1/8. Fibrinogen brescia: hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 Gly-->Arg mutation.The proposita suffered from liver cirrhosis and biopsy showed type 1 membrane-bound fiberglass inclusions. The hepatic inclusion bodies were weakly periodic acid-Schiff diastase-positive, and on immunoperoxidase staining reacted specifically with anti-fibrinogen antisera. Coagulation investigations revealed low functional and antigenic fibrinogen together with a prolonged thrombin time of 37 seconds (normal, 17 to 22 seconds) suggestive of a hypodysfibrinogenemia. dna sequencing of all three fibrinogen genes showed a single heterozygous mutation of GGG (Gly)-->CGG (Arg) at codon 284 of the gamma-chain gene. However, examination of purified fibrinogen chains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, reverse-phase high-performance liquid chromatography, ion-exchange high-performance liquid chromatography, and isoelectric focusing, failed to show any evidence of the mutant gamma(Br) chain in plasma fibrinogen. This finding was substantiated by electrospray ionization mass spectrometry, which showed only a normal gamma (and Bbeta) chain mass, but a large increase in the portion of their disialo isoforms. We speculate that misfolding of the variant protein causes hepatic retention and the subsequent hypofibrinogenemia, and that the functional defect (dysfibrinogenemia) results from hypersialylation of otherwise normal Bbeta and gamma chains consequent to the liver cirrhosis. These conclusions were supported by studies on six other family members with hypofibrinogenemia, and essentially normal clotting times, who were heterozygous for the gamma284 Gly-->Arg mutation.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
2/8. Identification of simultaneous mutation of fibrinogen alpha chain and protein C genes in a Japanese kindred.Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas protein c deficiency increases susceptibility to thrombosis in children or adolescence. Mutations of these genes have been, therefore, established as independent risk factors for coagulation disorders. We describe the homozygous mutation of the fibrinogen alpha chain gene and additional heterozygous mutation of the protein C gene in a male infant who showed prolonged umbilical bleeding after birth. On examination, the plasma fibrinogen was undetectable, and the activity and antigen level of protein C were reduced. The patient showed no fibrinogen Aalpha chain as well as Bbeta and gamma chains by Western blotting. The sequencing analysis showed the homozygous deletion of 1238 bases from intron 3 at position 2008 to intron 4 at position 3245 in the fibrinogen alpha chain gene. Both parents were heterozygous carriers of this mutation. In this patient, an additional mutation was also detected in the protein C gene: the heterozygous deletion of exon 7 at position 6161-6163 or 6164-6166, resulting the deletion of one amino acid (Lys150 or 151). His mother was also a carrier of this mutation. As the simultaneous mutation of the fibrinogen alpha chain and protein C genes has not been previously reported, the influence of the interaction between these two mutations on the clinical manifestations of this patient should be carefully monitored for a long period.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
3/8. Coexistence of congenital afibrinogenemia and protein c deficiency in a patient.A rare association of congenital afibrinogenemia and hereditary protein c deficiency is described in a 37-year-old female who suffered from ischemic necrosis in the left first toe. The diagnosis of afibrinogenemia was assessed by the absence of fibrinogen in clotting and immunological assays. The diagnosis of hereditary heterozygous type I protein c deficiency was based on the evidence of proportional decreases of activity and antigen of plasma protein C in the propositus, her mother, and two maternal aunts.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
4/8. Fibrinogen gamma375 arg-->trp mutation (fibrinogen aguadilla) causes hereditary hypofibrinogenemia, hepatic endoplasmic reticulum storage disease and cirrhosis.Hypofibrinogenemia is a rare inherited disorder characterized by low levels of circulating fibrinogen, caused by mutations within 1 of the 3 fibrinogen genes. We report here the case of a 61-year-old man with chronic liver function test alterations. Liver biopsy examination revealed chronic hepatitis complicated by cirrhosis and weakly eosinophilic globular cytoplasmic inclusions within the hepatocytes, faintly stained with PAS-diastase. On immunohistochemistry, the inclusions reacted strongly with human antifibrinogen antibodies. Coagulation investigations of the propositus and his 2 sons showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. A liver biopsy performed on the 28-year-old son demonstrated the same globular cytoplasmic inclusions, albeit without associated chronic liver disease. PCR amplification followed by sequencing showed that all 3 were heterozygous for a CGG>TGG mutation at codon 375 of the fibrinogen gamma-chain gene (FGG), corresponding to an Arg>Trp substitution. This is the first in an adult male and the second published case with a discernible hepatic fibrinogen endoplasmic reticulum storage disease due to an FGG Arg375Trp (fibrinogen Aguadilla) mutation. Our results suggest that familial hypofibrinogenemia should be considered in the differential diagnosis of a progressive liver disease associated to hepatocellular intracytoplasmic globular inclusions.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
