre os 200 animais que realizaram hemograma, 37 (5,2%) apresentaram esta alteração hematológica (32 canídeos e 5 felídeos). Foi possível diagnosticar a causa da trombocitopénia em 31 dos 32 cães, mas apenas em 2 dos 5 gatos. Constatou-se que quase 70% destes animais apresenta trombocitopénia imuno-mediada secundária a infecção. A bibliografia posiciona as infecções como segunda causa mais frequente de trombocitopénia imuno-mediada em cães, mas no contexto geográfico do local de estágio, uma área semi-rural, os agentes infecciosos transmitidos por vectores são endémicos, sobretudo a espécie Leishmania infantum. O hemoparasita do género Babesia e as bactérias dos géneros Ehrlichia e Rickettsia também foram implicados em casos clínicos de trombocitopénia imuno-mediada secundária a infecção, surgindo inclusivamente em infecções múltiplas no mesmo animal. Verificou-se ainda a ocorrência de trombocitopénia imuno-mediada secundária a neoplasia, que a bibliografia coloca como terceira principal causa de trombocitopénia imuno-mediada, embora se tenha verificado durante o período de estágio que este mecanismo é o mais prevalente (20%) a seguir às infecções. Em 8% dos casos foi diagnosticada uma trombocitopénia imuno-mediada induzida por fármacos e em apenas 4 % dos casos (1 cadela) existe um diagnóstico provável de trombocitopénia imuno-mediada idiopática. Segundo a bibliografia este último mecanismo é o mais frequente. O facto de ser tão raro na população incluída neste pequeno estudo prende-se com várias razões, entre as quais o reduzido número de animais susceptíveis e a inespecificidade dos sinais clínicos que pode originar.
ABSTRACT - IMMUNE-MEDIATED THROMBOCYTOPENIA IN SMALL ANIMAL PRACTICE Thrombocytopenia is a laboratory sign found occasionaly in dogs and cats presented with some evidence of disease to the veterinary clinic Vetarrábida. Thrombocytopenia may be secondary to a diversity of mechanisms, although this document sets off the decrease in platelet numbers due to immune-mediated destruction. This last mechanism is characterized by a reduction in platelet counts per blood volume unit, associated with a decrease in the mean volume of the platelet cells (Mean Platelet Volume or MPV). Among the 200 dogs that were submitted to a complete blood count, 37 (5,2%) presented this alteration (32 dogs and 5 cats). The cause of thrombocytopenia was diagnosed in 31 of the 32 dogs, but only in 2 of the 5 cats. Nearly 70% of these animals had a thrombocytopenia secondary to infection. Most authors refer the infections as the second most common cause of immune-mediated thrombocytopenia (next to the primary or idiopathic mechanism), but in this particular geographic environment, a semi-rural area, vector-bourne infectious agents represent an endemy, specially Leishmania infantum. Haemoparasites as Babesia spp. and bacteria as Ehrlichia spp. and Rickettsia spp. have also been implicated in clinical cases of infection-induced immune-mediated thrombocytopenia, as single or as co-infections affecting the same dog. In 20% of the dogs the cause of thrombocytopenia was neoplasia-induced immune-mediated destruction, which is considered by the literature as the third major condition inducing immune-mediated thrombocytopenia, next to the infections. In this study it was indeed less frequent than infection-induced destruction, but, in a global evaluation, it is the second major cause of immune-mediated thrombocytopenia. In 8% of the dogs the diagnosis was druginduced immune-mediated thrombocytopenia and in only 4% of the dogs (1 bitch) there is a strong suspicion of idiopathic immune-mediated thrombocytopenia. According to the literature, this last mechanism is the most prevalent in animals with thrombocytopenia caused by immune-mediated destruction. The reasons why it is so rare in the population evaluated in this small revue are probably the small number of animals susceptible to this affection and the possibility of subclinical disease.
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Simões, Cátia Isabel da Cruz Pires Martins. "Trombocitopénia imuno-mediada na clínica de animais de companhia." Bachelor's thesis, Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária, 2009. http://hdl.handle.net/10400.5/931.
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Dissertação de Mestrado Integrado em Medicina VeterináriaNa clínica veterinária onde decorreu o estágio, a trombocitopénia é um sinal laboratorial encontrado com alguma frequência em cães e gatos apresentados para consulta veterinária devido a alguma alteração do estado hígido. A trombocitopénia pode ser secundária a diversos mecanismos, embora nesta dissertação se realcem os fenómenos de diminuição da contagem de plaquetas devidos a destruição imuno-mediada. Esta última caracteriza-se pela redução da contagem de plaquetas por unidade de volume de sangue acompanhada pela redução do volume médio destas células (diminuição do Volume Plaquetário Médio ou MPV). Entre os 200 animais que realizaram hemograma, 37 (5,2%) apresentaram esta alteração hematológica (32 canídeos e 5 felídeos). Foi possível diagnosticar a causa da trombocitopénia em 31 dos 32 cães, mas apenas em 2 dos 5 gatos. Constatou-se que quase 70% destes animais apresenta trombocitopénia imuno-mediada secundária a infecção. A bibliografia posiciona as infecções como segunda causa mais frequente de trombocitopénia imuno-mediada em cães, mas no contexto geográfico do local de estágio, uma área semi-rural, os agentes infecciosos transmitidos por vectores são endémicos, sobretudo a espécie Leishmania infantum. O hemoparasita do género Babesia e as bactérias dos géneros Ehrlichia e Rickettsia também foram implicados em casos clínicos de trombocitopénia imuno-mediada secundária a infecção, surgindo inclusivamente em infecções múltiplas no mesmo animal. Verificou-se ainda a ocorrência de trombocitopénia imuno-mediada secundária a neoplasia, que a bibliografia coloca como terceira principal causa de trombocitopénia imuno-mediada, embora se tenha verificado durante o período de estágio que este mecanismo é o mais prevalente (20%) a seguir às infecções. Em 8% dos casos foi diagnosticada uma trombocitopénia imuno-mediada induzida por fármacos e em apenas 4 % dos casos (1 cadela) existe um diagnóstico provável de trombocitopénia imuno-mediada idiopática. Segundo a bibliografia este último mecanismo é o mais frequente. O facto de ser tão raro na população incluída neste pequeno estudo prende-se com várias razões, entre as quais o reduzido número de animais susceptíveis e a inespecificidade dos sinais clínicos que pode originar.
