thromboplastin and Renal-Insufficiency

Vascular endothelial cell dysfunction is linked to hemostatic abnormalities and accelerated atherosclerosis in patients receiving maintenance hemodialysis (HD). The relationships between pre-dialysis plasma levels of immunoreactive thrombomodulin, von Willebrand factor, tissue factor and its inhibitor were studied, and the effects of HD procedure on these endothelial markers were observed. All the markers were higher in 39 HD patients than in 15 healthy controls (p<0.0001). HD treatment resulted in a 50% increase in tissue factor pathway inhibitor (p<0.0001), but did not influence the other markers. This increment directly correlated with the post-dialysis decrease in diastolic (p=0.011) and mean arterial blood pressure (p=0.039), and the surface area of the dialysis membrane (p=0.007). There were no associations between the increase in tissue factor pathway inhibitor and the amount of fluid removed, dose of enoxaparin, or other HD-specific factors. In conclusion, HD is responsible for an increase in plasma tissue pathway factor inhibitor level. The release of tissue factor pathway inhibitor during HD is not only due to heparin injection but also to the contact between blood and artificial dialysis membrane, and to HD-activated hemodynamic forces.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Endothelium, Vascular; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Thrombomodulin; Thromboplastin; von Willebrand Factor

Dear Editor, Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to periosteal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socioeconomic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Herein, we present an illustrative case of scurvy in order to raise the awareness of this disorder. A 61-year-old Caucasian man was admitted to hospital due to fatigue, hypotension (80/50 mmHg), severe normocytic anemia (hemoglobin 76 g/L), kidney failure (estimated glomerular filtration rate of 6 mL/min/1.73m2) and mild elevation in C-reactive protein (30.9 mg/L). Prior medical history included radical cystoprostatectomy with an ileal conduit performed eight years ago due to a bladder tumor and moderate chronic kidney disease with recurrent urinary tract infections. The patient was also an alcoholic and tobacco smoker, with a very low-income and a poor diet. He did not use any medications. Heteroanamnestically, the current clinical state had developed slowly over several weeks. At admission, the patient was afebrile, lethargic, malnourished, and immobile due to generalized weakness, bone pains, and hip and knee contractures. He had generalized edema, mostly related to kidney failure, as well as severe hypoalbuminemia (serum albumin 19 g/L). There were multiple ecchymoses (Figure 1, a) and perifollicular bleedings (Figure 1, b) in the skin. The teeth were defective, and the patient's facial hair had a "corkscrew" appearance (Figure 1, c). The platelet count was normal, as was the serum fibrinogen level and the prothrombin- and activated partial thromboplastin times. Vancomycin-resistant Enterococcus faecium and multi-drug-resistant Acinetobacter baumanii were isolated from the urine. Therefore, hemodialysis, linezolid, and colistin were started. However, the patient continued to be lethargic, immobile, and with prominent skin bleed

Topics: Anemia; Anticoagulants; Ascorbic Acid; Ascorbic Acid Deficiency; C-Reactive Protein; Colistin; Contracture; Fatigue; Fibrinogen; Humans; Linezolid; Male; Middle Aged; Prothrombin; Renal Insufficiency; Scurvy; Serum Albumin; Thromboplastin; Vancomycin; Vitamins

Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with beta(2) glycoprotein I (beta2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.

Topics: Adult; Animals; Antibodies, Antiphospholipid; Antibodies, Monoclonal; Antigen-Antibody Reactions; Disease Models, Animal; Female; Humans; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Microvessels; Middle Aged; Renal Insufficiency; Thromboplastin; Thrombosis

Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. We hypothesized that blockade of factor X binding to the tissue factor-factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to tissue factor intravenously to block tissue factor-factor X binding. The animals were monitored physiologically for 34 h before being killed and their tissue harvested. The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all P < 0.05). It also attenuated fibrinogen depletion (P < 0.01) and decreased proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Blockade of factor X binding to the tissue factor-factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways.

