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Biomedical subjects

P R Ames

Publications and source records attributed to P R Ames.

At least 19 recordsLinked to original sources
PubMed2001

Thrombosis in Behçet's disease: a retrospective survey from a single UK centre.

OBJECTIVE: To contribute to knowledge of vascular occlusion in Behçet's disease (BD), prevalence and relative risk for thrombosis were ascertained retrospectively in a cohort of Caucasian patients with the disease. PATIENTS: The study included 73 BD patients (36 males, 37 females, mean age 45+/-11 yr) attending the Immunology/Rheumatology Department of Northwick Park Hospital. A group of 146 patients without BD, attending the same department, served as a control group. RESULTS: Thrombosis was more frequent in BD patients than in controls (23/73, 32% vs 7/146, 5%, P<0.001). This was accounted for by a higher prevalence of venous thrombosis in BD patients (18/73, 25% vs 4/146, 3%, P<0.001). Gender-adjusted data revealed an 11-fold risk of developing any thrombosis and a 14-fold risk of developing venous thrombosis in BD. After adjusting for differences in age at first symptoms, male BD patients showed a 6-fold higher risk of vein thrombosis. Males reported more often thrombophlebitis (13/36, 36% vs 0/0, P<0.001), folliculitis (8/36, 22% vs 1/37, 3%, P<0.01) and retinal vasculitis (13/36, 36%, vs 4/37, 11%, P=0.01) than females, in whom arthralgia prevailed (23/37, 62%, vs 12/36, 33%, P=0.01). CONCLUSION: In our population, BD confers a 14-fold risk of developing venous thrombosis. The risk is sixfold higher in male BD patients, who fare worse than females with regard to thrombophlebitis, folliculitis and retinal vasculitis.

Behcet Syndrome↗
PubMed2001

Improved confirmation of weak lupus anticoagulants by employing sensitive and insensitive reagents to the lupus anticoagulant.

Detection of a lupus anticoagulant (LA) is of major importance to detect a thrombotic tendency. Confirmation of its phospholipid dependency may represent a tricky step in the diagnostic algorithm for LA, as several tests may yield borderline results of little diagnostic help. To improve on this point, we had previously employed a procedure comparing sensitive [rabbit brain kaolin (RBK)] and insensitive [soy bean phosphatides (SBP)] reagents to LA to screen and confirm LA at the same time in activated partial thromboplastin systems (aPTT). Here we compared its performance against a platelet neutralization procedure (PNP). To allow comparisons of our procedures with the PNP, a percentage ratio correction was calculated according to the following formula: [(RBK ratio - SBP ratio) x 100]/ RBK ratio. Similarly for the PNP: percentage ratio correction = [(buffer ratio - platelet phospholipid ratio) x 100]/buffer ratio. On 44 known LA plasmas, the PNP, expressed in seconds, yielded 15 (34%) negative or borderline results. After ratio transformation, the PNP still yielded 10 of 15 (66%) uncertain results, whereas the RBK/SBP procedure did not give any uncertain results (P = 0.0002). The mean percentage ratio correction was far superior for the RBK/SBP procedure than for the PNP (53.24 +/- 15.93 versus 20.28 +/- 12.15%, P < 0.0001). The use of sensitive and insensitive reagents to the lupus anticoagulant increases the confirmatory yield of LA in aPTT systems and may deserve inclusion amongst the confirmatory procedures for its diagnosis.

Anticoagulants↗
PubMed2001

Comparative prevalence of antiphospholipid antibodies and thrombophilic genotypes in consecutive patients with venous thrombosis.

