High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease.
anemia
blood coagulation
high molecular weight
inflammation
kidney disease
kininogen
sickle cell
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
16
10
2019
revised:
10
06
2020
accepted:
12
06
2020
pubmed:
24
6
2020
medline:
20
5
2021
entrez:
24
6
2020
Statut:
ppublish
Résumé
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso-occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein-kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation. We hypothesize that HK contributes to the hypercoagulable and pro-inflammatory state that causes end-organ damage and early mortality in sickle mice. We evaluated the role of HK in the Townes mouse model of SCD. We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK-deficient background. We found that short-term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long-term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.
Sections du résumé
BACKGROUND
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso-occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein-kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation.
OBJECTIVE
We hypothesize that HK contributes to the hypercoagulable and pro-inflammatory state that causes end-organ damage and early mortality in sickle mice.
METHODS
We evaluated the role of HK in the Townes mouse model of SCD.
RESULTS/CONCLUSIONS
We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK-deficient background. We found that short-term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long-term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.
Identifiants
pubmed: 32573897
doi: 10.1111/jth.14972
pmc: PMC8043232
mid: NIHMS1684645
pii: S1538-7836(22)01666-X
doi:
Substances chimiques
Kininogen, High-Molecular-Weight
0
Thrombin
EC 3.4.21.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2329-2340Subventions
Organisme : American Heart Association
ID : 16POST30230002
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS102721
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL117659
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007149
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157441
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL117684
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL144817
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142604
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL146226
Pays : United States
Organisme : NINDS NIH HHS
ID : R01NS102721
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056350
Pays : United States
Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
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