Thrombin generation in patients with factor XI deficiency and clinical bleeding risk

Abstract

Factor XI (FXI) deficiency is a rare bleeding disorder. Most patients with FXI deficiency are mild bleeders but certain patients with similar FXI activity exhibit different bleeding phenotype. Routine laboratory assays do not help physicians to estimate the individual bleeding risk in these patients. Thrombin generation test (TGT) is a more comprehensive, global function test of the clotting system. We investigated whether or not the bleeding tendency of patients with FXI deficiency is correlated with features of the TGT. Twenty-four patients with FXI deficiency were divided in two groups: (i) severe bleeders (n = 9) and (ii) mild or non-bleeders (n = 15). All severe bleeders had a personal history of surgery-related severe bleeding. Thrombin generation (TG) was measured in platelet-rich plasma (PRP) using a low concentration of tissue factor 0.5 pm. In patients exhibiting severe bleeding tendency, independently of their FXI level, a dramatically impaired TG was observed. For example, despite a low plasma FXI = 1 IU dl(-1), a clinically non-bleeding individual exhibited normal TG results whereas another patient with severe bleeding history and FXI = 40 IU dl(-1) had a very low TG capacity. Low velocity and delayed TG were the main parameters suggesting a higher bleeding risk. DNA analysis of patients reported eight novel mutations of the FXI gene but neither mutation location nor secretion or not of the variant correlated with the bleeding tendency. The results of this study suggest that TG measurement in PRP may be a useful tool to predict bleeding risk in FXI deficiency and should be studied further in larger prospective clinical studies.

Thrombin generation in patients with a bleeding tendency of unknown origin

“…Recently, thrombin generation tests have been proposed to assess global haemostasis and its disorders [4]. Moreover, thrombin is a key factor in haemostasis, and the measurement of thrombin generation has been applied for investigating the risk of bleeding in patients with a bleeding disorder [6,[8][9][10][11].…”

“…For instance, a high thrombin generation potential has been reported to be associated with an increased risk for thrombotic disorders such as venous thromboembolism [6,7], while a decreased thrombin generation potential was found in patients at risk of bleeding, such as patients with haemophilia A and B, the vWD and other bleeding disorders [8][9][10][11].…”

Factor XI and traveling waves: the key to understanding coagulation in hemophilia?

“…Thrombin formation is affected more significantly [2,3]. Still, both effects can be observed only in a limited range of experimental conditions: absence of FXI plays a role when there is low or zero TF concentration [2][3][4][5]. In these cases, FXI deficiency can lead to delayed clot formation and decreased thrombin generation.…”

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

“…3 Patients with high levels of thrombin generation are at risk for thrombotic diseases such as acute ischemic stroke, 4 venous thromboembolism (VTE), [5][6][7][8] and myocardial infarction 9 while bleeding events are observed in presence of very low thrombin generation. 10 In addition, the role of thrombin generation extends far beyond the sole coagulation system. Several recent findings have emphasized its key impact in atherosclerosis, 11 diabetic nephropathy, 12,13 and inflammatory diseases such as sepsis, 14 Crohn disease, 15 and sickle cell disease.…”