Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease

Nsiri, Brahim; Gritli, Nasreddine; Bayoudh, Fethi; Messaoud, T.; Fattoum, S.; Machghoul, S.

doi:10.1007/s00282-996-0279-2

Cited by 64 publications

(57 citation statements)

References 8 publications

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“…These data suggest that PAI-1 levels correlated to sickle gene dosage or severity. Our data showing that MNC of SCD patients at steady state had increased levels of PAI-1 and that PAI-1 was induced by PlGF in HPMVEC are novel; our observation that PlGF is also elevated in SCD patients is consistent with previous studies (10,11).…”

Section: Discussionsupporting

confidence: 82%

“…Circulating levels of tPA in Berkeley SS and knock-in SS mice were significantly lower than corresponding controls (supplemental Fig. S1D), consistent with reports of lower tPA plasma levels in patients with SCD (10,11). To assess whether PlGF affected tPA levels, we stimulated primary HPMVEC with PlGF and measured release of tPA in the medium.…”

Section: Pai-1 Expression In Sickle Cell Anemia Mice and Humanmentioning

confidence: 51%

“…PAI-1, D-dimers, and tPA levels have been measured in patients with SCD at steady state and then following vaso-occlusion by Nsiri et al (10). These investigators found that PAI-1 and D-dimer levels were elevated nearly 2.5- 3-fold at steady state as compared with controls.…”

Section: Discussionmentioning

confidence: 98%

“…The factors that elevate PAI-1 in SCD (10,11) are unknown. In this study, we observed increased PAI-1 expression in pulmonary endothelial cells and macrophages of sickle mice and identified the molecular mechanisms of PlGF-mediated PAI-1 induction in primary HPMVEC.…”

Section: Discussionmentioning

confidence: 99%

“…SCD patients have increased levels of activated coagulation factors and decreased levels of anticoagulant proteins, including an abnormal fibrinolytic system (8,9). Elevated plasma levels of circulating tissue factor (4) and PAI-1 have been reported at steady state and are further increased during sickle vaso-occlusive crises (10,11). A prothrombotic state predisposes patients to pulmonary hypertension and stroke, two devastating complications of SCD (12).…”

Section: Scdmentioning

confidence: 99%

See 4 more Smart Citations

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Patel

Sundaram

Yang

et al. 2010

Journal of Biological Chemistry

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Sickle cell disease (SCD) is characterized by a prothrombotic state. Plasminogen activator inhibitor-1 (PAI-1) is known to modulate fibrinolysis, lung injury/fibrosis, and angiogenesis. However, its role in SCD is less understood, and the molecular mechanisms underlying increased PAI-1 are unknown. Herein, we show a novel link between PAI-1 and sickle erythropoiesis. Plasma PAI-1 levels were high in SCD patients at steady state and in two humanized sickle mouse models, with increased PAI-1 immunolabeling in sickle mouse lung, bronchial epithelial cells, alveolar macrophages, and pulmonary microvascular endothelial cells. Placenta growth factor (PlGF), released at high levels by sickle erythroblasts, induced PAI-1 expression in primary human pulmonary microvascular endothelial cells and monocytes through activation of c-Jun N-terminal kinase (JNK), NADPH oxidase, and hypoxia-inducible factor-1␣ (HIF-1␣). Analysis of the human PAI-1 promoter revealed this induction was mediated by hypoxia-response element (HRE)-1, HRE-2, and distal activator protein (AP-1) sites. We also identify the involvement of c-Jun, c-Jun/c-Fos, and JunD, but not JunB, in binding with AP-1 sites of the PAI-1 promoter upon PlGF induction. Consistent with these findings, levels of PAI-1 were low in PlGF knock-out mice and sickle-PlGF knock-out mice; overexpression of PlGF in normal mice increased circulating PAI-1. In conclusion, we identify a novel mechanism of PAI-1 elevation in SCD.

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Section: Discussionsupporting

confidence: 82%

Section: Pai-1 Expression In Sickle Cell Anemia Mice and Humanmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Scdmentioning

confidence: 99%

See 3 more Smart Citations

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Patel

Sundaram

Yang

et al. 2010

Journal of Biological Chemistry

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Prothrombin mutant, factor V Leiden, and thermolabile variant of methylenetetrahidrofolate reductase among patients with sickle cell disease in Brazil

et al. 1998

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The prevalence of the prothrombin gene variant (allele 20.210 A), factor V Leiden mutation, and homozygosity for transition 677C-->T in the methylenetetrahydrofolate reductase (MTHFR) gene was determined among patients with sickle cell disease (SCD). The group included 73 patients with median age of 32.3 years with a diagnosis of sickle cell anemia in 53 patients, hemoglobinopathy SC in 16 patients, and four with S/beta(0) thalassemia. Vascular complications such as ischemic stroke or deep vein thrombosis were diagnosed in nine patients. Heterozygosity for the prothrombin gene variant or factor V Leiden mutation was identified in four patients. However, only one patient, who developed ischemic stroke, was identified as a carrier of factor V Leiden mutation. None of the patients presented homozygosity for the thermolabile variant of the MTHFR. These data suggest a low clinical impact of inherited hypercoagulability risk factors in developing thrombosis, occlusive stroke, or mortality data among patients with SCD in Brazil.

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Central venous catheter complications in sickle cell disease

Jeng¹,

Feusner²,

Skibola³

et al. 2002

American J Hematol

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A review of patients with sickle cell disease (SCD) and central venous catheters (CVCs) was performed to evaluate the frequency of catheter complications (infections, thrombotic events, and premature CVC removal. Fifteen evaluable patients were identi®ed during our review of a 7.5-year period. The median age was 18 years (range, 1.5±30 years); 14 were African American, and 1 was Latino; 5 were male, and 10 were female. Forty-one CVCs were placed (36 Mediport and 5 Broviac catheters) for a total of 12,120 CVC days. We observed a median of 2 CVCs per patient (range, 1±8 CVCs per patient) with 67 discrete episodes of CVC-associated infection (range, 0±18 per patient) involving 10 patients. The rate of CVC-associated infection for patients with SCD at our institution was 5.5 infections per 1,000 CVC days; this rate was signi®cantly higher than the rate of CVC-associated infection in our patients with cancer (P < 0.001). We also determined that the rate of CVC-associated thrombosis was 0.99 events per 1,000 CVC days and involved 33% of the patients with SCD; the rate of premature CVC removal was 3.15 per 1,000 CVC days, and 78% of CVCs were removed prematurely. We conclude that patients with SCD are at high risk for CVC-related complications, and improved care and close monitoring of CVCs should be encouraged to decrease morbidity in these chronically ill patients.

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Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease

Cited by 64 publications

References 8 publications

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Prothrombin mutant, factor V Leiden, and thermolabile variant of methylenetetrahidrofolate reductase among patients with sickle cell disease in Brazil

Central venous catheter complications in sickle cell disease

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