scholarly journals Hepatitis C viral RNA in clotting factor concentrates and the development of hepatitis in recipients

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1898-1902
Author(s):  
M Makris ◽  
JA Garson ◽  
CJ Ring ◽  
PW Tuke ◽  
RS Tedder ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Diagnostic Criteria ◽  
Factor Ix ◽  
Factor Vii ◽  
Clotting Factor ◽  
Hcv Rna ◽  
Heat Treated ◽  
Volunteer Donor ◽  
Clotting Factor Concentrates ◽  
Donor Plasma

The polymerase chain reaction (PCR) was used to detect hepatitis C (HCV) viral sequences (HCV-RNA) in clotting factor concentrates that had been stored at 4 degrees C for 1 to 16 years. A total of 43 concentrates were tested, comprising 31 batches of factor VIII, 6 of factor IX, 2 of antithrombin III, 3 of FEIBA, and 1 of factor VII. HCV- RNA was detected in 13 of the 43 batches (30.2%). Concentrates that had not undergone viral inactivation during manufacture were significantly more likely to contain detectable HCV-RNA than concentrates that had been virally inactivated (56.3% v 14.5%, P = .006). HCV sequences were more commonly detected in concentrates made from paid donor plasma than in those made from volunteer donor plasma (44% v 11%, P = .041), and more commonly in virally inactivated concentrates with pre-1989 than with post-1989 expiration dates (50% v 0%, P = .004). Of the four batches of heat-treated products that were HCV-RNA positive, at least three transmitted non-A, non-B hepatitis (NANBH). An association between the presence of HCV-RNA in concentrates and the development of NANBH was demonstrated in nine previously untreated patients on prospective follow-up. HCV-RNA was detected in the concentrates administered to the six patients whose alanine aminotransferase (ALT) abnormalities met the diagnostic criteria for NANBH and who later seroconverted for HCV, but it was not detected in the concentrates administered to the three patients whose ALT abnormalities failed to satisfy the diagnostic criteria and who did not seroconvert. We suggest that the use of this PCR technique to monitor clotting factor concentrates derived from pooled blood may potentially contribute to product safety.

scholarly journals Hepatitis C viral RNA in clotting factor concentrates and the development of hepatitis in recipients

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1898-1902 ◽  
Author(s):  
M Makris ◽  
JA Garson ◽  
CJ Ring ◽  
PW Tuke ◽  
RS Tedder ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Diagnostic Criteria ◽  
Factor Ix ◽  
Factor Vii ◽  
Clotting Factor ◽  
Hcv Rna ◽  
Heat Treated ◽  
Volunteer Donor ◽  
Clotting Factor Concentrates ◽  
Donor Plasma

Abstract The polymerase chain reaction (PCR) was used to detect hepatitis C (HCV) viral sequences (HCV-RNA) in clotting factor concentrates that had been stored at 4 degrees C for 1 to 16 years. A total of 43 concentrates were tested, comprising 31 batches of factor VIII, 6 of factor IX, 2 of antithrombin III, 3 of FEIBA, and 1 of factor VII. HCV- RNA was detected in 13 of the 43 batches (30.2%). Concentrates that had not undergone viral inactivation during manufacture were significantly more likely to contain detectable HCV-RNA than concentrates that had been virally inactivated (56.3% v 14.5%, P = .006). HCV sequences were more commonly detected in concentrates made from paid donor plasma than in those made from volunteer donor plasma (44% v 11%, P = .041), and more commonly in virally inactivated concentrates with pre-1989 than with post-1989 expiration dates (50% v 0%, P = .004). Of the four batches of heat-treated products that were HCV-RNA positive, at least three transmitted non-A, non-B hepatitis (NANBH). An association between the presence of HCV-RNA in concentrates and the development of NANBH was demonstrated in nine previously untreated patients on prospective follow-up. HCV-RNA was detected in the concentrates administered to the six patients whose alanine aminotransferase (ALT) abnormalities met the diagnostic criteria for NANBH and who later seroconverted for HCV, but it was not detected in the concentrates administered to the three patients whose ALT abnormalities failed to satisfy the diagnostic criteria and who did not seroconvert. We suggest that the use of this PCR technique to monitor clotting factor concentrates derived from pooled blood may potentially contribute to product safety.

