Anticoagulant therapy in patients with congenital FXI deficiency.

The bleeding phenotype of factor XI (FXI) deficiency is unpredictable. Bleeding is usually mild and mostly occurs after injury. Although FXI deficiency renders antithrombotic protection, some patients might eventually develop thrombosis or atrial fibrillation, requiring anticoagulant therapy. There is almost no evidence on the bleeding risk in this scenario. Our retrospective study of 269 white FXI-deficient subjects (1995-2021) identified 15 cases requiring anticoagulation. They harbored 8 different F11 variants, mainly in heterozygosis (1 case was homozygote), and had mild to moderate deficiency (FXI:C: 20% to 70%). Two subjects (13.3%) had bleeding history before anticoagulation. Atrial fibrillation was the main indication (12/15; 80%). Fourteen patients started therapy with vitamin K antagonists (VKA), but 4 subjects were on direct oral anticoagulants (DOACs) at the end of follow-up. Over >1000 months of anticoagulation, 2 mild bleeding episodes in 2 patients (13.3%, 95% confidence interval: 3.7% to 37.9%) were recorded. No major/fatal events were reported. "Pre-post" bleeding localization and severity did not change despite treatment. On VKA, drug dosing and management were also standard, unaltered by FXI deficiency. We provide the largest description of anticoagulant use in FXI deficiency, and the first cases receiving DOACs. Although further studies are needed, our observations suggest that moderate FXI deficiency does not interfere with anticoagulant management nor bleeding risk.

Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study / Hemorragia ginecológica y obstétrica en mujeres caucásicas con deficiencia congénita de factor XI: Resultados de veinte años de registro observacional y retrospectivo

Introduction: Factor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. Objective: To describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. Material and methods: A retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994-2014) without clinical selection. Results: We identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. Conclusion: Women with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects

Introducción: La deficiencia del factor XI (FXI) es un trastorno hemorrágico leve, común entre los asquenazíes, que puede subestimarse en los caucásicos. El manejo de la deficiencia de FXI en las mujeres es un desafío, debido a la dificultad para predecir la tendencia hemorrágica y la poca evidencia disponible sobre este tema. Objetivo: Describir las complicaciones hemorrágicas ginecológicas/obstétricas y analizar la efectividad y la seguridad del tratamiento antihemorrágico en mujeres con deficiencia de FXI. Material y métodos: Estudio observacional retrospectivo de 214 sujetos caucásicos con deficiencia de FXI recogidos durante 20 años (1994-2014) sin selección clínica. Resultados: Se identificaron 95 mujeres con deficiencia de FXI. Cualquier evento hemorrágico fue comunicado por 26/95 (27.4%), siendo la hemorragia uterina anormal el más frecuente (12/95, 12.6%). Se registraron nueve hemorragias posparto de 136 partos (6,6%) en 57 mujeres. Se registraron cuatro complicaciones hemorrágicas posquirúrgicas en 25 cirugías ginecológicas (16%) en 20 mujeres. La hemorragia uterina anormal y las hemorragias postparto y posquirúrgicas se relacionaron con una historia positiva para hemorragia y valores de FXI:C ≤ 43.5%. La profilaxis con plasma fresco congelado, utilizado en 12/25 (48%) cirugías ginecológicas, no evitó la hemorragia postoperatoria en tres casos, pero dos desarrollaron reacciones adversas graves. Conclusión: Las mujeres con deficiencia de FXI, especialmente aquellas con una historia positiva para hemorragia o FXI:C ≤ 43.5%, están en riesgo de desarrollar hemorragias ginecológicas/obstétricas, la mayoría de ellas leves/moderadas. La profilaxis sistemática tiene una efectividad cuestionable, pero puede causar efectos secundarios graves

Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study.

INTRODUCTION: Factor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. OBJECTIVE: To describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. MATERIAL AND METHODS: A retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994-2014) without clinical selection. RESULTS: We identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. CONCLUSION: Women with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects.

Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency.

INTRODUCTION: Congenital FXI deficiency, a coagulopathy associated with low bleeding risk but thrombotic protection, is usually diagnosed by prolonged APTT and confirmed by coagulation assays. Recent evidences suggest that FXI deficiency might be underestimated. Sensitive and reliable methods to detect FXI deficiency are required. AIM: To examine the sensitivity of two methods and two contact activators on FXI deficiency screening. METHODS: 140 cases with FXI deficiency, 9 severe and 131 moderate, caused by 11different mutations were recruited. APTT and FXI:C were assessed in ACL-TOP 500coagulometer with silica-based (SynthASil) and ellagic acid-based (SynthAFax) reagents. F12 rs1801020 SNP was genotyped with Taqman probes. RESULTS: Severe FXI deficiency significantly prolonged APTT with both reagents. However, a high proportion of moderate deficiencies would not be detected using APTT, with false negatives of 22% for SynthASil and 12% for SynthAFax. False negatives results mainly corresponded to cases with qualitative deficiency (CRM+: p.Pro538Leu), which also had higher FXI coagulant activity. Using SynthASil, the common F12 rs1801020 variant, associated to low FXII levels, significantly prolonged APTT in moderate FXI deficiency subjects. FXI:C values were significantly higher with SynthAFax than with SynthASil (47.7±12.7 vs. 40.4±14.9), so SynthAFax rendered higher rate of false negatives than SynthASil (7% vs.2%). CONCLUSIONS: Moderate FXI deficiency, particularly CRM+, might be underestimated using current diagnostic methods. The activator, FXI and FXII levels may contribute to a higher rate of false negatives using APTT. Our results suggests that the best screening method for FXI deficiency is FXI:C using silica.