ABSTRACT - Thrombocytopenia is a laboratory sign found occasionaly in dogs and cats presented with some evidence of disease to the veterinary clinic Vetarrábida. Thrombocytopenia may be secondary to a diversity of mechanisms, although this document sets off the decrease in platelet numbers due to immune-mediated destruction. This last mechanism is characterized by a reduction in platelet counts per blood volume unit, associated with a decrease in the mean volume of the platelet cells (Mean Platelet Volume or MPV). Among the 200 dogs that were submitted to a complete blood count, 37 (5,2%) presented this alteration (32 dogs and 5 cats). The cause of thrombocytopenia was diagnosed in 31 of the 32 dogs, but only in 2 of the 5 cats. Nearly 70% of these animals had a thrombocytopenia secondary to infection. Most authors refer the infections as the second most common cause of immune-mediated thrombocytopenia (next to the primary or idiopathic mechanism), but in this particular geographic environment, a semi-rural area, vector-bourne infectious agents represent an endemy, specially Leishmania infantum. Haemoparasites as Babesia spp. and bacteria as Ehrlichia spp. and Rickettsia spp. have also been implicated in clinical cases of infection-induced immune-mediated thrombocytopenia, as single or as co-infections affecting the same dog. In 20% of the dogs the cause of thrombocytopenia was neoplasia-induced immune-mediated destruction, which is considered by the literature as the third major condition inducing immune-mediated thrombocytopenia, next to the infections. In this study it was indeed less frequent than infection-induced destruction, but, in a global evaluation, it is the second major cause of immune-mediated thrombocytopenia. In 8% of the dogs the diagnosis was drug-induced immune-mediated thrombocytopenia and in only 4% of the dogs (1 bitch) there is a strong suspicion of idiopathic immune-mediated thrombocytopenia. According to the literature, this last mechanism is the most prevalent in animals with thrombocytopenia caused by immune-mediated destruction. The reasons why it is so rare in the population evaluated in this small revue are probably the small number of animals susceptible to this affection and the possibility of subclinical disease.
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Murray, Neil A. "Circulating megakaryocyte progenitor and precursor cells in the healthy and thrombocytopenic neonate." Thesis, University of Aberdeen, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337398.
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Background: Thrombocytopenia is common in sick preterm babies in the first day of life. Despite this, platelet production in thrombocytopenic preterm babies has rarely been assessed. Methods: To address this problem I have developed miniaturised assays to study circulating megakaryocyte (MK) progenitors (BFU-MK and CFU-MK), total cultured MK precursors and mature MK, by culturing mononuclear cells purified from 0.5-1ml of preterm peripheral blood. MK lineage colonies and cells are identified by a MK specific anti-glycoprotein IIb/IIIa antibody (CD61) by APAAP. Results: i) Normal values for these cells at birth were established in cord blood from healthy term and preterm babies. ii) Circulating BFU-MK/CFU-MK, total cultured MK precursors and mature MK were then prospectively studied in 63 preterm babies (gestational age 24-34 wks). iii) At birth 18 (69%) of the thromocytopenic babies were also neutropenic. Conclusion: These data indicate that the principal cause of the thrombocytopenia and neutropenia in the preterm babies studied was reduced platelet and neutrophil production occurring as a consequence of reduced numbers of MK and neutrophil progenitors respectively. Taken together these data suggest the haematological abnormalities characteristic of new-born born to mothers with PIH or with IUGR (thrombocytopenia, neutropenia and polycythaemia) are a consequence of dysregulation of fetal haemopoiesis occurring proximal to committed MK and neutrophil progenitors, most likely at the level of the primitive multipotent haemopoietic stem cell (CFU-GEMM). Finally the value of miniaturised MK progenitor and precursor assays in evaluating rare or unusual cases of neonatal thrombocytopenia has been demonstrated. In the three examples investigated this approach provided unique insights into the pathogenesis of the thromocytopenia in each case.
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Bouwmans, Eva Lamberta Antonia. "Human platelet antigen-1a presentation and antibody generation." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610311.
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Mazzucco, Karina Lorenzi Marramarco. "Avaliação dos linfócitos T reguladores na púrpura trombocitopênica imune da infância." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/87155.
