Clinical Significance of Endothelial Damage Markers in Essential Mixed Cryoglobulinemia

Abstract

Essential mixed cryoglobulinemia (EMC) is a rheumatic disorder characterized by widespread vasculitis. To better define the nature of the vasculitic process and to possibly outline assessment methods reliable for using in a clinical context, we studied plasma levels of three endothelial related peptides: fibronectin (FN), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA), and those of thrombin-antithrombin IIIcomplexes (TAT) as markers of activation of the coagulation in 21 patients and in 16 controls. In EMC we found a picture consisting of reduced FN and increased vWF, t-PA, and TAT levels, suggesting a condition of endothelial cell damage with thrombin formation in vivo. Since we previously demonstrated the presence of chronic disseminated intravascular coagulation in these patients, we may assume that endothelial cells stressed by cryoprecipitation or stimulated by soluble mediators may be actively involved in the vasculitic process and possibly express procoagulant properties. This is a good example of the complex interplay existing between autoimmunity and coagulation mechanisms. We also suggest that FN, vWF, t-PA and TAT should be considered as additional clinical parameters when evaluating patients with EMC.

Structural and Functional Characterization of Plasma Fibronectin in Patients with Essential Mixed Cryoglobulinaemia

“…It can be seen that plasma fibronectin concentrations were significantly lower in the patients than in normal subjects (231.7 ± 15.3 vs 316.1 ± 16.6 mg/1, P < 0.0002), confirming our previous data obtained in a smaller group (20). In agreement with previously reported observations (36,44), SDS-PAGE of reduced plasma fibronection from both patients and controls showed a single polypeptide band with a relative molecular mass of about Mr 250 000, indicating size homogeneity of the purified protein.…”

“…This, in turn, could result in the consumption of the glycoprotein, leading to a reduction of its plasma concentration. The alternative hypothesis of an enzymatic cleavage of fibronectin by plasmin and/or thrombin produced in vivo in patients with essential mixed cryoglobulinaemia with loss of immunoreactive fragments, as suggested by recent data from our group (20), seems to be excluded on the basis of the western blotting results of the present study which demonstrate that plasma fibronectin concentrations are actually reduced in the disease. It has been shown experimentally that in different cell systems different fibronectin mRNAs originate by alternative splicing of a common precursor RNA.…”

“…However the possibility cannot be excluded that the reduced plasma fibronectin concentrations detected in cryoglobulinaemic patients are the result of an enzymatic cleavage of the molecule in vivo with loss of fragments essential for immunologic reactivity in the ELISA assays. This hypothesis seems to be supported by the demonstration by our group of increased concentrations of plasma tissue plasminogen activator and thrombin-antithrombin III complexes in these patients as a consequence of endothelial damage (20), suggesting that the fibronectin molecule is digested by plasmin produced by activation of the fibrinolytic pathway and/or by thrombin formed during the activation of the coagulation cascade (21)(22)(23).…”

“…Experimental studies by us and others have shown that plasma fibronectin may be associated with cryoglobulins and that it may participate in cryoprecipitate formation (17 -19). We also recently demonstrated that immunoenzymatically measured plasma fibronectin concentrations are reduced in patients with essential mixed cryoglobulinaemia suggesting that an impairment in plasma opsonic activity may be a feature of the disease and can therefore contribute to the abnormal persistence of cold-insoluble complexes in the circulation and to tissue damage (19,20). However the possibility cannot be excluded that the reduced plasma fibronectin concentrations detected in cryoglobulinaemic patients are the result of an enzymatic cleavage of the molecule in vivo with loss of fragments essential for immunologic reactivity in the ELISA assays.…”

Beyond Neurons: Evidence That Immune and Glial Cells Contribute to Pathological Pain States

“…Whatever the underlying etiology, induction of vasculitis in the peripheral nerve blood vessels results in an environment characterized by widespread occlusion of blood vessels due to clot formation within the lumen of these vessels (i.e., disseminated intravascular coagulation), increased attachment of immune cells to vessel walls, and disruption of the blood-nerve barrier leading to edema and endoneurial immune cell migration (263,311). VN typically occurs at multiple sites throughout the body, scattered randomly across nerves (i.e., an asymmetrical polyneuropathy) (102,337).…”