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Biomedical subjects

I R MacGregor

Publications and source records attributed to I R MacGregor.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease.

Haemostatic and rheological factors may predict cardiovascular disease. We studied patients with intermittent claudication to see if the progression of peripheral arterial disease and the risks of coronary events could be predicted by baseline packed cell volume, plasma fibrinogen, blood and plasma viscosites, von Willebrand factor antigen, cross-linked fibrin degradation products (XLFDP), urinary fibrinopeptide A, and plasma leucocyte elastase. In 617 patients with claudication followed up for one year, baseline XLFDP was related most strongly to coronary events, relative risk 4.4 (95% CI 1.3-19.0) between top and bottom quintiles. Plasma fibrinogen was the strongest independent predictor of death from coronary disease. XLFDP was the only factor, in addition to age and cigarette smoking, that was independently associated (p = 0.008) with deterioration in peripheral arterial disease. We conclude that, in patients with peripheral arterial disease, plasma concentration of XLFDP, a measure of ongoing fibrin formation and degradation, is a strong predictor of both disease progression and future coronary risk. These results accord with the hypothesis that fibrin formation contributes to progression of coronary and peripheral atherosclerosis.

Adult↗
PubMed1993

Coagulation and fibrinolytic systems in type I diabetes: effects of venous occlusion and insulin-induced hypoglycaemia.

1. The effects of venous occlusion on the coagulation and fibrinolytic systems were investigated in six patients with type 1 (insulin-dependent) diabetes and 11 age- and sex-matched non-diabetic control subjects. The coagulation parameters (fibrinogen, prothrombin time, partial thromboplastin time with kaolin, von Willebrand factor antigen) did not differ between patients and control subjects either before or after 20 min of venous occlusion. No rise was observed in von Willebrand factor antigen after venous occlusion in either group. 2. In the diabetic patients, chronic activation of the fibrinolytic system was found at baseline, which was indicated by a shortened euglobulin lysis time (P < 0.01), increased tissue plasminogen activator activity (P < 0.05) and decreased plasminogen activator inhibitor type 1 antigen level (P < 0.05), when compared with control subjects. In both groups venous occlusion resulted in significant increments in all measurements, except plasminogen activator inhibitor type 1 antigen level. The post-occlusion values did not differ between the two groups, except the plasminogen activator inhibitor type 1 antigen level, which remained significantly lower in the diabetic patients. The mean increments in each parameter did not differ between the two groups. 3. Coagulation and fibrinolysis were assessed in response to acute insulin-induced hypoglycaemia. Von Willebrand factor antigen levels increased significantly in both groups, with no difference in maximal increments. Significant activation of the fibrinolytic system occurred in response to hypoglycaemia, demonstrated by shortened euglobulin lysis time and increased fibrin plate lysis, tissue plasminogen activator antigen level and tissue plasminogen activator activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

A novel rat model of thrombogenicity: its use in evaluation of prothrombin complex concentrates and high purity factor IX concentrates.

A non-stasis rodent model of thrombogenicity has been used for dose-ranging studies with a conventional prothrombin complex concentrate (PCC) and to evaluate high purity factor IX concentrates from different manufacturers. Fibrin monomer (soluble fibrin) and fibrinopeptide A (FPA) were monitored before and after infusion of test solution. FPA was found to be the more sensitive and reproducible indicator of thrombogenicity and exhibited a dose-related elevation after infusion of the PCC at doses of between 100-300 IU/kg. In contrast the amounts of FPA generated after 300 IU/kg of the high purity factor IX products were similar to control infusions of albumin.

Animals↗
PubMed1992

The fibrinolytic system and proteins C and S in treated polycythaemia rubra vera.

This study was designed to assess whether factors other than high haemoglobin, thrombocytosis and abnormal platelet function predispose to thrombosis in polycythaemia rubra vera (PRV). Components of the fibrinolytic system and concentrations of the naturally occurring anticoagulants were measured in patients and controls in the resting state; the fibrinolytic capacity was reassessed after venous occlusion. The results were related to presence or absence of a history of thromboembolism. Under resting conditions, patients with PRV had reduced plasminogen activator inhibitor antigen levels and higher fibrin plate lysis area and tissue plasminogen activator activity. Protein C, protein S and factor V levels were reduced. Those patients with a history of thromboembolism had decreased tissue plasminogen activator activity after venous occlusion compared to those who had not experienced a thrombosis. We conclude that reduced fibrinolytic capacity may predispose to thrombosis in PRV. Despite treatment to normalize haemoglobin levels, the patients have persistent activation of their fibrinolytic systems. This, and reduced levels of proteins C and S, may be secondary to a chronic, clinically occult, disseminated intravascular coagulation.

Adult↗
PubMed1991

Comparison of high purity factor IX concentrates and a prothrombin complex concentrate in a canine model of thrombogenicity.

A non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.

Animals↗
PubMed1991

Use of factor VII-deficient beagles bred by artificial insemination to evaluate mechanisms of thrombosis associated with prothrombin complex concentrates.

