Thrombin generation and implications for hemophilia therapies: A narrative review

Abstract

Thrombin plays an essential role in achieving and maintaining effective hemostasis and stable clot formation. In people with hemophilia, deficiency of procoagulant factor (F)VIII or FIX results in insufficient thrombin generation, leading to reduced clot stability and various bleeding manifestations. A correlation has been found between the bleeding phenotype of people with hemophilia and the extent of thrombin generation, with individuals with increased thrombin generation being protected from bleeding and those with lower thrombin generation having increased bleeding tendency. The amount, location, and timing of thrombin generation have been found to affect the formation and stability of the resulting clot. The goal of all therapies for hemophilia is to enhance the generation of thrombin with the aim of restoring effective hemostasis and preventing or controlling bleeding; current treatment approaches rely on either replacing or mimicking the missing procoagulant (ie, FVIII or FIX) or rebalancing hemostasis through lowering natural anticoagulants, such as antithrombin. Global coagulation assays, such as the thrombin generation assay, may help guide the overall management of hemostasis by measuring and monitoring the hemostatic potential of patients and, thus, assessing the efficacy of treatment in people with hemophilia. Nevertheless, standardization of the thrombin generation assay is needed before it can be adopted in routine clinical practice.

Keywords: antithrombins; blood coagulation tests; fitusiran; hemophilia; hemostasis; therapies.

Graphical abstract

Figure 1

Overview of a cell-based model of coagulation: (1) initiation, (2) amplification, and (3) propagation leading to thrombin generation. FVIIIa, activated factor VIII; FXIa, activated factor XI; TF, tissue factor; VWF, von Willebrand factor

Figure 2

Factors that can impact bleeding phenotype in people with hemophilia

Figure 3

Global coagulation assays: pros and cons. aPTT, activated partial thromboplastin time; F, factor; ISTH SSC, International Society on Thrombosis and Haemostasis International Society on Thrombosis and Haemostasis; ROTEM, rotational thromboelastometry; TEG, thromboelastography; TF, tissue factor; TGA, thrombin generation assay

Figure 4

Comparison of parameters related to thrombin generation with different therapeutic approaches (factor vs nonfactor). The impact of the different therapies on the thrombin generation parameters is based on a general scheme rather than evidence-based observations and it should be noted that relative shortening or increasing of lag time or increases in thrombin peak/ETP may depend on the type of TGA and reagent composition being used. = unstable hemostasis (due to peaks and troughs in factor levels);  = very stable hemostasis (with no peaks and troughs in factor levels);  = peaks and troughs in factor levels;  = no direct impact on factor levels (activated prothrombin complex concentrate mimics prothrombin to enhance thrombin generation, rFVIIa targets and enhances thrombin generation, and nonfactor therapies impact on and target stable hemostasis rather than factor levels). ETP, endogenous thrombin potential; F, factor; TFPI, tissue factor pathway inhibitor; TGA, thrombin generation assay. ^aPostinfusion values. ^bTime to peak increased after dose after reaching steady state after 4 weeks of loading doses and in the maintenance phase of treatment [52]

Figure 5

Thrombin generation is greatly reduced in people with hemophilia A and B. Global coagulation assays reveal parameters including peak thrombin and endogenous thrombin potential are reduced in hemophilia. The figure is an example of a representative thrombogram of people with hemophilia A or B vs healthy controls