1231
(2-2 mg/kg in the aprotinin group and 2.0 mg/kg in the controls). In the aprotinin group, mean HDR was 14 mg/kg immediately after protamine, with no patients having an HDR less than 9 mg/kg, and by 30 min post-protamine HDR had decreased slightly to a mean of 12-3 mg/kg with only 2 patients having HDR under 9 mg/kg. However, in the control group, mean HDR was 8-6 mg/kg immediately post-protamine (with only 3 patients having HDR above 3 mg/kg), and had decreased to a mean 3-9 mg/kg 30 min later (with only 1 patient having HDR above 3 mg/kg). Thus, in aprotinin-treated patients, heparin requirements rose dramatically immediately post-protamine, and this apparent resistance to heparin persisted for at least 30 min. These findings have important implications when considering reinstitution of CPB in aprotinin-treated patients. To prevent coagulation of the extracorporeal circuit, much higher doses of heparin may be required than the 3 mg/kg currently considered adequate. In addition, there may be a subgroup of the "normal" population who have post-protamine heparin resistance, even when not pretreated with aprotinin. The heparin resistance may be due to an effect of aprotinin on the serine proteinase anti-thrombin III. A. C. C. A.
Cardiothoracic Unit, Brook General Hospital, London SE18 4LW, UK
R. FISHER R. BAILEY N. SHANNON K. WIELOGORSKI
1. Bidstrup
BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989; 97: 364-72. 2. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open heart surgery. Lancet 1987; ii: 1289-91. 3. Hunt BJ, Segal HC, Yacoub M. Guidelines for monitoring heparin by the activated dotting time when aprotinin is used during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992; 104: 211-12. 4. Horkay F, Martin P, Walker DR. Transient hypercoagulability in adult patients following open heart surgery. 12th annual San Diego cardiothoracic surgery symposium, 1992: 188 (abstr).
Bleeding oesophageal varices and transjugular intrahepatic portosystemic shunting SIR,-In your Aug 29 (p 515) editorial you mention treatment of bleeding oesophageal varices with transjugular intraheptiac portosystemic shuntings (TIPS). TIPS is a new procedure, with few published series. This lack of information makes it difficult for physicians to decide whether to participate in trials of TIPS versus endoscopic sclerotherapy. There have been several presentations of early experience with TIPS at radiology and gastroenterology meetings. Review of 343 cases presented so far provides this *
necessary information.* The age range of patients who have undergone TIPS is 25-84 years. In 278 of the 343 cases the severity of liver disease was stated as Child’s class A in 68, class B in 92, and class C in 118. In most cases the procedure was done because of recurrent bleeding from oesophageal varices despite sclerotherapy. In 24 cases the indication was acute bleeding varices, in 7 it was bleeding gastric varices, and in 10 cases it was refractory ascites. TIPS was successful at decompressing portal hypertension in
almost all cases. 23 of 24 acute bleeds were halted, the one failure being attributable to a bleeding duodenal ulcer. Ascites resolved completely in 27 of 29 patients. 36 deaths were reported among the 343 patients. Most were due to sepsis or multiorgan failure in Child’s class C patients. The one death that was directly attributable to TIPS resulted from uncontrollable haemorrhage in a patient with abnormal coagulation. Procedure-related complications were infrequent and included neck haematoma and bacteraemia. A rise in hepatic enzymes and serum ammonia level after TIPS has been recorded. This peaked after 1 week and stabilised after 4-8 weeks. 24 of 271 patients developed encephalopathy but in most cases this was mild and improved with treatment. 49 stents became *References for 12 published abstracts request.
