Major surgery in a severe haemophilia A patient with high titre inhibitor: use of the thrombin generation test in the therapeutic decision

Abstract

Summary. In haemophilia patients with inhibitor, elective orthopaedic surgery is usually performed under recombinant activated factor VII (rFVIIa). We report here the case of a severe haemophilia A patient with a high inhibitor who needed a bilateral total knee arthroplasty. Recombinant FVIIa was previously shown to be ineffective for the treatment of muscle and joint bleedings, and he had a history of excessive postoperative bleeding under activated prothrombin complex concentrate (APCC). Thrombin generation test (TGT) was used to assess the efficacy of Factor Eight Inhibitor Bypassing Activity (FEIBA). Insufficient correction of thrombin-generating capacity was observed after administration of 75 U kg(-1) FEIBA. In a multidisciplinary environment, a bilateral total knee arthroplasty was performed using a protocol combining immunoadsorption of inhibitors preoperatively associated with FVIII replacement during a first phase followed by FEIBA when the inhibitor reappeared. To our knowledge this is the first direct application of TGT in the management of haemophilia patients with inhibitor, which indicated that a sequential use of immunoadsorption, FVIII and FEIBA was the most appropriate treatment to perform this major elective surgery. This case demonstrates that this combined protocol can be safely used to cover major surgery in inhibitor patients. In addition, it also suggests that TGT may have a major contribution in the decision-making process of the most adapted therapy for the treatment of such high-risk patients.

Tests of global haemostasis and their applications in bleeding disorders

“…This correlation between clinical bleeding risk and thrombin generating capacity led to the evaluation of this technology as a surrogate marker for by-passing therapy in haemophilia patients with anti-FVIII/FIX alloantibodies [12]. It has also been shown that TGT is sensitive to hypercoagulability [13].…”

“…It has also been shown that TGT is sensitive to hypercoagulability [13]. Endogenous thrombin potential (ETP) representing the enzymatic activity of the generated thrombin during its life-time is the parameter that correlates with clinical bleeding or thrombosis [5,[11][12][13]. Moreover, there are several studies on the standardization of the TGT making its use suitable in clinical trials, in comparison with other global haemostasis assays, e.g.…”

Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery

“…The monitoring of this successful strategy using TGT throughout the perioperative period was previously described in a case report. 5 …”

“…Recently, we described the first application of TGT in a surgical setting, showing that the assay might be useful in guiding the choice of the most effective therapeutic option in inhibitor patients. 5 We report now a prospective clinical assessment of TGT and our results show a correlation between thrombin generation (TG) capacity and the clinical outcome of patients.…”

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

“…The TG assay, a biomarker of the functional status of blood coagulation, measures thrombin activity ex vivo in plasma using tissue factor to initiate the coagulation. The assay is used to demonstrate an anticoagulant effect and also suggested to identify risk of thrombosis and bleeding [21][22][23][24]. In the presence of a thrombin inhibitor the thrombin generation assay may underestimate the effect because of an interaction with α 2 -macroglobulin [25].…”