254 results on '"Ludlam CA"'
Search Results
2. The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers – two independent studies
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POLLER L, IBRAHIM S, KEOWN M, PATTISON A, JESPERSEN J, EUROPEAN ACTION ON A.N.T.I.C.O.A.G.U.L.A.T.I.O.N. COLLABORATORS: MARUN S, MUNTEAN W, ASPÖCK G, BAILLEUL E, WIJNS W, MICHEL T, JOCHMANS K, CHATELAIN B, MARCELIS L, NIJS AN, JOHNSTON M, KYNDE K, SYRÄJLÄ M, SAVOLAINEN ER, IVASKA K, RAJAMÄKI A, VANHARANTA R, JUHAN I, AILLAUD MF, GUILLIN MC, HUISSE MG, SIE P, LECOMPTE T, SCHMITT Y, HARENBERG J, PLESCH W, ARONIS S, THEODOSSIADES G, TSOUKANAS B, MARKALA D, DITSA M, CAHILL M, MADDEN M, FITZGERALD H, MCCARTHY D, COLLINS B, ROONEY S, NAPARSTEK E, MARONGIU F, ERBA N, TESTA S, MARIANI G, POTÌ R, MANNUCCI PM, TRIPODI A, BADER R, PENGO V, GRESELE P, D'INCÀ M, AGENO W, TOSETTO A, HENSGENS HE, IDEMA RN, OOSTERHOUT DH, MULDER AB, HAMULYAK K, VD DUSSEN H, MUSIAL J, GAGO T, PALMEIRO A, CAMPOS M, MARQUES DIAS DA, CUNHA MONTEIRO Á, ANGELA CUNHA M, DE GAIA WN, PETERNEL P, STEGNAR M, FONTCUBERTA J, BORRELL M, REVERTER JC, SANTASUSANA PD, LOPEZ FERNANDEZ MF, MONTERO J, RIBERA CASADO C, VICENTE V, EDLUND B, EGBERG N, LÄMMLE B, ALBERIO L, DE MOERLOOSE P, REBER G, MACHIN SJ, MACKIE I, LAWRIE A, LUCKIT J, SHANKS D, DOLAN G, FLAHERTY T, LUDLAM CA, WALKER ID, LAWSON DE, TRISCOTT M, MARLAR RA, HEIT JA, WATZKE H, WEISSER B, GALLUS AS, OSMOND J, CORNET I, MUNSTER AM, LEED B, CHILLOU C, DEFARD M, HORELLOU MH, HALKIN H, LOEBSTEIN R, KIRGNER I, DENTALI F, TRAPANI LOMBARDO V, SOTTILOTTA G, CONSIGLIO P, DE MICHELE S, MOIA M, CARPENEDO M, OLIVIERO B, MANOTTI C, TASSONI MI, PALARETI G, BRUSI C, LEGNANI C, PEGORARO C, ANDRIANI C, GRAZIA CIRIGLIANO M, RIBALDI E, ABBATE R, POLI D, PERRICONE C, SCHIAVULI M, CASIERA C, LUPONE MR, ROSSI E, CRIVELLI S, BIROLINI A, PARENTE F, MIGLIETTA AM, CAMPOBASSO M, SYDOR W, KREVEL B, FERNANDEZ MA, LOZANO M, SHIACH C, BOWYER C, CHARLES F., PALARETI, GUALTIERO, COSMI, BENILDE, POLLER L, IBRAHIM S, KEOWN M, PATTISON A, JESPERSEN J, EUROPEAN ACTION ON ANTICOAGULATION. COLLABORATORS: MARUN S, MUNTEAN W, ASPÖCK G, BAILLEUL E, WIJNS W, MICHEL T, JOCHMANS K, CHATELAIN B, MARCELIS L, NIJS AN, JOHNSTON M, KYNDE K, SYRÄJLÄ M, SAVOLAINEN ER, IVASKA K, RAJAMÄKI A, VANHARANTA R, JUHAN I, AILLAUD MF, GUILLIN MC, HUISSE MG, SIE P, LECOMPTE T, SCHMITT Y, HARENBERG J, PLESCH W, ARONIS S, THEODOSSIADES G, TSOUKANAS B, MARKALA D, DITSA M, CAHILL M, MADDEN M, FITZGERALD H, MCCARTHY D, COLLINS B, ROONEY S, NAPARSTEK E, PALARETI G, MARONGIU F, ERBA N, TESTA S, MARIANI G, POTÌ R, MANNUCCI PM, TRIPODI A, BADER R, PENGO V, GRESELE P, D'INCÀ M, AGENO W, TOSETTO A, HENSGENS HE, IDEMA RN, OOSTERHOUT DH, MULDER AB, HAMULYAK K, VD DUSSEN H, MUSIAL J, GAGO T, PALMEIRO A, CAMPOS M, MARQUES-DIAS DA, CUNHA