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Objetivo: Avaliar a freqüência das células T reguladoras (Tregs) em crianças com diagnóstico novo de Púrpura Trombocitopênica Imune (PTI) e a sua associação com a contagem de plaquetas na ocasião, comparando os achados com os de controles saudáveis. Pacientes e Métodos: Foi realizado um estudo caso-controle, no qual foram incluídos 19 pacientes com diagnóstico novo de PTI e 19 controles. Para cada um dos casos, foram coletadas quatro amostras de sangue em períodos distintos, sendo eles ao diagnóstico – antes da instituição de qualquer terapêutica – e após um, três e seis meses do mesmo. Para os controles, utilizou-se amostra de sangue de 19 pacientes saudáveis, coletadas eletivamente. Em todas as amostras de sangue foi realizada contagem de plaquetas através de hemograma e avaliação dos linfócitos Tregs (CD4+ CD25+ Foxp3) por citometria de fluxo. Resultados: A idade média ao diagnóstico de PTI foi de 6,53 ± 4,14 anos. Dos 17 pacientes tratados, 13 receberam apenas corticosteróide oral e quatro pacientes receberam corticosteróide e imunoglobulina endovenosa associada em algum momento do tratamento. Em relação à evolução da doença, 14 crianças apresentaram remissão completa, duas remissão e três PTI crônica. Houve diferença estatisticamente significativa no número de plaquetas entre os grupos caso e controle nas amostras 1 e 4. Não houve diferença significativa na contagem de Tregs entre os casos e os controles em nenhum momento de coleta. Não foi encontrada correlação estatisticamente significativa entre Tregs e o número de plaquetas entre os casos e os controles, nem nos pacientes do grupo caso ou do grupo controle analisados separadamente. Não houve diferença na contagem de células Tregs entre os grupos de pacientes crônicos e não crônicos. Conclusão: Os achados deste estudo não nos permitiu evidenciar correlação estatisticamente significativa entre Tregs e o número de plaquetas nos grupos caso e controle. As células T CD4+ CD25+ Foxp3 (Tregs) parecem não desempenhar um papel crucial na regulação da auto-imunidade em pacientes pediátricos com diagnóstico de PTI, provavelmente, devido à existência de outros mecanismos responsáveis pela auto-imunidade em crianças, ainda não identificados.Objective: To assess the frequency of regulatory T cells (Tregs) in children with a new diagnosis of Immune Thrombocytopenic Purpura (ITP), and its association with the counts of platelets on the occasion, and compare with healthy controls. Patients and Methods: A case-control study was conducted, in which 19 patients with new diagnosis of ITP and 19 controls were included. For each case, four blood samples were collected at different point times, that is, at the diagnosis – before the establishment of any treatment – and after one, three and six months. For the controls, electively collected blood samples from 19 healthy patients were used. For all blood samples, platelets were counted through a CBC and assessment of Treg lymphocytes (CD4+ CD25+ Foxp3) by flow cytometry. Results: The mean age at the ITP diagnosis was 6.53 ± 4.14 years. Of 17 treated patients, 13 received oral corticosteroid only, and four patients received corticosteroid and associated intravenous human immunoglobulin at some point in the treatment. Regarding the disease course, 14 children showed full remission, two partial remission, and three chronic ITP. There was a statistically significant difference in the number of platelets between the case and control groups in the samples 1 and 4. There was no significant difference in the counts of Tregs between cases and controls at any collection time. No statistically significant correlation was found between Tregs and number of platelets between cases and controls, neither in patients in the case group nor in the control group who were analyzed separately. There was no difference in the counts of Treg cells between the groups of chronic and non-chronic patients. Conclusion: The findings of this study did not show any statistically significant correlation between Tregs and number of platelets in the case and control groups. The T cells CD4+ CD25+ Foxp3 (Tregs) seems did not play a key role in the regulation of self-immunity in pediatric patients diagnosed with ITP. Other mechanisms, which aren’t still identified, are likely to account for self-immunity in children.
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Rabbolini, David John. "Genotyping and experimental modelling of inherited thrombocytopenias." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18144.
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Inherited thrombocytopenia’s (IT) are characterised by low platelet counts and bleeding tendencies in affected individuals. Diagnosis of IT is important to guide treatment, inform prognosis and provide genetic counseling. Unfortunately, standard testing methods that interrogate platelet function and structure lack sensitivity, specificity and standardisation. This thesis developed and employed a next generation sequencing (NGS) platform for the diagnosis of IT and explored mechanisms underpinning IT through laboratory investigation of novel variants detected through this method. NGS was performed for approximately 120 patients and identified pathogenic variants in a significant fraction. Most pathogenic variants were detected in the MYH9 gene (12.4% of the cohort) and included the description of a novel variant (W828R). Novel variants were also detected in transcription factors FLI1, GFI1B and RUNX1. Disease modelling experiments of novel variants confirmed their pathogenicity and in the case of the novel homozygous FLI1 variant (R324W), analysis consolidated knowledge of the aetiology of thrombocytopenia in patients with Paris-Trousseau syndrome. Acquisition of molecular data provided opportunity to assess diagnostic algorithms. We demonstrated the potential of mean platelet diameter measurements to streamline diagnostic algorithms and aid in initial classification of patients with IT. Finally, we performed disease modelling of GFI1B-RT to show that the clinical phenotype of GFI1B variants is dependent on the site disrupted by, and nature of, the GFI1B mutation. We show that GFI1B regulates the CD34 promoter and that transcriptional deregulation induced by mutant GFI1B underlies persistent platelet CD34 expression common to GFI1B variants. We conclude that a an approach using NGS is an effective diagnostic tool to examine IT and that data generated by molecular analysis provides a foundation to explore mechanisms of disease, and improve diagnostic algorithms.
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Keeling, David Michael. "Antiphospholipid antibodies : a study of the nature and possible role in thrombosis." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243973.
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Лішневська, А. Г. "Взаємозв'язок автоімунного статусу хворих на хронічний вірусний гепатит С з рівнем тромбоцитів у крові." Thesis, Сумський державний університет, 2017. http://essuir.sumdu.edu.ua/handle/123456789/64428.
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На сьогоднішній день однією з важливих
проблем хворих на хронічний вірусний гепатит С (ХВГС), які
перебувають на противірусній терапії є гематологічні
ускладнення, зокрема тромбоцитопенія. Останнім часом
науковці не відхиляють факту про можливість впливу вірусного
гепатиту С на запуск автоімунних реакцій. За даними літератури
імунна тромбоцитопенія при ХВГС має місце серед уражень системи крові. Результати сучасних досліджень HCV вказують
на те, що головним механізмом розвитку HCV-асоційованої
тромбоцитопенії, за відсутністю гіперспленізму та зниження
продукції тромбопоетину, є саме автоімунний.Viral hepatitis C at present remains one of the most pressing health issues in Ukraine and the world at large. Hematologic complications is important aspect of patients with chronic hepatitis C who are on antiviral therapy. Recently, scientists do not reject the fact of the possibility of exposure to hepatitis C start autoimmune reactions. According to the literature immune decreased platelets is among the affections of the blood system. HCV results of current research indicate that the main mechanism of HCVassociated decreased platelets, in the absence enlarged spleen and reduce production thrombopoietin, there is autoimmune.
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Rayment, Rachel. "Characterisation and tolerisation of the helper T-cell response in neonatal alloimmune thrombocytopenia." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441089.
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Fütterer, Jane Wong. "Characterisation of a novel protein, ANKRD18A, implicated in a severe form of thrombocytopenia." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7511/.
