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Biomedical subjects

B J Hunt

Publications and source records attributed to B J Hunt.

At least 91 records · Page 5Linked to original sources
PubMed1997

Activation of coagulation and fibrinolysis in childhood diarrhoea-associated haemolytic uraemic syndrome.

Diarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin producing Eschericia coli. We hypothesized that verotoxin binding to glomerular endothelial cells causes localised endothelial cell activation and thus activation of coagulation and reduction of fibrinolytic potential. We also proposed that treatment with fresh frozen plasma or dialysis would not affect these changes. Markers of activation of coagulation and fibrinolysis were measured in 30 children with acute D+ HUS serially, in healthy children and in children on dialysis. In acute D+ HUS, levels of thrombin-antithrombin III complex and prothrombin fragment 1+2 were significantly increased (p <0.001). The source of thrombin generation was unclear. Factor XIIa levels were increased in patients and controls with renal failure. Factor VIIa levels were not significantly raised in children with acute D+ HUS. D-dimers were increased, but fibrinolytic potential as measured by fibrin plate was reduced. Levels of plasminogen activator inhibitor antigen and activity and tissue plasminogen activator antigen were increased. Neither peritoneal dialysis nor administration of blood products, the most common treatments, altered parameters of coagulation or fibrinolysis.

Antithrombin III↗
PubMed1996

Genetically engineered serine protease inhibitor for hemostasis after cardiac operations.

BACKGROUND: The serine protease inhibitor aprotinin has been widely reported for its beneficial action in limiting blood loss after cardiopulmonary bypass (CPB). A potent human serine protease inhibitor known as protease nexin II or amyloid precursor protein has been recently isolated. A recombinant protein known as recombinant Kunitz protease inhibitor (rKPI; Scios Nova, Mountain View, CA) with sequence homology to the protease nexin II-amyloid precursor protein molecule has been manufactured. METHODS: Recombinant Kunitz protease inhibitor was assessed in an ovine model of CPB as a hemostatic agent after CPB. Sheep (n = 22) underwent CPB for 90 minutes. Two thoracic drains were sited and drain losses collected for a period of 3 hours after CPB. Wounds were subjectively assessed before closure for "dryness" using a visual analogue scale. Sheep were randomized to control (n = 8), aprotinin (n = 8), and rKPI (n = 6) groups. RESULTS: Control animals had a drain loss of 409.4 +/- 39.4 mL/3 h, compared with 131.3 +/- 20.3 mL/3 h for the aprotinin group and 163.7 +/- 34.3 mL/3 h for the rKPI group (p = 0.16). Hemoglobin loss was 11.6 +/- 3.6, 6.02 +/- 2.1, and 4.6 +/- 1.2 g/3 h for the control, rKPI, and aprotinin groups respectively (p = 0.25). The subjective analysis of the wounds at the end of CPB found aprotinin (1.25 +/- 0.16; p < 0.05) and rKPI (1.17 +/- 0.17; p < 0.05) animals to score significantly lower than control animals (2.63 +/- 0.42). CONCLUSIONS: On the basis of these in vivo findings, genetic modification may yield a more efficacious serine protease inhibitor with the inherent advantages of using a human-based protein.

Animals↗
PubMed1996

Activation of human prothrombin by porcine aortic endothelial cells--a potential barrier to pig to human xenotransplantation.

A potential solution to the shortage of human organs for transplantation lies in the use of animal organs with the pig as the most likely donor. Perfusion of porcine organs with human blood, however, results in hyperacute rejection (xenograft reaction) which occurs within minutes to hours and is characterised by intravascular thrombosis. The pathogenesis of this xenograft reaction is attributed to xenoreactive natural antibodies (XNA) binding to epitopes on porcine endothelium activating complement with subsequent haemostatic activation. We have investigated whether there is direct activation of human coagulation by porcine endothelium in the absence of XNA and complement. Previous experiments demonstrated possible pathological activation of the common pathway, thus human prothrombin and factor X were added separately to porcine endothelium and monitored for activation. Human prothrombin was activated by porcine but not human endothelium. There was no activation of factor X. Hirudin inhibited prothrombin activation suggesting that a conformational change may occur in prothrombin on binding to porcine endothelium, such that its catalytic centre is exposed with subsequent autocatalytic cleavages. If this in vitro observation of direct prothrombin activation is translated to the in vivo situation then this phenomenon may pose a non-immunological obstacle to pig to human xenotransplantation.

