thromboplastin and Glomerulonephritis

Tissue Factor is the principal cellular initiator of normal blood coagulation. It is frequently encrypted in the plasma membrane of cells in contact with blood, but under certain pathological conditions endothelial cells, monocytes or macrophages may express tissue factor; and hence trigger coagulation activation. Aberrant expression of tissue factor by these cells is thought to be responsible for the thrombophilia found in septic shock, atherosclerosis and cancer. Tissue factor is produced by tumor-associated macrophages where it is believed to play an important role in tumor growth and dissemination. It may also be involved in other cellular processes such as intracellular signalling, angiogenesis and embryonic blood-vessel development. Tissue factor can be found both as free (soluble tissue factor) and membrane bound forms. Several studies have shown that measurements of any of these forms may provide clinically significant information, particularly in patients with malignant and inflammatory diseases, and are cost-effective.

Topics: Blood Coagulation; Glomerulonephritis; Hematologic Tests; Humans; Neoplasms; Neovascularization, Pathologic; Thromboplastin

Topics: Animals; Basement Membrane; Blood Coagulation; Disease Models, Animal; Glomerulonephritis; Humans; Kidney Diseases; Kidney Glomerulus; Macrophages; Thromboplastin

The importance of the blood coagulation sequence as an integral part in the pathogenesis of diseases inside as well as outside the blood vessels is becoming increasingly apparent. Mononuclear phagocytes have important functions in initiation of coagulation by producing several procoagulant substances, including thromboplastin, the potent trigger of the extrinsic pathway. Increasing evidence demonstrates the clinical importance of monocyte and macrophage thromboplastin synthesis in the pathogenesis of a variety of diseases. This review surveys the role of monocyte/macrophage thromboplastin in relation to inflammatory diseases, cancer, disseminated intravascular coagulation and diseases of the blood vessels, thrombosis and atherosclerosis.

Topics: Arteriosclerosis; Arthritis, Rheumatoid; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Endopeptidases; Glomerulonephritis; Graft Rejection; Humans; Hypersensitivity, Delayed; Kidney Transplantation; Membrane Proteins; Monocytes; Neoplasm Proteins; Pulmonary Embolism; Thromboplastin

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Flow Velocity; Child; Child, Preschool; Clinical Laboratory Techniques; Dextrans; Female; Fibrinolytic Agents; Glomerulonephritis; Hemangioma, Cavernous; Heparin; Humans; Infections; Liver Cirrhosis; Male; Mycoses; Parasitic Diseases; Pregnancy; Pregnancy Complications; Purpura; Shock; Thrombocytopenia; Thromboplastin; Uremia

Crescentic glomerulonephritis (CresGN), an uncommon rapidly progressive disease, is characterized by severe glomerular inflammation with fibrin deposition. The lack of specific CresGN biomarkers delays diagnosis and threatens life. Because fibrin deposits in CresGN glomeruli indicate thrombin generation, we hypothesized that thrombin is excreted in urine and is a specific CresGN biomarker.. We measured urinary thrombin activity in 200 untreated patients (17 with CresGN, 183 with primary glomerulonephritis) and controls (8 patients with healed CresGN, 11 with nephrosclerosis, and 10 with tubulointerstitial nephritis, and 66 healthy volunteers). CresGN types included 15 pauci-immune and 2 immune complex. We assessed the diagnostic accuracy of thrombinuria in 169 patients with hematuria and proteinuria. Renal biopsy tissues were immunostained for tissue factor and fibrin. We analyzed the relationship of thrombinuria to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, glomerular fibrin deposition, antineutrophil cytoplasmic antibodies (ANCAs), and C-reactive protein (CRP). We studied changes in thrombin activities after glucocorticoid treatment in 12 patients with thrombinuria.. The highest thrombinuria occurrence was in CresGN (70.6%), followed by membranoproliferative glomerulonephritis (41.7%), IgA nephropathy (9.2%), and acute glomerulonephritis (0%). More than 75% of patients with nonproliferative glomerulonephritis manifested no thrombinuria. No controls had thrombinuria. Thrombinuria showed high CresGN specificity (90.1%) and moderate sensitivity (70.6%) and was detected in 4 of 7 patients with ANCA-negative CresGN. In CresGN, thrombinuria was associated with fibrin deposition in glomerular extracapillary tissue, where monocytes/macrophages expressed tissue factor. Thrombinuria in CresGN was unrelated to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, and CRP. After glucocorticoid treatment, thrombinuria in patients with CresGN rapidly disappeared but proteinuria and hematuria persisted.. Thrombinuria was specific for glomerular inflammation, was unaffected by systemic inflammation or coagulation, and demonstrated good diagnostic accuracy for CresGN including ANCA-negative cases. Thrombinuria measurement may provide risk-free diagnosis and screening for CresGN.

