Biomedical subjects
P L Giangrande
Publications and source records attributed to P L Giangrande.
Use of recombinant factor IX in subjects with haemophilia B undergoing surgery.
Recombinant human FIX (rFIX) was evaluated in 28 subjects, including 26 with mild, moderate, or severe haemophilia B and two haemophilia B carriers undergoing 36 surgical procedures. Preoperative rFIX dose was highly correlated with postinfusion FIX activity, r=0.61, P=0.0158. Peri- and post-operative estimated blood loss was similar to that expected in non-haemophilic individuals, and haemostasis was rated as excellent or good in 34 of 35 (97.1%) of the operative procedures. Transfusions were required in five of 36 (13.9%) procedures, including one liver transplantation, and three knee and one hip arthroplasties. Adverse events occurred in 15 of 28 (53.6%) subjects, but there were no perioperative haemorrhages, thromboembolic events, coagulation activation, viral transmission, or inhibitor formation. A transient low-responding FIX inhibitor developed in one subject preoperatively, but required no change in treatment and resolved 15 months later. Thus, rFIX was found to be safe and effective in achieving haemostasis in subjects with FIX deficiency undergoing surgery.
Treatment of haemophilia in the United Kingdom 1981-1996.
Explore the source record for details and available documents.
Guidelines on the diagnosis, management and prevention of hepatitis in haemophilia.
Explore the source record for details and available documents.
Presentation of severe haemophilia--a role for accident and emergency doctors?
BACKGROUND: The management of haemophilia has changed dramatically over the years and is constantly being improved. This study set out to discover if the diagnosis of haemophilia was being made early enough in those with no family history and looked at the different modes of presentation. METHOD: A questionnaire was sent to all patients with haemophilia under the age of 16 who had no family history before diagnosis. RESULTS: There were 28 replies from 34 patients contacted (82% response rate). Three were excluded because of a known family history. The mean number of attendances to a doctor before a diagnosis was considered was 4.13 (median = 3, interquartile range = 2.5). The mean age of diagnosis was 29.52 months (median = 14, interquartile range = 20. Most presentations were to the accident and emergency department and to the general practitioner. The most common presenting feature was easy bruising. CONCLUSION: There is a variable delay in diagnosis despite predictable presenting features.
Air travel and thrombosis.
It is now generally accepted that there is a link between long haul air travel and venous thromboembolism. A similar risk is also recognised with other modes of transport including long coach and car journeys, and the term 'traveller's thrombosis' is to be encouraged instead of 'economy class syndrome'. More research is required to quantify the precise risk, but the risk does appear to be small and largely confined to those with recognised risk factors, which include previous episode of thrombosis, hormonal therapy, recent surgery, malignancy and pregnancy. In addition, haematological abnormalities can predispose to thrombosis. Such thrombophilic disorders include the factor V Leiden mutation and deficiencies of natural anticoagulants such as antithrombin, protein C and protein S. General measures which can be taken to reduce the risk include leg exercises while seated. In addition, there is evidence to support the use of elasticated stockings, but evidence relating to the use of aspirin is less convincing.
Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation.
Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of plasma fibrinogen and by a bleeding tendency ranging from mild to moderately severe. Beside a deletion of the almost entire Aalpha-chain gene, only 2 missense mutations in the C-terminal domain of the Bbeta-chain have been very recently described as being associated with afibrinogenemia. We studied a Pakistani patient with unmeasurable plasma levels of functional and immunoreactive fibrinogen. Sequencing of the fibrinogen genes revealed a homozygous G-->A transition at position +5 of intron 1 of the gamma-chain gene. The predicted mutant fibrinogen gamma-chain would contain the signal peptide, followed by a short stretch of aberrant amino acids, preceding a premature stop codon. To demonstrate the causal role of the identified mutation, we prepared expression vectors containing a region of the fibrinogen gamma-chain gene spanning from exon 1 to intron 4 and carrying either a G or an A at position +5 of intron 1. Transient transfection of the mutated plasmid in HeLa cells, followed by RNA extraction and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, allowed us to demonstrate the production of an erroneously spliced messenger RNA (mRNA), retaining intron 1, as shown by direct sequencing. A normal splicing occurred in HeLa cells transfected with the wild-type plasmid. This is the first report of a mutation in the fibrinogen gamma-chain gene causing afibrinogenemia and indicates that, in addition to the Aalpha and Bbeta-chain genes, the gamma-chain gene must also be considered in mutation screening for afibrinogenemia.
Choice of replacement therapy for hemophilia: recombinant products only?
In the early 1980s it was recognized that coagulation factor concentrates prepared from plasma pooled from thousands of donors transmitted the hepatitis and the human immunodeficiency viruses. The last 15 years have witnessed the development of methods that, applied during concentrate manufacturing, inactivate viruses escaping the screening procedures. The adoption of these measures has dramatically reduced the risk of transmission of bloodborne infections by plasma-derived coagulation factor concentrates. The production of recombinant factor VIII and IX and their availability for patient treatment epitomize progress in hemophilia care through DNA technology. No transmission of infectious agents has been documented and the small amount of residual animal proteins, particularly in the early products, has not been associated with any clinically significant adverse reaction. There is little doubt that recombinant factor VIII and IX are the products of choice for the treatment of patients with hemophilia, particularly the second-generation products containing no plasma-derived human protein and fewer and fewer animal proteins. However, availability and cost still oblige most physicians to ration recombinant products and prioritize certain patient groups (previously untreated, previously uninfected).
The history of blood transfusion.
Explore the source record for details and available documents.