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Platelets (thrombocytes) mediate clot formation following vessel injury. Inherited thrombocytopenias, characterised by platelet counts below 150 x 109 L-1, have variable bleeding severity. Whole exome sequencing of two cousins with severe thrombocytopenia identified a shared single-codon deletion in ANKRD18A. ANKRD18A’s function is unknown. We hypothesise that this mutation in ANKRD18A is the aetiology of these children’s thrombocytopenia. Despite limited patients’ blood, quantitative real-time polymerase chain reaction demonstrated reduced ANKRD18A mRNA levels in patient leukocytes compared to controls. Patients’ platelets demonstrated decreased activity when stimulated with adenosine diphosphate, collagen related peptide and the synthetic peptide SFLLRN, which mimics the N-terminal sequence of protease activated receptors. Electron microscopy demonstrated macrothrombocytopenia. To assist characterisation studies, a recombinant fragment of ANKRD18A, the ankyrin repeat domain, was purified to generate a polyclonal antibody, α-25277. Experiments demonstrated possible specificity of α-25277. Cellular functions of ANKRD18A remain unclear, yet the availability of α-25277, once better characterised, will be instrumental in demonstrating the potential link between ANKRD18A and the observed thrombocytopenia. Another in-house antibody, α-21234, may also be effective. Antibody specificity can be proven by immunoblotting lysates of cells, where ANKRD18A is silenced by RNAi. Should both antibodies not be specific, generating a monoclonal antibody is requisite.
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Anwer, Faiz, Seongseok Yun, Anju Nair, Yusuf Ahmad, Ravitharan Krishnadashan, and H. Joachim Deeg. "Severe Refractory Immune Thrombocytopenia Successfully Treated with High-Dose Pulse Cyclophosphamide and Eltrombopag." Hindawi, 2015. http://hdl.handle.net/10150/617180.
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UA Open Access Publishing FundSevere refractory ITP is clinically challenging and a variety of single or combination chemotherapies have been tried with limited outcome. We report a case of ITP that was unresponsive to multiple agents including high-dose steroid, IVIG, Rho(D) immune globulin, rituximab, cyclosporine, azathioprine, vincristine, mycophenolate mofetil, romiplostim, and eltrombopag; however, it achieved complete remission with combination treatment of cyclophosphamide and eltrombopag.
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Wannack, Martin [Verfasser]. "Pathophysiologie der Blutbildung bei Patienten mit Thrombocytopenia absent radii (TAR)-Syndrom / Martin Wannack." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2011. http://d-nb.info/1026068770/34.
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Wihadmadyatami, Hevi [Verfasser]. "The role of antibodies against endothelial cells in immune mediated thrombocytopenia / Hevi Wihadmadyatami." Gießen : Universitätsbibliothek, 2016. http://d-nb.info/1114659010/34.
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Bösing, Hendrik [Verfasser]. "Klinische und funktionelle Untersuchungen zur Hämatopoese beim Thrombocytopenia Absent Radii (TAR-) Syndrom / Hendrik Bösing." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1160515301/34.
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Donada, Alessandro. "Physiopathological mechanisms of two congenical platelet disorders : filaminopathy-A and ANKRD26-related - Thrombocytopenia 5THC2." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/DONADA_Alessandro_2_complete_2018.zip.
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Les thrombopénies héréditaires sont une classe de maladies hématologiques congénitaux affectant principalement la lignée mégacaryocytaire. Elle s’accompagnant d'une diminution du nombre de plaquettes. Près de 50 gènes différents ont été associés à des thrombopénies héréditaires, et d'énormes différences existent entre chaque maladie, en ce qui concerne la manifestation clinique et la pathobiologie. Mes recherches ont porté sur deux thrombopénies héréditaires différentes: Filaminopathie A et THC2. La première maladie est un syndrome X-linked, associé à des mutations dans le gène FLNA (Filamine A). Ces patients, sur le point de vue hématologique, présentent une macrothrombopénie associée à une tendance à saigner toute la vie. La seconde maladie est transmise selon une mécanisme autosomale dominante, et elle est provoquée par des mutations dans le 5’ UTR du gène ANKRD26. Les patients montre une dysmégacaryopoïèse, une thrombopénie et un risque accru de développer des tumeurs malignes myéloïdes. Pour étudier la physiopathologie de ces deux maladies rares, j'ai exploité la technologie des cellules souches pluripotentes induites, pour développer plusieurs lignées cellulaires spécifiques au patient. Ces outils expérimentaux ont permis la compréhension de la physiopathologie pour les deux maladies, et m'ont permis de décrire en grand détail les mécanismes moléculaires sous-tendant le defaut de la formation de proplaquettes pour la Filaminopatie A, et la prédisposition à la leucémie pour la THC2. Pour effectuer de telles études, nous avons conçu un protocole de différenciation robuste, récapitulant efficacement la différenciation hématopoïetique et facilement adapté à la différenciation in vitro des plusieurs lignées cellulaires. En plus, nous avons exploité une technique de modification du génome pour introduire efficacement différents mutants, afin de disséquer le rôle moléculaire de la FLNa dans la mégacaryopoïèse.En ce qui concerne la filaminopathie A, nous avons pu décrire une relation originale entre une intégrine membranaire (IIb3), la Filamine A et une voie de signalization curciale (RhoA) pour la mégacaryopoïèse. Nos données supportent un modèle où l’absence de la FLNa induit une activité anormale de la voie RhoA, en réponse au lien entre l'intégrine IIb3 et le fibrinogène. Concernant la THC2, nous avons décrit un nouveau mécanisme associant l'augmentation de l'expression de ANKRD26 à une activité dérégulée de la voie de signalisation dépendante du G-CSF. Cette anomalie affecte la granulopoïèse et conduit à une amplification anormale de cette lignée cellulaire, augmentant éventuellement le risque d'acquisition d'autres mutations et de progression vers une leucémie myéloïde.En conclusion, avec ce travail, nous offrons une preuve de concept de la potentialité de cellules souches pluripotentes induites pour la modélisation de maladies. Nos résultats ouvrent la voie à d'autres études susceptibles de faire progresser notre compréhension de la physiopathologie des troubles plaquettaires héréditairesInherited thrombocytopenias are a class of congenital haematological disorders affecting primarily the megakaryocytic lineage and accomunated by a decrease in