5/8. Fibrinogen Denver: a dysfibrinogenemia associated with an abnormal Reptilase time and significant bleeding.This paper reports a new dysfibrinogenemia with an unusual pattern of laboratory assays. The patient, a 51-year-old female with a lifelong moderate bleeding history, was initially diagnosed with von Willebrand disease based on routine coagulation assays and the clinical bleeding presentation. During recent testing as part of a preoperative screen and without any current history of treatment, levels of von willebrand factor (VWF) antigen, VWF activity, and factor viii activity were all significantly elevated, which was unexpected given her previous diagnosis. Additional testing was performed looking for other heritable causes for her considerable bleeding tendency. Interestingly, the patient had a significantly prolonged Reptilase time, minimally short thrombin time, and an abnormal fibrinogen-crossed immunoelectrophoresis pattern. Clearly, this patient had a fibrinogen abnormality that had been missed when only routine coagulation screening assays were performed. A brief review of the fibrinogen literature revealed no other dysfibrinogenemias reported with a similar pattern of test results, and thus this defect was designated fibrinogen Denver.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
6/8. Prolonged hypofibrinogenemia and protein C activation after envenoming by Echis carinatus sochureki.Following envenomization by Echis carinatus sochureki, a professional snake handler developed a profound coagulopathy manifested by hemorrhage from the bite site, venipuncture sites and gums; coagulation testing revealed prothrombin and partial thromboplastin times greater than 150 seconds, a fibrinogen of 0 mg%, and marked elevation of fibrin degradation products. In addition, protein C antigen levels were undetectable. The coagulopathy was treated with cryoprecipitate; two different antivenoms were also administered with uncertain benefit. Subsequently, the properties of the venom and antivenoms were studied. Venom did not directly clot fibrinogen; however, venom concentrations as low as 0.2 micrograms/ml caused significant prothrombin activation. In addition, venom activated protein C in the absence of thrombomodulin, and this activity was inhibited by hirudin. The ability of four commercial antivenoms to neutralize the venom prothrombinase and hemorrhagic activity was measured. Three of the four antivenoms partially neutralized venom-induced prothrombin activation. Extreme differences in efficacy were found among the four antivenoms in neutralizing venom hemorrhagic activity in mice. This case illustrates the difficulty in managing the complex coagulopathy that can result from exotic snake envenomization, and identifies a new coagulant property of Echis carinatus venom (protein C activation).- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
7/8. Studies of the origin of platelet-associated fibrinogen.Platelet membranes and whole platelet preparations were examined by crossed immunoelectrophoresis in normal individuals, in a patient with congenital afibrinogenemia, and in two unrelated patients with Glanzmann's thrombasthenia (types I and II) to study the origin of platelet-associated fibrinogen. Results indicate: (1) platelet and plasma fibrinogen are probably derived from the same gene product, (2) platelet fibrinogen is not derived from the surrounding plasma milieu, (3) under basal conditions, platelet fibrinogen is located only within the alpha-granules and not on the platelet surface, (4) addition of trypsin to fibrinogen uncovers either a neoantigen or a hidden pool of platelet fibrinogen in the alpha-granules, (5) platelets from two patients with Glanzmann's thrombasthenia contain near-normal quantities of fibrinogen.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
8/8. Restoration of complement function in vivo by plasma infusion in factor I (C3b inactivator) deficiency.The serum complement activities of a 1-year-old infant with recurrent life-threatening bacterial infections and persistent C3-Coombs-positive red blood cells were investigated. The patient's serum had a depressed serum level of CH50, C3, factor B, and factor H as well as undetectable antigenic or functional factor I. The complement profile of the parents was normal, with the exception of factor I, which was approximately 50% of normal in each parent. The Coombs positivity of the patient's red blood cells could be reversed in vitro by incubation with normal serum containing factor I. Infusion of normal plasma into the patient resulted in increased levels of CH50, with concomitant increases in serum C3, factor B, and factor H levels. The patient's red blood cells became transiently Coombs negative. At no time after plasma infusion was factor I detectable in the patient's serum. All complement functions and the C3 Coombs reactivity of the patient's red blood cells returned to preinfusion levels within 14 days. These findings are consistent with an inherited deficiency of factor I and emphasize the critical role this protein plays in the regulation of the alternative complement pathway. plasma therapy may be an adjunct to the management of acute infection in patients with factor I deficiency.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |