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

Abstract

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.

A physiologically‐based pharmacokinetic/pharmacodynamic modeling approach for drug–drug‐gene interaction evaluation of S‐warfarin with fluconazole

“…This approach of treating coagulation factors as complexes is widely used in warfarin PK/PD modeling 63–66 . A series of Quantitative Systems Pharmacology (QSP) models of the coagulation cascade were also created 67 . Simplification of the QSP model is necessary to reduce complexity.…”

“… 63 , 64 , 65 , 66 A series of Quantitative Systems Pharmacology (QSP) models of the coagulation cascade were also created. 67 Simplification of the QSP model is necessary to reduce complexity. The PD model used in this study is simplified from one of the QSP models.…”

Critical evaluation of kinetic schemes for coagulation

“…Numerical models of the coagulation cascade are capable of capturing complex thrombin formation dynamics under physiological conditions. However, more work is needed to improve their reproducibility and their applicability in different clinical scenarios, as highlighted in the recent review by Chung et al [ 38 ]. In the current work, two well known models of the coagulation cascade were compared with TGA experimental results and proper modifications are suggested to improve their accuracy.…”

“…their reproducibility and their applicability in different clinical scenarios, as highlighted in the recent review by Chung et al [38]. In the current work, two well known models of the coagulation cascade were compared with TGA experimental results and proper modifications are suggested to improve their accuracy.…”