99 research outputs found
Glanzmann thrombasthenia: Genetic basis and clinical correlates
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by th
Risk of venous thromboembolism in children after general surgery
Background/purpose: The purpose of the study was to determine absolute and relative rates of venous thromboembolism (VTE) following general surgical procedures in children compared to the general population.
Methods: We analyzed data from all patients under the age of 18 years in the Clinical Practice Research Datalink, linked to Hospital Episode Statistics from England (2001–2011) undergoing a general surgical procedure and population controls. Crude rates of VTE and adjusted hazard ratios were calculated using Cox regression. Results We identified 15,637 children who had a surgical procedure with 161,594 controls. Six children undergoing surgery had a VTE diagnosed in the year after compared to five children in the population cohort. The overall rate of VTE following surgery was 0.4 per 1000 person years (pyrs) (95% confidence interval [CI] 0.15–0.88) compared to 0.04 per 1000 pyrs (95% CI 0.02–0.09) in the population cohort. This represented a 9 fold increase in risk compared to the population cohort (adjusted hazard ratio [HR] 8.80; 95% CI 2.59–29.94).
Conclusions Children are at increased risk for VTE following general surgical procedures compared to the general population however the absolute risk is small and given this the benefits of thromboprophylaxis need to be balanced against the risk of complications following its use
Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis
The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo-ring replacement strategy. The co-crystal structure of Mer with two compounds (7 & 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis
Common themes and challenges in hemophilia care: a multinational perspective
This is an Accepted Manuscript of an article published by Taylor & Francis in Hematology on 3 Aug 2018, available online: https://doi.org/10.1080/10245332.2018.150522
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Peptides derived from MARCKS block coagulation complex assembly on phosphatidylserine.
Blood coagulation involves activation of platelets and coagulation factors. At the interface of these two processes resides the lipid phosphatidylserine. Activated platelets expose phosphatidylserine on their outer membrane leaflet and activated clotting factors assemble into enzymatically active complexes on the exposed lipid, ultimately leading to the formation of fibrin. Here, we describe how small peptide and peptidomimetic probes derived from the lipid binding domain of the protein myristoylated alanine-rich C-kinase substrate (MARCKS) bind to phosphatidylserine exposed on activated platelets and thereby inhibit fibrin formation. The MARCKS peptides antagonize the binding of factor Xa to phosphatidylserine and inhibit the enzymatic activity of prothrombinase. In whole blood under flow, the MARCKS peptides colocalize with, and inhibit fibrin cross-linking, of adherent platelets. In vivo, we find that the MARCKS peptides circulate to remote injuries and bind to activated platelets in the inner core of developing thrombi
Fifth Ă…land Island conference on von Willebrand disease
The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016 – 90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis, and VWF inhibitors
Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium
The Role of Inflammation in Venous Thromboembolism
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters
Pediatric Venous Thromboembolism
Venous thromboembolism (VTE) occurs less often in children than adults and therefore remains underrecognized despite increasing in incidence. Due to the risk of mortality, short- and long-term morbidity, and increased healthcare costs associated with pediatric VTE, this entity merits better understanding and consideration. With this Research Topic, we aim to highlight some special considerations of pediatric VTE, namely risk factors and epidemiology, rare types of pediatric thrombosis and considerations unique to specific clinical patient subgroups, approaches to management and treatment, and preventio
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