Anti-HCV Agent, Ribavirin, Decreases Events of Bleeding in Hemophilia Patients, Possibly by Elevating the Clotting Activity of Factor VII.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3214-3214
Author(s):  
Koji Yamamoto ◽  
Takashi Honda ◽  
Satoshi Suzuki ◽  
Hidenori Toyoda ◽  
Tadashi Matsushita ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Combination Therapy ◽  
University Hospital ◽  
Factor Vii ◽  
Clotting Factor ◽  
Hcv Rna ◽  
Clotting Factors ◽  
Normal Human ◽  
Clotting Factor Concentrates ◽  
Induced Changes

Abstract Ribavirin has been used in combination with interferon-alpha (IFN-α) to treat chronic hepatitis C. This combination therapy has been reported to be more effective than IFN-α monotherapy for eradicating hepatitis C virus (HCV), including patients with concomitant hemophilia. Eight consecutive hemophilia patients were treated for HCV infection with IFN-α and ribavirin between June 2002 and May 2005 at Nagoya University Hospital as outpatients. Characteristics of patients and responses to anti-HCV treatment Patient Age (yrs) Hemophilia type Severity of hemophilia HIV infection Ribavirin load (mg/day) HCV genotype Eradication of HCV The eradication of HCV was considered positive when the absence of serum HCV RNA was maintained for 24 weeks after treatment was completed. 1 28 A moderate N 800 3a Yes 2 61 A severe N 800 3a Yes 3 50 A severe N 600 --> 400 1b No 4 42 B mild N 800 2a +1b Yes 5 44 A severe N 800 3a Yes 6 52 A mild N 600 2b Yes 7 37 A mild P 800 --> 600 1a No 8 44 B moderate N 800 1a Yes All patients were men with a mean age (SD) of 44.8 (10.0) years. Seven patients had hemophilia A, and 2 had hemophilia B. Hemophilia was severe in 4 patients, moderate in 2 and mild in 3. Four patients had been previously treated with IFN-α-2b alone (Intron A®, Schering Plough, K.K., Osaka, Japan) but HCV had not been eradicated. During this study, all patients were treated with the same 24-week regimen of IFN-α. Oral ribavirin (Rebetol, Schering-Plough, Kenilworth, N.J.) was administered at a dose of 600 mg/day for patients who weighed 60 kg or less and 800 mg/day for those who weighed more than 60 kg during 24 weeks. We observed the reduction of the frequency and dose of infusion with clotting factors as a hemostatic therapy in HCV-positive hemophilia patients who were administered with ribavirin. Figure Figure (Use of clotting factor concentrates 6 months before, during and 6 months after combination therapy with ribavirin and IFN-α. Use of clotting factors is presented as the average use per month.) In order to investigate the mechanism of this prophylactic effect of ribavirin to bleeding in hemophiliacs, we analyzed ribavirin-induced changes in the activity of factor VII in patients’ plasma. The clotting activity of factor VII in plasma has been elevated at 15% on an average in 9 HCV-positive hemophilia patients during treatment with ribavirin (without ribavirin: 86.3±7.6%; with ribavirin: 102.0±10.3%). Furthermore, a significant induction of factor VII mRNA was demonstrated in cultured normal human hepatocytes or HepG2 cells when treated with ribavirin at the therapeutic concentration. These observations indicate that ribavirin can elevate factor VII procoagulant activity in plasma, possibly due to the induction of factor VII in hepatocytes, thus, contributing to decreased events of bleeding in HCV-positive hemophiliacs.

scholarly journals Hepatitis C infection in children with hemophilia A and B

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 285-289 ◽  
Author(s):  
VS Blanchette ◽  
E Vorstman ◽  
A Shore ◽  
E Wang ◽  
M Petric ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Factor Viii ◽  
Hcv Infection ◽  
Clotting Factor ◽  
Blood Products ◽  
Donor Blood ◽  
Dry Heat ◽  
Single Donor ◽  
Heat Treated ◽  
Clotting Factor Concentrates

Abstract Antibodies to hepatitis C virus (anti-HCV) were quantitated in stored sera from selected groups of hemophilic children (less than or equal to 18 years of age). During the period 1987 to 1989, seropositivity rates were as follows: untransfused hemophiliacs 0% (0 of 11 cases), hemophiliacs treated exclusively with vapor-heated factor VIII or IX concentrates 0% (0 of 9 cases), hemophiliacs treated only with cryoprecipitate or single donor blood products 0% (0 of 9 cases), and hemophiliacs regularly treated with unheated or dry heat-treated factor VIII or IX concentrates 95% (21 of 22 cases). Corresponding alanine aminotransferase (ALT) results were similar: values were always below the upper limit of laboratory normal (40 U/L) in untransfused hemophiliacs, hemophiliacs treated with vapor-heated factor concentrates, or those who received only cryoprecipitate or single donor blood products. By contrast ALT values were greater than 40 U/L in 82% (18 of 22 cases) of hemophilic children regularly infused with unheated or dry heat-treated factor concentrates. Three conclusions are drawn from this data: (1) HCV is a major cause of chronic hepatitis in multitransfused hemophilic children, (2) unheated and dry heat-treated clotting factor concentrates carry a very high risk of transmitting HCV infection, and (3) clotting factor concentrates inactivated by vapor heating carry a very low and perhaps zero risk of transmitting HCV infection. These findings are of therapeutic significance for previously untransfused hemophiliacs susceptible to HCV infection.

