PB0190 - Hsp90 Activate the Kinin System Responsible for Hyperfibrinolysis in CARAC: unraveled by proteomics

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Ying ying Li, Graduate

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)

Co-Author(s)

LL

Lili Luo

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
JW

Jianghua Wu

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
ZW

Zhong Wu

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
JW

Jingming Wang

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
MD

Mengyi Du

doctor
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
HJ

Huiwen Jiang

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
HM

Heng Mei

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
wuhan, Hubei, China (People's Republic)
YH

Yu Hu

PhD
Institution of Hematology, Wuhan Union Hospital, Tongji medical college, Huazhong University of Science and Technology
wuhan, Hubei, China (People's Republic)

Background: Bleeding and hypofibrinogenemia are main features of CAR-T-associated coagulopathy (CARAC)，While, the underlying mechanisms have not been fully elucidated.

Aims: To explore the potential pathogenesis of CARAC.

Methods: Peripheral blood samples were collected at the timepoint of before fludarabine/cyclophosphamide lymphodepletion (pre-FC), D0, D7, D14, D28 and IL-6 peak after CAR T cell transfusion in two cohorts at Wuhan Union Hospital. Cohort 1 as a training set included 20 patients with acute B-lymphoblastic leukemia (B-ALL) using proteomic analysis. Cohort 2 included 75 patients with ALL and lymphoma as the validation set. CARAC is defined as cytokine release syndrome (CRS) combined with any abnormal coagulation indicators （D-Dimer, FDP, PT, APTT, fibrinogen, TT）.

Results: There was no difference in baseline characteristics in cohort 1 and cohort 2. Half of CARAC patients (n=10) were grade≥3 CRS，while non-CARAC patients (n=10) were all grade1-2 CRS. Compared with non-CARAC (n=10), there were 113 DEPs, which were mainly enrichment in the pathways of inflammation, coagulation and proteolysis. Compared with the non-CARAC group: 1) the protein expressions of vWF and VCAM1 in the CARAC group were markedly increased, indicating that the endothelial and coagulation system were significantly activated by CRS in CARAC patients; 2) The protein expression levels of HSP90AA1 and HSP90AB1 were increased, while kinin-fibrinolytic system inhibitor (PAI-3, A2M) and zymogen (KLKB1, PLG) were decreased, suggesting the activation of kinin-fibrinolytic system. Previous studies have shown that HSP90 can lead to the activation of the kinin system, and kallikrein can cause the hyperfibrinolysis by activating uPA. The above results were verified in cohort 2.

Conclusion(s): CRS is a key mechanism of CARAC and may activate kallikrein by promoting the release of HSP90 from endothelial cells, thereby activating uPA and causing hyperfibrinolysis.