PHARMACOGENETICS, BIOMARKERS, AND ANTITHROMBOTIC THERAPY

药物遗传学、生物标志物和抗血栓治疗

• 批准号: 7377237
• 负责人: BRIAN F GAGE
• 金额: $ 3.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377237
• 关键词: PHARMACOGENETICS; BIOMARKERS; ANTITHROMBOTIC; THERAPY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lower gastrointestinal hemorrhage is a common reason for hospital admission. Their morbidity is high, as is their economic impact. Certain genetic mutations in clotting factors and platelet aggregation have been identified that may increase the risk of bleeding: they have been observed in the setting of intracranial hemorrhage, subconjunctival hemorrhave, or intrathoracic hemorrhage following coronary artery bypass grafting, but they have not been investigated in gastrointestinal hemorrhage. In addition, other genetic mutations in clotting factors may be protective against hemorrhage. Factor XIII levels decrease both preoperatively and postoperatively in patients with hemorrhage after intracranial surgery. An increased prevalence of factor XIII Val34Leu polymrphism has been shown in patients with both subconjunctival and primary intracerebral hemorrhae, and is associated with decreased levels of factor XIII. Decreased platelet activating factor (PAF) acetylhydrolase activity has been shown in patients with intracranial hemorrhage. The Val279Phe mutation in the PAF acetylhydrolase gene, both heteroxygous and homozygous, is associated with decreased PAF acetylhydrolase activity and susceptibility to intracranial hemorrhage. Factor VII-323 deletion/insertion allele has also been associated with an increased risk of intracranial hemorrhage. Factor V Leiden has been demonstrated to protect against excessive intrathoracic blood loss and transfusion following cardiac surgery, and to be present in decreased frequency in patients with intracranial hemorrhage. A recent study suggests this is related to inhibition of in vivo fibrinolysis. This is a case-control study examinig the influence if these mutation on gastrointestinal hemorrhage. Retrospective cases and controls will be required to give a single venous blood specimen for genetic analysis. The use of the GCRC facilities would be limited to one visit for a single phlebotomy per patient for all retrospective patients. Enrollment is expected to be between 450 and 600 total patients. We expect an increased frequency of factor XIII Val34Leu, factor VII -323 del/ins, asnd PAF acetylhydrolase Val279Phe in patients with gastrointestinal bleeding, while Factor V Leiden is expected to be decreased in frequency in these patients. Through these results, we would hope to identify patietns at increased risk or gastrointestinal hemorrhage, especially when faced with the need for anticoagulation.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。下消化道出血是入院的常见原因。它们的发病率很高，经济影响也很大。凝血因子和血小板聚集的某些基因突变已被确定可能增加出血的风险：在颅内出血、结膜下出血或冠状动脉旁路移植术后胸内出血的情况下观察到了这些突变，但尚未对胃肠道出血进行研究。此外，凝血因子中的其他基因突变可能对出血有保护作用。 颅内手术后出血患者的凝血因子XIII水平在术前和术后均降低。在结膜下出血和原发性脑内出血患者中，因子XIII Val 34 Leu多态性的发生率增加，并与因子XIII水平降低有关。颅内出血患者血小板活化因子（PAF）乙酰水解酶活性降低。PAF乙酰水解酶基因的Val 279 Phe突变，无论是杂合型还是纯合型，都与PAF乙酰水解酶活性降低和颅内出血易感性相关。因子VII-323缺失/插入等位基因也与颅内出血风险增加相关。 已证明莱顿因子V可防止心脏手术后胸内失血过多和输血，并降低颅内出血患者的出现频率。最近的一项研究表明，这与抑制体内纤维蛋白溶解有关。 这是一项病例对照研究，检查这些突变对胃肠道出血的影响。回顾性病例和对照将需要提供一份静脉血标本用于遗传分析。对于所有回顾性患者，每例患者使用GCRC设施仅限于一次访视，进行单次静脉切开术。预计入组患者总数为450至600例。我们预期在胃肠道出血患者中，因子XIII Val 34 Leu、因子VII-323 del/ins和PAF乙酰水解酶Val 279 Phe的频率增加，而因子V Leiden的频率预期在这些患者中降低。通过这些结果，我们希望能够识别出风险增加或胃肠道出血的患者，特别是在需要抗凝治疗的情况下。