HEMOSTATIC DEFECTS AND THYROID HORMONE THERAPY

止血缺陷和甲状腺激素治疗

• 批准号: 3358745
• 负责人: WINIFRED J DODDS
• 金额: $ 10.2万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3358745
• 关键词: arginine vasopressin; autoantibody; autoimmune disorder; autoimmune thyroiditis; blood coagulation tests; coagulation factor VIII; disease /disorder model; dogs; fibrinogen receptors; hemophilia As; hemophilia B; hypothyroidism; platelets; radioimmunoassay; thrombocytopathy; thyroxine; tissue /cell culture; triiodothyronine; vascular endothelium; von Willebrand factor; von Willebrand's disease

Use of blood and its products for the treatment of bleeding disorders carries the risk for transmission of viral diseases such as non A, non B hepatitis and AIDS. The longterm objectives of this proposal are to establish the clinical efficacy and mechanism(s) of action of thyroid hormones in the treatment of hereditary and/or acquired hemostatic defects. A unique colony of dogs with well- characterized inherited defects and a clinical population of dogs referred for bleeding problems will be utilized. Thyroid dysfunction produces a number of hemostatic and immunohematologic abnormalities in man and dogs which can be corrected by oral thyroid therapy, but the mode(s) of action of thyroid hormones in these situations are unknown. The specific aims of this application are: 1) To evaluate the effect and mode(s) of action of thyroid hormones on hemostatic parameters in dogs with VWD (types I and III); hemophilias A and B, and a thrombopathia similar to Glanzmann's thrombasthenia. 2) Establish hemostatic responses to thyroid hormones in a clinical population of dogs with thyroid dysfunction and/or polyglandular autoimmune syndrome. 3) Determine the effectiveness of thyroid hormone and/or DDAVP therapy for treatment of dogs with VWD and/or thyroid dysfunction and a bleeding tendency. These goals will be achieved by establishing whether thyroid hormone therapy i) results in quantitative and/or qualitative changes in plasma factors essential for normal hemostasis (e.g. the FVIII complex); ii) enhances platelet production, availability and/or reactivity; iii) reduces levels of antithyroid antibodies present in autoimmune thyroiditis which may interfere with hemostasis; and iv) alters endothelial cell metabolism. Specific assays will be used to monitor changes in coagulation factors. The levels of FVIII:C, VWF:Ag and VWF:RCoF will be correlated with alterations in cuticle (toe nail) bleeding times and FVIII multimeric profiles. Platelet adhesion, aggregation, secretion and glass-bead retention (two-stage method) will be determined as will changes in platelet biochemistry including adenine nucleotide ratios, serotonin content, thromboxane A2 generation, cyclic AMP content and fibrinogen receptor availability. Finally, synthesis and release of VWF from cultured endothelial cells will be studied in the presence and absence of thyroid hormones.

使用血液及其产品用于治疗出血 疾病具有传播病毒疾病的风险 非A，非B肝炎和艾滋病。 这个长期目标 提案是建立临床功效和机制 甲状腺激素在治疗遗传和/或 获得的止血缺陷。 一个独特的狗的殖民地 遗传缺陷和狗的临床人群的特征 将使用引用出血问题的转介。 甲状腺 功能障碍会产生许多止血和 人和狗的免疫血液学异常可能是 通过口服甲状腺疗法纠正，但是 在这些情况下，甲状腺激素是未知的。 具体 该应用的目的是：1）评估效果和 甲状腺激素对止血参数的作用模式 在有VWD的狗中（I型和III型）；血友病A和B，A 血栓性疾病类似于格兰茨曼的血栓症。 2） 在临床中建立对甲状腺激素的止血反应 甲状腺功能障碍和/或多边形的狗的种群 自身免疫性综合征。 3）确定甲状腺的有效性 激素和/或DDAVP疗法用于用VWD治疗狗 和/或甲状腺功能障碍和出血趋势。 这些目标将通过确定甲状腺是否实现 激素治疗i）导致定量和/或定性 正常止血必不可少的血浆因子的变化（例如 FVIII综合体）； ii）增强血小板的产生，可用性 和/或反应性； iii）降低抗体抗体的水平 存在于自身免疫性甲状腺炎中，可能会干扰 止血；和iv）改变内皮细胞代谢。 具体的 测定将用于监测凝血因子的变化。 FVIII：C，VWF：AG和VWF：RCOF的水平将与之相关 随着角质层（脚趾指甲）出血时间和FVIII的改变 多聚剖面。 血小板粘附，聚集，分泌和 玻璃珠保留（两阶段方法）将被确定为 将变化血小板生物化学，包括腺嘌呤核苷酸 比率，5-羟色胺含量，血栓烷A2代，环状AMP 含量和纤维蛋白原受体的可用性。 最后，合成 将研究从培养的内皮细胞中释放VWF 在存在和不存在甲状腺激素的情况下。