Neurogenic Lower Urinary Tract Dysfunction in Asymptomatic Patients with Multiple Sclerosis.

Neurogenic lower urinary tract dysfunction (NLUTD) in asymptomatic patients with MS has been described in preliminary studies, but specific investigations of this topic are rare. Many authors advise early diagnosis and treatment of NLUTD in patients with MS. In contrast, clinical practice and different guidelines recommend neuro-urological diagnostics only in the presence of symptoms. Our aim was to investigate the characteristics of NLUTD and the correlations of clinical parameters with NLUTD in asymptomatic patients with MS. We evaluated bladder diaries, urodynamic findings, and therapy proposals. Correlations of the voided volume, voiding frequency, urinary tract infections, and uroflowmetry including post-void residual with the urodynamic findings were determined. In our study, 26% of the patients were asymptomatic. Of these, 73.7% had urodynamic findings indicative of NLUTD, 21.1% had detrusor overactivity, 13.2% had detrusor underactivity, 13.2% detrusor overactivity and detrusor sphincter dyssynergia, and 57.9% had radiologically abnormal findings of the bladder. No patients presented low bladder compliance or renal reflux. Clinical parameters from the bladder diary and urinary tract infections were found to be correlated with NLUTD, and the absence of symptoms did not exclude NLUTD in patients with MS. We observed that urinary tract damage is already present in a relevant proportion. Based on our results, we recommend that patients with MS be screened for NLUTD regardless of the subjective presence of urinary symptoms or the disease stage.

Activated Factor XI is Increased in Plasma in Response to Surgical Trauma but not to Recombinant Activated FVII-Induced Thrombin Formation.

AIM: Feedback activation of factor XI (FXI) by thrombin is believed to play a critical role in the amplification phase of thrombin generation and to contribute to thrombosis development and hemostasis. However, the activation of FXI by thrombin has been shown in vitro to require a cofactor. In this study, the role of thrombin in activated FXI (FXIa) formation in vivo is investigated. METHODS: The study population comprised probands in whom coagulation activation was triggered by low-dose (15 µg/kg) recombinant activated factor VII (rFVIIa, n=89), of whom 34 with (VTE+) and 45 without a history of venous thromboembolism (VTE-), and patients undergoing major orthopedic surgeries (n=45). FXIa was quantified via an enzyme capture assay using a monoclonal FXI-specific antibody. Thrombin formation was monitored using an oligonucleotide-based enzyme capture assay and the thrombin activation markers prothrombin fragment 1＋2 (F1＋2) and thrombin-antithrombin complex (TAT). RESULTS: In the rFVIIa cohort, FXIa and thrombin remained below their lower limit of quantification of 3.48 and 1.06 pmol/L, respectively. By contrast, during the surgeries, median FXIa levels increased from 3.69 pmol/L pre-operatively to 9.41 pmol/L mid-operatively (P=4·10-4) and remained significantly elevated 24 h thereafter, with 9.38 pmol/L (P=0.001). Peak levels of F1+2 were comparable in the VTE+, VTE-, and surgery cohort (235, 268, and 253 pmol/L), whereas peak TAT levels were higher in the surgery cohort (53.1, 33.9, and 147.6 pmol/L). CONCLUSIONS: Under in vivo conditions, the activation of FXI requires specific local features that are present at the wounded site including potential cofactors of thrombin.

Increased Activated Protein C Response Rates Reduce the Thrombotic Risk of Factor V Leiden Carriers But Not of Prothrombin 20210G>A Carriers.

RATIONALE: Carriers of the most common prothrombotic mutations FVL (factor V Leiden) and FII (prothrombin) 20210G>A show a highly variable clinical phenotype. Using standardized in vivo coagulation activation followed by activity pattern analysis we have recently shown, that the FVL mutation accelerates thrombin and APC (activated protein C) formation in carriers without a history of venous thromboembolism (VTE). OBJECTIVE: The aim of this prospective cohort study was to investigate, if the FII 20210G>A mutation induces a similar reaction pattern, and if the response rates differ in FVL and FII 20210G>A mutation carriers with prior VTE (VTE+). METHODS AND RESULTS: We comparatively analyzed 30 FVL carriers, 28 FII 20210G>A carriers (thereof 13 VTE+ each) and 15 healthy controls. Changes in plasma levels of thrombin, prothrombin activation fragment 1+2 (F1+2), TAT (thrombin-antithrombin complex), APC, and D-dimer were monitored over 8 hours after infusion of recombinant factor VIIa (15 µg/kg). An increase of F1+2 and TAT levels was observed, that did neither differ between FVL and FII 20210G>A carriers nor between asymptomatic and VTE+ carriers of these mutations. Median plasma levels of APC increased more (P=0.008) in FVL carriers (from 1.39 to 7.79 pmol/L) than in FII 20210G>A carriers (from 1.03 to 5.79 pmol/L), and more in FII 20210G>A carriers (P=2×10-4) than in healthy controls (from 0.86 to 3.00 pmol/L). Most importantly, however, the APC response was greater (P=0.015) in asymptomatic (n=13) than in VTE+ (n=12) heterozygous FVL carriers, with an increase of APC levels from 1.44 to 8.11 pmol/L versus 1.27 to 5.62 pmol/L. CONCLUSIONS: These in vivo data demonstrate that the FII 20210G>A and FVL mutations share an intermediate phenotype that is characterized by increased thrombin formation after coagulation activation. Furthermore, our data support the conclusion that the APC activating capacity of FVL carriers modifies the thrombotic risk of this common prothrombotic mutation.