Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI.
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http://dx.doi.org/10.1016/j.jaut.2012.05.005 | DOI Listing |
J Thromb Haemost
December 2024
Division of Cardiovascular Medicine, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:
Arterial and venous thromboses are the leading causes of morbidity and mortality worldwide. Numerous antithrombotic agents are currently available with antiplatelet, thrombolytic/fibrinolytic, and anticoagulant activity. However, all the currently available antithrombotic agents carry a risk of bleeding that often prevents their use.
View Article and Find Full Text PDFPol Arch Intern Med
December 2024
Fibrin formation is pivotal in hemostasis, serving as a temporary barrier to blood loss following vascular injury, while in thrombosis this process is involved in thrombus progression, stability, and recurrence. Growing evidence shows exceptional complexity of processes that determine fibrin clot structure and function, especially lysability, both in health and disease, which might be relevant in the pathogenesis of arterial and venous thromboembolic diseases. In this review, we summarized available data on novel factors that in recent years have been suggested to contribute to prothrombotic fibrin clot properties, involving formation of compact fibrin networks (reduced clot permeability) displaying impaired susceptibility to lysis (prolonged clot lysis time).
View Article and Find Full Text PDFRes Pract Thromb Haemost
October 2024
Department of Mathematics and Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA.
Background: In healthy individuals, plasma levels of clotting proteins naturally vary within a range of 50% to 150% of their mean values. We do not know how these variations modify thrombin generation.
Objectives: To assess the impact of protein level variations on simulated thrombin generation in normal and factor (F)VIII-, FIX-, or FXI-deficient blood.
Thromb Haemost
November 2024
Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.
Background: Increased clot permeability and susceptibility to lysis have been reported in women with heavy menstrual bleeding. We hypothesized that similar alterations in fibrin clot properties may also be present in women with postpartum hemorrhage (PPH) of unknown cause.
Objective: To determine fibrin clot properties and their determinants in women after PPH of unknown cause.
Semin Dial
November 2024
The 2nd Department of Foot and Ankle, Sichuan Provincial Orthopedics Hospital, Chengdu, China.
Coagulation Factor XI (FXI) and Factor XII (FXII) deficiencies are rare. FXI deficiency is associated with a bleeding disorder, while FXII deficiency is not, but both can cause chronic prolongation of activated partial thromboplastin time and impair thrombus formation, posing great challenges for hemodialysis anticoagulation. Traditionally, heparin or low-molecular-weight heparins (LMWHs) are not considered a safe anticoagulation option for patients with increased bleeding risk.
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