Fusae Deguchi

Plasma von Willebrand factor and thrombomodulin as markers of vascular disorders in patients undergoing regular hemodialysis therapy.

Increased plasma levels of von Willebrand factor antigen (vWF:Ag) are regarded as reflecting the release reaction by vascular endothelial cells and/or endothelial cell injury, and increased levels of thrombomodulin (TM) antigen as reflecting damage to endothelial cells. We investigated changes in plasma vWF:Ag and TM antigen levels during the course of regular hemodialysis treatment (RDT) in 14 patients undergoing RDT in order to evaluate the effect of hemodialysis (HD) on endothelial cells. vWF:Ag and TM were both measured by the sandwich EIA method. Predialysis levels of vWF:Ag and TM in RDT patients were both significantly higher than normal control values. Neither patient age nor blood pressure was not correlated with predialysis vWF:Ag and TM levels. Both vWF:Ag and TM levels significantly increased during a single HD session. There was a positive correlation between predialysis TM levels and duration of HD and an inverse correlation between the amount of vWF:Ag released during HD and duration of HD. It appears that HD procedures induce stimulation and damage of endothelial cells and that long-term, recurrent HD treatment may predispose to vascular disorders.

Coagulation and fibrinolysis in patients with chronic renal failure undergoing conservative treatment

Eighteen patients with chronic renal failure due to primary glomerular disease undergoing conservative treatment (CRF patients) were studied to evaluate whether coagulation and fibrinolytic activity in plasma are enhanced in the patients. We measured plasma levels of coagulation-fibrinolysis parameters including thrombin-antithrombin III complex (TAT) (an index of thrombin formation), alpha 2-plasmin inhibitor (alpha 2 PI)-plasmin complex (alpha 2 PIC) (an indicator of plasmin production) and cross-linked fibrin degradation products (XL-FDP) (an index of fibrinolysis secondary to coagulation). There was no correlation between plasma levels of TAT, alpha 2PIC and XL-FDP and serum creatinine levels in CRF patients. Both fibrinogen and TAT were found to be significantly higher in CRF patients than in normal controls. TAT was negatively correlated with serum albumin or total protein. Antithrombin III (ATIII) activity was significantly lower in CRF patients than in normal controls. CRF patients showed significantly but slightly higher alpha 2 PIC and XL-FDP when compared to normal controls. These results suggest that TAT, alpha 2PIC and XL-FDP are good indicators of coagulation-fibrinolysis even in patients with decreased renal function. Coagulation activity is significantly increased in CRF patients but fibrinolysis secondary to coagulation is only slightly enhanced.

Intraglomerular Deposition of Coagulation-Fibrinolysis Factors and a Platelet Membrane Antigen in Various Glomerular Diseases

The intraglomerular location of coagulation-fibrinolysis factors (CFF) and a platelet membrane antigen (glycoprotein IIb-IIIa; GPIIb-IIIa) was determined in 101 patients with various glomerular diseases. Renal biopsy specimens were examined by immunofluorescence microscopy, using antisera against fibrinogen/fibrin reactive antigen (FRA), cross-linked fibrin degradation products (XL-FDP), fibronectin (FN), factor XIII-subunit a (F-XIIIa), plasminogen (Plg), alpha 2-plasmin inhibitor (alpha 2-PI) and GPIIb-IIIa. Intraglomerular deposits of the CFF were found at high rates in patients with IgA glomerulonephritis (GN), membranous nephropathy (MN) and lupus GN. The coexistence of deposits of these factors was ascertained by the double-staining method. The deposition rates of XL-FDP and GPIIb-IIIa were very low in patients with minimal-change nephrotic syndrome and focal glomerulosclerosis. Some cases of diabetic glomerulosclerosis (DGS) showed CFF deposition. FRA deposits associated with F-XIIIa and FN may indicate the presence of the cross-linked fibrin. Furthermore, the presence of Plg deposits together with alpha 2-PI and XL-FDP suggests the deposition of fibrin followed by fibrinolysis, but not of fibrinogen, and the coexistence of GPIIb-IIIa suggests the involvement of platelets in the reactions. These studies provide evidence that stabilized fibrin deposition with subsequent fibrinolysis and platelet activation take place in glomeruli in a fairly large proportion of patients with IgA GN, MN and lupus GN and in some cases of DGS.

