Risk of hepatitis A virus infection in persons with hemophilia receiving plasma-derived products.
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Blood Component Transfusion↗
Biomedical subjects
B L Evatt
Publications and source records attributed to B L Evatt.
Establishing haemophilia care in developing countries: using data to overcome the barrier of pessimism.
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Canada↗
Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate.
BACKGROUND: Porcine clotting factor has been used for more than 15 years to treat severe bleeding episodes in persons with hemophilia who have antibodies to human clotting factor. In 1996, QC procedures revealed for the first time the presence of porcine parvovirus (PPV) in the product. This report describes an investigation to determine the extent of product contamination and to evaluate past recipients of porcine clotting factor (Hyate:C, Speywood Biopharm) for evidence of PPV infection. STUDY DESIGN AND METHODS: Stored specimens from 22 lots of previously released Hyate:C were tested for the presence of PPV DNA by PCR and nested PCR assays. Serum specimens from 98 recipients of Hyate:C and 24 controls who did not receive Hyate:C were tested for PPV antibodies by an immunofluorescence assay. RESULTS: PPV DNA was detected in product from 21 of the 22 lots of Hyate:C, primarily by nested PCR testing. In contrast, none of the serum specimens from the 98 Hyate:C recipients tested positive for PPV IgG antibodies. CONCLUSION: The risk of human disease from percutaneous exposure to low levels of PPV seems to be low. Nevertheless, the theoretical risk of human infection with PPV has led to manufacturing changes, including PCR screening of all porcine plasma, which are designed to eliminate this risk.
Adult↗
Genetic factors associated with thrombosis in pregnancy in a United States population.
OBJECTIVE: Polymorphisms in the genes for factor V (factor V Leiden), prothrombin, methylenetetrahydrofolate reductase, and angiotensin-converting enzyme have been associated with the occurrence of venous thrombosis. The objective of this study was to determine the relationships of these polymorphisms to thrombosis during pregnancy. STUDY DESIGN: This case-control study included 41 case patients with venous thrombosis during pregnancy and 76 control subjects matched for hospital and for race (white vs black) who had a normal pregnancy. RESULTS: Among white subjects, mutations in the genes for factor V and prothrombin were associated with increased risks of venous thrombosis during pregnancy (factor V: odds ratio, 18.3; 95% confidence interval, 2.7-432; P =.001; prothrombin: odds ratio infinity; 95% lower confidence limit, 1.7; P =.01). No black subject had either of these two mutations. For both black and white subjects the D/D genotype of the gene for angiotensin-converting enzyme entailed increased risk compared with the other genotypes (odds ratio, 2.7; 95% confidence interval, 1.2-6.3; P =.02). The polymorphism in the gene for methylenetetrahydrofolate reductase was unrelated to thrombosis during pregnancy among both blacks and whites. CONCLUSION: Women who had thrombotic complications during pregnancy demonstrated an increased prevalence of genetic mutations related to coagulation. The additional risk of thrombosis during pregnancy associated with such genetic mutations can be substantial.
Black People↗
Multiplex analysis of mutations in four genes using fluorescence scanning technology.
Multiplex analysis of genetic mutations using fluorescence scanning methodology is an accurate, efficient, and cost-effective approach to genotypic characterization. Fluorescence labeling during the synthesis of polymerase chain reaction primers allows the application of this technology to well-established protocols. We have simultaneously analyzed the four polymorphisms of factor V Leiden (G1691A), prothrombin G20210A, 5,10-methylenetetrahydrofolate reductase C677T, and cystathionine beta-synthase 844ins68. Three of these mutations have been associated with an increased risk of thrombosis. Following polymerase chain reaction with fluorescence-labeled primers, the polymerase chain reaction products were digested with an appropriate restriction enzyme (if necessary for detection of the mutation), diluted into one tube per sample for co-loading (multiplex loading), and analyzed with GeneScan software for fragment analysis following capillary electrophoresis on an ABI PRISM 310 Genetic Analyzer (Foster City, CA, USA). Multiplex loading increased throughput without compromising precision.
Cystathionine beta-Synthase↗
Haemophilia therapy: assessing the cumulative risk of HIV exposure by cryoprecipitate.
