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  1. Article ; Online: Plasma kallikrein supports FXII-independent thrombin generation in mouse whole blood.

    Wan, Jun / Dhrolia, Sophia / Kasthuri, Rohan R / Prokopenko, Yuriy / Ilich, Anton / Saha, Prakash / Roest, Mark / Wolberg, Alisa S / Key, Nigel S / Pawlinski, Rafal / Bendapudi, Pavan K / Mackman, Nigel / Grover, Steven P

    Blood advances

    2024  

    Abstract: Plasma kallikrein (PKa) is an important activator of factor (F)XII of the contact pathway of coagulation. Several studies have shown that PKa also possesses procoagulant activity independent of FXII, likely through its ability to directly activate FIX. ... ...

    Abstract Plasma kallikrein (PKa) is an important activator of factor (F)XII of the contact pathway of coagulation. Several studies have shown that PKa also possesses procoagulant activity independent of FXII, likely through its ability to directly activate FIX. We evaluated the procoagulant activity of PKa using a mouse whole blood (WB) thrombin generation (TG) assay. TG was measured in WB from PKa-deficient mice using contact pathway or extrinsic pathway triggers. PKa-deficient WB had significantly reduced contact pathway-initiated TG compared to wild-type controls and was comparable to that observed in FXII-deficient WB. PKa-deficient WB supported equivalent extrinsic pathway-initiated TG compared to wild-type controls. Consistent with the presence of FXII-independent functions of PKa, targeted blockade of PKa with either small molecule or antibody-based inhibitors significantly reduced contact pathway-initiated TG in FXII-deficient WB. Inhibition of activated FXII (FXIIa) using an antibody-based inhibitor significantly reduced TG in PKa-deficient WB, consistent with a PKa-independent function of FXIIa. Experiments using mice expressing low levels of tissue factor demonstrated that persistent TG present in PKa- and FXIIa-inhibited WB was driven primarily by endogenous tissue factor. Our work demonstrates that PKa contributes significantly to contact pathway-initiated TG in the complex milieu of mouse WB and that a component of this contribution occurs in a FXII-independent manner.
    Language English
    Publishing date 2024-04-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2024012613
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7153: Show issues Location:
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  2. Article ; Online: Contact system and intrinsic pathway activation in patients with advanced pancreatic cancer: a prospective cohort study.

    Bosch, Floris T M / Campello, Elena / Mulder, Frits I / Ilich, Anton / Henderson, Michael W / Prokopenko, Yuriy / Gavasso, Sabrina / Pea, Antonio / Salvia, Roberto / Wilmink, Hanneke W / Otten, Hans-Martin / van Es, Nick / Key, Nigel S / Büller, Harry R / Simioni, Paolo

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 21, Issue 10, Page(s) 2863–2872

    Abstract: Background: Despite high risk of venous thromboembolism (VTE) in patients with pancreatic cancer, there are little data on contact system activation in these patients.: Objectives: To quantify contact system and intrinsic pathway activation and ... ...

    Abstract Background: Despite high risk of venous thromboembolism (VTE) in patients with pancreatic cancer, there are little data on contact system activation in these patients.
    Objectives: To quantify contact system and intrinsic pathway activation and subsequent VTE risk in patients with pancreatic cancer.
    Methods: Patients with advanced pancreatic cancer were compared with controls. Blood was drawn at baseline and patients were followed for 6 months. Complexes of proteases with their natural inhibitors, C1-esterase inhibitor (C1-INH), antithrombin (AT), or alpha-1 antitrypsin (α1at), were measured for complexes containing kallikrein (PKa:C1-INH), factor (F)XIIa (FXIIa:C1-INH), and FXIa (FXIa:C1-INH, FXIa:AT, FXIa:α1at). The association of cancer with complex levels was assessed in a linear regression model, adjusted for age, sex, and body mass index. In a competing risk regression model, we assessed associations between complex levels and VTE.
    Results: One hundred nine patients with pancreatic cancer and 22 controls were included. The mean age was 66 years (SD, 8.4) in the cancer cohort and 52 years (SD, 10.1) in controls. In the cancer cohort, 18 (16.7%) patients developed VTE during follow-up. In the multivariable regression model, pancreatic cancer was associated with increased complexes of PKa:C1-INH (P < .001), FXIa:C1-INH (P < .001), and FXIa:AT (P < .001). High FXIa:α1at (subdistribution hazard ratio, 1.48 per log increase; 95% CI, 1.02-2.16) and FXIa:AT (subdistribution hazard ratio, 2.78 highest vs lower quartiles; 95% CI, 1.10-7.00) were associated with VTE.
    Conclusion: Complexes of proteases with their natural inhibitors were elevated in patients with cancer. These data suggest that the contact system and intrinsic pathway activation are increased in patients with pancreatic cancer.
    MeSH term(s) Aged ; Female ; Humans ; Male ; Anticoagulants ; Antithrombin III ; Endopeptidases ; Kallikreins ; Pancreatic Neoplasms ; Prospective Studies ; Venous Thromboembolism/diagnosis ; Middle Aged
    Chemical Substances Anticoagulants ; Antithrombin III (9000-94-6) ; Endopeptidases (EC 3.4.-) ; Kallikreins (EC 3.4.21.-)
    Language English
    Publishing date 2023-06-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1016/j.jtha.2023.06.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5805: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 295: Show issues

    Order via subito

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