Comment on Solovey et al, page
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.
Despite a detailed understanding of the genetics, molecular biology, and biochemistry of sickle hemoglobin and its myriad effects on the sickle erythrocyte, much remains unknown regarding the profound vascular dysfunction observed in patients with sickle cell disease (SCD). There is considerable evidence for increased levels of procoagulant proteins, tissue factor activity, thrombin generation, and vascular inflammation in patients with SCD. However, clinical trials with anticoagulant and anti-inflammatory therapies have been inconclusive. Therefore, it is unclear whether enhanced procoagulant or inflammatory activity directly contribute to the pathogenesis of sickle cell vaso-occlusive disease or merely reflects vascular injury caused by the sickle erythrocyte. The strong relationships between the inflammatory and hemostatic pathways further complicate this question.
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 FIG1
Examples of pulmonary vessels from a sickle mouse. See the complete figure in the article beginning on page .
Examples of pulmonary vessels from a sickle mouse. See the complete figure in the article beginning on page .
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.
