Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience.

INTRODUCTION: Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. METHODS: A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. RESULTS: A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. CONCLUSION: FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.

In vivo and in vitro morphometry of the human trachea.

Most morphometric studies of the human trachea have relied on plain radiographs with their attendant limitations. Reports using computed tomography (CT) have focused on the growing trachea or one particular dimension. The aim of this study was to document the morphometry of the adult trachea in vivo using high-resolution chest CT scans, supplemented by data from cadavers. Sixty anonymised high-resolution chest CT scans (aged 22-88 years, 40 males) were analyzed. Scans were performed using a standardized breath-holding technique in patients with no distorting intrathoracic pathology. Standardized tracheal measurements included: length, maximum antero-posterior and transverse diameters, volume, subcarinal angle, and carinal position in relation to the tracheal midline. Measurements were also made in 10 cadaver tracheas (aged 68-101 years, 7 males). CT data showed that mean tracheal length (males 105.1 +/- 9.8 mm, females 98.3 +/- 8.7 mm), maximum antero-posterior and transverse diameters, and tracheal volume (males 35.6 +/- 6.8 cm3, females 24.7 +/- 6.1 cm3) were all significantly greater in men (P < or = 0.01). The subcarinal angle was very variable (mean 78 +/- 20 degrees , range 36-121 degrees ) and showed no correlation with age or gender. The carina was sited to the left of the tracheal midline in 49 (81%) patients. Cadaver tracheas had 14-19 tracheal rings and the posterior membranous trachea was wider in men (17.7 +/- 4.4 mm vs. 11.8 +/- 3.0 mm, P = 0.07). In conclusion, there is marked sexual dimorphism in the morphometry of the human trachea. The variation in adult tracheal dimensions in vivo is greater than in standard descriptions. These data may be valuable when interpreting chest CT scans and when calculating respiratory dead space.

Novel insights into the elastic and muscular components of the human trachea.

Despite its probable importance in health and disease, the elastic tissue in the trachea has rarely been investigated. In addition, various aspects of the trachealis muscle are controversial. The aim of this study was to clarify this clinically relevant anatomy. Ten cadaveric tracheobronchial specimens (age range 68-101 years; seven males; no major airway pathology) were qualitatively investigated by microdissection. Serial histologic sections from multiple sites in three specimens were analyzed after staining for elastin. Findings were correlated with observations from video tracheobronchoscopies. An extensive and prominent meshwork of elastic tissue was found within the trachea and bronchi. Elastic fibers were predominantly longitudinal and aggregated into discrete bundles within the membranous wall of the trachea and main bronchi; a discrete fibroelastic membrane bridging the membranous wall of the trachea; and vertical laminae connecting the ends of successive cartilages. The longitudinal elastic bundles continued into the segmental bronchi, becoming thinner and more circumferentially distributed. Trachealis consisted of a transverse layer of smooth muscle deep to the fibroelastic membrane of the membranous wall of the trachea, together with scattered longitudinal muscle bundles, mostly embedded within the fibroelastic membrane in the distal half of the trachea. In conclusion, there is an extensive but relatively neglected elastic framework within the tracheobronchial tree. This is likely to have major clinical relevance to the pathophysiology of respiratory disease and ageing. The trachealis muscle is more complex than previously stated.