Sensitive and selective chromogenic sensing of carbon monoxide via reversible axial CO coordination in binuclear rhodium complexes.

The study of probes for CO sensing of a family of binuclear rhodium(II) compounds of general formula [Rh(2){(XC(6)H(3))P(XC(6)H(4))}(n)(O(2)CR)(4-n)]·L(2) containing one or two metalated phosphines (in a head-to-tail arrangement) and different axial ligands has been conducted. Chloroform solutions of these complexes underwent rapid color change, from purple to yellow, when air samples containing CO were bubbled through them. The binuclear rhodium complexes were also adsorbed on silica and used as colorimetric probes for "naked eye" CO detection in the gas phase. When the gray-purple colored silica solids containing the rhodium probes were exposed to air containing increasing concentrations of CO, two colors were observed, in agreement with the formation of two different products. The results are consistent with an axial coordination of the CO molecule in one axial position (pink-orange) or in both (yellow). The crystal structure of 3·(CO) ([Rh(2){(C(6)H(4))P(C(6)H(5))(2)}(2)(O(2)CCF(3))(2)]·CO) was solved by single X-ray diffraction techniques. In all cases, the binuclear rhodium complexes studied showed a high selective response to CO with a remarkable low detection limit. For instance, compound 5·(CH(3)CO(2)H)(2) ([Rh(2){(m-CH(3)C(6)H(3))P(m-CH(3)C(6)H(4))(2)}(2)(O(2)CCH(3))(2)]·(CH(3)CO(2)H)(2)) is capable of detection of CO to the "naked eye" at concentrations as low as 0.2 ppm in air. Furthermore, the binding of CO in these rhodium complexes was found to be fully reversible, and release studies of carbon monoxide via thermogravimetric measurements have also been carried out. The importance of the silica support for the maintenance of the CO-displaced L ligands in the vicinity of the probes in a noninnocent manner has been also proved.

Kinetico-mechanistic studies of the acidolysis of Rh-C bonds in monocyclometallated dirhodium(II) acetato complexes; influence of electronic and steric effects.

The protonation/demetallation reaction, in CD(3)COOD, of phosphine monometallated triacetato-bridged dirhodium(ii) complexes of general formulae [Rh(2)(µ-OOCCH(3))(3){(RC(5)CH(3))P(RC(6)H(4))(2)}(2)] has been studied from a kinetico-mechanistic perspective. The process has been monitored via the disappearance of the nuclear magnetic resonance signals of the protons present in the non-metallated ortho positions of the phosphine ligand and taking advantage of the relatively fast back metallation process that follows the acidolysis reaction, the sequence behaving as an overall equilibrium reaction. The process has a high associative character with important entropy demands, increasing both for the larger and the more electron withdrawing phosphine ligands. For the complexes with electron withdrawing CF(3) substituents on the cyclometallated phenyl ring, this demand is compensated by very low activation enthalpies. The data agree with an intimate mechanism that corresponds to the reverse of the electrophilic C-H bond activation, which has already been studied for this type of system, and requires the presence of a protonated acetato ligand in the axial position, close to the metallated Rh-C(aromatic) bond. The involvement of external solvent molecules, interacting via hydrogen bonds with the system, is also evident for systems which include CF(3) groups with the correct geometric arrangement.

Determination of equilibrium constants and computational interaction energies for adducts of [Rh2(RCO2)(4-n)(PC)n] (n = 0-2) with Lewis bases.

Properties of dirhodium catalysts with cyclometalated aryl phosphine ligands have been studied. We report here the study of the acid-base reaction of Rh2(RCO2)2(PC)2(H2O)2 catalysts (PC = cyclometalated aryl phosphine) with different Lewis bases. The determination of the equilibrium constants of these reactions can be used to study to which extent the properties of the axial coordination site of the catalyst, considered the active site, are affected by modification of the metalated phosphines, the carboxylate ligands, or the incoming axial ligand. The trends in the computational density functional theory interaction energies show good agreement with the major trends in the equilibrium constants, thus enabling a further study of the influence of the modification of the ligand core.

Isomerization processes on mixed ortho-metalated phosphine/succinimidato [Rh2(P(C5CH4)Ph2)2(OC4NH4O)2] complexes. A sliding movement of the succinimidato ligand.

An improved preparation of mixed ortho-metalated phosphine/succinimidato dirhodium(II) complexes, [Rh2(P(C5CH4)Ph2)2(OC4NH4O)2], allowed the isolation and characterization of a new isomeric form having both imidato N donors trans to P, 1', that adds up to the two already known having both, 1, or only one, 2, of the imidato N donors trans to the metalated C (Chart 3). The new complex, 1', isomerizes to the thermodynamically stable complex 2 similarly to what had already been observed for isomer 1. Stoichiometric and kineticomechanistic studies of both isomerization processes have been carried out. The reactions have been shown to occur via an intramolecular dissociatively activated process, despite the involvement of the labile axial Rh2 coordination sites in the formation of intermolecular adducts in solution that do not affect the processes. Density functional theory calculations show two transition states with similar energies for the isomerizations, in very good agreement with the kineticomechanistic measurements. The calculation of the charge generation in the two distinct transition states, TS1 and TS1', indicates an important increase in the N negative charge from the reactants, more pronounced for TS1'. This fact agrees very well with the acceleration observed for the processes in polar solvents, especially for the 1' to 2 reaction, when compared that for the reactions carried out in toluene.