Plasma levels of prothrombin fragment F1+2 during active disease and remission.

<p>Plasma levels of prothrombin fragment F1+2 were measured in 10 patients with chronic autoimmune urticaria (left panel) and 10 patients with bullous pemphigoid (right panel). Each line represents a single patient. Plasma levels of F1+2 were higher during active disease and significantly decreased during remission in both chronic autoimmune urticaria and bullous pemphigoid patients.</p

Plasma levels of D-dimer during active disease and remission.

<p>Plasma levels of D-dimer in 10 patients with chronic autoimmune urticaria (left panel) and 10 patients with bullous pemphigoid (right panel). Each line represents a single patient. Plasma levels of D-dimer were higher during active disease and significantly decreased during remission in both CAU and BP patients.</p

Plasma levels of C-reactive protein.

<p>Plasma levels of C-reactive protein (CRP) were measured in 30 healthy subjects (controls), 30 patients with active chronic autoimmune urticaria (CAU) and 30 patients with active bullous pemphigoid (BP). Mean plasma levels of CRP (indicated by the solid horizontal line) were significantly higher in both CAU and BP patients than in controls (ANOVA with Bonferroni’s post-hoc contrast analysis on log-transformed data). A more marked elevation was evident in BP patients.</p

Scores of tissue factor immunoreactivity in tissue samples.

<p>Immunoreactivity for tissue factor was evaluated in tissue samples from skin lesions of 20 patients with chronic autoimmune urticaria (CAU) and 20 patients with bullous pemphigoid (BP) compared with normal skin (20 cases). Both CAU and BP patients showed a marked immunoreactivity for tissue factor (P = 0.0001); the reactivity was significantly higher in BP than in CAU (P = 0.027). Tissue factor immunoreactivity was scored according to the number of immunoreactive cells per field (200X) as follows: O = No immunoreactive cells; l = 1–5 immunoreactive cells; 2 = 6–20 immunoreactive cells; 3 = >20 immunoreactive cells.</p

Immunohistochemical studies and in situ hybridization.

<p>Tissue factor expression was evaluated in lesional skin of chronic autoimmune urticaria and bullous pemphigoid. Immunohistochemical studies showed tissue factor reactivity in both chronic autoimmune urticaria (panel A) and bullous pemphigoid (panel B) (original magnification, X 200). In situ hybridization showed m-RNA of tissue factor, confirming a higher expression by inflammatory cells in bullous pemphigoid (panel D) than in chronic autoimmune urticaria (panel C).</p

Plasma measurements of prothrombin fragment F1+2.

<p>Plasma levels of prothrombin fragment F1+2 were measured in 30 healthy subjects (controls), 30 patients with active chronic autoimmune urticaria (CAU) and 30 patients with active bullous pemphigoid (BP). Mean plasma levels of F1+2 (indicated by the solid horizontal line) were significantly higher in both CAU and BP patients than in controls (ANOVA with Bonferroni’s post-hoc contrast analysis on log-transformed data). A more marked elevation was evident in BP patients.</p

Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case–Control Studies

<div><p>Background</p><p>Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies.</p><p>The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients.</p><p>Methods and Findings</p><p>We used data from a large population-based case–control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and <i>p</i> ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (<i>n =</i> 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case–control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case–control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case–control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy.</p><p>The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77–0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77–0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66–0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66–0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58–0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86–1.00) for the full model, an AUC of 0.92 (95% CI 0.76–0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92–0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91–0.99).</p><p>Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event.</p><p>Conclusions</p><p>These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.</p></div

Predictive performance of the L-TRiP(cast) score in plaster cast patients.

<p>*Presuming a prevalence of VTE in plaster cast patients of 2.5%.</p><p>Predictive performance of the L-TRiP(cast) score in plaster cast patients.</p

Distribution of individual L-TRiP(cast) scores in the plaster cast subgroup derived from the MEGA study.

<p>Distribution of individual L-TRiP(cast) scores in the plaster cast subgroup derived from the MEGA study.</p

AUC value after addition of each predictor into the restricted model.

<p>Vertical bars represent 95% CIs. Predictors: (1) age, (2) sex, (3) plaster cast and location, (4) prothrombin mutation, (5) current use of oral contraceptives, (6) family history of VTE (first-degree relative), (7) factor VIII activity, (8) bedridden within the past 3 mo, (9) surgery within the past 3 mo, (10) non-O blood type, (11) BMI.</p