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Biomedical subjects

F E Preston

Publications and source records attributed to F E Preston.

At least 109 records · Page 6Linked to original sources
PubMed1994

Increased soluble IL-2 receptor levels in HCV-infected haemophiliacs: a possible indicator of liver disease severity.

We have measured sIL-2R in 60 haemophiliacs and 20 male control subjects. Haemophiliacs were grouped according to their HIV/HCV antibody status. Group 1 (n = 20) comprised HIV + ve/HCV + ve, group 2 (n = 27) HIV - ve/HCV + ve and group 3 (n = 13) HIV - ve/HCV - ve. Group 4 comprised the normal control subjects. We also examined, retrospectively, the relationship between the severity of chronic liver disease, assessed histologically, and sIL-2R levels in selected patients. There was no significant difference between sIL-2R levels of the group 1 and group 2 patients, and the levels for both were significantly greater than those of either the group 3 patients or the control subjects. sIL-2 levels were also higher in selected patients with cirrhosis than in those with chronic active hepatitis (CAH) or chronic persistent hepatitis (CPH). We conclude that in haemophiliacs, chronic HCV-related liver disease is associated with increased plasma levels of sIL-2R and that the degree of elevation may reflect the severity of the associated chronic liver disease.

Adolescent↗
PubMed1994

A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane phospholipid composition.

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.

Blood Platelet Disorders↗
PubMed1994

Further evidence that activated protein C resistance can be misdiagnosed as inherited functional protein S deficiency.

A recent report that activated protein C (APC) resistance interferes with functional protein S (PS) assays prompted us to re-investigate two pedigrees previously diagnosed as having functional PS deficiency. APC resistance was demonstrated in all individuals with apparent functional PS deficiency. The latter diagnosis was shown to be due to the assay being non-linear, functional protein S becoming normal at higher dilutions. This observation, taken in conjunction with results of in vitro recovery studies with purified PS, leads us to conclude that APC resistance was the primary disorder in both pedigrees. The misdiagnosis of APC resistance as functional PS deficiency can be prevented by performing the PS assay at several dilutions, including concentrations lower than those recommended by PS assay manufacturers. Subjects previously diagnosed as having functional PS deficiency should be re-investigated for APC resistance.

Antigens↗
PubMed1994

High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis.

Recent findings have indicated the importance of factor V (FV) in causing resistance to activated protein C (APC) in a high proportion of patients with venous thrombosis. This prompted us to investigate whether resistance could be due to defective inactivation of FVa by APC. Consequently, we amplified a 3.2 kb fragment of the FV gene sequence encoding the heavy chain APC cleavage site. DNA analysis showed a guanine to adenine transition at nucleotide 1691 in all affected members of two families with inherited APC resistance associated with thrombosis and confirmed suspected homozygosity in two individuals. The mutation, in heterozygous form, was also found in approximately 3.5% of our normal population (n = 144) and correlated with low APC resistance. The high prevalence of this mutation suggests that it may be a major contributory factor in early thrombosis.

Base Sequence↗
PubMed1994

The development of antiphospholipid antibodies in haemophilia is linked to infection with hepatitis C.

In haemophilia the presence of antibodies to antiphospholipid has been linked with HIV infection, but other possibilities have not been fully explored and the specificity for various phospholipids not established. In order to investigate further the pathogenesis and clinical significance of these antibodies, we have determined IgG and IgM antibodies to a variety of phospholipids, including cardiolipin, in the serum of 52 haemophiliacs, and related our findings to the presence of antibodies to HIV and hepatitis C virus (HCV), as well as to clotting factor concentrate usage and blood markers of liver biochemistry. Our results demonstrate that the presence of infection with hepatitis C virus is strongly associated with raised serum levels of antiphospholipid antibody even in the absence of HIV infection. They suggest that earlier conclusions on the relationships of antiphospholipid to HIV infection in haemophilia should be revised and that chronic infection with the hepatitis C virus should be added to the list of infective causes for the development of antiphospholipid antibody.