Most of the world's haemophilia population live in countries with developing or emerging economies. As such, they do not have access to viral inactivated clotting product. Many are treated with cryoprecipitate made from locally supplied blood. The rationale for using cryoprecipitate instead of viral inactivated products is based on an implicit belief that because blood banks can provide reasonably safe products by using modern testing procedures, transmission of HIV and other blood-borne viruses is rare. However, the risk of acquiring a blood-borne infection is cumulative, and haemophilia patients treated with cryoprecipitate or fresh-frozen plasma are exposed to hundreds or thousands of donors during their lifetime. The risk that an HIV-infected person will be a donor during the 'window period' is directly related to the incidence of HIV in the country where the donation occurs. To illustrate the extent of this problem, we devise a model for estimating the risk that a person with haemophilia will encounter HIV-contaminated cryoprecipitate as a function of years of treatment and the underlying incidence rate of HIV among blood donors. We apply the model to two countries with different incidence rates of HIV, Venezuela and the USA. Over a lifetime of treatment (60 years), the cumulative risk of HIV exposure for a person with haemophilia receiving monthly infusion of cryoprecipitate prepared from plasma of 15 donors is significant, 2% in the USA and 40% in Venezuela. Considering the cumulative risk for transmitting HIV to patients with haemophilia through cryoprecipitate treatment, medical care providers should carefully evaluate the use of cryoprecipitate in any but emergency conditions or when no virally inactivated products are available.
Blood Preservation↗
Changes in hepatitis B serologic titers in HIV+ and HIV- children with haemophilia.
This longitudinal study examines differences in hepatitis B immune titres in children and adolescents with haemophilia to determine if they are dependent on how immunity was acquired (vaccination or natural infection), and whether they are related to the child's HIV status and/or are influenced by HIV disease progression. Serologic titres (HBcAb, HBsAb) and HBsAg were measured prospectively at baseline, and at years 1, 2 and 3 of follow-up in 126 HIV- and 207 HIV+ children and adolescents with haemophilia. Analyses were performed to assess the impact of HIV status on the measured titres, and for HIV+ subjects to examine the association with CD4+ lymphocyte counts and p24 antigen status. The results show that HIV+ children were more likely than HIV- children to lose vaccine-induced immunity as indicated by the loss of HBsAb. There was an increased risk of losing HBsAb with higher CD4+ counts and younger age. Re-immunization was not successful in seven of eight HIV+ children. Two subjects (one HIV+, one HIV-) entered the study HBsAg- but became HBsAg+ over the course of follow-up. Seven HIV+ subjects lost natural immunity as indicated by the loss of HBcAb. The loss of either HBsAb or HBcAb in HIV--subjects was negligible to absent. In conclusion, because of the loss of immunity in HIV+ children the viral safety of factor replacement concentrates for these children is an important consideration. HIV- children rarely lose immunity, therefore frequent measures of HBsAb are not necessary.
CD4 Lymphocyte Count↗
The relationship between polymorphisms in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans.
STUDY OBJECTIVES: To determine whether the polymorphic dinucleotide repeats found in intron 4 of the endothelial cell nitric oxide synthase (ecNOS) gene and the platelet GPIIIa PLA(1)/A(2) polymorphism are associated with myocardial infarction (MI) and venous thromboembolism (VTE) in African Americans. Because these two genes may interact physiologically, the third objective was to determine if there was a relationship between the polymorphisms with respect to MI and VTE. DESIGN: A hospital-based case-control study. After informed consent was obtained, blood used for DNA extraction was drawn from the subjects. SETTING: The study was conducted in the Anticoagulant Clinic and the Cardiology Clinic at Grady Memorial Hospital in Atlanta Georgia. PATIENTS: Subjects were recruited from African-American patients with a reported history of MI (n = 110) or VTE (n = 91). Control subjects (n = 185) without a history of cardiovascular or venous disease were recruited from an outpatient clinic. MEASUREMENTS AND RESULTS: The 393 ecNOS allele was more common among MI cases (36%; p = 0.01) and VTE cases (35%; p = 0.04) than among control subjects (26%). There was no association between the GPIIIa genotypes and either MI or VTE. However, among the MI subjects, there was a strong association between the ecNOS 393/393 genotype and the Pl(A2) allele. It was also found that the frequency of the 393 allele was higher in African-American persons (0.26) compared with what has been reported for Australian Caucasians (0. 14) and Japanese (0.10). CONCLUSIONS: The 393 allele but not the Pl(A2) allele was significantly associated with both MI and VTE in African Americans. Homozygosity for the 393 allele was significantly associated to the diagnosis of MI prior to the age of 45. The combination of the 393 allele and a Pl(A2) allele was also highly associated with MI. The frequency of the 393 allele was significantly higher in African Americans than what has been reported for other populations. This study furthers not only extends the association of the 393 allele to VTE but has demonstrated an interaction with the Pl(A2) allele with respect to MI.
