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- Lyons, Oliver, et al.
(författare)
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Human venous valve disease caused by mutations in FOXC2 and GJC2
- 2017
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 214:8, s. 2437-2452
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Tidskriftsartikel (refereegranskat)abstract
- Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation ("organization") of Prox1(hi) endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1(hi) endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1(hi) endothelial organization at postnatal day 0, and this likely underlies the VV defects seen in patients with GJC2 mutations. Knockout of Gja4 or Gjc2 resulted in reduced proliferation of Prox1(hi) valve-forming cells. At later stages of blood flow, Foxc2 and calcineurin-Nfat signaling are each required for growth of the valve leaflets, whereas Foxc2 is not required for VV maintenance.
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- Schmedes, Clare M., et al.
(författare)
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Circulating extracellular vesicle tissue factor activity during orthohantavirus infection is associated with intravascular coagulation
- 2020
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 222:8, s. 1392-1399
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Puumala (PUUV) orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS). HFRS patients have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine if circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients.METHODS: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n=27) and those who did not (n=61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, prothrombin time international normalized ratio, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and platelets.RESULTS: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity significantly associated with plasma tPA and PAI-1, suggesting endothelial cells as a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared to those who did not. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with AUC 0.63 (95% CI 0.51 - 0.76), p-value 0.046.CONCLUSIONS: Increased circulating EVTF activity during HFRS is associated with intravascular coagulation.
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- Sundler Björkman, Linda, et al.
(författare)
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Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema : a family study
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Ingår i: Blood. - 1528-0020.
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary angioedema (HAE) due to C1 inhibitor protein (C1-INH) deficiency was recently shown to be associated with increased risk of venous thromboembolism (VTE). This is the first national family study of HAE with the aim to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register during the period 1964-2018. Only HAE patients with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for HAE patients compared with relatives without HAE. Among 2,006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total 35 (9.6%) of HAE patients compared to 68 (4.1%) of non-HAE relatives were affected by VTE (p<0.001). The adjusted HR for VTE among HAE patients was 2.51 (95% CI 1.67-3.77). HAE patients were younger at the first VTE than their non-HAE relatives (mean age 51 versus 63 years, p<0.001). Before the age of 70 years the HR for VTE among HAE patients was 3.62 (95%CI 2.26-5.80). The HR for VTE for HAE patients born after 1964 was 8.29 (95%CI 2.90-23.71). The HR for VTE for HAE patients born 1964 or earlier was 1.82 (95%CI 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.
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