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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

基本信息

批准号：
10675669
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
项目类别：
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/10675669
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 Hemorrhage Heparin Heparin Binding Heterogeneity Hospitals In Vitro Incubated Institution Laboratories Length Life Mediating Methods Monoclonal Antibodies Morbidity - disease rate Outcome P-Selectin PF4 Gene Pathogenesis Pathogenicity Pathway interactions 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 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

项目摘要

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

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Monoclonal gammopathy of thrombotic/thrombocytopenic significance.

具有血栓形成/血小板减少意义的单克隆丙种球蛋白病。

DOI：
10.1182/blood.2022018797
发表时间：
2023
期刊：
Blood
影响因子：
20.3
作者：
Kanack,AdamJ;Schaefer,JordanK;Sridharan,Meera;Splinter,NoahP;Kohlhagen,MindyC;Singh,Bandana;DeLorenzo,SilvanaB;Mauch,EmilyE;Hussein,MaenA;Shaikh,Marwan;Kumar,Shaji;Wen,Renren;Wang,Demin;Murray,David;Padmanabhan,Anand
通讯作者：
Padmanabhan,Anand

Vaccine-induced immune thrombotic thrombocytopenia.

DOI：
10.1182/blood.2022017696
发表时间：
2023-04-06
期刊：
BLOOD
影响因子：
20.3
作者：
Cines, Douglas B.;Greinacher, Andreas
通讯作者：
Greinacher, Andreas

Cardiac surgery in acute heparin-induced thrombocytopenia managed with therapeutic plasma exchange and intravenous immunoglobulin.

通过治疗性血浆置换和静脉注射免疫球蛋白治疗急性肝素诱导的血小板减少症的心脏手术。

DOI：
10.1016/j.rpth.2023.100089
发表时间：
2023
期刊：
Research and practice in thrombosis and haemostasis
影响因子：
4.6
作者：
Grazioli,Alison;Splinter,NoahP;Plazak,MichaelE;Griffith,BartleyP;Dahi,Siamak;Bathula,AllisonH;Cheung,NoraH;Padmanabhan,Anand
通讯作者：
Padmanabhan,Anand

"Autoimmune HIT" antibodies in diagnostic samples are a potential artifact and not associated with more severe outcomes.

DOI：
10.1182/bloodadvances.2023009811
发表时间：
2023-08-22
期刊：
Blood advances
影响因子：
7.5
作者：
通讯作者：

Cerebral venous sinus thrombosis associated with SRA-negative heparin-induced thrombocytopenia: case report.

DOI：
10.1186/s12959-023-00490-7
发表时间：
2023-04-21
期刊：
THROMBOSIS JOURNAL
影响因子：
3.1
作者：
Silva, Floyd D. D.;Burnett, Allison E. E.;Padmanabhan, Anand;Rollins-Raval, Marian A. A.;Splinter, Noah P. P.;Desai, Masoom J. J.
通讯作者：
Desai, Masoom J. J.