Adult↗
The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C.
The protein C/protein S anticoagulant pathway has been proposed to be a common link between coagulation and inflammation. Studies have suggested that a component of the anticoagulant pathway, activated protein C (APC), may play a role in the inflammatory response by modulating the effects of cytokines such as TNF and by blocking neutrophil activation. Cytokines are known to be intimately involved in the inflammatory response and to function in part to restore hemostatic balance. To begin to delineate what role APC may have in the inflammatory response, we have investigated the effect of APC on the production of the proinflammatory cytokines IL-6 and IL-8 in primary HUVEC, human microvascular endothelial cells, and human coronary artery endothelial cells. Our results have demonstrated that physiologic concentrations of APC significantly up-regulated the production of both IL-6 and IL-8. This increase, which was seen at both the RNA and protein level, was not due to either thrombin or LPS contamination of the APC preparation. Additional studies also showed that the APC-mediated up-regulation of IL-6 and IL-8 was IL-1 independent. Although neither purified protein C nor protein S alone had an effect on cytokine production, protein S, the cofactor for APC, significantly enhanced the ability of APC to up-regulate IL-6/IL-8 production. These results provide further evidence for a role for APC in the inflammatory response.
Aprotinin↗
Public health and international health-care development for persons with haemophilia: operation improvement and operation access.
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Health Planning↗
Prions and haemophilia: assessment of risk.
Based on information accumulated to date, it is still difficult to assess the risk of Creutzfeldt-Jakob disease (CJD) and blood transfusion with any degree of confidence. However, it is reasonable to conclude that CJD is produced by a transmittable agent which is probably contained in low titer in the blood of infected people and animals. From the present clinical and epidemiological studies, transmission by blood or blood products appears to be a rare or non-existent cause of current and past cases of CJD in humans. Since blood products are necessary to prevent the immediate risk of death or significant morbidity in many clinical conditions, therapeutic decisions should be made after consideration of the known risk in these situations vs the theoretical long-term risk of the rare occurrence of CJD.
Animals↗
Hepatitis A virus infections associated with clotting factor concentrate in the United States.
BACKGROUND: Two cases of hepatitis A among persons exposed to the same lot of solvent/detergent-treated antihemophilic factor VIII concentrate were reported to a surveillance system. An investigation was conducted to find additional cases and determine the source of infection. STUDY DESIGN AND METHODS: A seroprevalence study was conducted among persons with exposure to the suspect lot for serologic evidence of recent infection with hepatitis A virus (HAV). RESULTS: Six cases of recent HAV infection were discovered: four of the patients had been infused with material from the suspect lot of factor VIII, and two had received infusions of factor IX concentrate made from plasma pools common to the suspect factor VIII lot. HAV was identified in one of the plasma pools, in the factor VIII product, and in serum or stool from two factor VIII recipients and one factor IX recipient. The genetics sequence of the virus in the plasma pool, the factor VIII lot, and the factor VIII recipients were identical, while that of the virus in the factor IX recipient differed by a single base. CONCLUSION: These data document the transmission of HAV by a factor VIII concentrate and implicate factor IX products manufactured from a common source-plasma pool.
Adolescent↗
The role of activated protein C resistance in the pathogenesis of venous thrombosis.
Venous thromboembolism (VTE) is the third most common cardiovascular disease in the United States. VTE is usually a consequence of either acquired or inherited alterations in hemostatic regulatory proteins. These regulatory proteins are predominantly those of the protein C/protein S natural anticoagulant pathway. Acquired deficiencies in this pathway are frequently a consequence of other clinical entities (eg, cancer, AIDS, and diabetes), while inherited deficiencies can be responsible for venous thrombosis in an otherwise healthy individual. The purpose of this article is to briefly describe the pathobiology of the anticoagulant protein system and to review the clinical implications of activated protein C resistance.