Artificial insemination with frozen semen was used to breed beagles homozygous for a deficiency in clotting factor VII, with plasma concentrations of 2-3% of normal adult beagle pooled plasma. The factor VII-deficient beagles were used to determine if factor VII activity has a role in the thrombogenic activity of prothrombin complex concentrates (PCCs) containing factors II, IX and X by evaluating changes in selected indicators of thrombogenicity. No differences were seen between the responsiveness of the factor VII-deficient and normal beagles, indicating that the thrombogenic activities of PCCs are mediated via effects on the intrinsic clotting system.

Animals↗
PubMed1991

Hypotensive effects of stroma-free haemoglobin solutions attributable to adenine nucleotides.

Aqueous solutions of stroma-free human haemoglobin are being evaluated as potential oxygen-carrying resuscitation fluids. There are indications, however, that such solutions may produce toxic side-effects in vivo. Stroma-free haemoglobin solution produced a 50% fall in mean arterial pressure when infused into a small animal model despite containing very low levels of non-haem protein and phospholipid contaminants. This effect was not produced by haemoglobin solutions after extensive dialysis. Red cell-derived adenine nucleotides were found to be present in concentrations high enough to cause such a response (80-85 micrograms/ml). We have developed a chromatographic assay capable of predicting hypotension in our animal model and consider that the complete absence of adenine nucleotides must be confirmed in all studies concerning the possible toxic side-effects of stroma-free haemoglobin solutions.

Adenine Nucleotides↗
PubMed1988

Fibrinolytic and haemostatic responses to desamino-D-arginine vasopressin (DDAVP) administered by intravenous and subcutaneous routes in healthy subjects.

DDAVP was administered at 0.4 microgram kg-1 intravenous (i.v.) and subcutaneous (s.c.) routes to 6 healthy subjects in a double blind crossover study. Both study treatments were well tolerated. Flushing occurred after both treatments but was more prominent after i.v. than after s.c. DDAVP. Mild transient local discomfort at the s.c. injection site occurred in 5 of 6 subjects. The mean peak factor VIII (FVIII) response was 369% and 247% of baseline after i.v. and s.c. DDAVP respectively and the maximum increase in FVIII occurred earlier with the i.v. route. Changes in FVIII antigen (FVIII:Ag) and von Willebrand factor antigen (vWF:Ag) were also monitored. Tissue-type plasminogen activator (t-PA) activity measured by a chromogenic assay employing soluble fibrin had a median peak value of 2.9 IU ml-1 at 20 min after i.v. and of 1.9 IU ml-1 at 60 min after s.c. DDAVP. t-PA antigen was also measured so that the specific activity of circulating t-PA could be determined. Preinjection median values of 14,650 and 13,700 IU mg-1 increased to peak median values of 236,200 IU mg-1 at 20 min after i.v. and 202,400 IU mg-1 at 60 min after s.c. DDAVP. Plasminogen activator inhibitor (PAI) activity fell following DDAVP and became undetectable in some subjects during the sampling period. The ratio of maximum fibrinolytic response was similar to the ratio of maximum haemostatic responses obtained by two routes of injection. Our results indicate that s.c. DDAVP might successfully replace i.v. DDAVP in several applications such as confirmation of haemostatic or fibrinolytic responsiveness in patient groups; for obtaining FVIII enriched plasma; as well as its obvious potential usefulness in home treatment of haemophilia A and von Willebrand's disease.

Adult↗
PubMed1988

An enzyme-linked immunosorbent assay (ELISA) used to study the cellular secretion of endothelial plasminogen activator inhibitor (PAI-1).

A two-site sandwich ELISA was developed to measure PAI-1 antigen and utilised a polyclonal antiserum produced against PAI-1 purified from human endothelial cell secretory products. The assay was calibrated against a preparation of pure PAI-1 whose protein concentration had been determined by amino acid analysis and the detection limit was 30 pg PAI-1 ml-1 sample. PAI-1 was detected in primate sera but not in a wide range of non-primate sera and no cross-reactivity with alpha 2-antiplasmin or antithrombin III was observed. The ELISA was used to study cellular secretion of PAI-1 which was confirmed as a major secretory protein in human umbilical vein endothelial cells (HUVEC). PAI-1 antigen accumulated in the medium in a linear fashion with time and accounted for approximately equal to 10% of total secreted protein. Specific activity of intracellular PAI-1 was typically 20-fold greater than that of PAI-1 in 24 h conditioned medium and a t1/2 for inactivation of secreted PAI-1 of 0.53 h was calculated. Purified endotoxin stimulated the secretion of PAI-1 antigen and raised the intracellular levels in HUVEC cultures showing that the anti-fibrinolytic actions of endotoxin are effected by increasing the rate of synthesis and secretion of PAI-1.

Cells, Cultured↗
PubMed1988

Plasminogen activator inhibitor (PAI-1) in plasma and platelets.

