Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow-cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. 785 65

Lupus anticoagulants (LA) and anticardiolipin antibodies (aCL) are known as thrombosis-related antiphospholipid antibodies. LA is not as well characterized as aCL, and the relation between LA and aCL is not clarified. Since standardized method for the detection of LA has not been established, we measured LA activities in outpatients with SLE by using two different methods (KCT and dRVVT), and analyzed the characteristics of LA in SLE. LA was detected in 29.8% of all samples (14.3% in both methods, 15.5% in one method). IgG-aCL and IgM-aCL was detected in 38% and 20%, respectively, of all LA positive samples. Though a good correlation was observed between LA activities and IgG-aCL levels, a considerable number of LA positive samples were negative for aCL. This indicated the presence of factors with LA activity other than aCL. On the contrary there was also a high percentage of LA negative samples with positive aCL (42.4% in IgG-aCL, 47.4% in IgM-aCL), suggesting the presence of aCL with poor or low LA activity. These findings showed the heterogeneity of antiphospholipid antibodies both in LA and in aCL. The platelet function tests showed increased platelet adhesiveness and normal platelet aggregation in LA positive patients with SLE even in the inactive phase. The serum levels of factors such as protein C, protein S, antithrombin III and thrombomodulin were within normal range. Clinical features such as hemolytic anemia, thrombosis and abortion were more frequently observed in LA positive population than in LA negative population. The clinical features tend to be different between patients with dRVVT-LA and those with KCT-LA, though not significant. Because of the heterogeneity in LA, a combination of more than two different methods including dRVVT was recommended for the detection and the evaluation of LA.
 ...
PMID:[Lupus anticoagulants in patients with systemic lupus erythematosus]. 871 33

In 1990, three groups simultaneously reported that putative IgG antibodies to anionic phospholipids were either not directed to phospholipids or at least required beta 2-glycoprotein-I (beta 2-GP-I) for reactivity in vitro. During the same year, our group described a patient with "idiopathic' hemolytic anemia with serum and erythrocyte-bound IgM antibodies to phosphatidylcholine later found to be independent of beta 2-GP-I for antigen recognition. Lately, the field has been expanded considerably with: (1) the description of other potential antigens such as prothrombin for some lupus anticoagulants, (2) the finding of crossreactivity between some antiphospholipid antibodies (aPL) with thrombomodulin, (3) the presence of serum antibodies to beta 2-GP-I (anti-beta 2-GP-I) in patients with SLE and thromboses, (4) the findings that the clinical manifestations of APS in SLE patients associate more strongly with anti-beta 2-GP-I than with aPL, (5) our finding of a group of SLE patients with the clinical manifestations of APS, with negative serum aPL, but with positive anti-beta 2-GP-I, (6) the description of a group of patients with the clinical manifestations of APS, without serum aPL, without serological nor clinical evidence of any autoimmune disease, but with IgG anti-beta 2-GP-I, and (7) the observation that serum anti-phosphatidylethanolamine antibodies detected in some patients with APS require kininogen (alone or complexed with the kininogen-binding protein), prekallikrein and/or factor XI for in vitro reactivity. Thus, there are antibodies that may be considered true aPL; other "aPL' require a protein cofactor for their detection in vitro, at least in the case of beta 2-GP-I it would appear that their epitope is present on the protein proper not on the phospholipid, hence these are pseudo aPL, and a third group of related anti-cofactor autoantibodies that are directed to the protein in the absence of phospholipid. Clearly, the term "antiphospholipid syndrome' has become obsolete. We propose the term "Antiphospholipid/Cofactor Syndromes' to cull the various syndromes.
 ...
PMID:The concept and classification of antiphospholipid/cofactor syndromes. 890 61

The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in recently described HO-1 targeted mice. This study presents not only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo.
 ...
PMID:Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. 988 42

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disease of an unknown etiology, characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, fever and acute thrombotic complications, especially within the cerebral circulation. Although anti-endothelial cell antibodies (AECA) have occasionally been shown to be present in TTP, their role in the pathogenesis of the disease has never been ascertained. In the current study we demonstrated the pathogenic activity of affinity-purified anti-endothelial cell F(ab)2 antibodies (AECA/TTP) from four consecutive patients with active TTP. These AECA/TTP bound to and activated only microvascular endothelial cells (EC) and not large vessel EC. The specificity of AECA/TTP binding to microvascular EC was confirmed by competition assay employing membranes derived from small and large vessels EC. Activation included enhanced IL-6 and von Willebrand factor release from the EC followed by increased expression of adhesion molecules P-selectin, E-selectin and vascular cell adhesion molecule-1 on the EC, as evaluated by ELISA. Increased expression of adhesion molecules was followed by an increase in monocyte adhesion to EC. The level of soluble thrombomodulin (TM) also increased in the culture medium of activated microvascular EC upon exposure to AECA/TTP antibodies and was directly correlated to a decrease in cell-associated TM. Our data suggest that AECA/TTP directed against microvascular EC could play a pathogenic role in the development of endothelial injury in TTP that leads to thrombosis.
 ...
PMID:Anti-endothelial cell antibodies from patients with thrombotic thrombocytopenic purpura specifically activate small vessel endothelial cells. 1115 53

Coagulation abnormalities are frequently reported in hemolytic anemias (HA). Several pathophysiologic mechanisms are common to different HA. In this review three different hemolytic disorders will be discussed. In sickle cell disease and in beta-thalassemia, a thrombophilic status has been well documented as multifactorial involving hemostatic changes and activation of the coagulation cascade. Moreover, in such disorders, elevated levels of endothelial adhesion protein (ICAM-1, ELAM-1, VCAM-1, von Willebrand factor, and thrombomodulin) are often increased, suggesting that endothelial activation may be involved in vascular occlusion. As an additional mechanism of hypercoagulability in thalassemia, a procoagulant status of thalassemic red cells was recognized. The main clinical manifestation of paroxysmal nocturnal hemoglobinuria (PNH) is HA, and the most common complications are thrombosis, pancytopenia, and myelodysplastic syndrome or acute leukemia. The intravascular hemolysis is explained by a deficiency of glycosil phosphatidylinositol (GPI)-anchored complement regulatory proteins such as CD59 and CD55 on the membrane of red blood cells (RBCs), but the mechanism responsible for the increased incidence of thrombotic events in PNH remains unclear. Recent advances have been made in understanding the coagulation involvement in a heterogeneous group of diseases, thrombotic microangiopathies (TMA) characterized by microangiopathic hemolytic anemia and thrombocytopenia due to platelet clumping in the microcirculation, leading to ischemic organ dysfunction with neurologic symptoms and renal impairment.
 ...
PMID:Coagulation in the pathophysiology of hemolytic anemias. 1802 12

Hemolytic uremic syndrome (HUS) is related to a renal thrombotic microangiopathy, inducing hypertension and acute renal failure (ARF). Its pathogenesis involves an activation/lesion of microvascular endothelial cells, mainly in the renal vasculature, secondary to bacterial toxins, drugs, or autoantibodies. An overactivation of the complement alternate pathway secondary to a heterozygote deficiency of regulatory proteins (factor H, factor I or MCP) or to an activating mutation of factor B or C3 can also result in HUS. Less frequently, renal microthrombi are due to an acquired or a constitutional deficiency in ADAMTS-13, the protease cleaving von Wilebrand factor. Hemolytic anemia with schistocytes, thrombocytopenia without evidence of disseminated intravascular coagulation, and renal failure are consistently found. In typical HUS, a prodromal diarrhea, with blood in the stools, is observed, related to pathogenic enterobacteria, most frequently E. Coli O157:H7. HUS may also occur in the post partum period, and is then related to a factor H or factor I deficiency. HUS may also occur after various treatments such as mitomycin C, gemcitabine, ciclosporin A, or tacrolimus, and as reported more recently bevacizumab, an anti VEGF antibody. Atypical HUS are not associated with diarrhea, may be sporadic or familial, and can be related to an overactivation of the complement alternate pathway. More recently, some of them have been related to a mutation of thrombomodulin, which also regulates the alternate pathway of complement. In adults, several HUS are encountered in the course of chronic nephropathies: nephroangiosclerosis, chronic glomerulonephritis, post irradiation nephropathy, scleroderma, disseminated lupus erythematosus, antiphospholipid syndrome. Overall the prognosis of HUS has improved, with a patient survival greater than 85% at 1 year. Chronic renal failure is observed as a sequella in 20 to 65% of the cases. Plasma infusions and plasma exchanges are effective in most of the cases to treat hemolysis and thrombocytopenia. Steroid therapy is debated, as well as immunosuppressive drugs, including rituximab, in autoimmune forms. A new monoclonal anti-C5 antibody is tested, and seems to be effective in atypical HUS with abnormal complement alternate pathway activation. If terminal renal failure occurs, renal transplantation can be performed but the risk of recurrence, which very low in post infectious forms of HUS, is about 70 to 80% in genetic forms of complement regulatory protein deficiency.
 ...
PMID:[Hemolytic uremic syndrome in adults]. 2039 68

Atypical hemolytic uremic syndrome (aHUS) is characterized by acute renal failure, thrombocytopenia and microangiopathic hemolytic anemia, and occurs with an estimated incidence in the USA of 2 per 1,000,000. Disease pathogenesis is related to dysregulation of the alternative pathway (AP) of the complement cascade at the level of the cell membrane secondary to mutations in a number of complement genes including complement factor H (CFH), complement factor H-related 5 (CFHR5), complement factor I (CFI), CD46 (MCP), complement factor B (CFB), complement component 3 (C3) and thrombomodulin (THBD). Since aHUS is rare, mutation rate data in large patient cohorts are scarce. Here we present the first cohort of American patients in whom mutation screening was completed on all genes currently implicated in aHUS. In addition to identifying a number of novel variants, we provide information on the relative frequency of mutations in these genes in an American aHUS population. Twelve percent (12%) of patients carrying disease-associated genetic variants segregated mutations in more than one gene mandating comprehensive genetic testing in the diagnosis and management of these patients.
 ...
PMID:Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. 2051 33

Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti-P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.
 ...
PMID:Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. 2164 43

Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.
 ...
PMID:Atypical hemolytic uremic syndrome. 2190 19


1 2 3 Next >>