Animals↗
PubMed1996

Transmission of donor Epstein-Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV-seronegative recipients.

Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD). To determine whether the donor EBV isolate is transmitted to the recipient via the allograft and causes PTLD, EBV isolates from four cases of PTLD in cadaveric heart and/or lung transplant recipients were compared with the donor isolates by PCR and DNA sequence analysis. Two recipients who were EBV seronegative at transplantation acquired an EBV isolate indistinguishable from that of the donor and developed PTLD. In contrast, in two patients who were seropositive before transplantation, the donor isolate differed from that present in PTLD of the recipient. The results suggest that the acquisition of donor EBV is a risk factor for PTLD development in a previously seronegative transplant recipient.

Adolescent↗
PubMed1996

Hyperfibrinolysis.

Explore the source record for details and available documents.

Antifibrinolytic Agents↗
PubMed1996

Endothelial cell activation in cutaneous vasculitis.

Markers of endothelial cell activation were measured in 28 patients presenting with various forms of limited or focal type cutaneous vasculitis. Plasma levels of tissue plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) and PAI-1 activity, fibrin plate, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and soluble thrombomodulin (sTM) were measured. In comparison with the control group (n = 20) there was a significant increase in t-PA:Ag, vWF:Ag and TF (P < 0.05, Mann-Whitney U-test) in the cutaneous vasculitis group. This study confirms that measurable degrees of endothelial activation occur in cutaneous vasculitis. Cutaneous vasculitis includes a diverse group of clinical conditions, which are associated with inflammatory changes in cutaneous blood vessels with local fibrin deposition. The aetiology and pathogenesis of the majority of these entities remain unknown. Causative mediators are thought to include immune complexes, anti-endothelial cell antibodies, cytotoxic lymphocytes and viruses. Histologically, immune complexes and complement are frequently detected on the vessel wall, and serologically anti-endothelial antibodies are often detected in patients with vasculitis and in systemic lupus erythematosus (SLE) which correlate with the severity of cutaneous vasculitis, arthritis and nephritis. Lymphocyte-mediated toxicity to endothelial cells has been reported in a small number of patients with giant cell arteritis and Takayasu's arteritis. The vascular endothelium plays a central part in the control of haemostasis. Under physiological conditions endothelial cells present an anticoagulant surface to blood constituents, partially due to surface expression of heparan sulphate and thrombomodulin (TM). Heparan sulphate binds antithrombin III (ATIII), thereby accelerating inactivation of intrinsic coagulation enzymes. Thrombomodulin is an endothelial cell surface glycoprotein which promotes anticoagulation by forming a complex with thrombin which then activates protein C. Activated protein C together with a cofactor, protein S, inactivates FVa and FVIIIa. von Willebrand factor (vWF) is synthesized by endothelial cells, stored in Weibel-Palade bodies and released into the circulation upon endothelial stimulation. vWF mediates the binding of platelets to the subendothelium and is the carrier molecule for FVIIIC. The endothelium controls fibrinolysis by producing t-PA and its inhibitor PAI-1. Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF) activate endothelial cells, causing a shift from an antithrombotic to prothrombotic state, including expression of tissue factor, increased synthesis of PAI-1 and decreased expression of TM. Fibrin deposition and intravascular thrombosis are seen in cutaneous vasculitis syndromes, suggesting local endothelial cell activation. The aim of this pilot study was to assess whether perturbation of the endothelium in cutaneous vasculitis could be detected in the patients' plasma samples. If so, further studies to assess any correlation in levels of these markers with disease activity might prove useful in the future.

Adult↗
PubMed1995

The management of thrombosis in the antiphospholipid-antibody syndrome.

