The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders.
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This study looked at 102 anti-hepatitis C virus (HCV)-positive, hepatitis B virus (HBV)-negative, and HIV-negative patients (median age, 45.1 years; range, 15-71) affected by hereditary bleeding disorders who have been infected with HCV for 15 to 34 years (median, 25.1). All these patients were infected before the mid 1980s because of non-virally inactivated pooled blood products. Fourteen patients (13.7%) were HCV-RNA negative with no signs of liver disease and were considered to have cleared the virus. Eighty-eight patients (86.3%) were HCV-RNA positive. The HCV genotype distribution was 1a in 20.5%, 1b in 36.4%, 2 in 17.0%, 3 in 15.9%, 4 in 3.4%, and mixed in 6.8% of cases. Twenty-four patients (23.5%) had serum cryoglobulins, symptomatic in 4 cases, and associated with liver disease and with genotype 1. Among the 88 HCV-RNA-positive patients, 15 (17.0%) had normal alanine aminotransferase levels and abdominal ultrasound, 61 (69.3%) had nonprogressive chronic hepatitis, and 12 (13.7%) had severe liver disease (6 [6.9%] liver cirrhosis, 4 [4.5%] hepatic decompensation, and 2 [2.3%] hepatocellular carcinoma) after a follow-up period of 25 years. There were 3 (3.4%) liver-related deaths. HCV genotype 1, patient's age at evaluation, duration of infection, and severity of congenital bleeding disorder were associated with more advanced liver disease. The results confirm the slow progression of HCV infection in HIV-negative hemophiliacs. (+info)
Quantification and facilitated comparison of von Willebrand factor multimer patterns by densitometry.
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The analysis of von Willebrand factor (vWF) multimers is an important laboratory tool for distinguishing among the numerous subtypes of von Willebrand disease (vWD). Comparability and reproducibility of this method are insufficient; standardization and external references are pending. Interlaboratory comparison of results therefore may be difficult. We applied densitometry to obtain a reproducible quantification of vWF multimer patterns in healthy donors, patients with vWD variants, and factor VIII/vWF concentrates to improve the reproducibility and comparability of vWF multimer analysis. Multimers were separated and visualized luminographically on x-ray films. Films were scanned and evaluated by densitometry. The variation inherent in vWF multimer analysis and the range of the normal could be quantified. In vWD variants and factor VIII/vWF concentrates, densitometry could quantify and visualize alterations of vWF multimer patterns and facilitate their comparison. Densitometry permits a precise quantitative comparison of sample patterns to a reference plasma. It could be a valuable tool offering reproducible quantification and additional visualization of normal and pathologic vWF multimer patterns, facilitating their comparison and contributing to a standardization of vWF multimer analysis. (+info)
Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins.
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Some families affected by von Willebrand disease type 1 show high penetrance with exceptionally low von Willebrand factor (VWF) levels. Previously, a mutation associated with this dominant phenotype, Cys1149Arg, was found to decrease the secretion of coexpressed normal VWF, and the mutation was proposed to cause intracellular retention of pro-VWF heterodimers. To demonstrate heterodimer formation, a model was developed in which subunits could be distinguished immunologically and by size. Recombinant VWF lacking domain A1 (dA1), A3 (dA3), or both (dA13) was secreted efficiently as a full range of multimers. Cotransfection of Cys1149Arg and dA13 resulted in the secretion of multimeric VWF containing about 250 kd (Cys1149Arg) and about 210 kd (dA13). Cell lysates contained pro-VWF forms of Cys1149Arg and dA13. Immunoprecipitation with an antidomain A1 antibody recovered both subunits in heterodimers, and subunit ratios were consistent with random dimerization. Similar results were obtained for cotransfection of Cys1149Arg and dA1. Normal VWF has a Cys1149-Cys1169 intrachain bond. When cotransfected with normal VWF, Cys1149Arg or the double mutant Cys1149Arg+Cys1169Ser caused a similar decrease in VWF secretion, suggesting that an unpaired Cys1169 does not explain the intracellular retention of Cys1149Arg. VWF Cys1149Arg was not secreted from BHK cells but was degraded intracellularly within about 4 hours, and the proteasome inhibitor lactacystin delayed its clearance more than 16 hours. Thus, dominant von Willebrand disease type 1 may be caused by heterodimerization of mutant and normal subunits in the endoplasmic reticulum followed by proteasomal degradation in the cytoplasm. A similar dominant negative mechanism could cause quantitative deficiencies of other multisubunit proteins. (+info)
Reduced von Willebrand factor survival in type Vicenza von Willebrand disease.