Topics: Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Female; Glomerular Filtration Rate; Glomerulonephritis; Glucocorticoids; Humans; Male; Middle Aged; Prospective Studies; Sensitivity and Specificity; Thrombin; Thromboplastin

Tissue factor (TF) is a transmembrane protein that is essential for coagulation. TF is expressed on podocytes and its cytoplasmic domain has cell signalling functions in epithelial cells.. Mice lacking the cytoplasmic domain of TF (TF(CT-/-) mice) were used to study its role in physiological albuminuria and pathological proteinuria following induction of glomerulonephritis (GN).. Absence of the cytoplasmic domain of TF was associated with increased albuminuria, podocyte effacement, reduced podocyte numbers and increased spontaneous glomerular tumour necrosis factor α(TNFα) production under physiological conditions. In mice developing GN, absence of the cytoplasmic domain of TF resulted in increased proteinuria and enhanced renal TNFα production without altering other parameters of renal inflammation and injury. Studies in TF(CT-/-) chimeric mice (created by bone marrow transplantation) showed increased proteinuria and renal TNFα mRNA in GN was associated with absence of the cytoplasmic domain of TF in the kidney and was independent of the leucocyte phenotype.. These studies demonstrate that the cytoplasmic domain of TF contributes to renal albumin retention and its renal expression protects against proteinuria in leucocyte-mediated renal inflammation. Increased glomerular production of TNFα in the absence of cytoplasmic domain of TF may contribute to podocyte injury resulting in albuminuria and proteinuria.

Topics: Albuminuria; Animals; Cytoplasm; Glomerulonephritis; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Podocytes; Protein Structure, Tertiary; Proteinuria; Thromboplastin; Tumor Necrosis Factor-alpha

Nephrotic syndrome (NS) is associated with numerous blood coagulation abnormalities and a marked predisposition to thromboembolism. Fibrin formation within the glomeruli occurs in various forms of human and experimental glomerulonephritis and may play an important role in progressive glomerular injury. The aim of this study was to measure the plasma concentrations of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and intravascular thrombin generation markers and to analyze their relationships in patients with primary glomerulonephritis.. The study population comprised 57 patients (mean age 35.2 years; range 18-63 years) with primary glomerulonephritis: 36 with NS (NS group) and 21 without (non-NS group). The control group consisted of 24 sex- and age-matched healthy volunteers. TF and TFPI antigen, prothrombin fragment F 1+2 (PF 1+2) and thrombin-antithrombin III complex (TAT) concentrations in plasma were estimated using commercially available kits.. Serum TF and TFPI concentrations in both the NS and non-NS groups were higher than those observed in the control group. Moreover, there were significant differences in TF and TFPI concentrations between the NS and non-NS groups. TF:TFPI ratios in both the examined groups were constant and significantly higher than those in the control group. Positive correlations between TF and both PF 1+2 and TAT concentrations in the total cohort of patients were shown. Furthermore, a positive correlation between TF and TFPI concentrations was observed.. Our data support the hypothesis concerning activation of coagulation pathways in patients with primary glomerulonephritis. An inadequate TFPI concentration as a result of an elevated TF:TFPI ratio characterizes not only patients with clinical manifestations of NS but also patients with mild proteinuria.

Topics: Adolescent; Adult; Antithrombin III; Blood Coagulation; Case-Control Studies; Disease Progression; Female; Glomerulonephritis; Humans; Lipoproteins; Male; Middle Aged; Nephrotic Syndrome; Peptide Fragments; Peptide Hydrolases; Protein Precursors; Proteinuria; Prothrombin; Thromboplastin

