Dual endothelin-1 receptor antagonism attenuates platelet-mediated derangements of blood coagulation in Eisenmenger syndrome.

Essentials Eisenmenger syndrome is characterised by thrombotic and hemorrhagic risks of unclear aetiology. Calibrated automated thrombography was used to assess these coagulation derangements. Platelet activity supported abnormalities in procoagulant and anticoagulant pathway function. Endothelin-1 antagonism appeared to ameliorate these derangements. SUMMARY: Aims The mechanisms underlying the competing thrombotic and hemorrhagic risks in Eisenmenger syndrome are poorly understood. We aimed to characterize derangements of blood coagulation and to assess the effect of dual endothelin-1 receptor antagonism in modulating hemostasis in this rare disorder. Methods In a 10-month recruitment period at a tertiary cardiology referral center, during which time there were over 14 000 outpatient consultations, consecutive subjects with Eisenmenger syndrome being considered for macitentan therapy (n = 9) and healthy volunteers (n = 9) were recruited. Plasma thrombin generation in platelet-rich and platelet-poor plasma was assessed by calibrated automated thrombography prior to and following therapy. Results Median peak plasma thrombin generation was higher in platelet-rich plasma obtained from Eisenmenger syndrome subjects relative to controls (median peak thrombin [25th-75th percentile]: 228.3 [206.5-258.6] nm vs. 169.9 [164.3-215.8] nm), suggesting a critical mechanistic role for platelets in supporting abnormal hypercoagulability in Eisenmenger syndrome. Abnormal enhanced sensitivity to the anticoagulant activity of activated protein C was also observed in platelet-rich plasma in Eisenmenger syndrome, suggesting that derangements of platelet activity may influence the activity of anticoagulant pathways in a manner that might promote bleeding in this disease state. Following 6 months of macitentan therapy, attenuations in the derangements in both procoagulant and anticoagulant pathways were observed. Conclusions Abnormal platelet activity contributes to derangements in procoagulant and anticoagulant pathways in Eisenmenger syndrome. Therapies targeting the underlying vascular pathology appear to ameliorate these derangements and may represent a novel strategy for the management of the competing prothrombotic and hemorrhagic tendencies in this disorder.

Coagulation indices in very preterm infants from cord blood and postnatal samples.

BACKGROUND: Very premature infants are at high risk of bleeding complications; however, few data exist on ranges for standard coagulation tests. OBJECTIVES: The primary objective of this study was to measure standard plasma coagulation tests and thrombin generation in very premature infants compared with term infants. The secondary objective was to evaluate whether an association existed between coagulation indices and intraventricular hemorrhage (IVH). PATIENTS/METHODS: Cord and peripheral blood of neonates < 30 weeks gestational age (GA) was drawn at birth, on days 1 and 3 and fortnightly until 30 weeks corrected gestational age. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen and coagulation factor levels were measured and tissue factor-stimulated thrombin generation was characterized. Control plasma was obtained from cord blood of term neonates. RESULTS: One hundred and sixteen infants were recruited. Median (range) GA was 27.7 (23.7-29.9) weeks and mean (SD) birth weight was 1020 (255) g. Median (5th-95th percentile) day 1 PT, APTT and fibrinogen were 17.5 (12.7-26.6) s, 78.7 (48.7-134.3) s and 1.4 (0.72-3.8) g L(-1) , respectively. No difference in endogenous thrombin potential between preterm and term plasma was observed, where samples were available. Levels of coagulation factors II, VII, IX and X, protein C, protein S and antithrombin were reduced in preterm compared with term plasma. Day 1 APTT and PT were not associated with IVH. CONCLUSION: In the largest cross-sectional study to date of very preterm infants, typical ranges for standard coagulation tests were determined. Despite long clotting times, thrombin generation was observed to be similar in very preterm and term infants.

Specific allergen immunotherapy use in 2012: an Irish Paediatric Surveillance Unit (IPSU) study.

