Biological determinants of bleeding in patients with heterozygous factor XI deficiency

Abstract

Summary Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non‐bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non‐bleeding patients. Thirty‐nine patients were included. BS significantly correlated with clinical assessment (P = 0·001), and a score over 3 discriminated between bleeding (n = 15) and non‐bleeding (n = 24) patients (P = 0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non‐bleeding patients [ristocetin cofactor activity (VWF:RCo) = 80·6 ± 29·7 iu/dl and 101·8 ± 29·5 iu/dl respectively, P = 0·043; and VWF antigen (VWF:Ag) = 84·0 ± 28·0 iu/dl and 106·3 ± 36·1 iu/dl respectively, P = 0·035; and TM = 17·7 ± 11·7 ng/ml and 23·6 ± 9·7 ng/ml respectively, P = 0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P = 0·042), which accounted for 11% of the variability in BS.

Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency

“…Consistent with published work, standard coagulation assays including FXI:C levels did not allow discrimination between bleeder and nonbleeder groups. 4,5,17,30 In contrast, TGA parameters (ETP and peak height) identified statistically significant differences between bleeder and nonbleeder groups in all sample conditions. However, only in PRP with CTI samples did the 2 groups become well separated on frequency plots.…”

“…[15][16][17][18] Two studies concluded that the TGA was unable to differentiate between bleeder and nonbleeder groups. However, those studies either did not inhibit contact activation (PPP without CTI at TF 1 pM, PRP without CTI at TF 0.5 pM) 17 or were performed in the absence of platelets (PPP with CTI at TF 1 pM), 18 and in both studies the cohorts were smaller than our own and different criteria were used to determine bleeding tendency. In contrast, a third study concluded that thrombin generation measured with TF 1 pM in PPP without CTI samples was able to distinguish between bleeders and nonbleeders.…”

“…15,16 However, conflicting conclusions have been reached about the ability of TGA to differentiate between FXI-deficient individuals with a history of bleeding ("bleeders") and those without ("nonbleeders"). [15][16][17][18] Given the different routes by which FXI can be activated, it is plausible that the sample conditions tested (ie, with or without platelets and with or without in vitro contact activation) will greatly affect which coagulation pathways are measured and therefore may significantly alter the ability of the test parameters to correlate with clinical bleeding.…”

The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency

“…Use of global assays as a tool to monitor and /or predict individual bleeding risk in FXIdeficient patients is still uncertain due to small sample size, different FXI activity levels and genotypes. In addition, no assay standardization has been achieved with respect to the use of PPP, PRP, TF, phospholipids or CTI [11,12,14,18,19]. Based on our data, the TF concentration used for TG assay is critical since different concentrations of TF may affect the sensitivity of the assay.…”

Le test de génération de thrombine

“…Il semble, qu'à l'instar de l'hémophilie, ce test soit utile pour évaluer le risque hémorragique chez un patient donné, qui n'est pas corrélé de faç on constante avec le taux de facteur Willebrand [28]. Les autres déficits congénitaux ont principalement fait l'objet d'articles disparates concernant, encore une fois, l'intérêt du TGT dans l'évaluation du risque hémorragique avec des résultats mitigés, semble-t-il négatifs dans les cas des facteurs VII [29] et XI [30] mais positifs dans le cas du facteur X [31]. De faç on anecdotique, on retrouve des études sur les pathologies plaquettaires [32] et les pathologies acquises de l'hémostase [33].…”