Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019087 (hemorrhagic diathesis)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The precipitous increase in the number of structurally defined fibrinogen defects in recent years has resulted from application of high performance liquid chromatography in combination with peptide mapping and sequencing procedures. More recently, application of DNA sequence of polymerase chain reaction products has accelerated the pace of identification of mutations. Highly frequent defects are Arg substitutions, accounting for eight mutation sites substituted by Cys or His and less frequently by Ser. Amino acid substitutions at different positions on all three chains have pointed to possible structures with polymerization-related functions. Also, substitutions yielding consensus sequences resulted in extra glycosylations of the appropriate Asn in four different mutation sites; the impaired polymerization was reported associated with undue bleeding in two of these. Among informative defects have been those of homozygous probands with A alpha 16Arg----His and A alpha 16Arg----Cys in that failure of release of peptide A (but not of B), as shown with A alpha 16Arg----Cys, resulted in markedly delayed polymerization of such fibrin monomers, in general agreement with conclusions reached in studies of normal fibrin. This dysfunction, as well as the slow rate of release of A shown with A alpha 16Arg----His, was associated with clinically significant hemorrhagic diathesis (in the homozygous probands), consistent with the known physiologic importance of peptide A cleavage in normal hemostasis. Also, defects on the A alpha 17-19 sequence resulting in impaired polymerization are consistent with the known role of this segment in polymerization. Of similar interest have been defects within a B beta chain span encoded its exon 2. Two defects resulting in impaired polymerization and thrombin binding were associated with clinical thrombosis commencing in early life, and this lends strong support to other evidence suggesting a role in polymerization and in noncatalytic thrombin binding by this B beta chain segment. Thrombosis associated with A alpha 554Arg----Cys in a heterozygous proband with impaired tPA interaction is unique and may shed light on this poorly understood but important interaction among fibrin, plasminogen, and tPA. A group of different defects within the gamma 275-375 sequence have pointed to a polymerization role, evidenced by delayed gelation and impaired binding of mutant D to normal fibrin E. An unusual example is a 15 residue insertion between gamma 350 and 351 resulting in impaired polymerization, gamma chain crosslinking, and platelet aggregation support and is associated with hemorrhagic diathesis and poor healing.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrinogen anomalies and disease. A clinical update. 140 80

Hemophilia B Kashihara is a severe hemorrhagic disorder in which the factor IX antigen is present in normal amounts but factor IX biological activity is markedly reduced. In addition, purified factor IX Kashihara is not activated by purified factor XIa in the presence of calcium ions. Amino acid sequence analysis of one of the tryptic peptides isolated from factor IX Kashihara indicated that Val-182 (equivalent to Val-17 in the chymotrypsin numbering system) had been replaced by Phe. No substitution was found in the members of the catalytic triad His-221, Asp-269, and Ser-365 of factor IX Kashihara. The Val-to-Phe replacement found in factor IX Kashihara appears to sterically hinder the cleavage of Arg 180-Val 181 by factor XIa required for the activation of this zymogen.
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PMID:Blood clotting factor IX Kashihara: amino acid substitution of valine-182 by phenylalanine. 275 73

An acquired hemorrhagic disorder developed in two patients in association with postsplenectomy thrombocytosis and leukocytosis during the course of the myeloproliferative syndrome. The presence of acquired von Willebrand's disease in these individuals was demonstrated by a decrease or absence of the larger von Willebrand factor (vWF) multimers, alteration of the repeating vWF multimeric "triplet," decreased ristocetin cofactor activity (vWF:RCo), and prolonged bleeding time. The bleeding stopped in both patients after treatment with either 1-deamino-[8-D-arginine]-vasopressin (DDAVP) or Cohn fraction I. Treatment with thrombocytapheresis and azathioprine or busulfan resulted in reduction of the elevated platelet and white cell counts and was associated with partial correction of the vWF abnormalities and remission of the hemostatic abnormalities. In five additional patients with the myeloproliferative syndrome, but without bleeding symptoms, large multimers of plasma vWF were diminished also. These findings suggest that acquired von Willebrand's disease should be considered when a bleeding diathesis develops during the course of the myeloproliferative syndrome.
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PMID:Acquired von Willebrand's disease in the myeloproliferative syndrome. 633 59