Protease-activated receptor-2 (PAR-2) is a cellular receptor expressed prominently on epithelial, mesangial, and endothelial cells in the kidney and on macrophages. PAR-2 is activated by serine proteases such as trypsin, tryptase, and coagulation factors VIIa and Xa. It induces pleiotropic effects including vasodilatation, increasing plasminogen activator inhibitor (PAI-1) expression, mesangial cell proliferation, and cytokine production by macrophages. The role of PAR-2 in renal inflammation was studied in antiglomerular basement membrane antibody-induced crescentic glomerulonephritis (CGN) using PAR-2-deficient (PAR-2(-/-)) mice and wild-type littermate controls. PAR-2(-/-) mice had reduced crescent formation, proteinuria, and serum creatinine compared with wild-type mice 21 days after initiation of CGN. Glomerular accumulation of CD4(+) T cells and macrophages and the number of proliferating cells in glomeruli were similar in both groups. Glomerular fibrin deposition was significantly reduced in PAR-2(-/-) mice, and this was associated with reduced renal plasminogen activator inhibitor expression and increased renal matrix-metalloprotinase-9 activity. These results demonstrate a proinflammatory role for PAR-2 in CGN that is independent of effects on glomerular leukocyte recruitment and mesangial cell proliferation. PAR-2-mediated augmentation of renal plasminogen activator inhibitor expression and inhibition of matrix-metalloprotinase-9 activity may contribute to increased glomerular fibrin accumulation and glomerular injury in CGN.

Topics: Animals; Fibrin; Glomerulonephritis; Kidney Glomerulus; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Receptor, PAR-2; Serpin E2; Serpins; Thromboplastin; Transforming Growth Factor beta1

Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of tissue factor (TF) induced coagulation. In addition to its anticoagulation activity, TFPI has other functions such as antiproliferation and inducing apoptosis. In the present study, we investigated whether or not TFPI induced apoptosis in cultured rat mesangial cells (MsCs) and the possible signal pathway that involved in the apoptotic process. We demonstrated that recombinant TFPI (rTFPI) induced apoptosis in cultured MsCs via its Kunitz-3 domain and C-terminal in a dose- and time-dependent manner by Hoechst 33258 assay, flow cytometry, nucleosomal laddering of DNA, caspase 3 assay. Because the serine/threonine protein kinase Akt has attracted attention as a mediator of survival (anti-apoptotic) signal in MsCs, we investigated the expression of phosphospecific-Akt and its downstream signal phospho-IkappaB-alpha and some other signal molecules like Fas and bcl-2. The results indicated that the process of apoptosis triggered by rTFPI is, at least in part, actively conducted by rat MsCs possibly through PI3-Kinase-Akt signal pathway not by binding to tissue factor. Our findings suggest that rTFPI has the potential usefulness in inducing apoptosis of MsCs under inflammatory conditions.

Topics: Animals; Apoptosis; Caspase 3; Cell Nucleus; Cells, Cultured; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; fas Receptor; Glomerulonephritis; Lipoproteins; Male; Mesangial Cells; Peptide Fragments; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Structure-Activity Relationship; Thromboplastin

Tissue factor (TF)-the most potent trigger of coagulation and emerging antiapoptotic, proliferative and angiogenic factor, along with its principal inhibitor (tissue factor pathway inhibitor, TFPI) are known to be involved in crescentic glomerulonephritis (GN). We studied the relationship between plasma and urinary levels as well as renal biopsy immunostaining of TF and TFPI antigens with reference to some clinical parameters in human chronic non-crescentic GN.. We examined plasma and urinary levels of TF and total TFPI (pre-biopsy, ELISA) and the intensity of TF, TFPI 1 and TFPI 2 staining (immunoperoxidase histochemistry) in kidney biopsy specimens from 30 chronic GN patients.. Plasma and urinary TF (uTF) were higher in patients than in 18 healthy individuals. In normal kidneys, TF and TFPI 1/2 antigens were undetectable in glomeruli while a distinct staining of both TFPI variants was observed in tubules and interstitial microvessels. In diseased kidneys, TF was strongly expressed in glomeruli but was undetectable in tubules. In contrast, staining for TFPI 1/2 was observed in glomeruli and tubules. Neither plasma nor urinary levels of the markers correlated with the intensity of TF and TFPI 1/2 staining in biopsy specimens. uTF was significantly associated with creatinine clearance (R = 0.489, P = 0.006) and urinary TFPI (R = 0.554, P = 0.014), and tended to be lower in proliferative vs non-proliferative GN [83 (0-617) vs 281 (10-805) pg/ml; P = 0.06].. The intrarenal TF/TFPI system is profoundly disturbed in chronic GN. Plasma and urinary concentrations of TF and TFPI probably do not reflect genuine activity of the disease, likely due to a confounding effect of kidney insufficiency. uTF measurement seems to be helpful in initial identification of proliferative GN, yet further studies are required to validate its use as a marker of glomerular injury in chronic GN.

Topics: Adolescent; Adult; Aged; Biopsy; Female; Glomerulonephritis; Humans; Immunohistochemistry; Lipoproteins; Male; Middle Aged; Thromboplastin

Glomerular fibrin deposition is a common histological feature of crescentic glomerulonephritis (CGN). Tissue factor (TF) is the most powerful activator of the coagulation system, whereas plasminogen activator inhibitor (PAI)-1 is a key modulator of the fibrinolytic pathway. Thrombin, released locally as the final step of the coagulation cascade and trapped within the fibrin clots, can induce the activation of glomerular cells, through the interaction with a specific receptor. To investigate the mechanisms underlying coagulation cascade activation and fibrin deposition and the role of this phenomenon in the pathogenesis of human CGN, TF, PAI-1, and thrombin receptor expression were studied in CGN biopsy specimens. Glomerular TF gene and protein expression were strikingly increased in CGN, in particular within the crescents and in the mesangial area, with the same distribution of fibrin deposits. Interestingly, very few infiltrating mononuclear cells were stained in TF immunohistochemistry. To better evaluate the involvement of monocytes in TF expression, TF mRNA and CD68 protein were studied by an in situ hybridization/immunohistochemistry combined technique. Only 16% of the cells expressing TF mRNA were CD68 positive. However, most of the TF signal was localized in the proximity of monocytes, suggesting that soluble mediator(s) released by these cells could induce TF expression. Indeed, interleukin-1 (IL-1), one of the main monocyte-derived cytokines, upregulated TF mRNA levels in cultured human mesangial cells in a time-dependent manner. Moreover, a striking increase in IL-1 expression was present within the cellular crescents in CGN biopsy specimens. Finally, we observed a marked upregulation of both PAI-1 and thrombin receptor mRNA levels in CGN with a pattern resembling TF and fibrin distribution. Surprisingly, thrombin receptor protein expression was strikingly downregulated in CGN, suggesting its continuous activation and degradation. In conclusion, we can hypothesize that TF and PAI-1, mainly expressed by resident cells, may play a pivotal role in the development and preservation of fibrin deposits in CGN. In addition, thrombin, released locally and accumulated within the fibrin clots, may represent a pathogenetic mediator of crescentic lesions.

Topics: Adolescent; Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blotting, Northern; Cells, Cultured; Fluorescent Antibody Technique; Glomerular Mesangium; Glomerulonephritis; Humans; Immunohistochemistry; In Situ Hybridization; Interleukin-1; Middle Aged; Plasminogen Activator Inhibitor 1; Receptors, Thrombin; Thrombin; Thromboplastin

Tissue factor (TF) pathway inhibitor (TFPI), the major endogenous inhibitor of extrinsic coagulation pathway activation, protects renal function in experimental crescentic glomerulonephritis (GN). Its glomerular expression and relationship to TF expression and fibrin deposition in human crescentic GN have not been reported.. Glomerular TFPI, TF, and fibrin-related antigen (FRA) expression were correlated in renal biopsies from 11 patients with crescentic GN. Biopsies from 11 patients with thin basement membrane disease and two normal kidneys were used as controls.. TFPI was undetectable in control glomeruli but was detectable in interstitial microvessels. In crescentic biopsies, TFPI was detected in cellular crescents and was more prominent in fibrous/fibrocellular crescents, indicating a correlation with the chronicity of crescentic lesions. TFPI appeared to be associated with macrophages but not endothelial or epithelial cells. TFPI was generally undetectable in regions of the glomerular tuft with minimal damage. In contrast, TF and FRA were strongly expressed in regions of minimal injury, as well as in more advanced proliferative and necrotizing lesions. Despite prominent TF expression, FRA was less prominent in fibrous/fibrocellular crescents in which TFPI expression was maximal.. These data suggest that TFPI is strongly expressed in the later stages of crescent formation and is inversely correlated with the presence of FRA in human crescentic GN. This late induction of TFPI may inhibit TF activity and favor reduced fibrin deposition in the chronic stages of crescent formation.

