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Biomedical subjects

C A Ludlam

Publications and source records attributed to C A Ludlam.

At least 37 records · Page 2Linked to original sources
PubMed2001

The coagulative and cardiorespiratory responses to reamed intramedullary nailing of isolated fractures.

We measured the changes during operation in seven markers of coagulation in a prospective series of 84 patients with fractures of the tibia or femur who were undergoing reamed intramedullary nailing. All patients were also continually monitored using transoesophageal echocardiography to assess marrow embolism. In a subset of 40 patients, intraoperative cardiopulmonary function was monitored, using pulmonary and systemic arterial catheterisation. The procedure produced a significant increase in prothrombin time, activated partial thromboplastin time, the level of prothrombin fragments F1+2 and D-dimers, and a decrease in the fibrinogen level, suggesting activation of both the coagulation and fibrinolytic pathways. There was evidence of both platelet hyper-reactivity and depletion, as estimated by an increase in beta-thromboglobulin levels and a decrease in the platelet count. In the patients who had invasive monitoring there was an incremental increase in mean pulmonary arterial pressure, with the changes being greatest during insertion of the guide-wire and reaming. The change in markers of coagulation, pulmonary artery pressure and arterial oxygen partial pressures correlated with the intraoperative embolic response. Greater changes in these parameters were observed during stabilisation of pathological fractures and in those patients in whom surgery had been delayed for more than 48 hours. Seven patients with pathological fractures developed more severe hypoxic episodes during reaming, which were associated with significantly greater arterial hypoxaemia, a fall in the right ventricular ejection fraction and an increase in the mean pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure and the pulmonary vascular resistance index. These changes suggested that the patients had transient intraoperative right heart strain. Eight patients developed significant postoperative respiratory compromise. They all had severe intraoperative embolic responses and, in the three who had invasive monitoring, there was a significantly greater increase in pulmonary artery pressure and alveolar-arterial oxygen gradient, and a fall in the ratio of arterial partial pressure of oxygen to the inspired oxygen concentration. Operative delay, intraoperative paradoxical embolisation and the scores for the severity of the coagulative and embolic responses were predictive of the development of postoperative respiratory complications on univariate logistic regression analysis. On multivariate analysis, however, only the embolic and coagulative scores were significant independent predictors of respiratory complications.

Cardiovascular Diseases↗
PubMed2001

Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding.

We examined recombinant activated factor VII (rVIIa) administered by continuous infusion to eight patients with inhibitors to factor VIII, undergoing elective surgery. rVIIa was infused at a fixed rate of 16.5 microg/kg/h for a median of 13.5 days (range 1-26). There was effective haemostasis at this infusion rate in only one of two minor procedures and two of six major operations. Three patients experienced excessive bleeding despite plasma factor VII activity around 10 IU/ml. Serious bleeding occurred in two other patients caused by procedural errors unrelated to rVIIa and required re-operation. The median rVIIa clearance on day 1 was 57 ml/h/kg (range 18-100) and on day 3 was 100 ml/h/kg (range 61-200). Clearance on the final infusion day was not significantly different from day 3. The infusion did not induce pathological activation of the coagulation mechanism. The only thrombotic adverse events were two episodes of superficial thrombophlebitis of the infused vein in one subject. In conclusion, the 16.5 microg/kg/h infusion rate reliably achieves plasma factor VII activity levels of 10 IU/ml, but this level does not provide reliable haemostasis.

Adult↗
PubMed2000

Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man.