Evaluation of the von Willebrand factor antigen (vWF-Ag) assay using an immuno-turbidimetric method (STA Liatest vWF) automated on the MDA 180 coagulometer.
The standard enzyme-linked immunosorbent assay (ELISA) test for von Willebrand factor antigen (vWF-Ag), though sensitive and specific, does not deliver the flexibility to handle single sample assessments economically or provide rapid, emergency testing capability. The present study examined the performance characteristics of an immuno-turbidimetric assay kit (STA Liatest) modified for automation on the MDA(R)180 coagulation analyser using a supplied protocol. One hundred and sixteen patient samples were assessed by both the standard and the modified method. The correlation coefficient was 0.98 across the range of values 1-487 IU/dl. Above 200 IU/dl, where specimen dilution was indicated, there was greater diversity (r = 0.86) between the techniques. Plotting the difference between methods against the mean of both showed excellent agreement between methods below 100 IU/dl vWF. The intra-assay and interassay coefficients of variation were less than 3% at both low and normal range levels. The MDA(R)180 automated vWF assay merits consideration as an alternative to ELISA testing that provides random access and result availability within 30 min.
Variation in inhibitor reactivity in acquired haemophilia A with different concentrates.
Acquired haemophilia A due to the development of auto-antibodies directed against factor VIII (FVIII) is a rare disorder that may result in serious haemorrhagic episodes. Although in many cases no associated underlying disorders are apparent, the condition has been reported in association with autoimmune disorders, haematological malignancies, treatment with certain drugs and pregnancy. The reaction kinetics of auto-antibodies to FVIII differ from those observed with allo-antibodies in congenital haemophilia. Previous studies in congenital haemophilia have raised the possibility that inhibitory antibodies vary in their reactivity with the factor VIII molecules in different concentrates used for treatment. However, the interaction of FVIII in concentrates and inhibitors in acquired haemophilia has never been previously studied. In this study, the effect of different FVIII concentrates was studied on neutralization in vitro by performing inhibitor titres using the New Oxford inhibitor assay method. The inhibitor titre in eight patients with acquired haemophilia A was assayed against five commercially available FVIII concentrates of varying purity. The intermediate purity concentrate 8Y and the high purity concentrate that contains normal amounts of von Willebrand's Factor (vWF) (Alphanate) gave lower titres than the high purity concentrates with low (Monoclate-P) or no (Kogenate) von Willebrand content. All but one antibody had very low reactivity with porcine FVIII. Further work will be required to establish whether concentrates manifesting a low level of in vitro reactivity with the inhibitor have a better haemostatic effect in vivo.
Increased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders.
The use of protease inhibitor (PI) drugs in treatment regimens for HIV-infected patients with hereditary bleeding disorders has been associated with an increased bleeding tendency. To characterize the nature of this bleeding tendency, a retrospective case record analysis was performed on 67 HIV-positive patients with hereditary bleeding disorders who had been treated with PI therapy. 34 patients (51%) developed an increased bleeding tendency on PI therapy, usually within the first few weeks of treatment. As well as an increase in usual joint bleeds, patients developed spontaneous atypical small joint, soft tissue and muscle bleeds. Haematuria was also common. Bleeding episodes tended to respond suboptimally to factor concentrate replacement. Ritonavir was most likely to be associated with bleeding. Nine patients switched first-line PI therapy as a direct consequence of bleeding and seven had no further bleeding problem on their second PI. Factor concentrate usage was significantly increased during the first 6 months of PI therapy compared to the 6 months preceeding treatment. PI therapy is frequently associated with increased bleeding in patients with hereditary bleeding disorders. The mechanism of the bleeding tendency remains to be elucidated.
Evaluation of a novel ELISA screening test for detection of factor VIII inhibitory antibodies in haemophiliacs.
Treatment of patients with haemophilia A with coagulation factor concentrates may result in the development of inhibitory antibodies directed against factor VIII (FVIII). In this study, a previously unpublished ELISA test for FVIII inhibitor screening (Genetic Testing Institute [GTI] FVIII inhibitor, Brookfield, WI, USA) was evaluated in 131 blood samples (124 samples from patients with haemophilia A, and seven serial samples from one patient with an acquired FVIII inhibitor). Comparisons were made with the routine screening assay (based on recovery of FVIII) and confirmed where positive (< 90% recovery) with the New Oxford assay. The ELISA kit had a sensitivity of 97.7% and specificity of 78.4%. The high negative predictive value of this new test (98.6%) suggests it may be useful as a reliable, rapid (< 2 h) and flexible (microwell strip format) tool for inhibitor screening of samples from both patients with haemophilia A and those with suspected acquired FVIII inhibitors.
Delayed splenic rupture in a haemophiliac.
We report an unusual case of post-traumatic delayed rupture of the spleen occurring in a 38-year-old man with haemophilia A. The time interval between injury and splenic rupture was at least 2 weeks. Although a rare event, the possibility of splenic rupture should always be considered in the differential diagnosis in patients with a bleeding disorder and abdominal pain, even when the patient does not initially give a history of abdominal injury. Radiological imaging, including ultrasound examination, is of great value in establishing the diagnosis. This case report includes a brief review of other similar cases.
Immune status in HIV-1-infected men and boys with haemophilia in the United Kingdom. UK Haemophilia Centre Directors' Organisation.
Explore the source record for details and available documents.
Hepatitis in haemophilia.
Explore the source record for details and available documents.
Management of pregnancy in carriers of haemophilia.
Explore the source record for details and available documents.
Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation.
BACKGROUND: Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS: We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.