thromboplastin and Acute-Kidney-Injury

Thrombocytopenia-associated multiple organ failure (TAMOF) is a clinical phenotype that encompasses a spectrum of syndromes associated with disseminated microvascular thromboses, such as the thrombotic microangiopathies thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) and disseminated intravascular coagulation (DIC). Autopsies findings in TTP, HUS, or DIC reveal specific findings that can differentiate these 3 entities. Von Willebrand factor and ADAMTS-13 play a central role in TTP. Shiga toxins and the complement pathway are vital in the development of HUS. Tissue factor is the major protease that drives the pathology of DIC. Acute kidney injury (AKI) is a common feature in patients with TAMOF.

Topics: Acute Kidney Injury; ADAM Proteins; ADAMTS13 Protein; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Complement System Proteins; Disseminated Intravascular Coagulation; Hemolytic-Uremic Syndrome; Humans; Multiple Organ Failure; Purpura, Thrombotic Thrombocytopenic; Shiga Toxins; Thromboplastin; von Willebrand Factor

Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation.

Topics: Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Fibrin; Inflammation; Ischemia; Kidney; Reperfusion; Reperfusion Injury; Thromboplastin; Urokinase-Type Plasminogen Activator

Microvesicles (MVs) play a role in inflammation, coagulation, and vascular homeostasis in liver disease.. To characterize circulating plasma MVs profile in patients with decompensated cirrhosis and acute kidney injury (AKI).. We measured the levels of total, endothelial, platelet, tissue factor (TF)+, leukocyte and hepatocyte MVs by new generation flow-cytometry in a prospective cohort of patients with decompensated cirrhosis with and without AKI.. Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Patients with cirrhosis with AKI had significantly higher calcein+ (total), endothelial, and platelet-MVs. Conversely, TF+, leukocyte, and hepatocyte-MVs were comparable between groups. Resolution of AKI was associated with significantly decreased total and endothelial-MVs that became comparable with those in patients without AKI. Platelet MVs significantly decreased but remained higher compared to patients without AKI. TF+MVs significantly decreased and became lower than patients without AKI. Leukocyte and hepatocyte-MVs remained unchanged. Creatinine (OR 4.3 [95%CI 1.8-10.7]), MELD (OR 1.13 [95%CI 1.02-1.27]), any bleeding (OR 9.07 [95%CI 2.02-40.6]), and hepatocyte-MVs (OR 1.04 [95%CI 1.02-1.07]) were independently associated with 30-day mortality.. AKI worsened vascular and cellular homeostasis in patients with cirrhosis, particularly by inducing endothelial dysfunction and platelet activation. AKI did not worsen systemic inflammation and hepatocytes activation.

Topics: Acute Kidney Injury; Aged; Biomarkers; Blood Platelets; Cell-Derived Microparticles; Endothelial Cells; Female; Hepatocytes; Humans; Leukocytes; Liver Cirrhosis; Male; Middle Aged; Platelet Activation; Prospective Studies; Thromboplastin

Severe sepsis is critical to health and can result in acute renal failure (ARF). Tissue factor (TF) and thrombomodulin (TM) play key roles in vascular endothelial functions by helping maintain microcirculation in the kidney. Budding uninhibited by benzimidazole-1 (Bub1) plays a role in Akt and JNK signaling, which control TF and TM, respectively. We hypothesized that Bub1 could control vascular endothelial function in sepsis. The aim of this study was to determine the role of Bub1 in septic ARF. We used Mouse cecum ligation and puncture (CLP) using low Bub1 expressing (Bub1) and wild-type (Bub1) mice in vivo and lipopolysaccharide (LPS) stimulation of human aortic endothelial cell (HAEC) in vitro. Bub1 mice had a higher survival rate after CLP than Bub1. Bub1 mice had more severe ARF after CLP than Bub1 with blood biochemical and pathological analyses. TF expression in Bub1 mice and control HAEC (control) significantly increased in the septic model compared with Bub1 and Bub1 silenced HAEC (siBub1). TM expression in the control significantly decreased after LPS stimulation compared with siBub1. Akt and JNK phosphorylation of siBub1 were attenuated after LPS stimulation. Associations of Bub1 with Akt or JNK after LPS stimulation of HAEC were detected using immunoprecipitation, suggesting that Bub1 is involved in the phosphorylation of Akt and JNK after LPS stimulation. Bub1 insufficiency attenuates TF expression and reduces TM suppression by blocking Akt and JNK phosphorylation, respectively, thus leading to the prevention of ARF and death caused by sepsis.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Endothelial Cells; Humans; Mice; Mice, Mutant Strains; Protein Serine-Threonine Kinases; Sepsis; Thrombomodulin; Thromboplastin