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Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype. (+info)
von Willebrand disease in China.
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PURPOSE: To review the molecular pathogenesis in Chinese patients with von Willebrand disease (vWD) and polymorphisms of von Willebrand factor (vWF) in Chinese population. DATA SOURCES: Both Chinese and English language literature search using MEDLINE (1985-1998), and original articles published in main Chinese and international journals. STUDY SELECTION AND DATA EXTRACTION: After reviewing of the literature, 19 articles of them were selected that specifically addressed the stated purpose. RESULTS: The molecular pathogenesis of vWD was variant. Six cases of point mutation have been found in Chinese patients with vWD. The system of site-directed mutagenesis and expression of vWF gene was constructed. The polymorphisms of vWF gene are very different between Chinese and Gaucasians. CONCLUSION: Combining to gene mutant in vWD patients, the use of site- directed mutagenesis and expression of vWF will help to understand the vWF function. The polymorphisms of vWF gene are useful marker in Chinese for carrier detection and prenatal diagnosis of vWD. (+info)
Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study.
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Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction. (+info)
The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease.
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Extracellular collagens modulate the rate of platelet activation and thereby markedly influence hemostasis and thrombosis. Platelet receptors for collagens, such as the integrin alpha(2)beta(1), platelet glycoprotein (GP) VI or, indirectly, the GPIb complex, are unexploited targets of pharmacological control, and polymorphisms of these receptors have recently become factored into the genetic risk for thrombosis. Seemingly contradictory findings already exist with regard to the contribution of GPIbalpha and integrin alpha(2) polymorphisms, but these discrepancies will be resolved once there is better standardization of clinical studies. There is already substantial evidence that GPIbalpha VNTR A or B alleles, the GPIbalpha-5C allele, and integrin alpha(2) allele 1 (T(807)) each contribute to increased risk for morbidity in thrombotic disease. However, larger, prospective genetic and epidemiological studies are needed to clarify the role of each of these polymorphisms, the contribution of other platelet receptor polymorphisms, and the synergistic effects of combinations of these factors. In addition, in vitro studies that establish the functional relevance of these polymorphisms will provide sound biological explanations for the results of clinical correlation studies. (+info)
Acquired von Willebrand factor abnormalities in myeloproliferative disorders and other hematologic diseases: a retrospective analysis by a single institution.
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BACKGROUND AND OBJECTIVES: Acquired von Willebrand syndrome (AVWS) is a rare acquired disorder. In most cases it is associated with lymphoproliferative disorders and monoclonal gammopathies, while less frequently myeloproliferative disorders (MPD) are involved. Although bleeding is the most important symptom, thrombotic complications have also been observed in cases associated with MPD. Our aim was to review the clinical and laboratory findings in AVWS patients from a single institution. DESIGN AND METHODS: The records of 99 patients with AVWS were reviewed to identify the underlying diseases, the symptoms and the laboratory parameters. RESULTS: In 75% of cases the AVWS was associated with MPD. The most frequent pattern was type 2 (67.7%). Abnormalities of bleeding time, factor VIII levels or platelet retention to glass beads were observed in 83.8% of cases. Bleeding was present in 38.4% of patients, more frequently in the not-MPD-associated (58.3%) vs. MPD-associated cases (32%) (p=0.022), with a significant predominance in females, irrespective of the underlying disease (p=0.0007). In 32% of patients with MPD, thrombotic manifestations, mostly microvascular and arterial episodes, were observed. INTERPRETATION AND CONCLUSIONS: AVWS in MPD seems to be mainly a laboratory diagnosis, without clinical symptoms in most cases, although bleeding as well as ischemic events can be present. In contrast, AVWS in not-MPD-associated cases is most frequently associated with severe bleeding symptoms. Performing appropriate laboratory tests may be useful for screening for AVWS. (+info)