Topics: Adult; Antigens; Arterioles; Basement Membrane; Biopsy; Disease Progression; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Glomerulonephritis; Humans; Kidney Glomerulus; Lipoproteins; Male; Middle Aged; Thromboplastin

Increased glomerular tissue factor (TF) expression is associated with glomerular fibrin deposition and renal failure in human and experimental crescentic glomerulonephritis (GN). However, the in vivo functional contribution of TF to the development of glomerular fibrin deposition, crescent formation, and renal failure in GN has not been established. The contribution of TF to fibrin deposition and renal injury was studied in a rabbit model of crescentic GN in which glomerular macrophage infiltration, augmented TF expression, and fibrin deposition are prominent. Administration of anti-TF antibody inhibited glomerular TF activity in nephritic glomeruli by 96%, without affecting macrophage accumulation or systemic indices of coagulation. Anti-TF antibody significantly reduced glomerular fibrin deposition (fibrin scores, 0.43 +/- 0.10 (treated) and 1.40 +/- 0.19 (control); P < 0.0005), crescent formation (0.33 +/- 0.05 (treated) and 1.0 +/- 0.06 (control); P < 0.0005), and development of renal failure (serum creatinine, 168 +/- 22 mumol/l (treated) and 267 +/- 35 mumol/l (control); P < 0.04). This was associated with significant reduction in proteinuria (1189 +/- 277 mg/24 hours (treated) and 2060 +/- 336 mg/24 hours (control); P < 0.03) and expression of MHC class II antigen in glomeruli (1.25 +/- 0.41 (treated) and 2.83 +/- 0.53 (control); P < 0.03) and in tubules and interstitial areas. These data demonstrate that TF is the major in vivo initiator of fibrin deposition in crescentic GN. The reduction in proteinuria and glomerular major histocompatibility class II antigen expression by TF inhibition suggests that TF may also activate other mediators that contribute to glomerular injury.

Topics: Animals; Antibodies; Blood Coagulation; Fibrin; Glomerulonephritis; Histocompatibility Antigens Class II; Immunoconjugates; Kidney Glomerulus; Male; Proteinuria; Rabbits; Renal Insufficiency; Thromboplastin

To investigate the significance of urinary tissue factor (uTF) concentrations in patients with glomerulonephritis.. Urine samples were collected from normal subjects (n = 57), patients with uncomplicated renal stones (n = 30), and patients with glomerulonephritis (n = 150). Samples were then centrifuged and the pellets solubilised in n-octyl-beta-glucopyranoside. uTF concentrations were determined using a one stage kinetic chromogenic assay.. The uTF concentration was higher in patients with glomerulonephritis than in normal controls (p < 0.01) or in patients with renal stones (p < 0.05). uTF activity correlated with the protein creatinine index (PCI, r = 0.41, p < 0.001) and seven patients with glomerulonephritis and a PCI < or = 0.1 g/mmol had raised uTF. Glomerulonephritis patients were subdivided into two groups depending on the PCI: < 0.2 g/mmol creatinine (mild to moderate proteinuria, group I) and > or = 0.2 g/mmol creatinine (heavy proteinuria, group II). In group I, uTF concentrations were higher in patients with either immune complex (IC) glomerulonephritis (p < 0.01) or non-IC (p < 0.05) glomerulonephritis than in normal controls. In group II, the IC glomerulonephritis group had higher uTF concentrations than normal controls (p < 0.001) or patients with renal stones (p < 0.01); and non-IC glomerulonephritis patients had higher uTF than normal controls (p < 0.01). When the glomerulonephritis groups were divided into broad WHO subtypes, the significance level varied with the type of glomerulonephritis.. uTF is increased in patients with glomerulonephritis, and its concentration may reflect the aetiopathogenesis of glomerulonephritis.

Topics: Biomarkers; Creatinine; Glomerulonephritis; Humans; Kidney Calculi; Proteinuria; Thromboplastin

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.

Topics: Aged; Cardiovascular Diseases; Creatinine; Diabetic Nephropathies; Endothelium, Vascular; Factor VII; Factor VIIa; Female; Glomerulonephritis; Humans; Male; Middle Aged; Renal Dialysis; Risk Factors; Thrombomodulin; Thromboplastin; Uremia

