Tissue factor expression by endothelial cells in sickle cell anemia.

Abstract

The role of the vascular endothelium in activation of the coagulation system, a fundamental homeostatic mechanism of mammalian biology, is uncertain because there is little evidence indicating that endothelial cells in vivo express tissue factor (TF), the system's triggering mechanism. As a surrogate for vessel wall endothelium, we examined circulating endothelial cells (CEC) from normals and patients with sickle cell anemia, a disease associated with activation of coagulation. We find that sickle CEC abnormally express TF antigen (expressed as percent CEC that are TF-positive), with 66+/-13% positive in sickle patients in steady-state, 83+/-19% positive in sickle patients presenting with acute vasoocclusive episodes, and only 10+/-13% positive in normal controls. Repeated samplings confirmed this impression that TF expression is greater when sickle patients develop acute vasoocclusive episodes. Sickle CEC are also positive for TF mRNA, with excellent concurrence between antigen and mRNA expression. The TF expressed on the antigen-positive CEC is functional, as demonstrated by a binding assay for Factor VIIa and a chromogenic assay sensitive to generation of Factor Xa. By establishing that endothelial cells in vivo can express TF, these data imply that the vast endothelial surface area does provide an important pathophysiologic trigger for coagulation activation.

Circulating endothelial cells in vascular disorders: new insights into an old concept

“…This chronic activation may be a risk factor for vaso-occlusion and``intermittent activation could account for apparently random vaso-occlusive crises'', as noted in Ref. 27.…”

“…Thus it seems likely that endothelial cell expression of TF can play a pathological role in exaggerated activation of coagulation. Among the factors supporting this notion are reports of increased levels of thrombin±antithrombin complexes and prothrombin fragments 1.2 and D-dimer, and of abnormal expression of TF on blood monocytes (27). In addition, regardless of clinical status, most CEC expressed adhesive receptors for leukocytes ICAM-1, VCAM-1, E and P selectins (9), suggesting that the vascular endothelium adopts a proin¯ammatory phenotype in sickle cell patients.…”

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

“…The repetitive vaso-occlusive episodes cause tissue ischemia and reperfusion injury, resulting in endothelial cell activation and inflammation [4,5]. Sickle patients have multiple indicators of an inflammatory response including elevated white counts [6][7][8][9], C-reactive protein levels [10][11][12][13], cytokines [14][15][16][17], as well as activated monocytes [13,18], neutrophils [19][20][21], platelets [18,[22][23][24][25][26][27][28], and endothelial cells [29,30] in circulation.…”

Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

“…Incompletely described signaling mechanisms also induce an inflammatory-like activation state in vascular endothelium indicated by elevated endothelial expression of F c receptor and the integrins ICAM-1, VCAM-1, and P-selectin (2)(3)(4)(5). There are also increased plasma levels of leukocytes (6), ''activated'' circulating endothelial cells, proinflammatory cytokines, platelet-activating factor, C-reactive protein, and angiogenic stimuli (7,8).…”