Thrombin generation and whole blood viscoelastic assays in the management of hemophilia: current state of art and future perspectives

Abstract

Hemophilia is a bleeding disorder that afflicts about 1 in 5000 males. Treatment relies upon replacement of the deficient factor, and response to treatment both in clinical research and practice is based upon subjective parameters such as pain and joint mobility. Existing laboratory assays quantify the amount of factor in plasma, which is useful diagnostically and prognostically. However, these assays are limited in their ability to fully evaluate the patient's clot-forming capability. Newer assays, known as global assays, provide a far more detailed view of thrombin generation and clot formation and have been studied in hemophilia for about 10 years. They have the potential to offer a more objective measure of both the hemophilic phenotype as well as the response to treatment. In particular, in patients who develop inhibitors to deficient clotting factors and in whom bypassing agents are required for hemostasis, these assays offer the opportunity to determine the laboratory response to these interventions where traditional coagulation assays cannot. In this article we review the existing literature and discuss several controversial issues surrounding the assays. Last, a vision of future clinical uses of these assays is briefly described.

Figure 1

Normal thrombin generation curve. The major parameters (lag time, time to peak thrombin generation, peak thrombin generation, and endogenous thrombin potential) of the thrombin generation curve are shown. For reference, a patient with severe hemophilia whereby all 3 parameters are severely affected is included.

Figure 2

Thrombin generation curve before and after treatment. Three thrombin generation curves are shown: normal (red), severe FVIII deficiency at baseline (green), and severe FVIII deficiency after an infusion of FVIII 50 IU/kg leading to a FVIII level of 103% (blue).

Figure 3

Normal thromboelastography curve. The normal thromboelastographic curve is shown along with the resultant parameters along the bottom of the figure. R represents the time to clot initiation and is measured at the point that the 2 lines have separated 2 mm. K represents the clot propagation and is measured as the time from R until the curves are 20 mm apart. The angle represents the tangential angle of the curve with the horizontal and also represents clot propagation. MA is the maximal amplitude represented as the distance in millimeters between the 2 curves once they are parallel and represents peak clot rigidity.

Figure 4

Thromboelastograph curve before and after treatment. The black horizontal line is the patient’s baseline, which is flat and demonstrates no clot formation. The green curve represents 15 minutes after a dose of the bypassing agent, FEIBA 75 IU/kg. The brown curve represents 4 hours after the FEIBA has been infused, demonstrating a degrading of the blood’s clot-forming ability. The blue curve represents 15 minutes after a dose of rFVIIa, 90 μg/kg, demonstrating the additive effect of the 2 agents.