Plasma Activated Factor VII Research Articles

Low levels of activated factor VII in systemic sclerosis

Recent investigations show that activated factor VII, the primary enzyme in the extrinsic pathway 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 sclerosis and to establish a potential association with pathogenesis and complications of this severe autoimmune disorder. 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. Activated factor VII level was also evaluated in 28 sex and age matched controls. Systemic sclerosis patients exhibited plasma activated factor VII activities significantly lower than those of healthy matched controls (15.2 versus 37.7 U/l, respectively; 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. Results of our investigation provide first evidence of low activated factor VII activity in patients with systemic sclerosis. Reduced activated factor VII activity might be involved in the pathogenesis of the ischemic complications, by modulating apoptotic and angiogenetic processes.

Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men.

Patients with diabetes have an increased prevalence of premature atherosclerotic vascular disease, and alterations in plasma coagulation proteins have been incriminated as a possible cause. The roles of hyperglycemia and hyperinsulinemia in the pathogenesis of these changes are unknown. To examine the effects of prolonged hyperglycemia and of selective hyperinsulinemia on the tissue factor pathway of blood coagulation, nine healthy young men were infused with glucose to maintain levels at 11.1 mmol/l (approximately 200 mg/dl) for 18-72 h (hyperglycemia-hyperinsulinemia group). Five normal men were infused with regular insulin to maintain levels comparable to that in the previous group (900 pmol/l, approximately 150 microU/ml) and with glucose to maintain levels at 5.6 mmol/l (approximately 100 mg/dl) (euglycemia-hyperinsulinemia group). Measured were plasma activated factor VII activity (FVIIa), FVII coagulant (FVIIC) activity, FVIII coagulant (FVIIIC) activity, tissue factor pathway inhibitor (TFPI) antigen, and thrombin markers; and serum glucose, insulin, and electrolytes. Plasma FVIIa, FVIIC, FVIIIC, and TFPI rose during hyperglycemic-hyperinsulinemia but not during euglycemic-hyperinsulinemia. Markers of thrombin generation rose transiently and inconsistently during hyperglycemia-hyperinsulinemia. We concluded that in normal subjects, hyperglycemia-hyperinsulinemia induced activation of the tissue factor pathway, reflected by increases in plasma FVIIa, FVIIC, and TFPI. This activation was independent of hyperinsulinemia, hypertriglyceridemia, and hyperosmolality. The elevations in plasma coagulation factors during hyperglycemia-hyperinsulinemia, characteristic of type 2 diabetes, may constitute a potential for enhanced thrombin generation and thrombosis when triggered by exposure of tissue factor, such as during arterial plaque rupture.

Plasma-activated factor VII level in patients positive for lupus anticoagulant.

We examined plasma levels of activated factor VII (F VIla) in 50 patients positive for lupus anticoagulant (LA), in 83 patients negative for LA, and in 10 healthy volunteers as controls. Plasma F VIIa was present in healthy volunteers; its level was significantly increased, compared to the level in the controls, in patients with thrombosis, collagen diseases, and disseminated intravascular coagulation (DIC), suggesting that it reflected a thrombotic state. Plasma F VIIa was correlated with thrombin-antithrombin complex (TAT) in patients negative for LA but showed no such correlation in those positive for LA. Plasma F VIIa was negatively correlated with activated partial thromboplastin time (APTT) in patients positive for LA, but not in those negative for LA, suggesting that LA could inhibit the F VIIa assay system. Plasma F VIIa level was significantly increased in patients with thrombotic diseases; however, in patients positive for LA, it is possible that increased plasma F VIIa level may not be correlated with thrombogenicity.

Clinical significance of activated protein C resistance as a potential marker for hypercoagulable state

The activated protein C (APC)-resistance test is a simple and reliable method for detecting reduced sensitivity to the anticoagulant action of this protein. We investigated the sensitivity to APC in 180 Japanese controls and in 96 Japanese patients with venous and arterial thrombosis (28 with deep vein thrombosis; 13 with pulmonary thromboembolism; 41 with cerebral infarction; and 14 with coronary artery disease). All of the patient groups showed significantly reduced sensitivity to APC, reflected by the lower normalized APC-sensitivity ratio (n-APC-SR), as compared with healthy control. The APC-sensitivity ratio was negatively correlated with plasma activated factor VII levels. These results suggest that the low n-APC-SR is related to venous or arterial thrombotic disease. The APC resistance may serve as a potential marker for assessing the hypercoagulable state.

Marked Increase of Activated Factor VII in Uremic Patients

We investigated plasma activated factor VII (FVIIa) levels in uremic patients (nondialysis group: n = 38; dialysis group: n = 36) and healthy controls (n = 32). We also measured the plasma levels of thrombomodulin (an indicator of endothelial cell injury) and tissue factor. Plasma FVIIa showed a marked increase in the nondialysis group (mean [95% confidence interval]: 4.6 [4.1-5.1] ng/ml, p < 0.0001) with the progressive impairment of renal function, as indicated by the serum creatinine level, when compared with the 32 controls (2.8 [2.5-3.1] ng/ml), and was further increased in the dialysis group (6.1 [5.5-6.8] ng/ml, p < 0.001 vs. nondialysis group). Plasma levels of thrombomodulin and tissue factor were also higher in the nondialysis group than the control group, and were further increased in the dialysis group. Plasma tissue factor levels did not show any correlation with FVIIa or thrombomodulin in both the nondialysis and dialysis groups. Thus, circulating tissue factor appears to be released by a different mechanism from thrombomodulin and may not contribute to the direct activation of factor VII in uremic patients. On the other hand, the plasma level of thrombomodulin was positively correlated with that of FVIIa in the nondialysis group, and this correlation was independent of renal function. Thus, enhanced conversion of factor VII zymogen to FVIIa, probably related to endothelial cell injury, may be a risk factor for cardiovascular events in uremic patients.

Coagulation disturbances following ascites recirculation

To investigate the effects of extra-corporeal ascites recirculation on coagulation, several coagulation variables were measured in ascitic return fluid and plasma before, during and after this procedure in 16 patients with diuretic resistant ascites. Small but significant reductions in plasma fibrinogen levels and platelet counts and increases in plasma X-oligomer were observed during and after the procedure compared with before. These findings are consistent with the view that ascites recirculation induces disseminated intravascular coagulation although this would appear to be only mild and of no clinical significance in the majority of patients. Although increased levels of activated factor VII were observed in ascitic fluid indicating activation of the extrinsic pathway of coagulation, a significant increase in plasma activated factor VII during the procedure was not demonstrated. Increased fibrinolytic activity was observed in ascitic fluid due to the presence of tissue plasminogen activator. Increased X-oligomer levels were observed in ascitic fluid indicating that lysis of cross-linked fibrin is also an active process within ascites.