scholarly journals Hepatitis C infection in children with hemophilia A and B

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 285-289
Author(s):  
VS Blanchette ◽  
E Vorstman ◽  
A Shore ◽  
E Wang ◽  
M Petric ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Factor Viii ◽  
Hcv Infection ◽  
Clotting Factor ◽  
Blood Products ◽  
Donor Blood ◽  
Dry Heat ◽  
Single Donor ◽  
Heat Treated ◽  
Clotting Factor Concentrates

Antibodies to hepatitis C virus (anti-HCV) were quantitated in stored sera from selected groups of hemophilic children (less than or equal to 18 years of age). During the period 1987 to 1989, seropositivity rates were as follows: untransfused hemophiliacs 0% (0 of 11 cases), hemophiliacs treated exclusively with vapor-heated factor VIII or IX concentrates 0% (0 of 9 cases), hemophiliacs treated only with cryoprecipitate or single donor blood products 0% (0 of 9 cases), and hemophiliacs regularly treated with unheated or dry heat-treated factor VIII or IX concentrates 95% (21 of 22 cases). Corresponding alanine aminotransferase (ALT) results were similar: values were always below the upper limit of laboratory normal (40 U/L) in untransfused hemophiliacs, hemophiliacs treated with vapor-heated factor concentrates, or those who received only cryoprecipitate or single donor blood products. By contrast ALT values were greater than 40 U/L in 82% (18 of 22 cases) of hemophilic children regularly infused with unheated or dry heat-treated factor concentrates. Three conclusions are drawn from this data: (1) HCV is a major cause of chronic hepatitis in multitransfused hemophilic children, (2) unheated and dry heat-treated clotting factor concentrates carry a very high risk of transmitting HCV infection, and (3) clotting factor concentrates inactivated by vapor heating carry a very low and perhaps zero risk of transmitting HCV infection. These findings are of therapeutic significance for previously untransfused hemophiliacs susceptible to HCV infection.

Antibody to Hepatitis G Mrus after a Vapour-Heated Factor Vlll Goncentrate

1990 ◽  
Vol 64 (02) ◽  
pp. 232-234 ◽  
Author(s):  
P M Mannucci ◽  
A R Zanetti ◽  
M Colombo ◽  
A Chistolini ◽  
R De Biasi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B ◽  
Factor Viii ◽  
Alanine Aminotransferase ◽  
Household Contact ◽  
Clotting Factor ◽  
Double Infection ◽  
Marked Elevation ◽  
Clotting Factor Concentrates

SummaryTo evaluate whether or not clotting factor concentrates exposed to virucidal procedures transmitted hepatitis C, sera obtained in 1984–1986 from 27 previously untreated hemophiliacs infused with a vapour-heated factor VIII concentrate were tested retrospectively for the antibody to the hepatitis C virus (anti- HCV). A 2-year-old hemophiliac, negative for anti-HCV before administration of concentrate, seroconverted at week 12 and remained anti-HCV positive thereafter. Both his parents were anti-HCV negative and he had no other household contact. The patient had also become HBsAg positive at week 8 and had at the same time a marked elevation of alanine aminotransferase. His double infection with the hepatitis B and C viruses indicates that hot vapour was not completely effective in inactivating these viruses.

Acute Hepatitis C in Haemophiliacs Due to “Virus-Inactivated” Clotting Factor Concentrates

1992 ◽  
Vol 68 (06) ◽  
pp. 781-781 ◽  
Author(s):  
A Gerritzen ◽  
B Scholt ◽  
R Kaiser ◽  
K E Schneweis ◽  
H-H Brackmann ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Acute Hepatitis ◽  
Clotting Factor ◽  
Acute Hepatitis C ◽  
Clotting Factor Concentrates

Clinical Factors Associated with Progression to AIDS in the Italian Cohort of HIV-Positive Hemophiliacs

1994 ◽  
Vol 72 (01) ◽  
pp. 033-038 ◽  
Author(s):  
N Schinaia ◽  
A M G Ghirardini ◽  
M G Mazzucconi ◽  
G Tagariello ◽  
M Morfini ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
National Registry ◽  
Factor Ix ◽  
Clotting Factor ◽  
Coagulation Disorders ◽  
Factors Associated ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Congenital Coagulation Disorders ◽  
Clotting Factor Concentrates