Specific immunotherapy (SIT) is a disease modifying treatment for allergic rhinitis (AR), with its benefits most evident in those who are refractory to medical treatment. It is used less frequently in UK than Europe/US. No data exist on SIT use in Ireland. We audited paediatric practice to evaluate patient selection, SIT modalities and adverse events (A.E.). A 9 item questionnaire was sent to Irish paediatricians, identified via the Irish Paediatric Surveillance Unit (IPSU) mailing list. 58 children have undertaken SIT (Subcutaneous SCIT =3, Sublingual = 55). This represents 0.01% of Irish children estimated to have AR. 33 (56%) had asthma; 18 (55%) had perennial asthma, 7 (21%) seasonal asthma. Adverse events occurred in 5 cases (8.6%). Three treatments (3-5%) were discontinued as a result. SIT is available across Ireland, though only extremely small numbers of children with AR are being treated yet. Co-morbid asthma is frequent and does not increase adverse events. This audit will raise awareness of SIT use for AR in Ireland.

Thought-action fusion in individuals with OCD symptoms.

Rachman (Rachman, S. (1993). Obsessions, responsibility, and guilt. Behaviour Research and Therapy, 31, 149-154) suggested that patients with OCD may interpret thoughts as having special importance, thus experiencing thought-action fusion (TAF). Shafran, Thordarson and Rachman (Shafran, R., Thordarson, D. S. & Rachman, S. (1996). Thought-action fusion in obsessive compulsive disorder. Journal of Anxiety Disorders, 710, 379-391) developed a questionnaire (TAF) and found that obsessives scored higher than non-obsessives on the measure. In the current study, we modified the TAF to include a scale that assessed the "likelihood of events happening to others" as well as ratings of the responsibility and cost for having these thoughts. Replicating previous findings, we found that individuals with OC symptoms gave higher ratings to the likelihood of negative events happening as a result of their negative thoughts. Individuals with OC symptoms also rated the likelihood that they would prevent harm by their positive thoughts higher than did individuals without OC symptoms. These results suggest that the role of thought-action fusion in OCs may extend to exaggerated beliefs about thoughts regarding the reduction of harm.

Improving pediatric residents' alcohol and other drug use clinical skills: use of an experiential curriculum.

OBJECTIVE: To evaluate the effectiveness of an experiential alcohol and other drug curriculum on pediatric residents' knowledge, attitudes, and skills in alcohol and other drug (AOD) issues. DESIGN: Nonrandomized control trial. SETTING: Two university pediatric residency programs. PARTICIPANTS: Pediatric residents (n = 44). INTERVENTION: Intervention residents received an experiential AOD curriculum consisting of participation in an adolescent assessment program, interactive didactic sessions, role-playing practice, and interviewing skills sessions. The control group received no formal training. MAIN OUTCOME MEASURES: Pretesting and posttesting each group using written and Objective Structured Clinical Examination evaluations using standardized patients. Evaluations were videotaped and scored by an expert panel using a standardized scoring process. RESULTS: Pretest comparisons of written knowledge and clinical skills as assessed by the Objective Structured Clinical Evaluation showed no significant differences between the intervention and the control groups. Analysis of written test scores revealed that residents' general knowledge as well as knowledge of screening techniques and management resources related to AOD issues increased significantly more for the intervention group than for the control group from pretest to posttest (P < .001). Evaluation of the videotapes showed significant improvement for the intervention group compared with controls in overall score and in the use of specific screening techniques and interviewing skills (P < .05). Self-assessment of residents' interest, confidence, and competence in AOD issues improved significantly for intervention residents vs controls (P < .05). CONCLUSIONS: Pediatric residents receiving an experiential AOD curriculum increased their knowledge and clinical skills in AOD issues significantly more than residents receiving no formal training. Similar curricula and evaluation could be used by other primary care residency programs and could be implemented in other areas of adolescent health risk behaviors.