J Thromb Thrombolysis (2006) 22:133–138 DOI 10.1007/s11239-006-8969-8 Low levels of activated factor VII in systemic sclerosis Alessandro Volpe ∗ · Gian Luca Salvagno ∗ · Giuseppe Lippi · Paola Caramaschi · Martina Montagnana · Sabrina Canestrini · Antonio Carletto · Lisa Maria Bambara · Domenico Biasi · Gian Cesare Guidi C  Springer Science + Business Media, LLC 2006 Abstract Introduction. Recent investigations show that ac- tivated factor VII, the primary enzyme in the extrinsic path- way of blood coagulation, exerts additional extra-coagulant functions, such as apoptosis and angiogenesis. On the basis of these recent acquisitions, the present study was aimed to evaluate activated factor VII in patients with systemic sclero- sis and to establish a potential association with pathogenesis and complications of this severe autoimmune disorder. Materials and methods. Activated factor VII level was measured in twenty-eight consecutive scleroderma patients (2 men and 26 women, mean age 49.7 ± 14.8 years). The main clinical correlates of disease, such as disease activity, renal function, skin, vascular and lung involvement, were evaluated by clinical and instrumental investigations. Acti- vated factor VII level was also evaluated in 28 sex and age matched controls. Results. Systemic sclerosis patients exhibited plasma ac- tivated factor VII activities significantly lower than those of healthy matched controls (15.2 versus 37.7 U/l, respec- tively; p < 0.001). No correlation was observed between plasma activated factor VII concentration and age, disease duration, disease subset, disease activity, renal, lung, skin and microvascular involvement. ∗ Contributed equally to this work. A. Volpe . P. Caramaschi . S. Canestrini . A. Carletto . L. M. Bambara . D. Biasi Dipartimento di Medicina Clinica e Sperimentale, Universit` a di Verona, Verona, Italy G. L. Salvagno . G. Lippi . M. Montagnana . G. C. Guidi () Laboratorio di Biochimica Clinica e Biologia Molecolare Clinica, Dipartimento di Scienze Morfologico-Biomediche, Universit` a di Verona, Verona, Italy e-mail:gsalvagno77@yahoo.it Conclusions. Results of our investigation provide first evi- dence of low activated factor VII activity in patients with sys- temic sclerosis. Reduced activated factor VII activity might be involved in the pathogenesis of the ischemic complica- tions, by modulating apoptotic and angiogenetic processes. Keywords Systemic sclerosis . Coagulation . Activated factor VII . Thrombosis Introduction Systemic sclerosis (SSc) is a multisystemic disorder of the connective tissue, characterized by microvascular dam- age with associated cutaneous and internal organ fibrosis. Histopathological hallmarks of SSc are perivascular infil- trates and a reduced capillary density, which precede the excessive accumulation of extracellular matrix proteins. The vascular involvement affects primarily small arteries and cap- illaries and causes reduced blood flow and tissue ischemia, supporting the typical clinical manifestations of this unique autoimmune disorder. The mechanisms involved in the en- dothelial injury are yet elusive and most biochemical evi- dences are often inconclusive or controversial. Endothelial cell apoptosis recently received major attention as a piv- otal event among the complex mechanisms involved in the pathogenesis of vascular injury and dysfunction [1]. More- over, impaired angiogenesis is a well-recognized characteris- tic of SSc. Thus, disorganized neoangiogenesis may be inter- preted as an attempt to supply to the capillary loss. Impaired vasculogenesis may also be involved in the pathogenesis of SSc, as demonstrated by the presence of a substantially re- duced number of bone-marrow-derived circulating endothe- lial precursors. The lowest values of these immature cells were observed in SSc patients with active fingertip ulcers, Springer