Assessment of Platelet Thrombus Formation under Flow Conditions in Patients with Acute Kawasaki Disease.

OBJECTIVE: To assess platelet thrombus formation (PTF) under flow conditions in patients with Kawasaki disease. Previously available platelet activation data were limited for nonphysiological shear stress condition. The total thrombus-formation analysis system (T-TAS) was developed for quantitative PTF analysis. STUDY DESIGN: In total, 33 patients with acute Kawasaki disease were assessed. Whole blood samples, obtained immediately before treatment and 1 week and 1 month after treatment, were assessed using the T-TAS with a collagen-coated platelet chip under high shear values (1000 s-1 [PL12] and 2000 s-1 [PL24]). Measures, such as time to reach 5 kPa above the base pressure (T5+α) and area under the curve for flow pressure curve for 10 minutes (AUC10) were analyzed to quantify PTF. RESULTS: Immediately before treatment, the median PL12-T5+α and PL24-T5+α were 3.3 minutes (IQR 2.0-4.5) and 1.3 minutes (0.9-1.9), respectively, and both values were significantly lower in adult controls (3.5 minutes [2.9-6.4] and 2.8 minutes [1.8-4.8]; P = .015 and P < .001, respectively). In addition, the PL12-AUC10 (151.7 U [94.5-279.9]) significantly decreased in adult controls (234.1 U [110.5-306.5], P = .007). By contrast, at 1 week and 1 month after the start of treatment, the T5+α was longer, and the PL12-AUC10 and PL24-AUC10 decreased. CONCLUSIONS: In patients with acute Kawasaki disease, the PTF had an early onset and weak stability.

Involvement of the ADAMTS13-VWF axis in acute Kawasaki disease and effects of intravenous immunoglobulin.

INTRODUCTION: ADAMTS13 modulates shear-dependent platelet thrombus formation (PTF) by limited proteolysis of von Willebrand factor (VWF). A high-plasma-ratio of VWF antigen to ADAMTS13 activity (VWF:Ag/ADAMTS13:AC) promotes PTF and aggravates shear-induced inflammation mediated by VWF. A role of ADAMTS13 in Kawasaki disease (KD) remains unknown, however. We investigated the involvement of ADAMTS13-VWF axis in the acute-phase of KD (acute-KD). METHODS: VWF:Ag and ADAMTS13:AC in 77 KD infants were measured at three time-points; immediately before (Pre), one-week (1 W) and one-month (1 M) after intravenous-immunoglobulin (IVIG) treatment. VWF multimer (VWFM) distribution and ADAMTS13-isoelectrofocusing (IEF) patterns were compared between the responders and non-responders to IVIG. RESULTS: A high VWF:Ag (195.7 ±â€¯85.6%, p < 0.05), low ADAMTS13:AC (60.3 ±â€¯23.8%, p < 0.05) and high VWF:Ag/ADAMTS13:AC ratio (3.70 ±â€¯2.12, p < 0.05) at Pre were seen compared to control plasmas. These parameters returned to normal levels time-dependently after IVIG treatment. Non-responders to IVIG demonstrated high VWF:Ag and low ADAMTS13:AC at Pre, and high VWF:Ag/ADAMTS13:AC ratio at 1 W compared to responders, but there were no significant differences in VWFM distribution between both groups. IEF analyses revealed the decreased free form of ADAMTS13 and increased complex form with ADAMTS13 and high-molecular-weight-VWFM at Pre in non-responders. A high VWF:Ag/ADAMTS13:AC ratio was associated with increased white blood cell counts, together with decreased serum albumin and sodium at Pre and 1 W. CONCLUSIONS: A high VWF:Ag/ADAMTS13:AC ratio in acute-KD persisted after primary treatment in non-responders, and unbalanced substrate-to-enzyme ratio appeared to associate with vascular endothelial damage. Analysis of existing mode of ADAMTS13 may help to clarify pathogenesis of IVIG resistance in acute-KD.

Dynamic evaluation of hemostasis in the acute phase of Kawasaki disease using comprehensive coagulation functional assays.

INTRODUCTION: Kawasaki disease (KD) is a systemic vasculitis involving coronary arteries, sometimes resulting in aneurysms and myocardial infarction. Hyper-coagulability in the acute-phase of KD is indicated in some circumstances based on changes of individual clotting factors. Comprehensive coagulation assays, clot waveform analysis (CWA) and thrombin/plasmin generation assay (T/P-GA), have been developed to assess physiological hemostasis, but these techniques have not been applied in KD. METHODS: We utilized both assays to analyze coagulation function in KD children (n = 42) prior to intravenous-immunoglobulin (IVIG) treatment (Pre), 1-week (1W) and 1-month (1M) post-IVIG. RESULTS: In CWA, the clot time (CT) pre-treatment was prolonged, and was significantly shortened at 1W and 1M. However, the maximum coagulation velocity (|min1|) and acceleration (|min2|) were ~2-fold greater relative to controls, indicating an overall hypercoagulable tendency. These parameters were related to fibrinogen concentration, and were decreased at 1W and declined to normal at 1M. In T/P-GA, the endogenous potentials of thrombin and plasmin were greater relative to control at each of three time-points, and measurements at 1W were greater than those Pre-treatment. The ratios of TG and PG relative to control were similar, however, suggesting well-balanced dynamic coagulation and fibrinolysis. In non-responders to IVIG, the |min1| and |min2| measurements were greater than those in responders at 1W and 1M, suggesting that non-responders remained hypercoagulable after primary treatment. CONCLUSION: The coagulation data observed in KD were consistent with hypercoagulability, although fibrinolytic function appeared to be well-balanced. Comprehensive assays of this nature could provide valuable information on coagulation potential in KD.

Influenza-associated thrombotic microangiopathy with unbalanced von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels in a heterozygous protein S-deficient boy.

Influenza infections often cause pneumonia, but there is limited information on thrombotic microangiopathy (TMA) in these circumstances. We report the case of an 11-year-old boy who developed TMA during the acute phase of H1N1 influenza. Plasma von Willebrand factor (VWF) was elevated, whereas a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity was mildly reduced in the absence of ADAMTS13-neutralizing autoantibody, resulting in low ratio of ADAMTS13 to VWF. The patient was treated intensively, including plasma exchange, and he recovered from the TMA. He developed pulmonary embolism (PE), however, after removal of the central venous catheter. The findings suggested that influenza-associated cytokines enhanced the release of unusually large VWF multimers from vascular endothelial cells and promoted the formation of platelet thrombi and TMA. Subsequent analysis further indicated the presence of familial protein S deficiency, and it seemed likely that the PE was more related to this heterozygous protein S defect.

Early onset of cardiomyopathy and intellectual disability in a girl with Danon disease associated with a de novo novel mutation of the LAMP2 gene.

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is characterized clinically by cardiomyopathy, myopathy and intellectual disability in boys. Because Danon disease is inherited in an X-linked dominant fashion, males are more severely affected than females, who usually have only cardiomyopathy without myopathy or intellectual disability; moreover, the onset of symptoms in females is usually in adulthood. We describe a girl with Danon disease who presented with hypertrophic cardiomyopathy and Wolff-Parkinson-White (WPW) syndrome at 12 years of age. Subsequently, she showed signs of mild learning disability and intellectual disability on psychological examinations. She had a de novo novel mutation in the LAMP-2 gene and harbored an identical c.749C > A (p.Ser250X) variant, resulting in a stop codon in exon 6. She showed decreased, but not completely absent LAMP-2 expression on immunohistochemical and Western blot analyses of a skeletal muscle biopsy specimen, which has been suggested to be caused by a 50% reduction in LAMP-2 expression (LAMP-2 haploinsufficiency) in female patients with Danon disease caused by a heterozygous null mutation. To our knowledge, our patient is one of the youngest female patients to have been given a diagnosis of Danon disease. In addition, this is the first documented case in a girl that was clearly associated with intellectual disability, which is very rare in females with Danon disease. Our findings suggest that studies of female patients with Danon disease can extend our understanding of the clinical features of this rare disease.

[Effects of parental parenting attitudes on adolescents' socialization via adolescents' perceived parenting].

The domain-specific approach to socialization has classified socialization mechanisms into several domains, including the protection and control domains, and postulates that parent­child interactions that promote socialization in each domain are different. However, there are few empirical investigations of the domain­specific approach. This study examined whether parental parenting attitudes affected early adolescents' empathy, including empathic concern and perspective taking, and social cognitive biases, including cognitive distortion and general beliefs about aggression, through the mediation of adolescents' perceptions. Junior high school students and their parents (N = 448) completed a questionnaire. Results of structural equation modeling indicated (a) parental acceptance and control increased empathy via adolescents' perceived acceptance and control, (b) parental acceptance and control decreased social cognitive biases via adolescents' perceived acceptance and control, and (c) parental control directly increased empathy. In addition, multiple group analyses indicated the validity of gender- and age-invariant models. These findings suggest that parental parenting attitudes are essential for appropriate socialization during early adolescence.