BACKGROUND: The antiphospholipid-antibody syndrome is a thrombophilic disorder in which venous or arterial thrombosis, or both, may occur in patients with antiphospholipid antibodies. The optimal treatment of these patients is unclear. We assessed the efficacy of warfarin, low-dose aspirin, or both in the secondary prevention of thrombosis in patients with the syndrome. METHODS: One hundred forty-seven patients (124 [84 percent] of whom were female) with the antiphospholipid-antibody syndrome and a history of thrombosis were studied retrospectively. The syndrome was primary in 62 patients and was associated with systemic lupus erythematosus in 66 patients and lupus-like disease in 19. Each patient's history was reviewed. RESULTS: One hundred one patients (69 percent) had a total of 186 recurrences of thrombosis. The median time between the initial thrombosis and the first recurrence was 12 months (range, 0.5 to 144 months). Treatment with high-intensity warfarin (producing an international normalized ratio of > or = 3) with or without low-dose aspirin (75 mg per day) was significantly more effective (P < 0.001 by the log-rank test) than treatment with low-intensity warfarin (producing an international normalized ratio of < 3) with or without low-dose aspirin or treatment with aspirin alone in preventing further thrombotic events (recurrence rates per patient-year, 0.013, 0.23, and 0.18, respectively). The rate of recurrence of thrombosis was highest (1.30 per patient-year) during the first six months after the cessation of warfarin therapy. Complications involving bleeding occurred in 29 patients during warfarin therapy and were severe in 7 (0.071 and 0.017 occurrence per patient-year, respectively). CONCLUSIONS: The risk of recurrent thrombosis in patients with the antiphospholipid-antibody syndrome is high. Long-term anticoagulation therapy in which the international normalized ratio is maintained at or above 3 is advisable in these patients.

Adolescent↗
PubMed1995

Changes in the contact system during orthotopic liver transplantation with and without aprotinin.

The main cause of nonsurgical bleeding during orthotopic liver transplantation has been attributed to be hyperfibrinolysis due to high plasma levels of tissue plasminogen activator. The aim of this study was to investigate contact activation and its possible contribution to fibrinolysis during OLT with and without aprotinin. Aprotinin or placebo was given to 20 patients undergoing OLT as part of a randomized double-blind trial. Plasma samples were collected before, during, and after OLT. There were decreased preoperative levels of prekallikrein and factor XIIa (P < 0.05), with a trend for kallikrein and factor XIIa activity to increase during OLT peaking on reperfusion (P < 0.05). Kallikrein inhibition, C1 esterase inhibitor, and alpha-2-macroglobulin levels were normal before surgery, with low normal levels of antithrombin III and alpha-2-antiplasmin; these levels decreased during OLT with no specific change on reperfusion. In the aprotinin-treated group, kallikrein inhibition levels increased (P < 0.05) from preoperative mean (+/- SD) values of 101 +/- 47% to 154 +/- 42% and antiplasmin levels increased (P < 0.05) from 72 +/- 28% to 243 +/- 53% during the anhepatic phase, reflecting the effect of aprotinin. The antifibrinolytic effect of aprotinin was demonstrated by decreased levels of D-dimer on reperfusion (P < 0.05) and at the end of OLT (P < 0.001) in the aprotinin-treated group. We have shown that contact activation during OLT is minimal and that aprotinin does not alter the pattern of contact activation, but provides an antikallikrein effect.

Adult↗
PubMed1995

The effects of cardiopulmonary bypass on systemic and coronary levels of von Willebrand factor.