Hemophilia B Chapel Hill is a mild hereditary hemorrhagic disorder in which the factor IX antigen is present in normal amounts but factor IX biological activity is markedly reduced. Previous studies have demonstrated that purified factor IX Chapel Hill has 8% of the activity of normal human factor IX and that the activation of factor IX Chapel Hill is defective in that only one of the two peptide bonds hydrolyzed during activation of normal factor IX is cleaved. The tryptic peptides from normal human factor IX and factor IX Chapel Hill were subjected to analysis by high-performance liquid chromatography. Comparison of the elution profile of the peptides obtained from factor IX Chapel Hill and normal factor IX demonstrated that the tripeptide Leu-Thr-Arg, which is derived from the normal molecule (positions 143-145) immediately amino-terminal from the Arg-Ala peptide bond at 145-146 that is cleaved during the activation of factor IX with factor XIa, was absent in the digest obtained from factor factor IX Chapel Hill. The elongated "activation peptide" from factor factor IX Chapel Hill was obtained by further high-performance liquid chromatographic fractionation and subjected to primary structure analysis. The following sequence, corresponding to positions 143-147, was obtained: Leu-Thr-His-Ala-Glu. Thus, the primary molecular defect in factor factor IX Chapel Hill is the substitution of histidine for arginine at position 145. This substitution precludes cleavage by factor XIa at this peptide bond, and the activation peptide region remains associated with the light chain of factor IXa Chapel Hill.
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PMID:Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145. 660 18

The onset of vascular leakage and hemorrhagic diathesis is one of the life-threatening complications occurring in dengue patients, yet the pathogenic mechanisms are not well understood. In this study, we demonstrated that Abs against dengue virus nonstructural protein 1 (NS1) generated in mice cross-reacted with human endothelial cells and mouse vessel endothelium. After binding, mouse anti-NS1 Abs induced endothelial cell apoptosis in a caspase-dependent manner. Inducible NO synthase expression could be observed; it showed a time- and dose-dependent correlation with NO production. Endothelial cell apoptosis, characterized by exposure of phosphatidylserine on the cell surface and nuclear DNA fragmentation, was blocked by treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-x(L) decreased in both mRNA and protein levels, whereas p53 and Bax increased after anti-NS1 treatment. Cytochrome c release was also observed. All of these effects could be inhibited by N(omega)-nitro-L-arginine methyl ester. Taken together, anti-NS1 Abs act as autoantibodies that cross-react with noninfected endothelial cells and trigger the intracellular signaling leading to the production of NO and to apoptosis. Endothelial cell damage may cause vascular leakage that contributes to the pathogenesis of dengue disease.
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PMID:Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. 1209 67

A 1967 report described the first known case of congenital factor XIII (FXIII) deficiency in the United States in a male patient with a severe hemorrhagic disorder. The patient's family presented no symptoms of the disorder, but the members were found to have half the normal FXIII activity. Although the molecular basis of the disorder could not be evaluated at the time, the results suggested an autosomal recessive inherited disorder. We sequenced all of the exons and the flanking regions in the genes for the FXIII A and B subunits of the patient, his family, and 18 unrelated individuals. We report the novel combination of an Arg-to-Cys mutation at codon 78 and a G-to-C mutation at the intron 5/exon 6 splice junction in the patient's FXIIIA gene. The missense-splice junction mutation combination appears to have caused the patient's FXIIIA deficiency, because the remaining family members, who present no symptoms and have no clinical diagnoses of FXIII deficiency, have one or the other of the 2 mutations but not both. Additionally, the 18 unrelated individuals are homozygous wild type at these loci. The molecular consequences of these mutations appear to be an abnormality in protein conformation or folding and/or a reduced production of messenger RNA transcripts of varying length that likely result in a nonfunctional, unstable FXIII protein.
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PMID:Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States. 1651 32