Correlations between global clotting function tests, duration of operation, and postoperative chest tube drainage in pediatric cardiac surgery.

BACKGROUND: Systemic coagulation disorders after cardiac surgery represent serious postoperative complications. There have been few reports, however, identifying preoperative coagulation tests that predict postoperative bleeding. The aim of the present study was to investigate the relationship between postoperative hemorrhage and coagulation parameters determined by global coagulation assays, to define potential predictive markers. METHODS: Twenty-one pediatric patients were enrolled. Blood samples were collected before and 24 h after cardiac surgery. Laboratory investigations included platelet count, hematocrit, classical coagulation tests [prothrombin time, activated partial thromboplastin time, thrombin-antithrombin complex (TAT)], rotation thromboelastometry (ROTEM), and the thrombin generation test (TGT). The duration of the surgical procedure was recorded. Chest tube drainage was monitored for 24 h after operation as an index of postoperative hemorrhage. RESULTS: Comparisons between preoperative and postoperative results indicated that TAT increased significantly after operation, whereas ROTEM parameters did not show a hypercoagulable pattern. Preoperative endogenous thrombin potential (ETP) measured in the TGT and clot formation time (CFT) in the ROTEM correlated with chest tube drainage. The classical coagulation tests were not informative. Postoperatively, peak height and ETP in TGT, all ROTEM parameters, and duration of surgery were correlated with chest tube drainage. Duration of surgery was correlated with postoperative ROTEM parameters but not with TGT. Postoperative maximum clot firmness and AUC were correlated with platelet count decrease ratio. CONCLUSIONS: The preoperative CFT and ETP provide useful indices for predicting postoperative chest tube drainage volume. In addition, the duration of surgery also correlated with chest tube drainage and affected ROTEM parameters.

[Effects of neighborhood collective efficacy and violence on antisocial behavior: dual mediation of socialization and routine activities].

The authors examined the effects of neighborhood collective efficacy and violence on adolescents' antisocial behavior tendencies by means of the dual mediation of socialization indices (i.e., social information-processing and self regulation) and routine activities. Collective efficacy and violence exposure were assessed by neighborhood "informal social control" and "social cohesion and trust" during the elementary and junior high school years, and the frequency of violence in the community during junior high and high school years. Normative beliefs about aggression, cognitive distortions, social rule appropriateness and self regulation were used to assess both the positive and negative indices of socialization. Routine activities were assessed by the experience in unstructured socializing activities. Antisocial tendencies were assessed by evaluations of the seriousness and past experience of delinquent behaviors. The results of structural equation modeling revealed that the effect of collective efficacy on antisocial tendencies was perfectly mediated by the socialization indices, whereas experienced violence was partly mediated by routine activities. Possible improvements of this dual mediation model were discussed.

Respiratory inhibition after crying in infants.

BACKGROUND: Among full-term neonates, the authors discovered infants who showed respiratory inhibition after crying which involved a marked decrease in SpO2. The infants were found to present increased echogenicity or a cyst in a cranial region termed the ganglionic eminence, or to have a subependymal cyst. The authors prospectively examined the relationship between respiratory inhibition after crying and these changes to examine the prevention and treatment of the episode. METHODS: The authors conducted cranial ultrasonography to screen 381 full-term neonates who showed no abnormalities at birth and whose parents requested ultrasonographic screening of the head, followed by polygraphy of infants who showed increased echogenicity or a cyst in ganglionic eminence, or had a subependymal cyst. The authors similarly conducted polygraphy for 50 neonates without cranial ultrasound abnormalities; the former constituted the control group. Respiratory inhibition was defined to be central apnea immediately after crying with a decrease in SpO2 to <60%. RESULTS: Among 381 neonates examined, 104 showed cranial ultrasound abnormalities; 60 of the 104 neonates indicated respiratory inhibition after crying. Oxygenation failed to improve the episode in 17 neonates with severe respiratory inhibition. However, theophylline alleviated the episode, and SpO2 no longer decreased to <60%. Theophylline was discontinued successfully by 6 months after birth, while 50 neonates in the control group showed no respiratory inhibition after crying. CONCLUSION: Respiratory inhibition after crying which involved a marked decrease in SpO2 was observed in full-term neonates who showed no abnormalities after birth. These neonates could be screened by cranial ultrasonography.