platelet numbers. Almost 50 different genes have been associated to inherited platelet disorders, and huge differences exist between each disorder, in regard to clinical manifestation and pathobiology. My research interest have been focused on two different congenital thrombocytopenias: Filaminopathy A and Thrombocytopenia 2. The first disease is a X-linked syndrome associated to mutations in the gene FLNA (Filamin A), and patients display a mild to severe macrothrombocytopenia, associated with a lifelong bleeding tendency. The second disorder is an automal dominant condition caused by mutations in the 5’ UTR of the ANKRD26 gene. It is associated with dysmegakaryopoiesis, mild to severe thrombocytopenia and an increased risk to develop myeloid malignancies. To study the physiopathology of those two rare diseases, we have exploited the induced pluripotent stem cell technology to develop several patient specific cell lines. Those experimental tools revealed invaluable for the understanding of the disease physiopathology, and allowed us to describe in great details the molecular mechanisms underlying the reduction in proplatelet formation for Filaminopathy A and the predisposition to leukemia for Thrombocytopenia 2. To perform such studies, we devised a robust differentiation protocol, recapitulating efficiently the haematopoietic differentiation and easily adapted to the in vitro differentiation of multiple cell lineages. Furthermore, we exploited a genome editing technique to introduce efficiently different protein mutants, in order to dissect the molecular role of Filamin A in megakaryopoiesis. In regard of Filaminopathy A, we have been able to describe an original and novel relationship between a membrane integrin (IIb3), Filamin A and a crucial signalling pathway (RhoA) for megakaryopoiesis. Our data support a model where the absence of FLNa induces an abnormal activity of the RhoA pathway, in response to the integrin IIb3 binding to fibrinogen. Concerning the thrombocytopenia 2, we described a novel mechanism that associated the increased expression of ANKRD26 to a deregulated activity of the G-CSF-dependent signalling pathway. This anomaly impacts the normal granulopoiesis and lead to an abnormal amplification of this cell lineage, possibly increasing the risk of acquiring other mutational hits and progress towards a myeloid malignancy.In conclusion, with this work we offer a proof of concept of the potentiality of disease modeling via induced pluripotent stem cells. Our results pave the way for further studies that could advance our understanding of the physiopathology of inherited platelet disorders
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Fiedler, Janine [Verfasser]. "Biochemische und genetische Charakterisierung der Thrombopoietin-induzierten Signaltransduktion beim Thrombocytopenia-absent-radii-Syndrom / Janine Fiedler." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/102985162X/34.
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Bolliger, Sabine. "Antibody studies in a patient with acute thrombocytopenia following infusion of plasma containing anti-PlA1 /." [S.l : s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Saultier, Paul. "Pathologies plaquettaires constitutionnelles associées aux défauts des facteurs de transcription FLI1, ETV6 et GATA1." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0262.
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Les thrombopénies constitutionnelles (TC) sont des maladies encore incomplètement caractérisées. Ce travail de thèse concerne les TC liées à 10 variants des gènes codant les facteurs de transcription FLI1, ETV6 et GATA1, dont 9 n’avaient jamais été décrits. Ces pathologies ont été étudiés à partir de patients recruté dans un réseau national (Centre de Référence des Pathologies Plaquettaires CRPP) et un réseau international (BRIDGE consortium).Nous montrons qu’il existe un déficit sévère en granules denses dans les plaquettes des patients porteurs de variants FLI1 du fait d’un probable défaut de biogénèse. Ce travail, et d’autres études publiées récemment, ont permis de définir la TC liée aux variants ETV6 en tant que nouveau syndrome de prédisposition aux hémopathies malignes. Les variants FLI1 s’associent à une diminution d’activité transcriptionnelle et d’accumulation nucléaire de la protéine et à des anomalies de la différenciation mégacaryocytaire. Les variants ETV6 s’associent à un défaut d’activité répressive et les mégacaryocytes dérivés des patients montrent un excès de prolifération et un défaut marqué de formation des proplaquettes. Les plaquettes de patients porteurs de variants GATA1 ont montré une expression anormale de la protéine MYH10, ce qui suggère un défaut de répression du gène MYH10 au cours de la mégacaryopoïèse. Une analyse in silico de données de ChIP-seq a ainsi montré l’existence d’une fixation de GATA1 dans le promoteur et dans un intron de MYH10 dans le mégacaryocyte.Ce projet a permis d'apporter des connaissances sur les causes génétiques, le phénotype, le diagnostic, le pronostic et les mécanismes physiopathologiques des TCConstitutional thrombocytopenia (CT) is a group of diseases incompletely characterized. This thesis focused on CTs due to 10 variants in genes encoding the transcription factors FLI1, ETV6 and GATA1, of which 9 had never been described. These diseases were studied in French and European patients recruited using national (French national reference center for inherited platelet disorders CRPP) and international (BRIDGE consortium) networks.We showed that the platelets of patients carrying FLI1 variants harbored a severe dense granule defect probably due a biogenesis defect. Our work, associated with data published by other groups, has defined ETV6-related CT as a new hematological malignancy predisposition syndrome. FLI1 variants are associated with a decreased transcriptional activity, a decreased nuclear accumulation of the protein and abnormal megakaryocyte differentiation. ETV6 variants led to a decreased repressive activity and the megakaryocytes derived from patients showed increased proliferation and a marked defect in proplatelet formation. The platelets of GATA1 variant carriers showed aberrant expression of MYH10 protein suggesting a defective silencing of MYH10 gene during megakaryopoiesis. Consistently, in silico analysis of ChIP-seq data showed that GATA1 binds the promoter and an intronic region of the MYH10 in megakaryocytes.This project has provided insights into genetic causes, phenotype, diagnosis, prognosis and pathophysiological mechanisms of CTs
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Sarpatwari, Ameet Vilas. "Disease pathogenesis, treatment effectiveness, and co-morbid burden among adult patients with primary immune thrombocytopenia (ITP)." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/229513.
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Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease involving autoantibody-mediated platelet destruction, suboptimal platelet production, and T-cell-mediated platelet lysis. These processes cause a decreased peripheral blood platelet count (< 150 x 109/L), resulting in an increased susceptibility to bleeding events. While thecourse of primary ITP is often acute (< 6 months) among children, it is generally chronic in adults. Despite a marked increase in epidemiological research over the past decade, unresolved questions remain with regard to disease pathogenesis, treatment effectiveness, and co-morbid burden among adults with primary ITP. Objectives: 1. To launch a registry for adults with primary ITP in the United Kingdom (UK); 2. To evaluate associations of candidate single nucleotide polymorphisms (SNPs) with primary ITP; 3. To assess the effectiveness of 111In-labelled platelet studies in predicting outcomes from splenectomy; 4. To document health-related lifestyle concerns among patients; 5. To gauge the effectiveness of Helicobacter pylori (H. pylori) eradication in elevating platelet counts; 6. To characterise associations of primary ITP with both arterial and venous thromboembolic events (TEs). Data sources: 1. The UK Adult ITP Registry (17 centres, 327 patients); 2. The UK Adult ITP Registry-affiliated, 111In-Labelled Platelet Study Database (117 centres, 256 patients); 3. The Wellcome Trust Case-Control Consortium (WTCCC) 1958 British Birth Cohort (3,000 individuals); 4. The General Practice Research Database (GPRD) (500+ centres, 4 million+ patients); 5. The UK ITP Support Association Health-Related Lifestyle Survey (790 patients); 6. Systematic reviews of published epidemiological studies. Methods and Results: SNP Study: Caucasian patients from the UK Adult ITP Registry were gender-matched (1:3) with healthy controls from the WTCCC 1958 British Birth Cohort. Six functional candidate SNPs in cytokine or cytokine receptor genes were measured in cases and retrieved for controls from the European Genome-phenome Archive. Associations were evaluated using logistic regression models. A statistically significant per allele odds ratio (OR) of 1.34 (95% confidence interval [CI], 1.03-1.75) was observed for TNFA -308 g>a, implicating increased disease susceptibility among carriers of the rare allele. 111In Study: The effectiveness of autologous 111In-labelled platelet sequestration studies in predicting short (1-3 months), medium (6-12 months), and long-term (last follow-up) complete response (CR; count < 100 x 109/L) to splenectomy in patients with primary ITP was evaluated using multivariable logistic regression models. Significant adjusted (gender, age at splenectomy, and mean platelet lifespan) ORs were uncovered for short (7.47 [95% CI, 1.89-29.43]), medium (4.85 [95%CI, 1.04-22.54]) and long-term (5.39 [95% CI, 1.34-21.65]) CR in patients with purely or predominantly splenic versus mixed or hepatic splenic platelet sequestration, highlighting the utility of platelet sequestration studies as an adjunct predictive tool prior to splenectomy. H. pylori Eradication Study: A systematic literature review was conducted of studies evaluating the effects of H. pylori eradication on platelet count in patients with primary ITP. Twenty-five studies were identified, encompassing 696 evaluable patients. The weighted mean complete response (count > 100 x 109/L) and overall response (platelet count > 30 x 109/L) were 42.7% (95% CI, 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. Observed responses were higher in countries with a higher prevalence of H. pylori infection and in patients with milder thrombocytopenia. These findings support the benefits of H. pylori detection and eradication in patients with primary ITP. Health-Related Lifestyle Study: A 43-question, closed-field questionnaire was used to identify health-related lifestyle concerns among patient members of the UK Adult ITP Support Association. Completed surveys were returned by 790 (44.7%) members, with nearly one-third of adults reporting having an elective surgery delayed due to a low platelet count and experiencing difficulty in obtaining travel insurance. Notably, 12.5% of all patients reported 'always' or 'often' missing work or school due to fatigue. These results highlight several promising avenues for future health-related quality of life (HRQoL) research. Thromboembolic Event Studies: Using the GPRD, 1,070 adults with primary ITP were matched (1:4) with 4,280 ITP-free controls by age, gender, practice, and observation time. Comparative risks of TEs were assessed using Cox proportional hazards models. Over a median time of 47.6 months (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48) and 1.37 (95% CI, 0.94-2.00) were found for venous and arterial TEs, respectively. A similar investigation was conducted comparing age and sex-stratified incidence rates of TEs among patients in the UK Adult ITP Registry with population-based estimates for the general adult population, yielding significant standardised rate ratios of 2.43 (95% CI, 1.01-5.83) and 2.45 (95% CI,1.48-4.06) for venous and arterial TEs, respectively. These results collectively highlight an increased risk of venous and arterial TEs in adults with primary ITP. Conclusions: Primary ITP is a pro-inflammatory (i.e., TH-1-mediated), pro-thrombotic disease in adults. Available evidence supports testing for and eradication of H. pylori infection in patients with primary ITP and the utility of autologous 111Inlabelled platelet sequestration studies in identifying patients likely to respond to splenectomy. The development of a prospective, international registry will help assemble the sample sizes needed for promising further research, namely genome-wide disease association studies and investigations into the effects of the eradication of strain-specific H. pylori infection on platelet count, the precise relative risk of non-response to splenectomy in patients with mixed or hepatic platelet sequestration, and the associations of TEs with primary ITP in antiphospholipid antibody-negative.
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Chung, Delgado Kocfa, Montag Alejandro Revilla, Bravo Sonia Guillén, Díaz Hugo Ríos, and Muñoz José C. Alva. "Refractory Thrombocytopenia Responds to Octreotide Treatment in a Case of Evans Syndrome with Gastric Neuroendocrine Tumor." Hindawi Publishing Corporation, 2014. http://hdl.handle.net/10757/314004.