OBJECTIVES: Angiotensin II and bradykinin are potent endogenous vasoactive peptides which may play a role in the regulation of endogenous fibrinolysis and, thereby, contribute to the beneficial actions of ACE inhibitors. The aims of the study were to determine the acute effect of angiotensin II and bradykinin on the local vascular release of tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), and the endothelium-derived haemostatic factor, von Willebrand factor (vWf) from the forearm. METHODS: Blood flow, and plasma haemostatic and fibrinolytic factors, were measured in both forearms of sixteen healthy men: eight subjects received intra-arterial angiotensin II (5, 50 and 500 pmol/min) which was coinfused with sodium nitroprusside (SNP; 0.3, 1.5 and 7.5 microg/min, respectively), and eight received intra-arterial bradykinin at 10-3000 pmol/min. RESULTS: Despite substantial rises in plasma angiotensin II concentrations (P<0.001) which caused pressor effects (P<0.003) at the highest dose, angiotensin II infusion did not affect local plasma t-PA, PAI-1 or vWf concentrations. In contrast, bradykinin caused substantial dose-dependent increases in blood flow and t-PA release (>100 ng/100 ml of tissue/min) in the infused forearm (P<0. 001 for both) without affecting plasma PAI-1 or vWf concentrations. CONCLUSIONS: Despite high local concentrations with breakthrough of significant systemic effects, angiotensin II did not affect acute endothelial cell t-PA, PAI-1 or vWf release in healthy men. In contrast, bradykinin is a potent vasodilator and selective stimulus for acute local t-PA release. This may, at least in part, explain the fibrinolytic actions of ACE inhibitors in heart failure and ischaemic heart disease.

Adult↗
PubMed2000

Thrombosis in a duplicated superficial femoral vein in a patient with haemophilia A.

Venous thrombosis is a very rare occurrence in patients with haemophilia A. We report the case of a haemophiliac in whom initially a calf haematoma was suspected, but neither this nor deep venous thrombosis (DVT) could be confirmed on ultrasound scanning. Subsequently, a high segment venous thrombosis was diagnosed by venography in a portion of a duplicated superficial femoral vein. Treatment with factor VIII (FVIII) and low molecular weight heparin led to a successful resolution. The only other case we have been able to find in the literature occurred during FVIII replacement therapy, which was not the situation with our patient.

Adult↗
PubMed2000

Haemophilia care in central Scotland 1980-94. I. Demographic characteristics, hospital admissions and causes of death.

To estimate the resources required to manage patients with haemophilia in Scotland, we studied the demographic features, hospital admissions and causes of deaths for individuals with haemophilia A and B and von Willebrand disease, treated with blood products, during the period 1980-94 living in central Scotland. Data were obtained from 413 adults and children (93% ascertainment). The age distribution in 1980 revealed a paucity of individuals over 60 years but the number in this age group increased over the study period. Of those with haemophilia A and B, 63 and two respectively, became HIV positive. Hospital admissions rose from 103 to 168 per annum; the number of annual bed days utilized also increased, but there was marked annual fluctuation (790-1832). The rate of admission was greater for those with severe haemophilia A and this increased during the 15-year period mainly due to the clinical consequences of human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The admission rate for haemophilia B was significantly lower than that for haemophilia A, and was similar for all degrees of severity of the disorder. Throughout the 15-year period the incidence of admissions for acute bleeds was constant, as was the average duration in hospital. For those with a factor VIII inhibitor, the rate of admission was about double the rate of those without an inhibitor, although the duration of hospital stay was similar for both groups. There were 61 deaths; the death rate increased during the study period principally due to HIV and HCV, and 12 patients died from haemorrhage. We conclude that: (i) the life expectancy for haemophiliacs in Scotland was generally increasing, although HIV and HCV caused increasing mortality and morbidity (as shown by the increase in hospital admissions); (ii) hospital bed usage for the treatment of acute bleeds continued to be required, but fluctuated greatly; and (iii) the clinical impression that haemophilia B is less clinically severe than haemophilia A is confirmed by objective data. The planning implications for haemophilia care in Scotland and similar countries are discussed.

Adolescent↗
PubMed2000

Acquired haemophilia in recipients of depot thioxanthenes.

We present two cases in which the occurrence of acquired haemophilia is associated with the use of depot preparations of the thioxanthenes zuclopenthixol and flupenthixol. These drugs have not previously been implicated in the aetiology of acquired haemophilia.

Adult↗
PubMed2000

Prevalence of pernicious anaemia in patients with Type 1 diabetes mellitus and autoimmune thyroid disease.

