From Principle to Practice: Bridging the Gap in Patient Profiling

Abstract

The standard clinical coagulation assays, activated partial thromboplastin time (aPTT) and prothrombin time (PT) cannot predict thrombotic or bleeding risk. Since thrombin generation is central to haemorrhage control and when unregulated, is the likely cause of thrombosis, thrombin generation assays (TGA) have gained acceptance as “global assays” of haemostasis. These assays generate an enormous amount of data including four key thrombin parameters (lag time, maximum rate, peak and total thrombin) that may change to varying degrees over time in longitudinal studies. Currently, each thrombin parameter is averaged and presented individually in a table, bar graph or box plot; no method exists to visualize comprehensive thrombin generation data over time. To address this need, we have created a method that visualizes all four thrombin parameters simultaneously and can be animated to evaluate how thrombin generation changes over time. This method uses all thrombin parameters to intrinsically rank individuals based on their haemostatic status. The thrombin generation parameters can be derived empirically using TGA or simulated using computational models (CM). To establish the utility and diverse applicability of our method we demonstrate how warfarin therapy (CM), factor VIII prophylaxis for haemophilia A (CM), and pregnancy (TGA) affects thrombin generation over time. The method is especially suited to evaluate an individual's thrombotic and bleeding risk during “normal” processes (e.g pregnancy or aging) or during therapeutic challenges to the haemostatic system. Ultimately, our method is designed to visualize individualized patient profiles which are becoming evermore important as personalized medicine strategies become routine clinical practice.

Global assays of hemostasis

“…Each individual’s unique plasma composition (n=30) was evaluated at baseline, days 3, 5, 7, 14 and 30. Results show that most individuals at day 3 of warfarin anticoagulation generated more thrombin (increased thrombotic risk) prior to being stably anticoagulated [17]. These results relate to the relatively short half-life of protein C compared to other vitamin K dependent proteins [102].…”

Models for thrombin generation and risk of disease

“…In this review, a few of the populations that have been studied utilizing these approaches are described, including: (i) Healthy controls and cases from the Leiden Thrombophilia Study (LETS); (ii) a severe hemophilia A population in which whole blood analyses, factor composition, and bleeding phenotype was evaluated; (iii) an atrial fibrillation population ( n = 20, aged 59 ± 6 years) studied from baseline through warfarin anticoagulation at days 3, 5, 7, 14, and 30. Plasma was collected and factor analyses performed as described .…”

Personalized Approaches to the Treatment of Hemophilia A and B

“…future science group Personalized approaches to the treatment of hemophilia A & B Review there is a significant momentum towards personalizing hemophilia care by tailoring treatment regimens to individual patients [42,45,46,55].…”