Correlations between glomerular expression of tissue factor (TF) activity and antigen and cellular localization of TF mRNA was studied in crescentic glomerulonephritis (GN) in rabbits. Glomerular TF activity increased 8.7-fold 24 hours after initiation of GN (234 +/- 49 mU/10(3) glomeruli; normal, 27 +/- 10 mU/10(3) glomeruli; P = 0.003) in association with a 2.1-fold increase in TF antigen (154 +/- 34 ng/10(3) glomeruli; normal, 72 +/- 10 ng/10(3) glomeruli; P = 0.055), early macrophage infiltration, and no significant increase in TF mRNA. At the peak glomerular macrophage infiltration (day 4), TF activity remained augmented (230 +/- 63 mU/10(3) glomeruli) and TF mRNA, colocalized within macrophages, was significantly increased compared with normal (267 +/- 42%; P = 0.001). TF antigen was not increased in glomeruli (114 +/- 17 ng/10(3) glomeruli), although significant urinary excretion of TF antigen was detectable (478 +/- 121 ng/24 hours; normal, < 1 ng/24 hours; P = 0.032). At this time, the M(r) of glomerular TF (49 to 61 kd) was increased compared with TF in normal glomeruli (49 to 58 kd) as a result of increased glycosylation. At day 7, TF activity and antigen within glomeruli had decreased, although urinary excretion of TF antigen and glomerular TF mRNA remained elevated. These studies suggest that early up-regulation of TF activity is largely a result of functional up-regulation of constitutive TF in intrinsic glomerular cells. In more advanced disease, infiltrating macrophages are the major site of TF synthesis. The increased M(r) of glomerular TF, as a result of synthesis of more highly glycosylated protein by macrophages and the shedding of TF into the urine, suggests that substantial turnover of glomerular TF occurs at this stage.

Topics: Animals; Antibodies, Monoclonal; Glomerulonephritis; In Situ Hybridization; Kidney Glomerulus; Male; Proteinuria; Rabbits; RNA, Messenger; Thromboplastin

Fibrin deposition is prominent in delayed-type hypersensitivity (DTH) reactions and is initiated by antigen-specific, T-lymphocyte-directed macrophage expression of human tissue factor (HTF). To examine the role of DTH in glomerular fibrin deposition, 10 fibrin-positive and 24 fibrin-negative biopsy specimens from patients with glomerulonephritis (GN) and samples from normal controls were studied with monoclonal antibodies against T cells, macrophages, and HTF. Fibrin-positive sections showed intense glomerular staining for HTF and significantly more T cells and macrophages than fibrin-negative specimens. All the essential elements of DTH reactions can therefore be simultaneously demonstrated within glomeruli from patients with fibrin-related GN. These findings suggest a role for cell mediated immunity in GN.

Topics: Adolescent; Adult; Aged; Factor VIII; Female; Fibrin; Glomerulonephritis; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Macrophages; Male; Middle Aged; T-Lymphocytes; Thromboplastin

Mechanisms for initiation of glomerular fibrin deposition were studied using renal tissue obtained from two patients with rapidly progressive, crescentic glomerulonephritis. Histological examination showed extensive glomerular monocyte infiltration and fibrin deposition in both patients. Sonicated cell suspensions of isolated glomeruli from these patients contained markedly augmented levels of procoagulant activity (PCA) compared with the levels found in normal glomeruli. This PCA was characterized as tissue factor by its functional dependence on Factors VII and V, independence of Factors VIII and XII, inhibition by concanavalin A and phospholipase C, and association with cell membranes. Its coagulant activity was also inhibited by a specific monoclonal anti-human tissue factor antibody. Tissue factor could be identified in glomeruli from these two patients by indirect immunofluorescence using this antibody. These studies implicate extrinsic pathway activation via tissue factor in intraglomerular deposition of fibrin in these patients. Activated monocytes, known to be a potent source of procoagulant activity and seen in large numbers within glomeruli from these patients, are a likely source of this tissue factor.

Topics: Adolescent; Aged; Blood Coagulation Disorders; Blood Coagulation Factors; Concanavalin A; Female; Glomerulonephritis; Humans; Kidney Cortex; Kidney Glomerulus; Male; Thromboplastin; Type C Phospholipases

