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Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma.
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Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma.

Thromb Haemost. 2017 May 24;:

Authors: Yetman RJ, Barrett YC, Wang Z, Adamczyk R, Wang J, Ramacciotti E, Frost C

Abstract
The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223-0.295 IU/ml; 110 ng/ml: 1.212-1.474 IU/ml). Endogenous baseline factor X levels were 43 %-68 % lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4-53.2 s to 64.5-70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.

PMID: 28536722 [PubMed - as supplied by publisher]




Differential integrin activity mediated by platelet collagen receptor engagement under flow conditions.
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Differential integrin activity mediated by platelet collagen receptor engagement under flow conditions.

Thromb Haemost. 2017 May 24;:

Authors: Pugh N, Maddox BD, Bihan D, Taylor KA, Mahaut-Smith MP, Farndale RW

Abstract
The platelet receptors glycoprotein (Gp)VI, integrin α2β1 and GpIb/V/IX mediate platelet adhesion and activation during thrombogenesis. Increases of intracellular Ca(2+) ([Ca(2+)]i) are key signals during platelet activation; however, their relative importance in coupling different collagen receptors to functional responses under shear conditions remains unclear. To study shear-dependent, receptor-specific platelet responses, we used collagen or combinations of receptor-specific collagen-mimetic peptides as substrates for platelet adhesion and activation in whole human blood under arterial flow conditions and compared real-time and endpoint parameters of thrombus formation alongside [Ca(2+)]i measurements using confocal imaging. All three collagen receptors coupled to [Ca(2+)]i signals, but these varied in amplitude and temporal pattern alongside variable integrin activation. GpVI engagement produced large, sustained [Ca(2+)]i signals leading to real-time increases in integrins α2β1- and αIIbβ3-mediated platelet adhesion. αIIbβ3-dependent platelet aggregation was dependent on P2Y12 signalling. Co-engagement of α2β1 and GpIb/V/IX generated transient [Ca(2+)]i spikes and low amplitude [Ca(2+)]i responses that potentiated GpVI-dependent [Ca(2+)]i signalling. Therefore α2β1, GpIb/V/IX and GpVI synergize to generate [Ca(2+)]i signals that regulate platelet behaviour and thrombus formation. Antagonism of secondary signalling pathways reveals distinct, separate roles for αIIbβ3 in stable platelet adhesion and aggregation.

PMID: 28536721 [PubMed - as supplied by publisher]




Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice.
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Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice.

Thromb Haemost. 2017 May 24;:

Authors: Amadio P, Tarantino E, Sandrini L, Tremoli E, Barbieri SS

Abstract
Deep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2(-/-) thrombi have greater fibrin content, higher number of F4/80(+), TF(+) and ANXA2(+) cells, and lower S100A10(+) cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2(-/-) monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2(-/-) macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macrophages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.

PMID: 28536720 [PubMed - as supplied by publisher]




Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex(®) technique.
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Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex(®) technique.

Thromb Haemost. 2017 May 24;:

Authors: Liang Q, Qin H, Ding Q, Xie X, Wu R, Wang H, Hu Y, Wang X

Abstract
Von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency, heterogeneous laboratory phenotype and race specific distribution of mutations. The present study aimed to determine the correlation of genotype and phenotype in 200 Chinese individuals from 90 unrelated families with VWD. Next generation sequencing (NGS) of the whole coding VWF, copy number analysis of VWF by CNVplex® technique as well as a comprehensive phenotypic assessment were carried out in all index patients (IPs). We identified putative mutations in all IPs except five mild type 1 (85/90, 94.4 %). In total, 98 different mutations were detected, 62 (63.3 %) of which were reported for the first time (23 missense mutations, 1 regulatory mutation, 12 splice site mutations and 26 null mutations). Mutations p.Ser1506Leu and p.Arg1374His/Cys/Ser were the most frequent mutations in 2A (33 % of cases) and 2M VWD (67 % of cases), respectively. In addition, mutation p.Arg816Trp was detected repeatedly in type 2N patients, while mutation p.Arg854Gln, extremely common in Caucasians, was not found in our cohort. Thirty-three patients had two or more putative mutations. Unlike most cases of type 1 and type 2 VWD, which were transmitted dominantly, we presented seven severe type 1, two type 2A and one type 2M with autosomal recessive inheritance. Here the phenotypic data of patients with novel mutations will certainly contribute to the better understanding of the molecular genetics of VWF-related phenotypes.

PMID: 28536718 [PubMed - as supplied by publisher]




Increased risks of venous thromboembolism in patients with psoriasis. A Nationwide Cohort Study.
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Increased risks of venous thromboembolism in patients with psoriasis. A Nationwide Cohort Study.

Thromb Haemost. 2017 May 24;:

Authors: Chung WS, Lin CL

Abstract
Systemic inflammation and hypercoagulability in psoriasis are related to cardiovascular morbidity. The aim of the study was to investigate the incidence and risk of venous thromboembolism (VTE) in patients with psoriasis in Taiwan. We identified inpatients aged ≥ 18 years with a diagnosis of psoriasis and controls at a 1: 1 ratio of frequency matched by sex, age, frequency of medical visits, length of stay, and comorbidities between 2000 and 2010 in the Taiwan National Health Insurance Research Database. Each patient was traced to the date of VTE occurrence, loss to follow-up, death, or the December 31, 2011, whichever occurred first. We analysed 8945 patients with psoriasis and 8945 controls. The patients with psoriasis exhibited a greater incidence rate of VTE (19.2 vs 9.88 per 10 000 person-years) than did the controls. After adjustment for covariates, the patients with psoriasis presented a 2.02-fold risk of VTE (adjusted hazard ratio [aHR] = 2.02, 95 % confidence interval [CI] = 1.42-2.88) compared with that in the control cohort. The aHR of VTE was significantly higher in the first year of follow-up (aHR = 3.30, 95 % CI = 1.45-7.55) than after one year (aHR = 1.68, 95 % CI = 1.13-2.49).

PMID: 28536717 [PubMed - as supplied by publisher]