The distribution of PAI-1 in the plasma and platelets of normal individuals and of patients with platelet abnormalities was studied. An ELISA, capable of measuring PAI-1 in plasma at 1.5 ng/ml, and a functional assay of t-PA inhibition were used to assay platelet-free plasma (PFP), platelet-rich plasma in which the platelets were lysed (PRP) and serum. The PAI-1 concentration of normal PFP was 21.0 +/- 7.2 ng/ml (mean +/- SD) and those of PRP and serum were 282.6 +/- 68.0 and 270.3 +/- 71.9 ng/ml. The concentration of PAI-1 in PRP was proportional to the platelet count with 0.67 +/- 0.18 ng/10(6) platelets. Patients with thrombocytopenia had approximately normal PAI-1 concentrations in PFP; the extremely low concentrations in serum or PRP reflected the platelet count. A patient with grey platelet syndrome showed a comparable pattern, confirming that PAI-1 occurs in the platelet alpha-granules and indicating that the plasma concentration of PAI-1 is independent of the platelet pool of PAI-1. The median inhibitory activities towards t-PA were 1.6, 8.7 and 8.3 units/ml in normal PFP, PRP and serum respectively. PAI-1 in PFP had a median specific activity (units/mg PAI-1) about 5-fold higher than platelet PAI-1. Plasma and platelets represent two distinct pools of PAI-1, both of which should be considered in studies on the relationship between circulating PAI-1 and thrombotic disease.

Adult↗
PubMed1988

Release of highly-sulphated glycosaminoglycans and histamine from human basophils.

A new assay for highly-sulphated glycosaminoglycans (GAGs) has been applied to the study of allergen (Dermatophagoides pteronyssinus)-induced release of GAG from human basophils. Highly-sulphated GAG, which was not heparin, was found only in basophil-containing cellular fractions of whole blood. Its release, like that of histamine, was Ca++-dependent. However, allergen-induced release of GAG from the basophils of atopic individuals exhibited a different time-course and dose-response from that of histamine, and may occur at least in part by a different mechanism.

Adult↗
PubMed1987

Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization.

An inhibitor of plasminogen activator was purified to apparent homogeneity from human umbilical vein endothelial cell conditioned medium. The purification was achieved by a speedy and simple two-step procedure, without the use of denaturants. The purified protein was a single-chain glycoprotein with apparent molecular mass of 48 kDa. The purified inhibitor had a specific activity of 8500 U/mg protein and the activity could be stimulated about fourteenfold by treatment with denaturants. An antiserum to the purified inhibitor was raised in rabbits. It recognised plasminogen activator inhibitor from platelets and plasma as well as from cultured endothelial cells. The immunoglobulin fraction of the antiserum neutralised the functional activity of the inhibitor from all these sources.

Animals↗
PubMed1986

Tandem purification of mouse IgM monoclonal antibodies produced in vitro using anion-exchange and gel fast protein liquid chromatography.

A tandem chromatographic procedure was used to isolate rapidly mouse IgM monoclonal antibodies produced by cultivation of hybridomas in vitro. Hybridoma culture supernatants containing mouse IgM monoclonal antibodies were first chromatographed on an anion-exchange Mono Q column connected to a fast protein liquid chromatography system. This anion-exchange step offers the advantage of obtaining IgM antibodies in a concentrated form. The IgM-rich fractions from the Mono Q column were then injected on a gel filtration Superose 6 column equilibrated with a low-ionic strength buffer and eluted with a high-ionic strength buffer. Assessment of the purity of isolated IgM monoclonal antibodies was performed by sodium dodecyl sulphate polyacrylamide gel electrophoresis together with a Coomassie Brillant Blue R 250 staining technique. Assessment of the immunoreactivity of isolated IgM monoclonal antibodies was performed by an enzyme linked immunosorbent assay using a solid phase adsorbed antigen against which IgM monoclonal antibodies were directed. The chromatographic procedures described allows the rapid isolation of mouse IgM monoclonal antibodies produced in vitro at a high degree of purity and in an immunoreactive state.

Animals↗
PubMed1985

Metabolism of sodium pentosan polysulphate in man measured by a new competitive binding assay for sulphated polysaccharides--comparison with effects upon anticoagulant activity, lipolysis and platelet alpha-granule proteins.

Three human volunteers were injected with a range of doses of pentosan polysulphate, SP54, i.v. or s.c. A competitive binding assay (CBA) for sulphated polysaccharides was used to detect circulating SP54 after doses as low as 1 mg i.v. and a linear relationship was observed between the peak plasma concentration of SP54 measured by CBA and the administered dose. A comparison was made between the clearance of SP54 measured by CBA and its anticoagulant and lipolytic activities. SP54 was detectable by CBA after doses which caused no alteration in activated partial thromboplastin time (APTT) or anti-factor Xa activity but after which a small increase of lipase activity was measurable. After SP54 at 10 mg i.v. or 100 mg s.c. anti-factor Xa activity was 4-6 times greater than would be expected from the in vitro activity of the concentrations of SP54 measured by CBA. Like heparin and other heparin analogues, SP54 caused an increase in plasma concentrations of platelet factor 4 (PF4) without a concomitant rise in beta-thromboglobulin (beta-TG). It is concluded that the newly developed CBA will provide a more sensitive means than conventional bioassays for the determination of plasma concentrations of SP54.

Adult↗