Full textAbstract:
A 37-year-old woman with history of Evans Syndrome with poor response to high-dose corticoid treatment presented to the
emergency department with gastrointestinal and vaginal bleeding. The patient was later diagnosed with severe thrombocytopenia
and a stage G1, well-differentiated gastric neuroendocrine tumor, confirmed by a biopsy. A total gastrectomy was performed
to eradicate the tumor. After being treated with a total splenectomy for her Evans Syndrome with no clinical or laboratory
improvement, she began regular treatment with octreotide on the basis of a possible hepatic metastasis. Days after the
initiation of the octreotide, an increase in the platelet count was evidenced by laboratory findings, from 2,000 platelets/mm3 to
109,000 platelets/mm3
. Weeks later, the hepatic metastasis is discarded by a negative octreotide-body scan, and the octreotide
treatment was interrupted. Immediately after the drug interruption, a progressive and evident descent in the platelet count was
evidenced (4000 platelets/mm3
). The present case report highlights the possible association between octreotide treatment and a
severe thrombocytopenia resistant to conventional treatment.
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Dandiala, Sireesha [Verfasser]. "Assessment of Clinical Profile and Mangement of Viral Fever with Thrombocytopenia In Paediatric Patients / Sireesha Dandiala." München : GRIN Verlag, 2020. http://d-nb.info/1214808972/34.
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Ghevaert, Cedric. "Recombinant anti-bodies with a modified non-destructive constant region for the treatment of fetomaternal alloimmune thrombocytopenia." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489916.
Full textAbstract:
Alloimmunisation against paternal human platelet antigen (HPA) can result in fetomaternal alloimmune thrombocytopenia (FMAIT) and intracranial haemorrhage (ICH) in the fetus, both in the antenatal and perinatal period. Analysis of 200 confirmed cases of FMAIT, showed that HPA-1a antibodies accounted for 75% of all cases and ICHs, with long-term neurological disabilities in 72%. Clinical data showed that antenatal treatment of alloimmunised pregnancies with intrauterine transfusions (lUT) carried a 15% risk of intrauterine death (lUD) and that postnatal treatment with HPA-1a negative platelet was effective but not used consistently.
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Stegner, David [Verfasser], and Bernhard [Akademischer Betreuer] Nieswandt. "Novel Aspects of Platelet Signaling and of the Pathogenesis of Immune Thrombocytopenia / David Stegner ; Betreuer: Bernhard Nieswandt." Würzburg : Universität Würzburg, 2018. http://d-nb.info/1160876819/34.
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Allen, David L. "A study of the Human Platelet Antigen 1a (HPA-1a) antibody response in neonatal alloimmune thrombocytopenia (NAIT)." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:44a10539-de5d-44dc-9c51-5f43cf3c3a82.
Full textAbstract:
Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal alloantibodies against fetal platelet antigens inherited from the father and which are absent from maternal platelets. In Caucasians, antibodies against the Leu33 (HPA-1a) polymorphism of integrin β3 (part of the platelet αIIbβ3 complex) account for >70% of cases. Antenatal screening for these antibodies does not currently take place in the UK, partly because of the absence of sensitive, predictive tests. We hypothesized that the poor sensitivity and predictive abilities of current assays are due to the use of β3 in an inappropriate conformation, resulting in sub-optimal binding of HPA-1a antibodies. We hypothesized firstly that in vitro induced changes to αIIbβ3 might alter accessibility of the HPA-1a epitopes to alloantibodies, thus reducing assay sensitivity. Secondly, we hypothesized that HPA-1a antibodies are stimulated by, and preferentially recognise, β3 in association with αv, a molecule present on placental syncytiotrophoblasts, and that reactivity against platelet αIIbβ3 reflects only cross-reactivity with αvβ3. Our first hypothesis was proven by demonstrating that use of the cation chelating compound EDTA, used by many diagnostic laboratories as a component of assay reagents or present in blood samples as anticoagulant, resulted in significantly reduced assay sensitivity. These findings were confirmed in an international workshop. Support for our second hypothesis was provided by demonstrating enhanced reactivity of a small panel of examples of anti-HPA-1a against αvβ3 compared to αIIbβ3 and by molecular modelling data. We also showed that HPA-1a antibodies can inhibit platelet function by using a novel application of the ROTEM® delta thromboelastograph and an immunofluorescence assay in which we demonstrated blocking of platelet function using a monoclonal antibody, PAC-1, that binds only to activated αIIbβ3. These studies provide possible explanations for the poor sensitivity and predictive abilities of current assays and suggest further areas for research.
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Preham, Olivier. "Study of the mechanisms responsible for anemia and thrombocytopenia in an experimental mouse model of visceral leishmaniasis." Thesis, University of York, 2016. http://etheses.whiterose.ac.uk/13654/.
Full textAbstract:
Visceral leishmaniasis (VL) is a neglected tropical disease caused by protozoan parasites of the Leishmania genus causing between 20 000 and 50 000 deaths per annum. The parasites have developed a range of mechanisms to avoid the host’s immunity and establish chronic infection of the spleen, liver and bone marrow as intracellular parasites of macrophages. The non-exhaustive list of syndromes associated with VL include hepatomegaly, splenomegaly, fever and pancytopenia. The causes for the reduction of red blood cells, platelets or leukocytes are still unclear. Many studies have focused on the immunological aspects of VL, both in humans and experimental models, but the mechanisms causing haematological disorders remain unclear. In this study, it is shown that mice chronically infected with Leishmania donovani (L. donovani) develop haematological abnormalities, namely anaemia and thrombocytopenia. Erythropoiesis was quantified in the bone marrow, the main site of haematopoiesis in adult mammals. The number of late erythroid precursors was severely reduced in infected animals. Reduction of medullar erythropoiesis was associated with a reduction of stromal support in the bone marrow shown by a reduction of stromal macrophages expressing high levels of CD169 and a loss of CXCL12-producing stromal fibroblasts. The granulocyte-colony stimulating factor (G-CSF) known to deplete stromal macrophages and inhibit CXCL12 expression was systematically up-regulated in infected mice. Splenomegaly correlated with compensatory extramedullary erythropoiesis confined to the red pulp. Infection of splenectomised mice demonstrated that anaemia was independent of the spleen since medullar erythropoiesis was still impaired in these mice. Infection caused an increase in CD4 and CD8 T cells in the bone marrow and infected B6 RAG2-/- mice lacking mature T and B cells were not anaemic and had no repression of medullar erythropoiesis nor splenomegaly. Alterations of bone marrow stromal cells or up-regulation of G-CSF did not occur in these mice. Splenomegaly was relevant because it was shown to be responsible for thrombocytopenia. Megakaryopoiesis was unaltered by chronic infection and infected splenectomised mice had higher platelet counts than their sham-operated counterparts. Platelet production could be stimulated by injections of recombinant thrombopoietin (TPO) in chronically infected mice. Efficacy of TPO treatment in curing thrombocytopenia correlated negatively with the severity of splenomegaly. The original contribution of this work is the demonstration of a complex immunopathological mechanism causing haematological changes in an experimental model of VL. Better understanding of haematological alterations of VL is a step forward for the improvement of VL therapy, in which these alterations have been associated with the lethality of the disease.