Adolescent↗
PubMed1994

A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate.

A prospective cross-over study was carried out on 19 patients with haemophilia B. comparing the pharmacokinetics of a purified factor IX concentrate prepared by metal chelate affinity chromatography (9MC) with a conventional three-factor prothrombin complex concentrate (9A). The highly purified factor IX concentrate was shown to have a half-life comparable to the PCC; the in vivo recovery of the purified concentrate was significantly greater than that of the complex (P < 0.01). The 20% change in the value of the International Standard for Factor IX Concentrate, introduced in 1988, might have been expected to lower the recovery values. However, the in vivo recovery for both concentrates was somewhat higher than reported previously, particularly in the older literature. In nine patients, serial assays for fibrinopeptide A, prothrombin fragment F1+2 and thrombin-antithrombin complexes (TAT) were performed to assess the potential thrombogenicity of the two concentrates. Evidence was obtained that there was significantly less activation of coagulation following administration of purified factor IX (9MC), as compared to the activation that occurred after the PCC.

Blood Coagulation↗
PubMed1994

Changes in haematological indices, blood viscosity and inhibitors of coagulation during treatment of endometriosis with danazol.

The effects of treatment with danazol (600 mg daily) on haemostatic and haematological function were investigated in 18 pre-menopausal women with endometriosis. Blood samples were taken at 2 pre-treatment visits, at 6, 12 and 24 weeks on treatment, and at 6 weeks after discontinuation of the drug. Haemoglobin, red cell count, haematocrit and platelet count all rose significantly during treatment with danazol (p < 0.01 vs. baseline). Plasma fibrinogen levels fell significantly (p < 0.01), while whole blood viscosity increased during treatment and remained significantly elevated at follow-up. The prothrombin time shortened, but remained within normal limits, and there were no significant changes in factor VII:C, VIIa, or fibrinopeptide A. No significant changes were found in platelet function. Plasma B-beta 15-42 increased significantly. Functional levels of protein C, protein S, and antithrombin III, all rose significantly, above the normal range, while C4b-binding protein levels fell. We conclude that the observed changes in coagulation inhibitors and fibrinolytic activity may be considered beneficial in the context of venous thromboembolism. The rheological effects, however, indicate a degree of caution in the use of the drug in individuals considered to be at risk from arterial cardiovascular disease.

Adult↗
PubMed1994

Thromboplastin related differences in the determination of international normalised ratio: a cause for concern? Steering Committee of the UK National External Quality Assessment Scheme in Blood Coagulation.

When the International Normalised Ratio (INR) is used for control of oral anticoagulant therapy the same result should be obtained irrespective of the laboratory reagent used. However, in the UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation INRs determined using different reagents have been significantly different. For 18 NEQAS samples Manchester Reagent (MR) was associated with significantly lower INRs than those obtained using Diagen Activated (DA, p = 0.0004) or Instrumentation Laboratory PT-Fib HS (IL, p = 0.0001). Mean INRs for this group were 3.15, 3.61, and 3.65 for MR, DA, and IL respectively. For 61 fresh samples from warfarinised patients with INRs of greater than 3.0 the relationship between thromboplastins in respect of INR was similar to that observed for NEQAS data. Thus INRs obtained with MR were significantly lower than with DA or IL (p < 0.0001). Mean INRs for this group were 4.01, 4.40, and 4.59 for MR, DA, and IL respectively. We conclude that the differences between INRs measured with the thromboplastins studied here are sufficiently great to influence patient management through warfarin dosage schedules, particularly in the upper therapeutic range of INR. There is clearly a need to address the issues responsible for the observed discrepancies.

Animals↗
PubMed1993

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

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.

Alanine Transaminase↗
PubMed1993

Chronic hepatitis in haemophilia.