Acute kidney injury (AKI) is associated with hypercoagulability. Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade activate protease-activated receptor 2 (PAR2). Previously, we have shown that PAR2-mediated inflammation aggravates kidney injury in models of diabetic kidney disease and adenine-induced renal fibrosis. However, the role of PAR2 in AKI remains unclear. To clarify the role of PAR2, we administered cisplatin, one of the most common causal factors of AKI, to wild-type and PAR2-deficient mice. The expression levels of tissue factor and PAR2 were significantly increased in the kidneys of mice that were administered cisplatin. A lack of PAR2 corrected the levels of plasma blood urea nitrogen and creatinine as well as ameliorated the acute tubular injury score in the kidney. A lack of PAR2 corrected the infiltration of neutrophils and the gene expression levels of proinflammatory cytokines/chemokines in these mouse kidneys. Similarly, apoptotic markers, such as cleaved caspase-3-positive area and Bax/Bcl2 ratio, were attenuated via PAR2 deletion. Thus, elevated PAR2 exacerbates cisplatin nephrotoxicity, and targeting PAR2 is a novel therapeutic option that aids in the treatment of patients with cisplatin-induced AKI.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Blood Urea Nitrogen; Cisplatin; Creatinine; Cytokines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Receptor, PAR-2; Thromboplastin

Tissue factor (TF) is involved in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity. It is not known whether MCT/LPS can cause renal toxicity and whether TF is involved in this toxicity. Thus, the present study was undertaken to investigate the potential renal toxicity after MCT/LPS co-treatment and the involvement of TF in this toxicity. MCT was delivered to ND4 male mice (200 mg/kg) per os followed 4 h later by treatment with LPS ip (6 mg/kg) to investigate its effect on kidney. We injected TF antisense oligonucleotide (TF-AS) intravenously (i.v) in mice prior to LPS treatment, to block TF, and measured their blood urea nitrogen (BUN), creatinine (CRE), alkaline phosphatase (ALP), and potassium. In MCT/LPS co-treated group, fibrin was detected on the glomerular capillary lumina, distal tubules of renal cortex, and the necrotic tubules of renal medulla. An elevation of BUN, creatinine, and the BUN/creatinine ratio was seen in mice with MCT/LPS co-treatment, compared to animals receiving LPS or MCT alone. Simultaneously, an aggressive tubular necrosis was seen in the medullary tubules in the same group which may account for the oliguria observed in these animals. Fourfold inductions in the plasma TF level was detected at 10 h after MCT/LPS co-treatment which increased to 18-fold at 24 h. Increased blood level of leptin, interleukin-6 (IL-6) and downregulation of tubular chemokine (C-X-C motif) ligand 16 (CXCL16) are characteristic features in MCT/LPS co-treated animal. On the other hand, mice injected with TF-AS in the presence of MCT/LPS co-treatment showed no elevation of the blood BUN, creatinine, potassium, and normal levels of the proinflammatory molecules. TF-AS injection significantly prevented glomerular and tubular fibrin deposition, tubular necrosis, and improvement of the animal survivability. Renal toxicity involving TF can be prevented successfully by the use of TF-AS.

Topics: Acute Kidney Injury; Alkaline Phosphatase; Animals; Blood Urea Nitrogen; Chemokine CXCL16; Chemokine CXCL6; Creatinine; Fibrin; Interleukin-6; Kidney; Leptin; Lipopolysaccharides; Male; Mice; Monocrotaline; Oligonucleotides, Antisense; Potassium; Thromboplastin

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.

