New approaches to the pathophysiology, diagnosis and management of heparin-induced thrombocytopenia

肝素诱导的血小板减少症的病理生理学、诊断和治疗的新方法

• 批准号: 10470249
• 负责人: Anand Padmanabhan
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470249
• 关键词: Affect; Alpha Granule; American Society of Hematology; Antibodies; Anticoagulant therapy; Anticoagulants; Anticoagulation; Antigens; Area; Benign; Binding; Biochemical; Biological Assay; Blood Platelets; Blood specimen; Cessation of life; Characteristics; Chondroitin Sulfate A; Chondroitin Sulfates; Chromatography; Coagulation Process; Complex; Dangerousness; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Early Diagnosis; Environment; Enzyme-Linked Immunosorbent Assay; Epidemic; Evaluation; Event; Functional disorder; Generations; Goals; Gold; Hemorrhage; Heparin; Heparin Binding; Heterogeneity; Hospitals; In Vitro; Institution; Laboratories; Lead; Length; Life; Mediating; Methods; Monoclonal Antibodies; Morbidity - disease rate; Outcome; P-Selectin; PF4 Gene; Pathogenesis; Pathogenicity; Pathway interactions; Patient Isolation; Patients; Platelet Activation; Proteins; Research; Research Infrastructure; Research Personnel; Risk; Sampling; Serology; Serotonin; Specificity; Sulfate; Surface; Syndrome; Testing; Therapeutic; Thrombin; Thrombocytopenia; Thrombosis; Time; Whole Blood; Work; accurate diagnosis; base; drug candidate; heparin-induced thrombocytopenia; improved; in vivo; inhibitor; innovation; insight; mortality; mouse model; murine monoclonal antibody; new therapeutic target; novel; novel strategies; prevent; rapid diagnosis

PROJECT SUMMARY/ABSTRACT Heparin-induced thrombocytopenia (HIT) is a severe, antibody (ab)-mediated prothrombotic syndrome with high morbidity and mortality. The biochemical basis of the distinction between “pathogenic” platelet-activating antibodies and “benign” non-activating HIT antibodies is not well understood. This results in significant diagnostic challenges and in excessive use of non-heparin alternative anticoagulation that have worse bleeding profiles than heparin. Outcomes in HIT are suboptimal despite current therapy with direct thrombin inhibitors: One-third of affected patients develop thrombosis and one in ten patients dies. The proposed studies will explore key unanswered questions in areas of HIT pathophysiology, diagnosis and treatment. For Aim 1, we hypothesize the existence of multiple functional classes of HIT antibodies: (1) Pathogenic antibodies that recognize PF4-treated platelets with or without reactivity to PF4-heparin complexes, and (2) Benign abs that recognize PF4-heparin but not platelets treated with PF4. We will identify and characterize these antibody classes by chromatography-based isolation from patient samples and will generate novel HIT monoclonal antibodies in each of these functional classes. Generated monoclonal antibodies will be tested for pathogenicity in a HIT mouse model and results will be correlated with their serologic characteristics. Obtaining and processing normal donor platelets is a major challenge that limits the availability of functional “gold standard” testing in HIT. In Aim 2, we will develop a rapid HIT diagnostic test using the patient’s own platelets treated with PF4/heparin. This will facilitate “in-hospital” HIT diagnosis leading to early detection of this condition. Currently used non-heparin alternative anticoagulants do not address the most proximal event in HIT: Activation of platelets by HIT antibodies. Given this, breakthrough thrombosis is frequently seen in patients under treatment and so is unintended bleeding caused by the potent non-heparin anticoagulants used. In Aim 3, we will use platelet-derived and synthetic chondroitin sulfates of various sulfation levels and saccharide lengths to evaluate their ability to inhibit HIT-antibody mediated platelet activation in vitro and to ameliorate thrombocytopenia in a HIT murine model. In Aim 1, we expect to successfully separate and characterize multiple functional classes of HIT antibodies which will suggest new ways to selectively detect only the pathogenic ones. Developing and optimizing a diagnostic method using the patient’s own platelets in Aim 2 will transform platelet-activation based HIT testing by moving it from the reference laboratory environment to the in-hospital setting. Finally, studies described in Aim 3 will introduce a new class of therapeutics in HIT, chondroitin sulfates, that will prevent thrombosis, but unlike current therapies, will not increase the risk of bleeding. In summary, we anticipate that all three aims of this proposal will lead to a significant impact on pathophysiology, diagnosis and treatment of HIT.

项目总结/文摘