Chronic hepatitis affects almost all haemophiliacs treated with non-virally inactivated clotting factor concentrates. The virus responsible is hepatitis C (HCV) and most patients have non-neutralising antibodies with circulating virus. Although the majority also have evidence of past infection with hepatitis B, less than 5% are chronic carriers of HBsAg. Chronic hepatitis C can be associated with severe and progressive liver disease but the development of complications is slow. Treatment with recombinant interferon alpha given subcutaneously normalises the liver function in 50% of patients, but 50% of responders relapse on stopping treatment. Liver transplantation is successful in patients with advanced liver disease and it offers the added advantage of phenotypic cure of the haemophilic state.

Hemophilia A↗
PubMed1993

Thromboxane and prostacyclin synthesis in experimental pancreas transplantation. Changes in parenchymal and vascular prostanoids.

The principal causes of failure of a pancreas transplant are rejection and vascular thrombosis. There is an unusually high attrition rate for pancreas transplants, but study models have been difficult to develop. In a rat model that allows study of acute rejection to the exclusion of nonspecific effects of transplant surgery on the pancreas, in vitro synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2) by transplanted pancreas and the blood vessels transplanted with it was measured using an RIA for their stable hydrolysis products 6-keto-prostaglandin F1 alpha and thromboxane B2 (TXB2). TXB2 synthesis was significantly greater in allotransplanted pancreas than isotransplanted pancreas from the 5th day after transplantation. Rejection was complete in the allografted group 7-9 days after transplantation. 6-Keto-prostaglandin F1 alpha synthesis was similar in the pancreas for both allografts and isografts. Similar changes were seen in aorta, celiac artery, superior mesenteric artery, and portal vein transplanted with the pancreas. In the transplanted aorta, TXB2 was significantly greater in the allograft group from the third posttransplant day. A group of CsA-treated allografts sampled after 9 days had transplanted pancreatic parenchymal and vascular prostanoid synthesis in the isograft range. The changes in PGI2 and TXA2 synthesis that accompany cellular rejection may mediate vascular failure in rejecting pancreas transplants, and changes in PGI2 and TXA2 synthesis in blood vessels transplanted with the pancreas could promote early vascular thrombosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Identity of viridans streptococci isolated from cases of infective endocarditis.

The oral streptococci have undergone considerable taxonomic revision in recent years but there is still little information concerning associations between the newly defined species and disease. This study examined the identities of 47 strains of oral streptococci collected from 42 confirmed cases of infective endocarditis. By means of recently described physiological schemes, the most common species identified were Streptococcus sanguis sensu stricto (31.9%), S. oralis (29.8%) and S. gordonii (12.7%). Other related species including S. mitis and "S. parasanguis" were less common. This indicates that attention should be focused on S. sanguis sensu stricto and S. oralis when considering possible pathogenic mechanisms involved in viridans streptococcal endocarditis.

Endocarditis, Bacterial↗
PubMed1993

Mechanisms of platelet aggregation by Streptococcus sanguis, a causative organism in infective endocarditis.

The ability of certain strains of Streptococcus sanguis to aggregate human platelets in vitro may be related to their virulence in the pathogenesis of infective endocarditis. We have studied the mechanisms of aggregation of human platelets by S. sanguis strain NCTC 7863. Platelet aggregation follows incubation of S. sanguis cells with platelet-rich plasma from normal, healthy adults, after a lag of 7-19 min. Platelet aggregation was accompanied by 5-hydroxytryptamine release and thromboxane B2 production. Aggregation was prevented by aspirin and by EDTA. Platelets from two patients with Glanzmann's thrombasthenia did not respond to bacteria. Fixed, washed platelets resuspended in normal plasma were not agglutinated by S. sanguis. Blocking the glycoprotein Ib receptor with a monoclonal antibody inhibited aggregation of PRP. However, S. sanguis did not induce von Willebrand factor (vWF) binding to platelets; nor did the bacteria prevent ristocetin-induced platelet agglutination or vWF binding. The aggregation response was not related to plasma vWF activity levels in normal subjects or in patients with von Willebrand's disease. The platelet response to S. sanguis therefore resembles true aggregation, requiring the cyclo-oxygenase pathway and the presence of glycoprotein IIb/IIIa. The mechanism also involves glycoprotein Ib, but not apparently through irreversible binding of vWF.

