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Graphical abstract Highlights • The Stormorken syndrome causing mutation in STIM1 (R304W) causes perinatal lethality in homozygous mice. • Stim1R304W mice show muscle degeneration and reduced growth. • The STIM1 R304W gain-of-function is counteracted by reduced STIM1 expression in fibroblasts from Stim1R304W mice. • STIM1 loss in haematopoietic cells similarly causes absent SOCE and impaired platelet activation in Stim1R304W mice. • Unlike humans, mice compensate for constitutive activity of Stim1R304W by reduced expression of the mutant allele. Abstract STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity. [ABSTRACT FROM AUTHOR]

Objective: We evaluated whether reduced platelet activity detected by point-of-care (POC) testing is a better predictor of hematoma expansion and poor functional outcomes in patients with intracerebral hemorrhage (ICH) than a history of antiplatelet medication exposure.Methods: Patients presenting with spontaneous ICH were enrolled in a prospective observational cohort study that collected demographic, clinical, laboratory, and radiographic data. We measured platelet activity using the PFA-100 (Siemens AG, Germany) and VerifyNow-ASA (Accumetrics, CA) systems on admission. We performed univariate and adjusted multivariate analyses to assess the strength of association between those measures and (1) hematoma growth at 24 hours and (2) functional outcomes measured by the modified Rankin Scale (mRS) at 3 months.Results: We identified 278 patients for analysis (mean age 65 ± 15, median ICH score 1 [interquartile range 0-2]), among whom 164 underwent initial neuroimaging within 6 hours of symptom onset. Univariate association with hematoma growth was stronger for antiplatelet medication history than POC measures, which was confirmed in multivariable models (β 3.64 [95% confidence interval [CI] 1.02-6.26], P = .007), with a larger effect size measured in the under 6-hour subgroup (β 7.20 [95% CI 3.35-11.1], P < .001). Moreover, antiplatelet medication history, but not POC measures of platelet activity, was independently associated with poor outcome at 3 months (mRS 4-6) in the under 6-hour subgroup (adjusted OR 3.6 [95% CI 1.2-11], P = .023).Conclusion: A history of antiplatelet medication use better identifies patients at risk for hematoma growth and poor functional outcomes than POC measures of platelet activity after spontaneous ICH. [ABSTRACT FROM AUTHOR]

Disorders of metal elements and platelet dysfunction are common in patients with trauma-induced coagulopathy (TIC). The aim of this study was to explore the potential role of plasma metal elements in platelet dysfunction in TIC. Thirty Sprague-Dawley rats were divided into control, hemorrhage shock (HS) and multiple injury (MI) groups. At timepoints of 0.5 and 3 h after trauma and being documented as HS 0.5 h , HS 3 h , MI 0.5 h or MI 3 h , blood samples were harvested for inductively coupled plasma mass spectrometer, conventional coagulation function and thromboelastograph. The plasma zinc (Zn), vanadium (V) and cadmium (Ca) decreased initially in HS 0.5 h and recovered slightly in HS 3 h , whereas their plasma concentrations continued to decrease from beginning till MI 3 h (p < 0.05). In HS, plasma Ca, V and nickel were negatively correlated to the time taken to reach the initial formation (R), whereas R was positively correlated to plasms Zn, V, Ca and selenium in MI (p < 0.05). In MI, plasma Ca was positively correlated to maximum amplitude, and plasma V was positively correlated to platelet count (p < 0.05). The plasma concentrations of Zn, V and Ca appeared to contribute to platelet dysfunction in HS 0.5 h , HS 3 h , MI 0.5 h and MI 3 h , which were trauma type sensitive. • Metal elements and platelet function show trauma type-dependent features in hemorrhage shock and multiple injury. • The plasma Zn, V and Cd decrease and recover in hemorrhage shock, but continue decreasing in multiple injury. • Metal elements might be associated with platelet dysfunction in trauma-indued coagulopathy. [ABSTRACT FROM AUTHOR]

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Abstract: Background- Haemorrhage after Cardio Pulmonary Bypass (CPB) Surgery is a well recognised complication that leads to significant morbidity and mortality. The incidence varies between 5–25% depending upon the clinical situation. Several factors are implicated as causative but none have been precisely proved. Methods- Our study was an attempt to evaluate the haemostatic defect with particular reference to platelet function abnormalities during cardio pulmonary bypass surgery, in order to reduce the morbidity and mortality associated with post CPB haemorrhage. Flow cytometric evaluation of different platelet glycoproteins like GPIb/IX, GPIIb/IIIa and GMP-140 was done. Results: The marker expression showed deregulation during surgery which returned to base after bypass was terminated. In contrast, the cases with bleeding showed significant variation. P-Selectin (GMP 140) expression decreased progressively till 3rd post-operative day showing lack of activation of platelets in cases of severe bleeding. Conclusion- Longer duration of CPB initiates plasmin generation through heparin, which raises the PAI-1-tPA complex and thereby down regulating the functions of platelets. This suggests a link between duration of CPB, bleeding, platelet dysfunction and fibrinolysis. Hence serial estimations of the levels of GMP-140 and tPA can predict severe bleeding. [Copyright &y& Elsevier]

The great advances in the knowledge of inherited thrombocytopenias (ITs) made since the turn of the century have significantly changed our view of these conditions. To date, ITs encompass 45 disorders with different degrees of complexity of the clinical picture and very wide variability in the prognosis. They include forms characterized by thrombocytopenia alone, forms that present with other congenital defects, and conditions that predispose to acquire additional diseases over the course of life. In this review, we recapitulate the clinical features of ITs with emphasis on the forms predisposing to additional diseases. We then discuss the key issues for a rational approach to the diagnosis of ITs in clinical practice. Finally, we aim to provide an updated and comprehensive guide to the treatment of ITs, including the management of hemostatic challenges, the treatment of severe forms, and the approach to the manifestations that add to thrombocytopenia. [ABSTRACT FROM AUTHOR]