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Blood, 1 August 2004, Vol. 104, No. 3, pp. 595-596.
The chicken or the egg? Tissue factor and inflammation in sickle cell diseaseMEDICAL COLLEGE OF WISCONSIN; BLOOD CENTER OF SOUTHEASTERN WISCONSIN
Increased tissue factor, the primary initiator of the coagulation cascade, may both cause and result from vascular inflammation in sickle cell disease; statins may break this vicious cycle.
Tissue factor (TF), the primary physiologic initiator of blood coagulation, is a transmembrane lipoprotein expressed primarily by extravascular cells.1 In bacterial sepsis or following exposure to proinflammatory cytokines or acute phase proteins, TF is induced on activated monocytes and injured endothelial cells within the vascular system.2 In a positive feedback loop, the TF–factor VIIa–factor Xa ternary complex promotes proinflammatory cytokine and chemokine synthesis via protease-activated receptor-1 (PAR-1) and PAR-2.3
Studies of patients with SCD have provided evidence for increased TF activity with increased thrombin levels and decreased factor VII levels consistent with higher factor VII turnover. Injured vascular endothelium and circulating monocytes with increased TF expression likely contribute to this augmented factor VII consumption. This concept is supported by the fact that plasma from patients with SCD has increased levels of circulating TF-positive microparticles derived from both monocytes and endothelial cells; the levels of TF-positive microparticles increase further during acute vaso-occlusive crises.4 Moreover, circulating intact endothelial cells recovered from patients with SCD have increased TF expression.5
In this issue, Solovey and colleagues provide the first evidence for increased in vivo tissue factor expression on both pulmonary venules and circulating monocytes in murine models of severe SCD. They also found that exposure to hypoxia followed by reoxygenation, designed to induce an ischemia-reperfusion injury that mimics the intermittent vascular obstruction observed in SCD, increased levels of TF expression in milder SCD mice to levels seen in untreated severe SCD mice. Interestingly, the increased TF expression was not associated with vascular thrombi during the time frame of the study. Using a novel therapeutic approach, Solovey and colleagues proceeded to treat SCD mice with statin therapy to block selected inflammatory pathways prior to the hypoxia/reoxygenation injury with a strikingly effective result. These findings lead one to ponder whether therapies that target vascular inflammation, such as the statins, may effectively control the enhanced coagulant activity that is so prominent in patients with SCD. References
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