AIMS: To determine the prevalence of pernicious anaemia in patients with Type 1 diabetes mellitus and autoimmune thyroid disease. METHODS: A randomly selected asymptomatic group of 63 patients with Type 1 diabetes who also had autoimmune thyroid disease was studied. Blood samples were taken and assayed for serum B12. Those subjects with serum B12 concentrations below the reference range had a further blood sample taken for determination of intrinsic factor antibody. RESULTS: One patient had been diagnosed previously to have pernicious anaemia. Three patients had low serum B12 concentration and positive intrinsic factor antibody, confirming the diagnosis of pernicious anaemia. The prevalence of pernicious anaemia in this population with Type 1 diabetes and concomitant autoimmune thyroid disease was 6.3%. In female patients the prevalence of pernicious anaemia was 8.5%. CONCLUSIONS: Patients who have both Type 1 diabetes mellitus and autoimmune thyroid disease are at risk of developing pernicious anaemia.

Aged↗
PubMed2000

Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease. Role of interleukin-6.

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin > or = 70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses > or = 300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001: r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.

Adult↗
PubMed1999

Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibition after myocardial infarction is associated with an improvement in plasma fibrinolytic parameters. The aim of the present study was to determine whether acute ACE inhibition and angiotensin II type 1 (AT1) receptor antagonism have similar effects in patients with heart failure. METHODS AND RESULTS: Twenty patients with moderately severe chronic heart failure received enalapril 10 mg and losartan 50 mg on 2 separate occasions in a single-blind, randomized, crossover design. Plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) antigen and activity were measured at baseline and 6 hours after the dose. Acute administration of losartan but not of enalapril reduced plasma t-PA (11%; P=0.003) and PAI-1 (38%; P<0.001) antigen concentrations, which was associated with increases in t-PA (29%; P=0.03) and decreases in PAI-1 (48%; P=0.01) activity. Changes in plasma fibrinolytic parameters were more marked during losartan treatment (P<0.02), with a 3-fold greater reduction in plasma PAI-1 antigen concentrations (P<0.05). CONCLUSIONS: Acute AT1 antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters that is greater than during ACE inhibition. These beneficial effects of AT1 antagonism and ACE inhibition would therefore appear to be mediated principally through suppression of angiotensin II.

Aged↗
PubMed1999

Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction.

BACKGROUND: Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P-induced tPA release in vivo in humans. METHODS AND RESULTS: Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively. CONCLUSIONS: Cigarette smoking causes marked inhibition of substance P-induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

Adult↗
PubMed1999

Coagulation and fibrinolysis in patients undergoing operation for ruptured and nonruptured infrarenal abdominal aortic aneurysms.

PURPOSE: Hemorrhage and thrombosis predisposing to myocardial infarction, multiple organ failure, and thromboembolism account for the majority of the morbidity and mortality associated with repair of ruptured and nonruptured abdominal aortic aneurysms (AAAs). The aim of this study was to examine coagulation and fibrinolysis in patients operated on for ruptured and nonruptured infrarenal AAAs. METHODS: Ten patients operated on for ruptured and 9 patients operated on for nonruptured AAAs were studied. Tissue plasminogen activator (t-PA) antigen, thrombin-antithrombin (TAT), and D-dimer were measured before induction of anesthesia. Plasminogen activator inhibitor (PAI) activity, t-PA activity, and prothrombin fragment (PF) 1+2 were measured before induction of anesthesia, immediately before aortic clamp release, and 5 minutes and 24 hours after aortic clamp release. RESULTS: Preoperatively, ruptured AAA was associated with significantly elevated t-PA antigen (median 15.7 ng/mL, range 9. 0 to 22.1 ng/mL versus nonrupture: median 6.6 ng/mL, range 4.7 to 16. 4 ng/mL; P <.01, Mann-Whitney test), increased PAI activity (median 36.5 arbitrary units/mL, range 20.6 to 38.8 arbitrary units/mL versus nonrupture: median 8.2 arbitrary units/mL, range 3.2 to 21.7 arbitrary units/mL; P <.001), reduced t-PA activity (median 0.12 IU/mL, range 0.06 to 0.4 IU/mL versus nonrupture: median 0.49 IU/mL, range 0.14 to 3.2 IU/mL; P <.01), elevated TAT (median 135.5 microg/L, range 61.2 to 209.4 microg/L versus nonrupture: median 21. 6 microg/L, range 6.6 to 180.4 microg/L; P <.02) and elevated PF 1+2 (median 9.0 nmol/L, range 5.4 to 11.6 nmol/L versus nonrupture: median 2.2 nmol/L, range 0.7 to 7.1 nmol/L, P <.001). There was no significant difference in preoperative D-dimer levels (median 3460 ng/mL, range 1236 to 7860 ng/mL versus nonrupture: median 1642 ng/mL, range 728 to 5334 ng/mL; P =.07). The differences in PAI activity, t-PA activity, and PF 1+2 persisted throughout the course of surgery, but there was no significant difference between the groups at 24 hours. CONCLUSION: These novel data demonstrate that ruptured AAA repair is associated with inhibition of systemic fibrinolysis and intense thrombin generation. Similar changes are seen in nonruptured AAA but are of a lesser magnitude. This procoagulant state may contribute to the microvascular and macrovascular thrombosis that leads to myocardial infarction, multiple organ failure, and thromboembolism.

