1/60. Familial overexpression of beta antithrombin caused by an Asn135Thr substitution.We have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (approximately 70% antigen and activity) of antithrombin. Direct sequencing of amplified dna showed a mutation in codon 135, AAC to ACC, predicting a heterozygous Asn135Thr substitution. This substitution alters the predicted consensus sequence for glycosylation, Asn-X-Ser, adjacent to the heparin interaction site of antithrombin. The antithrombin isolated from plasma of the proband by heparin-sepharose chromatography contained amounts of beta antithrombin (the very high affinity fraction) greatly increased (approximately 20% to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wild-type and variant protein were translated and exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represents a novel cause of antithrombin deficiency, removal of glycosylation concensus sequence, and highlights the potentially important role of beta antithrombin in regulating coagulation.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
2/60. Renal involvement of thrombotic thrombocytopenic purpura: special reference to the glomeruloid structures.We report the case of a 9-year-old girl with biopsy-proven renal thrombotic microangiopathy in thrombotic thrombocytopenic purpura (TTP), with particular reference to the glomeruloid structures. The renal biopsy sample from this TTP patient revealed platelet thrombus deposition, a glomeruloid structure and aneurysm with relative sparing of the glomeruli. The glomeruloid structure displayed a proliferation of mainly capillary-sized channels lined by factor viii-related, antigen-positive plump endothelial cells embedded in the edematous connective tissue. These glomeruloid vessels communicated with the aneurysmal segment at the end portion of the arteriolar branch. We believe that the glomeruloid structures in TTP represent not merely organization or recanalization of thrombus but rather active angiogenesis through aneurysmal dilation in the arteriolized vessel, probably initiated by platelet agglutination.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
3/60. Reactive angioendotheliomatosis in association with the antiphospholipid syndrome.A 50-year-old woman with systemic lupus erythematosus developed extensive necrotic skin lesions on her chest and abdomen after the discontinuation of warfarin. The presence of antiphospholipid antibodies suggested a diagnosis of antiphospholipid syndrome. Histopathology from a skin lesion demonstrated marked expansion of the dermal microvasculature by intravascular cellular proliferation and focal thrombosis. The intravascular cells stained positive for the endothelial cell markers CD31 and factor viii-associated antigen confirming reactive angioendotheliomatosis (RAE). This report is the first to identify RAE occurring in the context of the antiphospholipid syndrome. We suggest that intravascular endothelial proliferation, in concert with thrombosis, contributed to the angio-occlusive pathology.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
4/60. Combined Ala601-Thr-type dysplasminogenaemia and antiphospholipid antibody syndrome in a patient with recurrent thrombosis.A 44-year-old man was admitted to our hospital because of recurrent thrombosis. Laboratory findings showed that he had antiphospholipid antibody syndrome (APS) associated with systemic lupus erythematosus. plasminogen activity was reduced (21%), but its antigenic level was rather elevated (16.4 mg/dl). The discrepancy of plasminogen activity and antigen levels was also found in his three daughters. Gene analysis revealed a homozygous missense mutation (Ala601-->Thr) at exon 15 of the plasminogen gene in the patient and a heterozygous mutation in his three daughters, suggesting that the patient has dysplasminogenaemia, which was reported as "plasminogen Tochigi." Although it still remains controversial whether both dysplasminogenaemia and plasminogen deficiency are relevant independent thrombotic risk factors, the combination of this deficiency and APS should be considered as a strong predisposition to thrombosis in this patient.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
5/60. protein c deficiency caused by homozygosity for a novel PROC D180G mutation--in vitro expression and structural analysis of the mutation.Homozygosity for a novel D180G mutation in the protease domain of protein C, associated with plasma protein C activity and antigen levels of 8% of normal was identified in a thrombosis prone family. Transient expression of protein C in HK-293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein as compared with wild-type protein was reduced by 79% while the intracellular contents were similar. Computer analysis of the X-ray structure of activated protein C and of a theoretical model of the zymogen predicts that the mutation destabilises the molecule locally. Our results are compatible with a relatively unstable mutant molecule that could be trapped inside the cell and degraded. However, if secreted the mutant molecule could have a relatively normal catalytic activity and structure consistent with the plasma levels of protein C activity and the late onset of thrombosis.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