Enhanced Coagulation and Fibrinolysis during Treatment with Recombinant Human Erythropoietin in Patients Undergoing Chronic Hemodialysis

Twenty-two patients on regular hemodialysis treatment suffering from renal anemia were treated with intravenous recombinant human erythropoietin (rhEPO) for more than 8 weeks. Before and 4 and 8 weeks after the start of rhEPO administration, we measured prothrombin time, activated partial thromboplastin time, fibrinogen (FBG), antithrombin III activity (ATIII), plasminogen activity (PLG), alpha 2-plasmin inhibitor activity (alpha 2 PI), alpha 2-plasmin inhibitor-plasmin complex (alpha 2 PIC), and cross-linked fibrin degradation products (XL-FDP) in citrated plasma to determine whether rhEPO treatment enhances coagulation and fibrinolytic activity. The pretreatment values of FBG, alpha 2 PIC, and XL-FDP were significantly higher than the normal control values. The pretreatment values of ATIII, PLG, and alpha 2 PI were significantly lower than the normal control values. Platelet count and FBG were significantly increased 4 and 8 weeks after treatment with rhE-PO. The prothrombin time was significantly shortened 8 weeks after rhEPO treatment, but the activated partial thromboplastin time did not change. PLG was significantly decreased 4 and 8 weeks after rhEPO treatment, and ATIII and alpha 2 PI were significantly decreased 8 weeks after rhEPO treatment. alpha 2 PIC was significantly increased 8 weeks after rhEPO treatment, and XL-FDP was significantly increased 4 and 8 weeks after rhEPO treatment. These data suggest that in patients on regular hemodialysis treatment coagulation and fibrinolysis are already enhanced before the start of rhEPO treatment and that rhEPO administration further enhances these disorders.

Plasma Thrombomodulin in Primary Glomerular Disease and Lupus glomerulonephritis

Although thrombomodulin (TM) in circulating blood is regarded as an indicator of vascular endothelial disorders, blood TM levels are also known to be affected by renal dysfunction. We measured plasma TM levels in primary glomerular disease (PGD) and lupus glomerulonephritis (GN) with the EIA method, and assessed the extent to which renal dysfunction and endothelial disorders contribute to plasma TM levels in these diseases. The plasma TM/serum creatinine (TM/Cr) ratio was significantly higher in lupus GN patients than in PGD patients or normal controls. A significant positive correlation was found between plasma TM and serum Cr levels in both PGD and lupus GN patients, but the slope (A) of the regression line (TM = A.Cr+B) in lupus GN patients was significantly steeper than in PGD patients. We conclude that plasma TM levels are greatly influenced by renal dysfunction, but that not only renal dysfunction but endothelial disorders may be an important determinant of increased plasma TM levels in diseases such as lupus GN.

Study of five patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-positive rapidly progressive glomerulonephritis during the course of interstitial pneumonitis

Five patients with rapidly progressive glomerulonephritis (RPGN) that developed during the management of interstitial pneumonitis at our hospital in the past 5 years were studied. In these patients, chronic interstitial pneumonitis preceded the onset of nephritis by periods of 0 to 11 years. All patients had a high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) when RPGN was diagnosed. One patient had anti-proteinase-3 antibodies and another had anti-glomerular basement membrane antibodies. Renal biopsy was performed in all patients. All patients showed necrotizing and crescentic glomerulonephritis, without the deposition of immunoglobulins, and were diagnosed as having pauci immune RPGN. The relationship between MPO-ANCA-related RPGN and chronic interstitial pneumonitis remains unclear. Our present findings indicate that interstitial pneumonitis is important as a preceding condition in some patients with MPO-ANCA-related RPGN. Four patients were older than 70 years. Therefore, particular attention should be paid to the possibility of MPO-ANCA-related RPGN in elderly patients with chronic interstitial pneumonitis.