Revised model of the tissue factor pathway of thrombin generation: Role of the feedback activation of FXI

Lakshmanan, Hari Hara Sudhan; Estonilo, Aldrich; Reitsma, Stéphanie E.; Melrose, Alexander R.; Subramanian, Jayaram; Zheng, Tony J.; Maddala, Jeevan; Tucker, Erik I.; Gailani, David; McCarty, Owen J. T.; Puy, Cristina

doi:10.1111/jth.15716

Cited by 22 publications

(14 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We reviewed over 80 SB and QSP models published over the past 32 years [ 2 , 3 , 4 , 5 , 6 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ...…”

Section: Reusabilityunclassified

A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability

Chung¹,

Bakshi

Graaf

2023

Pharmaceutics

View full text Add to dashboard Cite

Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the interactions between proteases, cofactors, regulators, fibrin, and therapeutic responses under different clinical scenarios. We aim to review the literature on QSP models to assess the unique capabilities and reusability of these models. We systematically searched the literature and BioModels database reviewing systems biology (SB) and QSP models. The purpose and scope of most of these models are redundant with only two SB models serving as the basis for QSP models. Primarily three QSP models have a comprehensive scope and are systematically linked between SB and more recent QSP models. The biological scope of recent QSP models has expanded to enable simulations of previously unexplainable clotting events and the drug effects for treating bleeding or thrombosis. Overall, the field of coagulation appears to suffer from unclear connections between models and irreproducible code as previously reported. The reusability of future QSP models can improve by adopting model equations from validated QSP models, clearly documenting the purpose and modifications, and sharing reproducible code. The capabilities of future QSP models can improve from more rigorous validation by capturing a broader range of responses to therapies from individual patient measurements and integrating blood flow and platelet dynamics to closely represent in vivo bleeding or thrombosis risk.

show abstract

Section: Reusabilityunclassified

A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability

Chung¹,

Bakshi

Graaf

2023

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Extrinsic coagulation initiates upon vessel damage, exposing tissue‐factor‐bearing cells, such as vascular smooth muscle cells (SMCs) and adventitial fibroblasts (AFs), to blood constitutents 6,7 . Circulating Factor VII binds to exposed tissue factor, initiating coagulation through this complex's ability to enzymatically activate Factor X 8 …”

Section: Introductionmentioning

confidence: 99%

“… 6 , 7 Circulating Factor VII binds to exposed tissue factor, initiating coagulation through this complex's ability to enzymatically activate Factor X. 8 …”

Section: Introductionmentioning

confidence: 99%

“…6,7 Circulating Factor VII binds to exposed tissue factor, initiating coagulation through this complex's ability to enzymatically activate Factor X. 8 Both innate and adaptive immune responses play an essential role in the development of cardiovascular diseases and its complications. 4,9,10 Physiological inflammation is a common defense mechanism in response to infection or cell injury upon stimulation by inflammatory cytokines or the secretion of chemical factors by the injured cells.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Complement component C1q initiates extrinsic coagulation via the receptor for the globular head of C1q in adventitial fibroblasts and vascular smooth muscle cells

Freda

Ghebrehiwet

Rubenstein

2023

Immunity Inflam & Disease

View full text Add to dashboard Cite

Background Vascular diseases are highly associated with inflammation and thrombosis. Elucidating links between these two processes may provide a clearer understanding of these diseases, allowing for the design of more effective treatments. The activation of complement component 1 (C1) is a crucial contributor to innate immunity and is associated with significant concentrations of circulating C1q. Many pathological pathways initiate when C1q interacts with gC1qR. This interaction plays a major role in inflammation observed during atherosclerosis and the initiation of intrinsic coagulation. However, the effects of C1 and the role of C1q/gC1qR on extrinsic coagulation, which is the more physiologically relevant coagulation arm, has not been studied. We hypothesized that C1q binding to gC1qR enhances the expression of tissue factor (TF) in adventitial fibroblasts and vascular smooth muscle cells, the primary TF bearing cells in the body. Methods Using an enzyme‐linked immunosorbent assay approach, TF expression and the role of gC1qR was observed. Cells were conditioned for 1 h with C1q or a gC1qR blocker and C1q, to assess the role of gC1qR. Additionally, cell growth characteristics were monitored to assess changes in viability and metabolic activity. Results Our results indicate that the expression of TF increased significantly after incubation with C1q as compared with unconditioned cells. Cells conditioned with gC1qR blockers and C1q exhibited no change in TF expression when compared with cells conditioned with the blocking antibodies alone. Our results show no significant differences in metabolic activity or cell viability under these conditions. Conclusions This indicates that gC1qR association with C1q induces TF expression and may initiate extrinsic coagulation. Overall, this data illustrates a role for C1q in the activation of extrinsic coagulation and that gC1qR activity may link inflammation and thrombosis.

show abstract

“…Thrombin is a serine protease in the blood plasma that demonstrates both procoagulant and anticoagulant properties, as well as crosstalk with pathways governing platelet activation, endothelial cell (EC) barrier function, and inflammation by cleaving various substrates. 4,5 One such substrate that thrombin can cleave is coagulation factor (F) XI, [6][7][8] a soluble protease precursor that further amplifies the extrinsic and intrinsic pathway of coagulation. The active form of FXI, FXIa, in turn activates FIX, as part of a feedback pathway that amplifies thrombin generation itself.…”

mentioning

confidence: 99%

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Lira

Kohs

Moellmer

et al. 2023

Semin Thromb Hemost

Self Cite

View full text Add to dashboard Cite

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important.

show abstract

Revised model of the tissue factor pathway of thrombin generation: Role of the feedback activation of FXI

Abstract: Background: Biochemical reaction networks are self-regulated in part due to feedback activation mechanisms. The tissue factor (TF) pathway of blood coagulation is a complex reaction network controlled by multiple feedback loops that coalesce around the serine protease thrombin.

Cited by 22 publications

References 52 publications

A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability

A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability

Complement component C1q initiates extrinsic coagulation via the receptor for the globular head of C1q in adventitial fibroblasts and vascular smooth muscle cells

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Contact Info

Product

Resources

About