Aging↗
Absence of mutations at APC cleavage sites Arg306 in factor V and Arg336, Arg562 in factor VIII in African-Americans.
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Arginine↗
Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor.
We have recently demonstrated that the proinflammatory cytokine, interleukin-6 (IL-6), could upregulate the production of protein S in the human hepatoma cell line, HepG-2, but not in endothelial cells. In this study, we have demonstrated that the combination of exogenous IL-6 and soluble IL-6 receptor (sIL-6R) could significantly upregulate protein S production in both primary human umbilical vein endothelial cells (HUVEC) and in the immortalized human microvascular endothelial cell line, HMEC-1. The IL-6/sIL-6R complex was also able to rapidly induce tyrosine phosphorylation of the IL-6 transducer, gp130. Neutralizing antibodies directed against either IL-6 or gp130 blocked protein S upregulation by the IL-6/sIL-6R complex. It was also observed that exogenous sIL-6R could also upregulate protein S by forming a complex with IL-6 constitutively produced by the endothelial cell. Two other cytokines which also utilize the gp130 receptor, oncostatin M (OSM) and leukemia inhibitory factor (LIF), were also able to upregulate endothelial cell protein S. This study demonstrates a mechanism that allows endothelial cells to respond to IL-6 and also illustrates the potential importance of circulating soluble receptors in the regulation of the anticoagulation pathway.
Antigens, CD↗
Oligonucleotide ligation assay for detection of the factor V mutation (Arg506-->Gln) causing protein C resistance.
A point mutation in the Factor V (FV) gene at the activated protein C cleavage site, FV Arg (R)506-->FV Gln (Q)506, is the reported molecular basis for resistance to activated protein C (APC-R). This mutation has been reported in approximately 20-50% of individuals with previously unexplained thrombophilia and 3-5% of the general population. We have adapted an oligonucleotide ligation assay (OLA) for nonisotopic detection of the FV:Q506 mutation which permits rapid screening for this mutation. First, the polymerase chain reaction (PCR) was used for target DNA amplification, thus permitting nonisotopic reporters in the DNA analysis. Then thermostable ligase was used for ligation or covalent coupling of adjacent wild-type and mutant oligonucleotide probes which occurs only when the probes are annealed to a matched amplicon. A colorimetric ELISA-based detection assay was then used to capture 5' biotinylated probes in 96-well streptavidin-coated plates and by virtue of ligation, detection of a 3' digoxigenin reporter probe. Following the addition of anti-digoxigenin conjugate and enhanced alkaline phosphatase signal amplification, colorimetric substrate change was measured in an ELISA plate reader. This assay correctly identified FV genotypes of 290 samples.
Base Sequence↗
A racial difference in the prevalence of the Arg506-->Gln mutation.
Several recent studies have reported that the factor V Arg506-->Gln mutation is present in 3-10% of adults of European descent. To determine if the prevalence is comparable among Blacks, we have initiated a case-control study in a large urban hospital in Atlanta which serves a substantial black population. We have evaluated 131 black subjects with confirmed venous or arterial thrombosis and 61 black subjects without a history of thrombosis. Only one case and one control were positive for the Arg506-->Gln mutation. We conclude that the mutation is more common among Whites than Blacks.
Arginine↗
TNF-alpha suppresses IL-1 alpha and IL-6 upregulation of C4b-binding protein in HepG-2 hepatoma cells.
C4b-binding protein (C4BP) is a regulatory protein involved in the regulation of the classical pathway of complement and the natural anticoagulant pathway. C4BP is synthesized by the liver, a target organ of the IL-6 proinflammatory cytokine. C4BP is an acute-phase protein and its basal levels may increase by as much as 4-fold during an inflammatory response. IL-6 which plays a major role in the modulation of the acute-phase proteins, including C4BP, also has been shown by our group to significantly increase hepatocyte production of the anticoagulant protein, protein S. In this study, we have examined the role of cytokine combinations on the production of the C4BP regulatory protein in the HepG-2 hepatoma cell line and report that IL-1 alpha and IL-6 in combination as well as IL-1 alpha and Oncostatin M (OSM) were approximately additive in the upregulation of C4BP while IL-6 and OSM were not and that TNF-alpha blocked both IL-1 alpha and IL-6 but not OSM upregulation of C4BP.
Carcinoma, Hepatocellular↗