are
available from The Lancet
on
or stenosed. 39 of these were successfully treated by thrombolysis or restenting (occlusions) or by angioplasty (stenoses). Occlusions arose earlier than stenoses and were due to thrombosis, hepatic parenchymal overgrowth, or neointimal hyperplasia. The stenoses were usually caused by neointimal hyperplasia in the hepatic veins. The largest series showed a 30% occlusion or
occluded
restenosis rate and a 10% rebleed rate during the first two years. Results so far therefore show TIPS to be effective with a low procedure-related morbidity and mortality. Stent occlusion and hepatic-vein stenosis rather than encephalopathy seem to be the commonest long-term problems, but these complications can be treated. A controlled trial of TIPS versus sclerotherapy for the treatment of bleeding varices is indicated, and the early success of TIPS is such that all physicians caring for patients with oesophageal varices should be encouraged to participate. Department of Diagnostic Radiology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Acute hepatitis A in
VINCENT MCDERMOTT
haemophiliacs
SIR,-Mannucci et all reported an outbreak of acute hepatitis A in Italian
haemophiliacs related to a factor VIII preparation (Emoclot Octa VI, Aima Derivati, Rieti, Italy). The presence or origin of hepatitis A virus (HAV) in this preparation has never been clearly identified, but it was suggested that the processing water of the factor VIII production site in Rieti could have been contaminated by HAV-containing sewage, because the water was only purified by reverse osmosis. We report a cluster of HAV infections in haemophiliacs who received factor VIII produced by the same procedure with distilled water and in other production sites (Octavi, Octapharma, Diisseldorf). Since 1988,46 patients susceptible to HAV infection (median age 21 years) have been treated at the Bonn Haemophilia Centre with these preparations. 13 (median age 10) have become infected with HAV (4 in 1988,3 in 1990,4 in 1991,2 in 1992), whereas only 1 of23 HAV-susceptible patients (median age 26) treated with other clotting factor preparations was infected. This patient was the brother of a patient who had received Octavi and who had developed hepatitis A some weeks before. Diagnosis was generally based on anti-HAV seroconversion from formerly negative (titre 210) in the HAVAB enzyme immunoassay (EIA, Abbott). The HAVAB M EIA for detection of IgM antibodies to HAV was reactive: over six times the cutoff in 11 of 13 cases, and twice the cutoff in a twelfth patient. Clinical disease and/or alanine aminotransferase peaks above 100 IU/1 were observed in 10 of the 13 cases when IgM anti-HAV was detectable. Antibodies to hepatitis C virus (HCV) had been present in 7 patients for a long time before acute HAV infection, but liver enzymes in these patients had only occasionally been increased, if at all, and never exceeded moderate values. 1 of the patients reported a known risk for acquiring HAV infection (recent travel to Israel), but no other risks could be clearly identified. Until May, 1990, Octavi from production sites at Rieti, Hagen (Germany), and Vienna were administered to our patients. Thereafter, only German and Austrian products were used. 4 patients with HAV infections in late 1991 and early 1992 received one batch (1367214) produced in Vienna, for which the plasma had been collected in former East Germany. Professor Flehmig’s group (including A. G. and H.-H. B.) from Tubingen (pl232) detected HAV RNA by antigen-capture polymerase chain reaction in this batch. We could not detect antibodies to HAV (with the HAVAB EIA or the IMx HAVAB EIA) which would have neutralised the HAV in this batch. We conclude that acute HAV infections in haemophiliacs treated with virus-inactivated (solvent/detergent method) factor VIII are not restricted to Italy and Italian factor VIII preparations. The source of HAV in these preparations could be the plasma pools2 from unsuspected but infectious donors because HAV causes strong viraemia during its incubation period.3 Factor VIII preparations are treated with solvent/detergent to inactivate enveloped viruses such as HIV, HCV, or hepatitis B virus. HAV,
(2-2 mg/kg in the aprotinin group and 2.0 mg/kg in the controls). In the aprotinin group, mean HDR was 14 mg/kg immediately after protamine, with no patients having an HDR less than 9 mg/kg, and by 30 min post-protamine HDR had decreased slightly to a mean of 12-3 mg/kg with only 2 patients having HDR under 9 mg/kg. However, in the control group, mean HDR was 8-6 mg/kg immediately post-protamine (with only 3 patients having HDR above 3 mg/kg), and had decreased to a mean 3-9 mg/kg 30 min later (with only 1 patient having HDR above 3 mg/kg). Thus, in aprotinin-treated patients, heparin requirements rose dramatically immediately post-protamine, and this apparent resistance to heparin persisted for at least 30 min. These findings have important implications when considering reinstitution of CPB in aprotinin-treated patients. To prevent coagulation of the extracorporeal circuit, much higher doses of heparin may be required than the 3 mg/kg currently considered adequate. In addition, there may be a subgroup of the "normal" population who have post-protamine heparin resistance, even when not pretreated with aprotinin. The heparin resistance may be due to an effect of aprotinin on the serine proteinase anti-thrombin III. A. C. C. A.
Cardiothoracic Unit, Brook General Hospital, London SE18 4LW, UK
R. FISHER R. BAILEY N. SHANNON K. WIELOGORSKI
1. Bidstrup
BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989; 97: 364-72. 2. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open heart surgery. Lancet 1987; ii: 1289-91. 3. Hunt BJ, Segal HC, Yacoub M. Guidelines for monitoring heparin by the activated dotting time when aprotinin is used during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992; 104: 211-12. 4. Horkay F, Martin P, Walker DR. Transient hypercoagulability in adult patients following open heart surgery. 12th annual San Diego cardiothoracic surgery symposium, 1992: 188 (abstr).
