A Family with Reduced Plasminogen Activator Activity in Blood Associated with Recurrent Venous Thrombosis

Jørgensen, Marie Birk; Mortensen, J.Z.; Madsen, Anne Grete; Thorsen, Sixtus; Jacobsen, B.

doi:10.1111/j.1600-0609.1982.tb00586.x

Cited by 52 publications

(4 citation statements)

References 9 publications

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“…The risk of a permanent flow‐disrupting thrombus increases if this local regulation system is impaired. In support of this, several families with impaired capacity for t‐PA release have been reported to suffer from early‐onset, often recurrent, venous thrombosis . Furthermore, previous reports, including data from the Framingham Heart Study, have shown that genetically impaired t‐PA secretion causes a three‐fold increase in the adjusted risk for arterial thrombosis, i.e.…”

Section: Introductionmentioning

confidence: 78%

Valproic acid selectively increases vascular endothelial tissue‐type plasminogen activator production and reduces thrombus formation in the mouse

Larsson

Alwis

Niego

et al. 2016

Journal of Thrombosis and Haemostasis

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Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.

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Section: Introductionmentioning

confidence: 78%

Valproic acid selectively increases vascular endothelial tissue‐type plasminogen activator production and reduces thrombus formation in the mouse

Larsson

Alwis

Niego

et al. 2016

Journal of Thrombosis and Haemostasis

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“…Several clinical studies have reported a possible association between defective fibrinolysis and TED (17). At least three families with TED were reported in which the affected members showed a defective release of t-PA activity after venous occlusion of the arm and/or intravenous infusion of DDAVP (18)(19)(20). It was shown recently that poor fibrinolytic response to venous occlusion occurred in 35% of patients with deep vein deep vein thrombosis and 10% was due to deficient t-PA release (9,21).…”

Section: Discussionmentioning

confidence: 99%

Tissue plasminogen activator levels in different types of polycythemia

Cohen

Gelvan

Kadouri

et al. 1990

European J of Haematology

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The plasma level of tissue plasminogen activator antigen (t‐PA‐Ag) was examined in 86 patients with polycythemia (29 polycythemia vera, 11 secondary polycythemia and 46 with spurious polycythemia) and 24 healthy volunteers. Tissue plasminogen activator antigen was significantly decreased in patients with polycythemia vera in comparison with healthy controls. On the other hand, in patients with spurious polycythemia and secondary polycythemia t‐PA‐Ag concentration was significantly increased. There was no significant difference in t‐PA‐Ag levels in polycythemic patients with or without thromboembolic disease. A significant correlation was detected between t‐PA‐Ag level and hemoglobin or hematocrit concentration in patients with polycythemia vera (p = 0.02, r = 0.43). However, in patients with secondary polycythemia and spurious polycythemia, no significant correlation between t‐PA‐Ag and hemoglobin level was found. Plasminogen activator inhibitor (PAI) levels in patients with polycythemia vera and healthy volunteers did not differ significantly.

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“…A study has reported that rare deleterious genetic variations in PLAT may be associated with prolonged illness duration and poorer prognosis in patients with early onset of Alzheimer's disease 19 . Several earlier papers highlighted the association of familial defects in tPA release with venous thromboembolic events 20,21 . However, in the context of thrombophilia, pathogenetic mutations in PLAT have rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

“… 19 Several earlier papers highlighted the association of familial defects in tPA release with venous thromboembolic events. 20 , 21 However, in the context of thrombophilia, pathogenetic mutations in PLAT have rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

Tissue‐type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease

Tao,

Ma,

Feng

et al. 2023

MedComm

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Tissue‐type plasminogen activator (tPA) encoded by PLAT is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in PLAT associated with venous thromboembolism have rarely been reported. Here, we report the first case of a homozygous point mutation c.1411T>C (p.Y471H) in PLAT leading to thromboembolic events and conduct related functional studies. The corresponding tPA mutant protein (tPA‐Y471H) and wild‐type tPA (tPA‐WT) were synthesized in vitro, and mutant mice (PLATH/H mice) were constructed. The molecular docking and surface plasmon resonance results indicated that the mutation impeded the hydrogen‐bonding interactions between the protease domain of tPA and the kringle 4 domain of plasminogen, and the binding affinity of tPA and plasminogen was significantly reduced with a difference of one order of magnitude. mRNA half‐life assay showed that the half‐life of tPA‐Y471H was shortened. The inferior vena cava thrombosis model showed that the rate of venous thrombosis in PLATH/H mice was 80% compared with 53% in wild‐type mice. Our data suggested a novel role for the protease domain of tPA in efficient plasminogen activation, and demonstrated that this tPA mutation could reduce the fibrinolysis function of the body and lead to an increased propensity for thrombosis.

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A Family with Reduced Plasminogen Activator Activity in Blood Associated with Recurrent Venous Thrombosis

Cited by 52 publications

References 9 publications

Valproic acid selectively increases vascular endothelial tissue‐type plasminogen activator production and reduces thrombus formation in the mouse

Valproic acid selectively increases vascular endothelial tissue‐type plasminogen activator production and reduces thrombus formation in the mouse

Tissue plasminogen activator levels in different types of polycythemia

Tissue‐type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease

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