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Casati, Silvia. "Development of in vitro tests to predict thrombocytopenia : standardisation of the colony-forming unit-megakaryocyte (CFU-MK) assay." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395459.
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Soe, Soe Win Polrat Wilairatana. "Hematological changes in malaria /." Abstract, 2006. http://mulinet3.li.mahidol.ac.th/thesis/2549/cd388/4838792.pdf.
Full textAbstract:
Thematic paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2006.LICL has E-Thesis 0012 ; please contact computer services. LIRV has E-Thesis 0012 ; please contact circulation services.
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Caboz, Mariana. "Clínica de animais de companhia." Master's thesis, Universidade de Évora, 2013. http://hdl.handle.net/10174/18390.
Full textAbstract:
estágio na área da Clínica de Animais de Companhia, assim como os casos
acompanhados, e, ainda, uma breve monografia relativa ao tema “Trombocitopenia
imunomediada”. Os canídeos foram a espécie mais representativa durante o
período de estágio (58%) e a área com maior valor representativo foi a Patologia
Médica (71,8%). A trombocitopenia imunomediada (TIM) é a manifestação de um
distúrbio de hipersensibilidade, na qual anticorpos são direcionados contra as
plaquetas levando à sua fagocitose e destruição pelos macrófagos. A sua
prevalência pode chegar até 1% dos animais hospitalizados, sendo mais comum
em canídeos e representando a causa mais frequente de síndrome hemorrágica no
cão. Foi documentada uma grande variedade de causas para a TIM e o seu
diagnóstico específico pode ser um desafio; Abstract:
COMPANION ANIMAL MEDICINE
IMMUNE-MEDIATED THROMBOCYTOPENIA
This report briefly describes the activities undertaken during the internship in the
field of Companion Animal Medicine, as well as the followed cases, and also a brief
monograph on the theme "Immune-Mediated Thrombocytopenia". The dogs were
the most representative species during the training period (58%) and the area
with the most representative value was the Medical Pathology (71.8%). The
immune-mediated thrombocytopenia (TIM) is a manifestation of a
hypersensitivity disorder in which antibodies are directed against platelets leading
to their destruction and phagocytosis by macrophages. Its prevalence can reach up
to 1% of the hospitalized animals, being more common in dogs and represents the
most frequent cause of hemorrhagic syndrome in this species. There have been
documented a variety of causes of TIM and its specific diagnosis can be very
challenging.
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Kimmerle, Sabine. "Rapid determination of Anti-Heparin/Platelet factor 4 antibody titers in the diagnosis of Heparin-induced Thrombocytopenia$cSabine Kimmerle." Bern : [s.n.], 2003. http://www.stub.unibe.ch/html/haupt/datenbanken/diss/bestell.html.
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Bender, Brendan. "Pharmacometric Models for Antibody Drug Conjugates and Taxanes in HER2+ and HER2- Breast Cancer." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-292617.
Full textAbstract:
In oncology, there is a need to optimize drug treatment for efficient eradication of tumors, minimization of adverse effects (AEs), and prolonging patient survival. Pharmacometric models can be developed to streamline information between drug development phases, describe and quantify response to treatment, and determine dose regimens that balance toxicity and efficacy. In this thesis, data from trastuzumab emtansine (T-DM1) and taxane drug treatment were used to develop pharmacometric models of pharmacokinetics (PK), AEs, anti-tumor response, and survival, supporting drug development. T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex distribution of T-DM1 was elucidated through PK models developed using in vitro and in vivo rat and cynomolgus monkey DAR data. Mechanism–based PK/pharmacodynamic (PKPD) models were also developed for T-DM1 that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. Variable patterns of platelet and transaminase (ALT and AST) response were quantified, including an effect of Asian ethnicity that was related to higher incidences of TCP. Model simulations, comparing dose intensities (DI) and Grade 3/4 incidences between the approved T-DM1 dose (3.6 mg/kg every three weeks) and weekly regimens, determined that 2.4 mg/kg weekly provided the highest DI. Docetaxel and paclitaxel are taxane treatment options for HER2–negative breast cancer. Tumor response data from these treatments were used to develop a mechanism–based model of tumor quiescence and drug–resistance. Subsequently, a parametric survival analysis found that tumor baseline and the model–predicted time to tumor growth (TTG) were predictors of overall survival (OS). This tumor and OS modeling approach can be applied to other anticancer treatments with similar patterns of drug–resistance. Overall, the pharmacometric models developed within this thesis present new modeling approaches and provide understanding on ADC PK and PKPD (TCP and hepatotoxicity), as well as drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards dose finding for anticancer drugs in development, especially ADCs.
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Koide, Rie. "Experimental infection of Japanese macaques with simian retrovirus 5." Kyoto University, 2019. http://hdl.handle.net/2433/242425.
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Rose, Leburn. "A computer based model for the simulation of platelet dosage size and platelet dosage interval in patients with stable thrombocytopenia." Thesis, London South Bank University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288172.
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Pirker-Krassnig, Daniela Karoline Polrat Wilairatana. "Hematological changes in patients with severe malaria from Bangkok Hospital for tropical diseases /." Abstract, 2006. http://mulinet3.li.mahidol.ac.th/thesis/2549/cd388/4838786.pdf.
Full textAbstract:
Thematic Paper ((M.C.T.M. Clinical Tropical Medicine))--Mahidol University, 2006.LICL has E-Thesis 0012 ; please contact computer services. LIRV has E-Thesis 0012 ; please contact circulation services.