The prevalence of antiphospholipid antibodies (aPL) and thrombophilic genotypes was compared and their reciprocal interactions assessed in consecutive patients with venous thrombosis (n = 101; 58 male, 43 female; mean age, 56 +/- 16 years) and in blood donors (n = 121; 55 male, 46 female; mean age, 43 +/- 12 years). Multiple aPL were detected by enzyme-linked immunosorbent assay (ELISA) and factor V Leiden (FVL), methylenetetrahydrofolate reductase (MTHFR) C677 <-- T and prothrombin (PT) G20210 <-- A by polymerase chain reaction. A pro-thrombotic state, including aPL, was found in 81% (82/101) of patients and 23% (29/121) of controls (P < 0.0001, odds ratio = 13.69, 95% confidence interval = 7.14-26.25). The prevalence of total aPL-positives was lower than MTHRF+/+ (homozygous state), FVL and PT G20210 <-- A (P < 0.0001) in the control group, but in line with the prevalence of total thrombophilic genotypes in the patient group: MTHFR+/+, 29%; FVL, 19%; PT, 14%; aPL, 20%. Having variously combined aPL and thrombophilic genotypes, only aPL remained as the most common pro-thrombotic factor in the patient group (P = 0.003). In patients without circumstantial factors for thrombosis, carriers of MTHFR+/+ + aPL showed a lower age at event than carriers of MTHFR+/+ alone or aPL alone (38 +/- 24 versus 65 +/- 10 years, P < 0.05 and 38 +/- 24 versus 63 +/- 16 years, P < 0.05, respectively). In the same patients, mean plasma homocysteine measured by an ELISA method was significantly higher in the MTHFR+/+ + aPL group than in the MTHFR+/+ alone or aPL alone groups (P = 0.01). Antiphospholipid antibodies are as common as thrombophilic genotypes in patients with venous thrombosis, and the interaction of aPL with MTHFR+/+ may influence age at first event via elevated plasma homocysteine.

Adult↗
PubMed2001

Impact of plasma homocysteine and prothrombin G20210 A on primary antiphospholipid syndrome.

The prevalence of prothrombin (PT) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677 <-- T was assessed in 40 patients with primary antiphospholipid syndrome (APS) (14 male, 26 female; mean age, 37 +/- 14 years) and in 27 persistent carriers of antiphospholipid antibodies (aPL) (five male, 22 female; mean age, 40 +/- 16 years) without underlying diseases. Non-APS thrombotic patients (n = 100; 47 female, 53 male; mean age, 40 +/- 10 years) and healthy subjects (n = 100; 46 female, 54 male; mean age, 56 +/- 16 years) served as control groups. Plasma homocysteine (HC) (enzyme-linked immunosorbent assay) was measured in all aPL patients and in 51 subjects from the healthy control group (mean age, 38 +/- 16 years). Heterozygous prothrombin PT G20210A was more frequent in the thrombotic group without APS (18%) than in the control (4%), APS (12%) or aPL (11%) groups, whereas homozygous MTHFR C677 <-- T was equally distributed. After genotype sub-grouping, plasma HC was higher in APS patients with homozygous MTHFR C677 <-- T compared with non-homozygous APS patients (22 +/- 5.4 versus 11 +/- 1.3 micromol/l; P < 0.01) and with homozygous MTHFR C677 <-- T controls (22 +/- 5.4 versus 15 +/- 2.0 micromol/l). In the APS group, mean age at first event was lower in homozygous MTHFR C677 <-- T patients than in non-homozygous patients (26 +/- 7.5 versus 36 +/- 13 years; P = 0.008). In the same group, homozygous MTHFR C677 <-- T patients suffered an increased average number of events per person than non-homozygous patients (1.9 versus 1.3; P = 0.04). Heterozygous PT G20210A contributes little to the thrombotic tendency of primary APS whereas plasma HC may influence age at first event and number of events. Measurement of plasma HC in aPL subjects may identify patients at increased thrombotic risk requiring HC lowering.

Adult↗
PubMed2001

High prevalence of thrombophilic genotypes in patients with acute mesenteric vein thrombosis.