SummaryThis study updates estimates of the cumulative incidence of AIDS among Italian patients with congenital coagulation disorders (mostly hemophiliacs), and elucidates the role of age at seroconversion, type and amount of replacement therapy, and HBV co-infection in progression. Information was collected both retrospectively and prospectively on 767 HIV-1 positive patients enrolled in the on-going national registry of patients with congenital coagulation disorders. The seroconversion date was estimated as the median point of each patient’s seroconversion interval, under a Weibull distribution applied to the overall interval. The independence of factors associated to faster progression was assessed by multivariate analysis. The cumulative incidence of AIDS was estimated using the Kaplan-Meier survival analysis at 17.0% (95% Cl = 14.1-19.9%) over an 8-year period for Italian hemophiliacs. Patients with age greater than or equal to 35 years exhibited the highest cumulative incidence of AIDS over the same time period, 32.5% (95% Cl = 22.2-42.8%). Factor IX recipients (i.e. severe B hemophiliacs) had higher cumulative incidence of AIDS (23.3% vs 14.2%, p = 0.01) than factor VIII recipients (i.e. severe A hemophiliacs), as did severe A hemophiliacs on less-than-20,000 IU/yearly of plasma-derived clotting factor concentrates, as opposed to A hemophiliacs using an average of more than 20,000 IU (18.8% vs 10.9%, p = 0.02). No statistically significant difference in progression was observed between HBsAg-positive vs HBsAg-negative hemophiliacs (10.5% vs 16.4%, p = 0.10). Virological, immunological or both reasons can account for such findings, and should be investigated from the laboratory standpoint.

scholarly journals Coagulation Disturbances in Patients with Argininemia

2018 ◽  
Vol 140 (4) ◽  
pp. 221-225 ◽  
Author(s):  
Ertugrul Kiykim ◽  
Tanyel Zubarioglu ◽  
Mehmet Serif Cansever ◽  
Tiraje Celkan ◽  
Johannes Häberle ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Urea Cycle ◽  
International Normalized Ratio ◽  
Factor Ix ◽  
Factor Vii ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Hepatic Involvement ◽  
Prolonged Aptt ◽  
Liver Transaminases

Background: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. Methods: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. Results: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. Conclusions: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms.

EXPRESSION IN MAMMALIAN CELLS OF FUSION PROTEINS BETWEEN HUMAN FACTORS IX AND VII

1987 ◽  
Author(s):  
K L Berkner ◽  
S J Busby ◽  
J Gambee ◽  
A Kumar
Keyword(s):  
Fusion Protein ◽  
Fusion Proteins ◽  
Factor Ix ◽  
Biologically Active ◽  
Factor Vii ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Mammalian Expression ◽  
Plasma Factor ◽  
Gla Domain

The vitamin K-dependent plasma proteins demonstrate remarkable similarities in their structures: all have multiple domains in common and extensive homology is observed within many of these domains. In order to investigate the structure-function relationship of these proteins, we have interchanged domains of one protein (factor IX) with that of another (factor VII) and have compared the expression of these fusion proteins with recombinant and native factors IX and VII. Oligonucleotide-directed mutagenesis was used to generate four fusion proteins: factor IX/VII-1, which contains the factor IX leader and gla domain fused to the growth factor and serine protease of factor VII; factor VII/IX-1, a reciprocal fusion protein of factor IX/VII-1; factor IX/VII-2, which contains the factor IX leader adjoined to the mature factor VII protein sequence; and factor VII/IX-2, the reciprocal fusion protein of factor IX/VII-2. The cDNAs encoding all four proteins were cloned into mammalian expression vectors, and to date three of these (factors IX/VII-1, 2 and VII/IX-1) have been transfected into baby hamster kidney (BHK) cells or 293 cells and characterized. Factors IX/VII-1 and VII/IX-1 were both secreted at levels comparable to recombinant factors IX and VII. The factor IX/VII-1 was identical in molecular weight to native or recombinant factor VII (i.e., 53 K). Factor VII/IX-1 was expressed as two proteins with molecular weights around 68 kd, as observed with recombinant factor IX. The factor IX/VII-1 protein has been purified to homogeneity and has been found to possess factor VII biological activity, but at a specific activity approximately 20% that of plasma factor VII. Thus, the gla domain of one clotting factor is capable of directing the activation of another and of generating biologically active protein. In contrast, no activity was observed with the factor IX/VII-2 fusion protein, indicating that there are limits to the interchanges which can generate functional blood clotting factors.

scholarly journals Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 492-495 ◽  
Author(s):  
JJ Goedert ◽  
MG Sarngadharan ◽  
ME Eyster ◽  
SH Weiss ◽  
AJ Bodner ◽  
...  
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Factor Ix ◽  
Clotting Factor ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Seronegative Patient ◽  
Human T Cell ◽  
Clotting Factor Concentrates ◽  
Leukemia Viruses

Abstract The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.

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