Summary. More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33-48%). The terminal infection was heralded by upper respiratory tract syndromes in 72AE6% and by gastroenteritis in 13AE7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9AE8%, therapy complications 7AE0%, splenic sequestration 6AE6%, pulmonary emboli/thrombi 4AE9%, renal failure 4AE1%, pulmonary hypertension 2AE9%, hepatic failure 0AE8%, massive haemolysis/red cell aplasia 0AE4% and left ventricular failure 0AE4%. Death was frequently sudden and unexpected (40AE8%) or occurred within 24 h after presentation (28AE4%), and was usually associated with acute events (63AE3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.

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We infused Escherichia coli endotoxin, 0.07-1.33 microgram/kg, intravenously into chronically instrumented unanesthetized sheep and measured pulmonary arterial and left atrial pressures, lung lymph flow, lymph and blood plasma protein concentrations, and arterial blood gases. Endotoxin caused a biphasic reaction: an early phase of pulmonary hypertension and a long late phase of steady state increased pulmonary vascular permeability during which pulmonary arterial and left atrial pressures were not increased significantly and lung lymph flow was 5 times the baseline value. Lymph: plasma total protein concentration ratio during the late phase (0.76 +/- 0.04) was significantly (P less than 0.05) higher than during baseline (0.66 +/- 0.03). The lymph response was reproducible. Lung lymph clearance of endogenous proteins with molecular radii (r) 35.5 to 96 A was increased during the steady state late phase of the reaction, but, as during baseline, clearance decreased as r increased. The endotoxin reaction was similar to the reaction to infusing whole Pseudomonas bacteria, except that endotoxin had less effect on pressures during the steady state response and caused a relatively larger increase in lymph clearance of large proteins. We conclude that E. coli endotoxin in sheep causes a long period of increased lung vascular permeability and may have a greater effect on large solute pathways across microvessels than do Pseudomonas bacteria.

Background: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed. Conclusions: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management.

Abstract-In the present study, we demonstrate that lung microvascular endothelial cells express a Ca v 3.1 (␣ 1G ) T-type voltage-gated Ca 2ϩ channel, whereas lung macrovascular endothelial cells do not express voltage-gated Ca 2ϩ channels. Voltage-dependent activation indicates that the Ca v 3.1 T-type Ca 2ϩ current is shifted to a positive potential, at which maximum current activation is Ϫ10 mV; voltage-dependent conductance and inactivation properties suggest a "window current" in the range of Ϫ60 to Ϫ30 mV. Thrombin-induced transitions in membrane potential activate the Ca v 3.1 channel, resulting in a physiologically relevant rise in cytosolic Ca 2ϩ . Furthermore, activation of the Ca v 3.1 channel induces a procoagulant endothelial phenotype; eg, channel inhibition attenuates increased retention of sickled erythrocytes in the inflamed pulmonary circulation. We conclude that activation of the Ca v 3.1 channels selectively induces phenotypic changes in microvascular endothelial cells that mediate vaso-occlusion by sickled erythrocytes in the inflamed lung microcirculation.