OBJECTIVES: Mesenteric vein thrombosis is a rare but severe abdominal emergency, often requiring intestinal resection. New genetic prothrombotic defects such as factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype have been described in association with venous thrombosis. Our goal was to assess prevalence and clinical significance of genetic thrombophilia in mesenteric vein thrombosis. METHODS: Twelve patients with acute mesenteric vein thrombosis were compared with 431 healthy people from the same geographical area. The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype were identified by polymerase chain reaction and restriction analysis. RESULTS: A thrombophilic genotype was present in 9 patients (75%): the methylenetetrahydrofolate reductase TT677 genotype was present in 6 (50%), the factor V Leiden in 3 (25%), and the prothrombin transition G20210A in 3 (25%). Combined mutations were present in 4 (33%) patients. CONCLUSIONS: The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype are important predisposing factors in the pathogenesis of mesenteric vein thrombosis. Their identification bears strong clinical implications for management of patients with mesenteric vein thrombosis.

Acute Disease↗
PubMed2000

Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.

The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with cirrhosis without hepatocellular carcinoma are not clearly defined. The role of thrombophilic genetic factors is well established in other venous thrombotic diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin [PTHR A(20210)], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR C677-->T]) have been identified and associated with increased risk of venous thrombosis. The aim of our study was to investigate the role of these thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty-three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons served as controls. The FVL, PTHR A(20210), and MTHFR C(677)-->T genotypes were identified by a polymerase chain reaction and restriction analysis. The frequencies of FVL, PTHR A(20210) mutation, and homozygous MTHFR C(677)-->T were 13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in cirrhotic patients without PVT, respectively. Five patients in the former group had associated defects. A thrombophilic genotype was detected in 69.5% of the patients with PVT. Identification of this high-risk group may have implications in patients who are candidates for major surgery or liver transplantation, and may influence the duration of oral anticoagulation.

Adolescent↗
PubMed2000

Antioxidant susceptibility of pathogenic pathways in subjects with antiphospholipid antibodies: a pilot study.

The pathogenesis of antiphospholipid antibody (aPL) related thrombosis is multifactorial and includes, amongst others, enhanced coagulation activation measured as prothrombin fragment 1 + 2 (F1 + 2), elevated plasma levels of von Willebrand factor (vWF), plasminogen activator inhibitor (PAI) and endothelin-1 (ET-1) as well as heightened thromboxane generation and lipid peroxidation. To evaluate the antioxidant susceptibility of some of the above pathways, probucol (500 mg/d orally, a cholesterol lowering agent bearing antioxidant properties) was administered for a three week period to 14 subjects with aPL and to seven healthy controls. At baseline aPL participants showed higher plasma levels of vWF (P = 0.006), ET-1 (P = 0.0002) and enhanced urinary excretion of 11-dehydro-thromboxane-B2 (TXB2) (P = 0.0004), F2-isoprostanes (marker of lipid peroxidation) (P = 0.02) and albumin (P = 0.04) than controls. In the aPL group baseline IgG anticardiolipin (aCL) titre positively related with urinary TXB2 (r2 = 0.43, P = 0.01) and inversely with urinary NOx (r2 = -0.6, P = 0.005) whereas urinary NOx and TXB2 were negatively correlated (r2 = -0.42, P = 0.01). After the treatment period significant decreases from baseline values were noted for PAI (P = 0.01), ET-1 (P = 0.006), TXB2 (P = 0.02), F2-isoprostanes (P = 0.01) and albuminuria (P = 0.01) in aPL participants but not in controls. These pilot data support oxidative sensitive mechanisms and a potential role for antioxidant treatment in the pathogenesis of aPL induced vasculopathy.

Adult↗
PubMed2000

Fibrinogen in systemic lupus erythematosus: more than an acute phase reactant?