Topics: Acute Kidney Injury; Animals; Antigens, CD; Cytokines; Disease Models, Animal; Drug Monitoring; Escherichia coli Infections; Factor VIIa; Hemodynamics; Inflammation; Interleukin-6; Interleukin-8; Lung Compliance; Male; Papio; Pulmonary Gas Exchange; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Respiratory Distress Syndrome; Sepsis; Severity of Illness Index; Thromboplastin

Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 x 10(10) CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.

Topics: Acute Kidney Injury; Animals; Bacteremia; Blood Coagulation; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Factor VIIIa; Fibrinogen; Hemodynamics; Inflammation; Interleukin-6; Kidney Function Tests; Lung Compliance; Male; Papio; Pulmonary Edema; Pulmonary Gas Exchange; Random Allocation; Respiratory Distress Syndrome; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Acute Kidney Injury; Blood Coagulation Tests; Heparin; Humans; Renal Dialysis; Thrombin; Thromboplastin

A summarized account of our experiences over 1 1/2 years is given, in relation to a minimum heparinisation technique during haemodialysis. This novel technique was made possible by the introduction of an APTT bedside method. In a comparison between the techniques employed so far for preventing a heparin-caused risk of haemorrhage and our method, the clear advantage of our method was apparent. In addition to a discussion of our methods, we describe the cases treated so far. The amounts of heparin required for dialysis are so small that a necessary coagulation can occur even in a part of the organism where there is a danger of haemorrhage. Thereby it was possible to extend the range of indication for haemodialysis substantially. By using minimum heparinisation, it is possible to perform an immediate postoperative haemodialysis. The healing of wounds, which is impaired in cases of renal insufficiency, may be improved by early dialysis without the risk of haemorrhage. Our results show that the minimum heparinisation signifies a decisive achievement in acute dialysis therapy.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation Tests; Female; Hemorrhage; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Monitoring, Physiologic; Renal Dialysis; Risk; Thromboplastin; Wounds and Injuries

The clinical and laboratory features of a case of alphamethyldopa-induced thrombocytopenia are described. This is the second reported case in which the presence of alpha-methyldopa-induced platelet antibodies have been demonstrated.

Topics: Acute Kidney Injury; Antibody Formation; Aortic Aneurysm; Blood Coagulation Tests; Blood Platelets; Coombs Test; Female; Humans; Hypertension; Methyldopa; Middle Aged; Thrombocytopenia; Thromboplastin

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Blood Coagulation Disorders; Endotoxins; Histamine Release; Humans; Hypotension; Hypoxia; Intestinal Absorption; Ischemia; Mononuclear Phagocyte System; Pulmonary Atelectasis; Shock; Shock, Septic; Thromboplastin

Heparin therapy in 114 patients was controlled by daily blood tests-the whole blood coagulation time, kaolin-activated partial thromboplastin time of plasma, and plasma heparin assay. Bleeding episodes occurred in 7 out of 92 patients (7.6%) who had normal haemostatic mechanisms before therapy and in 11 out of 22 patients (50%) with defective haemostasis, mostly due to intravascular coagulation or renal failure. The dose of heparin ranged from 20,000 to 60,000 units in each 24-hour period. In some patients bleeding was related to overdosage, but in others the laboratory tests indicated satisfactory or suboptimal dosage at the time of bleeding. Though there were positive correlations between the results of the three tests, these were not close, and no one test was preferable. Hence laboratory control of heparin therapy is unsatisfactory and patients may bleed despite careful control of the dose by all three methods.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hemorrhage; Heparin; Humans; Kaolin; Male; Middle Aged; Thromboplastin

Topics: Acute Kidney Injury; Anemia, Hemolytic; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Coronary Disease; Female; Heart Arrest; Hemorrhagic Disorders; Humans; Hyaline Membrane Disease; Infant, Newborn; Ischemia; Kidney Transplantation; Male; Obstetric Labor Complications; Pregnancy; Shock, Septic; Shwartzman Phenomenon; Thrombocytopenia; Thromboembolism; Thromboplastin; Toxemia; Wounds and Injuries