Agglutination↗
PubMed1993

Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate.

We have looked for evidence of coagulation activation in six subjects with haemophilia B by performing a single-blind active control cross-over study comparing a recently developed factor IX concentrate with a conventional prothrombin complex concentrate (PCC). Samples were obtained before infusion and at 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h for assay of factor IX, prothrombin time, fibrinopeptide A (FPA), prothrombin fragment F1 + 2, D-dimer, thrombin-antithrombin complexes (TAT) and antithrombin III (ATIII). Following administration of the PCC there was evidence of coagulation activation in five of the six recipients for up to 6 h after the infusion. The factor IX concentrate induced a moderate degree of coagulation activation in one subject. There was no significant difference between the two products in respect of either recovery or half-life. This study provides further evidence that the new high purity preparations of factor IX concentrates produce significantly less coagulation activation than currently available PCCs. It remains to be established whether this will result in a corresponding reduction in thromboembolic complications in clinical use.

Adolescent↗
PubMed1993

Reduced tissue type plasminogen activator activity of the gastroduodenal mucosa in peptic ulcer disease.

The gastroduodenal mucosa has a rich blood supply. An active fibrinolytic system is presumably required to maintain vascular patency, and impairment may result in reduced blood flow, focal tissue necrosis, and peptic ulcerogenesis. Tissue type and urokinase type plasminogen activator activity (expressed as mIU/mg protein) and plasminogen activator inhibitor type-1 antigen were assayed in homogenates of gastric and duodenal biopsy specimens taken from patients with: normal endoscopy (controls) (n = 14); active duodenal ulcer (n = 21); healed duodenal ulcer (n = 12); and active benign gastric ulcer (n = 15). In controls mean duodenal tissue type plasminogen activator activity was 4110 and urokinase type plasminogen activator activity 150; gastric tissue type plasminogen activator was 2760 and urokinase type plasminogen activator 170; plasminogen activator inhibitor type-1 was generally undetectable. At the edge of active duodenal ulcers tissue type plasminogen activator was considerably reduced, 2220 (p < 0.001) whereas urokinase type plasminogen activator was raised, 290 (p < 0.01). At the edge of active benign gastric ulcers tissue type plasminogen activator was substantially reduced, 1160 (p < 0.001) but urokinase type plasminogen activator was unchanged. At the scar of healed duodenal ulcers tissue type plasminogen activator was slightly reduced, 3290, but urokinase type plasminogen activator was increased, 308 (p < 0.05). H2 receptor antagonist treatment had little effect on tissue type or urokinase type plasminogen activator activity. Plasminogen activator inhibitor type-1 was increased at the edge of active ulcers (p < 0.05) especially when tissue type plasminogen activity was low (r = -0.61, p < 0.05). These findings are consistent with the hypothesis that impaired fibrinolytic activity may be implicated in peptic ulcerogenesis.

Duodenal Ulcer↗
PubMed1993

Interferon alfa for chronic hepatitis C in haemophiliacs.

Chronic hepatitis C virus (HCV) associated liver disease is an important cause of morbidity and mortality in haemophilia. Recombinant interferon alfa-2b was used in a randomised controlled liver biopsy trial to treat haemophiliacs with chronic HCV. All 18 patients entered had antibodies to HCV. During the first year of the study, 10 patients were randomised on the basis of histology to receive interferon alfa-2b, 3 million units subcutaneously, thrice weekly and eight to receive no treatment (control group). After 12 months, all patients had a second liver biopsy and the control group patients were offered interferon at the same dosage but for only six months. The alanine aminotransferase (ALT) activity had returned to normal in four of 10 patients treated for one year and five of six patients treated for six months, compared with none of the eight patients in the control group (p < 0.01). Although the histological scores of the two groups were similar at entry into the study, after one year the biopsy specimens in the treated group showed significant improvement compared with controls (p < 0.01). It is concluded that interferon alfa-2b is effective in returning ALT values to normal and improving liver histology in at least 50% of patients treated.

Adult↗