OBJECTIVE: To investigate whether plasma fibrinogen (FNG) measured longitudinally in a cohort of patients with systemic lupus erythematosus (SLE) increased over observational time faster than in a control group, and whether its increase might depend upon age, disease duration, disease activity, and medications. METHODS: Hospital based retrospective study with repeated measurements of plasma FNG and C-reactive protein (CRP) for patients and controls and erythrocyte sedimentation rate (ESR) and lupus activity index (LAI) for patients only. Study groups included patients with SLE: n = 96 (95% female), and healthy controls: n = 39 (95% female). Of the patients, 42% had SLE only, 23% had SLE with antiphospholipid antibodies (aPL), and 34% had SLE with aPL related thrombosis. RESULTS: Median baseline FNG was higher in patients (357 mg/dl; 95% CI 339-375) than in controls (271 mg/dl; 95% CI 251-291) by 86 mg/dl (95% CI 56-115, p < 0.001); in older subjects than younger (in patients and in controls); in patients with thrombosis than in other patient groups (by an average of 35 mg/dl; 95% CI 9-61 mg/dl): and in patients with longer disease duration (p = 0.05). Mean FNG increased faster in patients (19 mg/dl/year; 95% CI 12-26 mg/dl) than in controls (2.6 mg/dl/year; 95% CI 2.0-3.2 mg/dl). The increase was faster than the age effect and independent of patient group and disease activity. CONCLUSION: Plasma FNG in patients with SLE increases throughout followup regardless of disease activity, mimicking the age related increment observed in population based studies. The rapidity of the increment may reflect the prematurity of vascular disease typical of SLE.

Acute-Phase Proteins↗
PubMed1999

Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement.

OBJECTIVE: To evaluate the occurrence and clinical significance of lipid peroxidation (oxidative stress) in rheumatic diseases characterized by vascular involvement. PATIENTS AND METHODS: Plasma 8-epi-PGF2alpha (oxidative stress marker) was measured by gas chromatography-mass spectrometry in 36 patients with systemic lupus erythematosus (SLE), 13 with systemic sclerosis (SSc), 13 with systemic vasculitis [Wegener's granulomatosis (WG), n = 4; Churg Strauss syndrome (CSS), n = 3; Behcet syndrome, n = 6], 12 with rheumatoid arthritis (RA) and in 23 healthy controls (n = 23). RESULTS: 8-epi-PGF2alpha levels were higher in patients with SLE (P = 0.007), SSc (P < 0.001) and vasculitis (P = 0.001) than in controls. In SLE, a positive Coombs' test and arterial hypertension independently predicted 8-epi-PGF2alpha concentrations (P = 0.004 and P = 0.001, respectively). SLE patients not taking prednisolone showed higher 8-epi-PGF2alpha concentrations than SLE patients on prednisolone (P = 0.02). In the latter group, a dose response relationship was noted between 8-epi-PGF2alpha and steroid dosage (r = 0.6, P = 0.0003). In WG and CSS, 8-epi-PGF2alpha concentrations correlated with disease activity (r = 0.8, P = 0.01) and were higher than in patients with Behcet disease (P = 0.003). CONCLUSIONS: Oxidative stress may be pathogenetically relevant in some autoimmune rheumatic diseases with vascular involvement. Amelioration of some clinical manifestations of these diseases may be envisaged by targeting lipid peroxidation with dietary or pharmacological antioxidants.

Adult↗
PubMed1998

Elevated plasma lipoprotein(a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome.

OBJECTIVE: To assess the significance of lipoprotein(a) [Lp(a)], a risk factor for atherothrombosis, and its relationship with fibrinolysis in a cohort of patients with antiphospholipid syndrome (APS). METHODS: Plasma levels of Lp(a) were measured in 68 patients with APS (42 primary, 26 secondary to systemic lupus erythematosus). RESULTS: Elevated plasma levels of Lp(a) were found in patients with APS compared to 22 healthy controls (p = 0.0001). The significance persisted after comparing Lp(a) levels in 3 APS subgroups (arterial thrombosis, n = 37; venous thrombosis, n = 31; recurrent miscarriages, n = 24) with those of controls (p < 0.0001). Patients with APS with maximal elevation of Lp(a) showed a lower fibrinolytic activity (lower D-dimer and higher plasminogen activator inhibitor) than patients whose Lp(a) was within a normal range. CONCLUSION: These findings suggest that Lp(a) may represent a marker of APS and that Lp(a) has a negative effect on the fibrinolytic system that might contribute to the thrombotic tendency of APS.