Topics: Animals; Antibodies, Monoclonal; Blood Circulation; Capillary Permeability; Cells, Cultured; Cytokines; Endothelial Cells; Escherichia coli Infections; Factor X; Humans; Immunoglobulin Fab Fragments; Inflammation Mediators; Lipopolysaccharides; Male; Papio; Renal Insufficiency; Respiratory Insufficiency; Thromboplastin

Atherosclerotic cardiovascular disease is the leading cause of the increased morbidity and mortality observed in uremic patients. Thrombosis is an important contributor to the evolution of atherosclerotic lesions. The physiologically-relevant blood clotting depends on binding of activated factor VII (FVIIa) to exposed tissue factor (TF) on activated/damaged cells.. A cross-sectional study was performed on three age- and sex-matched groups of individuals: one group of 50 patients on maintenance hemodialysis (D group), one of 50 patients with a non-dialysed renal insufficiency (ND group) and one of 50 healthy controls (HC group). We studied basal plasma concentrations of FVIIa, factor VII-related antigen (FVIIAg), soluble TF, tissue factor pathway inhibitor (TFPI), TF-dependent circulating monocytes procoagulant activity (TF-dMPA), tissue factor-dependent plasma reactivity to activated protein C (TF-aPC), D-dimers (D-Di), and circulating markers of cellular activation/injury: soluble thrombomodulin (sTM), circulating microparticles (microP), soluble leukocyte, endothelial and platelet selectins (sL-selectin, sE-selectin, sP-selectin), soluble intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 (sICAM-1 and sVCAM-1). Their variations induced, in hemodialysis patients, by a dialysis run were thereafter studied. Values of FVIIa, FVIIa/FVIIAg ratio, sTF, TFPI, TF-dMPA, D-Di, sTM, microP, sL, sE and sP selectins, sICAM-1 and sVCAM-1 increased all along the hierarchy HC group/ND group/D group. Microparticles were mainly of platelet origin, to a lesser extent of monocyte origin. Dialysis induced an increase of FVIIa, sTF, TF-dMPA and circulating markers of cellular activation/injury. Strong correlations were observed between FVIIa/FVIIAg ratio and serum creatinine levels, sTF, TF-dMPA, sTM, sE-selectin, sVCAM-1. The TF-aPC was impaired in the ND and the D group, and the lower values were, in the D group, associated with antecedents of vascular access thrombosis.. Renal insufficiency is associated to an activation of the tissue factor coagulation pathway, to a platelet, monocyte and endothelial activation/injury and to a deficient tissue-factor induced response to activated protein C which culminate in end-stage disease and are increased by hemodialysis runs. This contributes to linked coagulation and cellular conditions for an enhanced atherosclerosis progression. Due to the TF pathway activation, the therapeutic use of recombinant TFPI should be evaluated.

Topics: Activated Protein C Resistance; Adult; Aged; Blood Coagulation; Blood Coagulation Factors; Case-Control Studies; Cell Adhesion Molecules; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Thrombophilia; Thromboplastin

Topics: Acute Disease; Adult; Aged; Chronic Disease; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Insufficiency; 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

We examined plasma antigen levels of tissue factor (TF) in 95 cases of disseminated intravascular coagulation (DIC), to investigate the role of TF in DIC. A significant elevation of plasma antigen levels of TF was observed in cases of DIC associated with cancer. However, no such significant elevation was observed in cases of DIC associated with acute promyelocytic leukemia (APL), acute leukemia except APL, blastic crisis of chronic myelogenous leukemia, non-Hodgkin lymphoma (NHL), sepsis or fulminant hepatitis. No significant elevation of TF was observed in patients without DIC, except 4 cases of cancer who developed DIC thereafter. Plasma antigen levels of TF were higher in both cases of DIC with renal failure and chronic renal failure without DIC than its levels in those without renal failure. Therefore, plasma antigen levels of TF in DIC patients with renal failure were considered to be carefully estimated. The levels of TF were decreased with the clinical improvement in some cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. Thus, plasma antigen levels of TF is an important marker to predict the development and/or prognosis of DIC, especially in patients with cancer.

Topics: Adult; Disseminated Intravascular Coagulation; Female; Humans; Male; Neoplasms; Prognosis; Renal Insufficiency; Thromboplastin