High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease

Abstract

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.

The contact activation system and vascular factors as alternative targets for Alzheimer's disease therapy

“…61,109,110 Therefore, blocking the contact system in patients would not increase the risk of hemorrhage. The 3E8 anti-HK antibody or other contact system inhibitors could be effective at ameliorating not only vascular and inflammatory pathologies in AD but also other diseases and vascular pathologies in which the contact system is also dysregulated, such as hereditary angioedema, 111 sickle cell anemia, 112 lupus, 113 rheumatoid arthritis, 114 multiple sclerosis-associated neuroinflammation, 66,115 infection (sepsis/endotoxemia), 116,117 and colitis. 118…”

Drugs of the Kallikrein–Kinin System: An Overview

“…The biomarkers of kinin-mediated disorders include the consumption of kininogen(s) and the detection of circulating kinin metabolites such as fragments BK 1-5 and BK 2-9 , and the detection of plasma kallikrein activity, for instance, using the synthetic substrate based on the C-terminal BK sequence HD-Pro-Phe-Arg-pNA. These assays are technically challenging, but one or more of them have been applied to hereditary angioedema (HAE), either during attacks or in remission [15,16] to other edematous conditions such as ascites, secondary to liver cirrhosis [17] and chronic urticaria [18,19], and to animal models of sepsis and sickle cell disease [20,21].…”

Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo

“…Dysregulation of the contact system is involved in various disease conditions, such as sickle cell anemia, 23 hereditary angioedema, 24 , 25 , 26 inflammatory bowel disease, 27 , 28 Alzheimer disease, 7 , 29 , 30 sepsis, 31 lupus, 32 arthritis, 33 , 34 cancer metastasis, 35 and other pathological conditions. 3 , 16 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 Importantly, patients with a deficient contact system do not bleed, 11 making it an ideal target for developing inhibitors.…”