Adult↗
PubMed1998

Thrombophilic genotypes in subjects with idiopathic antiphospholipid antibodies--prevalence and significance.

To evaluate the significance of common thrombophilic genotypes in subjects with idiopathic antiphospholipid antibodies (aPL) we determined the methylenetetrahydrofolate reductase C677-->T (MTHFR) and factor V A506-->G (FV Leiden) polymorphisms in 49 subjects with idiopathic aPL (57% of whom suffered spontaneous vein thrombosis), in 70 subjects with a history of spontaneous vein thrombosis and in 193 healthy subjects. The prevalence of MTHFR C677-->T+/+ (homozygotes) was 25%, 18% and 17% respectively amongst aPL thrombotics, non aPL thrombotics and controls and that of MTHFR C677-->T+/- (heterozygotes) was 53%, 59% and 53% respectively in the same groups. The prevalence of FV Leiden was higher in aPL thrombotics (14%) and in non aPL thrombotics (18%) than in controls (4%) (p < or = 0.05). APL thrombotics with MTHFR C677-->T+/+ had a lower mean age at first thrombotic event (22 +/- 6 years) than aPL thrombotics with MTHFR C677-->T+/- and non mutated considered together (38 +/- 14 years, p = 0.0004) and than non aPL thrombotics with MTHFR C677-->T+/+ (38 +/- 14 years, p = 0.003). FV Leiden may contribute to the hypercoagulability of a small, albeit significant proportion of thrombotic aPL subjects, whereas the association between MTHFR C677-->T+/+ and aPL may have an impact on age at first occlusive event and suggests a possible pathogenetic interaction.

Adult↗
PubMed1997

The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome.

Systemic sclerosis (SSc) is a disease characterized by progressive microvascular occlusion and fibrosis resulting in irreversible organ damage, the pathogenesis of which is felt to be of vascular origin. To gain a comprehensive view of the coagulation/fibrinolytic balance in SSc, a number of haemostatic and fibrinolytic variables were measured in 26 SSc patients (11 limited, 15 diffuse) and in 22 control subjects. Of the coagulation activation markers, the mean plasma level of prothrombin fragment 1 + 2 (F1 + 2), but not of thrombin-antithrombin complexes (TAT), was higher in SSc patients than in controls (P < 0.001). Plasma levels of fibrin split product D-dimer (DD), fibrinogen (FNG) and von Willebrand factor (vWF) were higher amongst patients than controls (P < 0.001). vWF and FNG levels were positively correlated (P < 0.001). Mean levels of DD and vWF were more elevated in patients with diffuse than limited disease (P = 0.001 and P = 0.04, respectively). On the fibrinolytic side, defective tissue plasminogen activator (tPA) release (venous occlusion test, stimulated level < basal level) was noted in 46% (12/26) of SSc patients, but only in 4% (1/22) of controls. Patients had higher mean levels of tPA inhibitor (PAI) than controls (P < 0.001), levels being more elevated amongst patients with diffuse than limited disease (P = 0.01). An abnormally high lipoprotein (a) [Lp(a)] level was found in 9% (2/20) of control subjects, but in 30% (8/26) of SSc patients (P = 0.04) where it clustered with fibrinolytic defects. Altogether, these data suggest that patients with SSc are in a hypercoagulable state characterized by elevated plasma levels of FNG and vWF, by a dual hypofibrinolytic pattern (defective tPA release and elevated PAI), and by increased thrombin generation with enhanced fibrin formation. Higher levels of vWF, DD and PAI in patients with diffuse disease are consistent with more extensive (micro)vascular involvement, although no causal relationship can be inferred. The lack of a parallel increase of TAT with F1 + 2, in the presence of normal levels of antithrombin III (ATIII), indirectly suggests an impairment of the heparan sulphate-ATIII system which would favour thrombin generation. Since thrombin may act as a mitogen for fibroblasts, may upregulate vWF, PAI and endothelin production by endothelial cells, and may promote fibrin deposition on the vessel wall leading to worsening of microvascular occlusions, limitation of thrombin generation, besides fibrinolytic enhancement, could represent a possible coadjuvant interventional strategy.

