Is some better than none: are TEG and TGA profiles different in severe FVIII‐deficient patients with inhibitors?

Abstract

Severe factor VIII (FVIII)-deficient patients with and without FVIII inhibitors cannot be distinguished using FVIII levels. The FVIII assay is sensitive to detect factor levels below 1%. While severe FVIII-deficient, non-inhibitor patients have FVIII < 1%, they may retain unmeasurable residual factor activity. In contrast, inhibitor patients have a FVIII antibody that presumably fully eliminates FVIII activity. It is unknown whether thromboelastography (TEG) and thrombin generation assay (TGA) can differentiate between patients with FVIII < 1% with and without the presence of FVIII inhibitors. The primary objective was to discern whether TEG and TGA could differentiate between severe FVIII-deficient patients with and without the presence of FVIII inhibitors. A secondary objective was to correlate TEG and TGA to annualized bleeding rates. This observational study performed TEG and TGA in healthy volunteers (N = 15), severe FVIII-deficient (N = 15) and severe FVIII-deficient patients with inhibitors (N = 15). Kaolin-activated TEG was better at differentiating reaction time (31.3 vs. 120 min respectively, P = 0.004) and kinetics time (6.1 vs. 23.1 min respectively, P = 0.028) between the non-inhibitor and inhibitor patients. TEG activated by tissue factor in plasma-containing corn trypsin inhibitor failed to differentiate groups. The TGA failed to differentiate peak thrombin, endogenous thrombin potential and lag time between groups. There was no correlation between TEG and TGA with annualized bleeding rates. Kaolin-activated TEG, but not TGA, differentiated between severe FVIII-deficient patients with and without inhibitors. These assays did not find a correlation to annualized bleeding rate.

Thrombin generation and bleeding in haemophilia inhibitor patients during immune tolerance induction

“…In this study, we had the opportunity to assess thrombin generation by TGA in unique samples from patients undergoing immune tolerance at one of the two dose levels, the lower of which was associated with significantly greater clinical bleeding. The TGA assay confirmed the presence of clot forming ability in haemophilia inhibitor patients, as previously shown [24,[26][27][28][29][30][31][32][33], but failed to differentiate clinical bleeding severity between haemophilia inhibitor patients undergoing low-dose and high-dose immune tolerance induction. While the TGA is recognized as a global assay of coagulation that correlates with haemophilia pheno-type better than factor VIII or IX activity [18][19][20][21], several recent studies report that the assay does not predict clinical bleeding severity or bleeding score in haemophilia patients with or without inhibitors [24,[26][27][28][29][30][31][32][33][34].…”

The pharmacokinetics and pharmacodynamics of single‐dose and multiple‐dose recombinant activated factor VII in patients with haemophilia A or B

“…Interestingly, this work showed improvements in TEG profiles, similar to our results, more than 2 hours after rFVIIa dosing, suggesting the possible use of longer time intervals of rFVIIa dosing depending on individual clinical response. Although, recently, kaolin‐activated‐TEG has been reported as helpful in differentiating patients based on inhibitor status, other studies have questioned the value of kaolin‐activated TEG for evaluating response to treatment in patients without inhibitors . In this latter study, only r‐time correlated with levels of FVIII/FIX and no correlation between TEG profile and clinical outcome were found.…”

The thrombin generation assay distinguishes inhibitor from non‐inhibitor patients with severe haemophilia A

“…(2015) showed that while kaolin‐activated thromboelastography (TEG) was able to discriminate between non‐inhibitor and inhibitor patients, there was no difference between them pertaining to the TG capacity. A direct comparison between Salinas' and our findings is difficult, because in that study inhibitor samples were obtained not only from 15 patients but also by spiking plasma of 15 healthy controls and 14 non‐inhibitor patients with a polyclonal goat anti‐human FVIII antibody . In vitro spiking was chosen to demonstrate that any difference found was due to the inhibitors rather than to other factors .…”

“…A direct comparison between Salinas' and our findings is difficult, because in that study inhibitor samples were obtained not only from 15 patients but also by spiking plasma of 15 healthy controls and 14 non‐inhibitor patients with a polyclonal goat anti‐human FVIII antibody . In vitro spiking was chosen to demonstrate that any difference found was due to the inhibitors rather than to other factors . The TGA methods used in this and that study share the same principle, but only PPP was used by Salinas et al .…”

“…The TGA methods used in this and that study share the same principle, but only PPP was used by Salinas et al . , who indeed hypothesized that the insensitivity of their TGA might be related to the absence of platelets in the tested plasmas. In our study the TGA was able to distinguish inhibitor from non‐inhibitor patients both in PRP and PPP.…”