Aged↗
PubMed1999

TGF-beta is not the principal immunosuppressive component in coagulation factor concentrates.

Coagulation factor concentrates are known to inhibit a variety of immune reactions when assessed in vitro. This study assessed the immunomodulatory activity of a wide range of coagulation factor concentrates by measuring their inhibition of PHA-stimulated lymphocyte proliferation and reduction in IL-2 secretion. The hypothesis that TGF-beta is responsible for most of these effects was tested by measuring biologically active TGF-beta and immunoreactive TGF-beta1 in the concentrates and comparing the levels recorded with immunosuppressive activity. In addition, the coagulation factors were compared directly with a standard preparation of TGF-beta in a TGF-beta-specific bioassay and in lymphocyte proliferation assays. Although there was a broad correlation between levels of total or active TGF-beta and immunosuppressive activity across all of the coagulation factors tested, individual data sets showed clear discrepancies. Implying that TGF-beta probably serves as a surrogate marker for other immunomodulatory contaminants and that neither TGF-beta nor any other single substance could account for all of the immunosuppressive activity observed. Furthermore, there was a difference of more than 100-fold in the relative potencies of coagulation factors and pure TGF-beta, when compared in immunosuppression assays, indicating that the different assays did not measure the same substance. Whereas anti-TGF-beta antibody almost completely blocked the activity of coagulation factor concentrates (TGF-beta-specific bioassay) and abrogated the effect of authentic TGF-beta (immunosuppression assays) at high concentrations it achieved <50% reversal of the immunosuppressive effects of coagulation factors in immunosuppression assays. These findings indicated that TGF-beta accounted for only a minor proportion of the immunosuppressive activity in most coagulation factor concentrates.

Animals↗
PubMed1999

Warfarin-induced skin necrosis.

Skin necrosis is a rare but serious side-effect of treatment with warfarin. At particular risk are those with various thrombophilic abnormalities, especially when warfarinization is undertaken rapidly with large loading doses of warfarin. With the increasing number of patients anticoagulated as out-patients for thromboprophylaxis, we are concerned that the incidence of skin necrosis may increase. If skin necrosis does occur, prompt remedial action may be of benefit in preventing permanent tissue damage.

Adult↗
PubMed1999

Does avascular necrosis cause collapse of the dome of the talus in severe haemophilia?

Arthropathy of the ankle joint is commonly observed in people with severe haemophilia. A review of the radiological appearance of ankle arthropathy provides evidence that the changes in the talar bone of the ankle joint are probably due to avascular necrosis. This may arise due to impairment to the arterial supply, as it enters the talar neck, secondary to the increased pressure at the time of haemarthroses.

Hemophilia A↗