The mechanism involved in glomerular fibrin deposition was investigated during mercuric chloride (HgCl2)-induced autoimmune glomerulonephritis in the Brown Norway rat. To ascertain whether the local hemostatic system was activated secondarily to the immunological conflict, the ability of glomerular lysates to induce coagulation in vitro was assessed in treated and control rats. Glomerular procoagulant activity (PCA) of HgCl2-injected rats was measured on day 12 (latent phase of the disease), day 20 (acme), and days 32 and 42 (recovery phase) after the first mercury injection. PCA rose 3-fold (p less than 0.02) at day 20 and then almost returned to control values. Proteinuria, PCA, and the incidence of glomerular fibrin deposits peaked concomitantly at day 20. Glomerular PCA was characterized as thromboplastin. The number of Ia positive cells detected by monoclonal OX-6 antibody was not different from the control number at any phase of the disease; the number of macrophages per glomerular section detected by electron microscopy at day 20 in HgCl2-injected rats was 1.80 +/- 0.60, versus 0.30 +/- 0.11 in the controls. No correlation was found between glomerular PCA and either the number of monocytes/macrophages or of Ia-positive cells present in the glomeruli. Since glomerular PCA was maximal at the onset of fibrin formation in the glomeruli and then decreased toward its basal level, and since the fibrin disappeared, it is concluded that increased production of thromboplastin by glomeruli, with activation of the extrinsic coagulation pathway, may contribute to intraglomerular fibrin deposition in HgCl2-induced glomerulonephritis.

Topics: Animals; Autoimmune Diseases; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Glomerulonephritis; Histocompatibility Antigens Class II; Kidney Glomerulus; Macrophages; Male; Mercuric Chloride; Proteinuria; Rats; Rats, Inbred BN; Thromboplastin

Topics: Animals; Anticoagulants; Fibrin; Glomerulonephritis; Humans; Inflammation; Macrophages; Microcirculation; Monocytes; Rabbits; Rats; Thromboplastin

A telescoped model of nephrotoxic nephritis in the rabbit, using guinea pig antiglomerular basement membrane IgG in rabbits preimmunized with guinea pig IgG, reproducibly induced crescentic nephritis. Procoagulant activity (PCA) was measured in sieve-isolated glomeruli that had been either sonicated or cultured for 48 hours. In both sonicated and cultured glomeruli PCA peaked on days 5 and 6. The time course for appearance of PCA corresponded precisely with the appearance of proteinaceous material containing fibrin in Bowman's space as measured by a light microscopic histologic scoring system and confirmed by immunofluorescence and electron microscopy. Glomerular PCA returned to baseline by days 9 and 10 in spite of progression of glomerular injury. PCA also appeared in urine. Urine PCA peaked on day 8 and persisted through day 12 when glomerular PCA had returned to baseline. Glomerular and urine PCA were characterized using human coagulation factor-deficient plasmas and antithromboplastin IgG. Both glomerular PCA and urine PCA were inhibited by antithromboplastin IgG, showing that thromboplastin (tissue factor) contributed to PCA. The PCA in glomerular sonicates was dependent on factor X, but independent of factor VII or Hageman factor, suggesting that factor VII was present. Following glomerular culture for 48 hours the PCA had changed and in some cases was dependent on Hageman factor, factor IX, and factor VII for full PCA expression. Urine PCA was uniformly Hageman factor dependent and sometimes independent of factors VII and X. No active thrombin was present. The forms of glomerular and urine PCA were, therefore, complex. They seemed to be primarily driven by thromboplastin but also appeared to require the presence of the intrinsic coagulation pathway for full expression of PCA.

Topics: Animals; Basement Membrane; Blood Coagulation Factors; Disease Models, Animal; Fibrin; Glomerulonephritis; Immunoglobulin G; Kidney Glomerulus; Macrophages; Rabbits; Thromboplastin; Time Factors

Topics: Acute Disease; Blood Coagulation Disorders; Blood Urea Nitrogen; Factor VIII; Fibrin; Fibrinolysin; Fibrinolysis; Glomerulonephritis; Humans; Thromboplastin; Time Factors

Topics: Adolescent; Adult; Age Factors; Aged; Aminohippuric Acids; Biopsy; Blood Glucose; Blood Pressure; Cell Nucleus; Child; Child, Preschool; Cholesterol; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Glomerulonephritis; Humans; Kidney Glomerulus; Lipids; Middle Aged; Nitrogen; Thromboplastin

Topics: Arteriosclerosis; Chronic Disease; Erythrocytes; Fibrinogen; Glomerulonephritis; Humans; Kidney Diseases; Lipid Metabolism; Thromboplastin

Topics: Animals; Electrons; Female; Fibrin; Glomerulonephritis; Humans; Kidney Diseases; Kidney Glomerulus; Microscopy; Microscopy, Electron; Pathology; Phagocytosis; Pre-Eclampsia; Pregnancy; Rabbits; Research; Sepsis; Thromboplastin