6/60. sirolimus-induced thrombotic microangiopathy in a renal transplant recipient.A rare but well-documented serious adverse reaction to the administration of the calcineurin inhibitors tacrolimus and cyclosporine in renal transplant recipients is the development of medication-induced thrombotic microangiopathy. The recently introduced immunosuppressive medication sirolimus has a very similar molecular structure to tacrolimus and also binds to the same intracellular proteins. Despite these similarities with tacrolimus, sirolimus has a different side-effect profile and reportedly lacks documented specific renal toxicity. This is a case report of the isolated administration of sirolimus without a concomitant calcineurin inhibitor being associated with the development of renal transplant biopsy-proven thrombotic microangiopathy. The patient is a 47-year-old African-American woman whose primary cause of renal failure was not thrombotic micrangiopathy, and she received a 5-antigen mismatched cadaveric renal transplant. Because of preexisting nephrosclerosis in the renal transplant, this patient was never administered a calcineurin inhibitor but was always maintained on sirolimus. With recent animal data showing that sirolmus can be nephrotoxic in a renal ischemic-reperfusion model (similar to what happens with a renal transplant), the authors speculate on a mechanism for this adverse reaction.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
7/60. Immune-complex disease with unilateral renal vein thrombosis.The sequence of events in the relationship between membranous nephropathy and renal vein thrombosis is controversial. We postulate that occasionally, the thrombosis may precede the nephropathy and that release of autologous antigens from renal tissue damaged by occlusion of the vein may incite an autologous immune-complex disease. In a case of membranous nephropathy associated with renal vein thrombosis, renal tubular epithelial antigen (RTE) was localized in the glomerulus, along with the host immunoglobulins and complement components. Cryoproteins isolated from the serum contained RTE and anti-RTE. In addition, immunoglobulin eluted from the diseased glomeruli showed antibody activity to RTE. The membranous nephropathy was demonstrated to be secondary to an autologous immune-complex nephritis. Although the sequence of events is inconclusive, it is possible that the renal vein thrombosis preceded and was involved in the etiopathogenesis of the autologous immune-deposit nephropathy.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
8/60. Late-onset homozygous protein c deficiency manifesting cerebral infarction as the first symptom at age 27.We report a 31-year-old female who had repeated thrombosis and was diagnosed as having congenital homozygous protein c deficiency based on decreased protein C antigen and activity, and the findings of family history. This patient had shown no symptom of thrombosis until the age of 27 years, when she had cerebral infarction as the first symptom. Low molecular weight heparin was useful for disseminated intravascular coagulation (DIC) that complicated protein c deficiency in this patient.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
9/60. Intra-cardial thrombosis with systemic and pulmonary embolism as main symptoms in a patient with protein s deficiency.This report describes the unusual occurrence of both left and right atrial thrombosis with peripheral arterial and pulmonary embolism, respectively, as presenting symptoms of congenital protein s deficiency in a 31-year-old man. The coagulation study performed in the coumarin-treated propositus indicated a heterozygous protein S state. The finding of reduced free protein S antigen and protein S activity levels with normal total protein S and C4B-bp levels in five other family members (father, sister, and three relatives on the paternal side) confirmed the inherited nature of the defect. Since there is an increased frequency of arterial thrombosis in patients suffering from protein s deficiency, any case of idiopathic intra-cardial thrombosis requires careful haemostatic screening. In addition, the possibility of intra-cardial thrombosis should be considered in any thromboembolic event seen in inherited protein s deficiency.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
10/60. Congenital protein c deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis.A 29-year-old man with congenital protein c deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor ii, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein c deficiency.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
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