Adult↗
PubMed1997

Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosus: experience in sixteen consecutive patients.

We review the efficacy, tolerability and safety of low-dose thalidomide in the treatment of refractory disfiguring rash in 16 patients with cutaneous manifestations of lupus. Rashes, which included discoid lupus erythematosus (DLE), subacute cutaneous lupus (SCLE), photosensitive malar rash and non-specific chronic erythema, were diagnosed on clinical grounds, supported by skin biopsy in 11/16 patients. Using starting doses of 50-100 mg/day, 7/16 (44%) patients gained complete or near-complete remission of skin disease and 6/16 (37%) partial remission. Three out of 16 patients failed to respond. Maximum benefit was achieved within 16 weeks in all patients. Doses of 25-50 mg/day were effective in maintaining response. Rapid relapse occurred in 6/8 (75%) patients following drug withdrawal, but the response to thalidomide in those requiring repeat courses appeared to be maintained. There was no detectable improvement in systemic disease. One patient developed symptoms of mild peripheral neuropathy which resolved on drug withdrawal. Our experience suggests that thalidomide is effective in the treatment of severe skin manifestations of lupus refractory to other treatment and can be used safely in specialist rheumatological practice.

Adult↗
PubMed1997

A rapid screen for lupus anticoagulant with good discrimination from oral anticoagulants, congenital factor deficiency and heparin, is provided by comparing a sensitive and an insensitive APTT reagent.

Lupus anticoagulants (LA) are associated with an increased risk of thrombosis and laboratory detection is of major importance. Various tests are available for LA screening and confirmation, but they differ in sensitivity and specificity, frequently lacking the ability to discriminate between the presence of LA, heparin and oral anticoagulants. We noticed that a patient with LA who had a prolonged activated partial thromboplastin time (APTT) by our routine method, gave a normal result with a different APTT reagent. This latter reagent, which contained soy bean phosphatides (SBP), was compared with a reagent containing rabbit brain phospholipids complexed with kaolin (RBK), for APTT measurement in a variety of patients. There was no significant difference in APTT ratio between the two reagents in plasma samples from healthy normal subjects. In LA samples, SBP gave consistently lower APTT ratios than RBK (mean +/- SEM, 1.04 +/- 0.05 and 2.08 +/- 0.19 for SBP and RBK respectively; P < 0.001). In LA patients receiving oral anticoagulants for antithrombotic prophylaxis or treatment, the APTT ratio was again significantly shorter with SBP (1.60 +/- 0.17 and 3.40 +/- 0.67; P < 0.05). In LA negative patients receiving oral anticoagulants, the relationship was reversed, and a higher APTT ratio was obtained with SBP than RBK (1.61 +/- 0.13 and 1.31 +/- 0.12; P < 0.001). In addition, there were no significant differences in APTT ratios for the two reagents when samples from patients receiving heparin therapy, or patients with acquired factor VIII deficiency or inherited deficiency of factor VIII or IX were studied. The use of the SBP reagent alongside a LA sensitive APTT reagent allows a rapid screening for LA, as well as a confirmation of the phospholipid dependency of the inhibitor.

Administration, Oral↗