Bleeding oesophageal varices and transjugular intrahepatic portosystemic shunting SIR,-In your Aug 29 (p 515) editorial you mention treatment of bleeding oesophageal varices with transjugular intraheptiac portosystemic shuntings (TIPS). TIPS is a new procedure, with few published series. This lack of information makes it difficult for physicians to decide whether to participate in trials of TIPS versus endoscopic sclerotherapy. There have been several presentations of early experience with TIPS at radiology and gastroenterology meetings. Review of 343 cases presented so far provides this *
necessary information.* The age range of patients who have undergone TIPS is 25-84 years. In 278 of the 343 cases the severity of liver disease was stated as Child’s class A in 68, class B in 92, and class C in 118. In most cases the procedure was done because of recurrent bleeding from oesophageal varices despite sclerotherapy. In 24 cases the indication was acute bleeding varices, in 7 it was bleeding gastric varices, and in 10 cases it was refractory ascites. TIPS was successful at decompressing portal hypertension in
almost all cases. 23 of 24 acute bleeds were halted, the one failure being attributable to a bleeding duodenal ulcer. Ascites resolved completely in 27 of 29 patients. 36 deaths were reported among the 343 patients. Most were due to sepsis or multiorgan failure in Child’s class C patients. The one death that was directly attributable to TIPS resulted from uncontrollable haemorrhage in a patient with abnormal coagulation. Procedure-related complications were infrequent and included neck haematoma and bacteraemia. A rise in hepatic enzymes and serum ammonia level after TIPS has been recorded. This peaked after 1 week and stabilised after 4-8 weeks. 24 of 271 patients developed encephalopathy but in most cases this was mild and improved with treatment. 49 stents became *References for 12 published abstracts request.
are
available from The Lancet
on
or stenosed. 39 of these were successfully treated by thrombolysis or restenting (occlusions) or by angioplasty (stenoses). Occlusions arose earlier than stenoses and were due to thrombosis, hepatic parenchymal overgrowth, or neointimal hyperplasia. The stenoses were usually caused by neointimal hyperplasia in the hepatic veins. The largest series showed a 30% occlusion or
occluded
restenosis rate and a 10% rebleed rate during the first two years. Results so far therefore show TIPS to be effective with a low procedure-related morbidity and mortality. Stent occlusion and hepatic-vein stenosis rather than encephalopathy seem to be the commonest long-term problems, but these complications can be treated. A controlled trial of TIPS versus sclerotherapy for the treatment of bleeding varices is indicated, and the early success of TIPS is such that all physicians caring for patients with oesophageal varices should be encouraged to participate. Department of Diagnostic Radiology, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Acute hepatitis A in
VINCENT MCDERMOTT
haemophiliacs
SIR,-Mannucci et all reported an outbreak of acute hepatitis A in Italian
haemophiliacs related to a factor VIII preparation (Emoclot Octa VI, Aima Derivati, Rieti, Italy). The presence or origin of hepatitis A virus (HAV) in this preparation has never been clearly identified, but it was suggested that the processing water of the factor VIII production site in Rieti could have been contaminated by HAV-containing sewage, because the water was only purified by reverse osmosis. We report a cluster of HAV infections in haemophiliacs who received factor VIII produced by the same procedure with distilled water and in other production sites (Octavi, Octapharma, Diisseldorf). Since 1988,46 patients susceptible to HAV infection (median age 21 years) have been treated at the Bonn Haemophilia Centre with these preparations. 13 (median age 10) have become infected with HAV (4 in 1988,3 in 1990,4 in 1991,2 in 1992), whereas only 1 of23 HAV-susceptible patients (median age 26) treated with other clotting factor preparations was infected. This patient was the brother of a patient who had received Octavi and who had developed hepatitis A some weeks before. Diagnosis was generally based on anti-HAV seroconversion from formerly negative (titre 210) in the HAVAB enzyme immunoassay (EIA, Abbott). The HAVAB M EIA for detection of IgM antibodies to HAV was reactive: over six times the cutoff in 11 of 13 cases, and twice the cutoff in a twelfth patient. Clinical disease and/or alanine aminotransferase peaks above 100 IU/1 were observed in 10 of the 13 cases when IgM anti-HAV was detectable. Antibodies to hepatitis C virus (HCV) had been present in 7 patients for a long time before acute HAV infection, but liver enzymes in these patients had only occasionally been increased, if at all, and never exceeded moderate values. 1 of the patients reported a known risk for acquiring HAV infection (recent travel to Israel), but no other risks could be clearly identified. Until May, 1990, Octavi from production sites at Rieti, Hagen (Germany), and Vienna were administered to our patients. Thereafter, only German and Austrian products were used. 4 patients with HAV infections in late 1991 and early 1992 received one batch (1367214) produced in Vienna, for which the plasma had been collected in former East Germany. Professor Flehmig’s group (including A. G. and H.-H. B.) from Tubingen (pl232) detected HAV RNA by antigen-capture polymerase chain reaction in this batch. We could not detect antibodies to HAV (with the HAVAB EIA or the IMx HAVAB EIA) which would have neutralised the HAV in this batch. We conclude that acute HAV infections in haemophiliacs treated with virus-inactivated (solvent/detergent method) factor VIII are not restricted to Italy and Italian factor VIII preparations. The source of HAV in these preparations could be the plasma pools2 from unsuspected but infectious donors because HAV causes strong viraemia during its incubation period.3 Factor VIII preparations are treated with solvent/detergent to inactivate enveloped viruses such as HIV, HCV, or hepatitis B virus. HAV,