Von Willebrand factor antigen (vWF Ag) is a marker of endothelial injury which has been shown to rise during surgical procedures, including cardiopulmonary bypass (CPB). The aim of this study was to determine whether intermittent aortic cross-clamping during CPB causes the release of vWF Ag from the coronary vascular bed, which would suggest coronary vascular endothelial cell perturbation. Fifteen consecutive patients undergoing CPB with aortic cross-clamping during coronary artery bypass surgery and/or valve replacement by the same surgeon were studied. Paired venous and coronary sinus samples were taken pre- and post-thoracotomy, prior to cross-clamping on CPB, and 1, 5 and 10 minutes after release of the aortic cross-clamp. Plasma vWF Ag (IU/ml) was measured by ELISA. Venous vWF Ag measured prior to skin incision was 0.75 +/- 0.11 IU/ml (mean +/- SEM) and fell to 0.53 +/- 0.07 IU/ml after institution of CPB but prior to aortic cross-clamping (P < 0.01 vs pre-incision sample). Coronary sinus vWF Ag measured prior to aortic cross-clamping was 0.54 +/- 0.06 IU/ml (P = NS vs paired venous sample). At 1, 5 and 10 min after release of the aortic cross-clamp there was a progressive rise in vWF Ag in both venous and coronary sinus samples (1 min: 0.67 +/- 0.05 IU/ml vs 0.75 +/- 0.10 IU/ml, 5 min: 0.73 +/- 0.07 IU/ml vs 0.76 +/- 0.09 IU/ml, 10 min: 0.74 +/- 0.08 IU/ml vs 0.79 +/- 0.09 IU/ml; P = NS venous vs coronary sinus, respectively). Levels of vWF Ag were highest immediately prior to the termination of CPB (venous: 0.95 +/- 0.12 IU/ml; coronary sinus: 0.91 +/- 0.14 IU/ml). We conclude that cardiac surgery using CPB with aortic cross-clamping is associated with a progressive rise in coronary sinus and venous levels of vWF Ag.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Thrombophilic factors in ischaemic and non-ischaemic idiopathic retinal vasculitis.

Two common causes of visual loss in idiopathic retinal vasculitis (RV) are retinal ischaemia and cystoid macular oedema. This study investigated whether thrombophilic factors are more prevalent in patients with ischaemic RV than non-ischaemic RV. Twenty patients with RV (10 ischaemic, 10 non-ischaemic) were prospectively recruited before starting systemic immunosuppression. Twenty-one different haemostatic parameters were tested. Seventeen patients had at least one haemostatic abnormality. Three patients had low Protein S, one had low Protein C. Three patients had positive anticardiolipin antibody titres, 1 had poor fibrinolytic activity, 3 had raised fibrinogen levels. Ten patients had raised lipoprotein (a) levels. Fibrinogen levels were higher in the smokers (p = 0.02). Although all von Willebrand's factor levels were within the normal range, they were higher in the ischaemic group (p = 0.008), in which smoking was more prevalent. This study has shown a high prevalence of thrombophilic abnormalities in RV patients, and implicates smoking in the aetiology of ischaemic RV.

Adult↗
PubMed1995

The use of recombinant factor VIIa in a patient with acquired haemophilia A undergoing surgery.

An elderly woman with acquired haemophilia A secondary to a monoclonal gammopathy, required elective surgery for a parotid tumour but was unable to tolerate conventional treatment. Recombinant activated factor VII (rVIIa) was used successfully to cover a biopsy and then subsequent resection of the tumour. The use of rVIIa in the management of acquired inhibitors is discussed.

Aged↗
PubMed1995

Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia.

The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.

Adolescent↗
PubMed1994

Fibrinolytic activity during orthotopic liver transplantation with and without aprotinin.

Hyperfibrinolysis during orthotopic liver transplantation (OLT) has been attributed to high plasma levels of tissue plasminogen activator (t-PA). This study investigated the contribution of urokinase plasminogen activator (u-PA) to hyperfibrinolysis and the effects of high-dose perioperative aprotinin (Trasylol) on fibrinolytic activation. Plasma samples were collected before, during, and after OLT in fifty five patients receiving either high dose aprotinin or placebo in a randomized double-blind trial. t-PA antigen and u-PA antigen and activity levels were increased preoperatively compared with normal controls (P < 0.05). Hyperfibrinolysis was seen during the anhepatic phase as shown by shortened euglobulin clot lysis times (ECLT) and an increase in D-dimer titers. t-PA levels peaked on reperfusion and fell at the end of the operation, and u-PA levels did not increase during OLT, but showed a decrease at the end of the operation. With aprotinin treatment, t-PA levels were lower on graft reperfusion than the placebo group (P < 0.05), but there was no difference in u-PA antigen or activity levels between groups. Fibrinolytic inhibition during OLT by aprotinin was demonstrated by prolonged ECLT (P < 0.05), reduced D-dimer levels (P < 0.05), and an increase in antiplasmin activity (P < 0.05). This study showed that the main antifibrinolytic action of aprotinin is as an antiplasmin agent with some effect on t-PA-but not u-PA-mediated fibrinolysis.

Adult↗