MONTEIRO Á, ANGELA CUNHA M, DE GAIA WN, PETERNEL P, STEGNAR M, FONTCUBERTA J, BORRELL M, REVERTER JC, SANTASUSANA PD, LOPEZ-FERNANDEZ MF, MONTERO J, RIBERA CASADO C, VICENTE V, EDLUND B, EGBERG N, LÄMMLE B, ALBERIO L, DE MOERLOOSE P, REBER G, MACHIN SJ, MACKIE I, LAWRIE A, LUCKIT J, SHANKS D, DOLAN G, FLAHERTY T, LUDLAM CA, WALKER ID, LAWSON DE, TRISCOTT M, MARLAR RA, HEIT JA, WATZKE H, WEISSER B, GALLUS AS, OSMOND J, CORNET I, MUNSTER AM, LEED B, CHILLOU C, DEFARD M, HORELLOU MH, HALKIN H, LOEBSTEIN R, KIRGNER I, DENTALI F, TRAPANI LOMBARDO V, SOTTILOTTA G, CONSIGLIO P, DE MICHELE S, MOIA M, CARPENEDO M, OLIVIERO B, MANOTTI C, TASSONI MI, COSMI B, BRUSI C, LEGNANI C, PEGORARO C, ANDRIANI C, GRAZIA CIRIGLIANO M, RIBALDI E, ABBATE R, POLI D, PERRICONE C, SCHIAVULI M, CASIERA C, LUPONE MR, ROSSI E, CRIVELLI S, BIROLINI A, PARENTE F, MIGLIETTA AM, CAMPOBASSO M, SYDOR W, KREVEL B, FERNANDEZ MA, LOZANO M, SHIACH C, BOWYER C, CHARLES F., Interne Geneeskunde, Biochemie, and RS: CARIM School for Cardiovascular Diseases
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INR correction ,endocrine system ,medicine.medical_specialty ,coagulometers ,Prothrombin Time/*standard ,Reproducibility of Result ,PT ,World Health Organization ,International Normalized Ratio/*standard ,Thromboplastin ,Automation ,Laboratory/standard ,ECAA plasmas ,Predictive Value of Tests ,health services administration ,medicine ,Animals ,Humans ,heterocyclic compounds ,International Normalized Ratio ,cardiovascular diseases ,thromboplastins ,Blood Coagulation ,Reference standards ,Mathematics ,Automation, Laboratory ,Observer Variation ,Prothrombin time ,Analysis of Variance ,medicine.diagnostic_test ,business.industry ,fungi ,Reproducibility of Results ,Hematology ,Reference Standards ,Surgery ,INR Line ,Multicenter study ,Calibration ,Linear Models ,Prothrombin Time ,Cattle ,Rabbits ,Observer variation ,Nuclear medicine ,business - Abstract
The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP).The value of a new simpler procedure to derive international normalized ratio (INR), the PT/INR Line, based on only five European Concerted Action on Anticoagulation (ECAA) calibrant plasmas certified by experienced centres has been assessed in two independent exercises using a range of commercial thromboplastins and coagulometers. INRs were compared with manual certified values with thromboplastin IRP from expert centres and in the second study also with INRs from local ISI calibrations.In the first study with the PT/INR Line, 8.7% deviation from certified INRs was reduced to 1.1% with human reagents, and from 7.0% to 2.6% with rabbit reagents. In the second study, deviation was reduced from 11.2% to 0.4% with human reagents by both local ISI calibration and the PT/INR Line. With rabbit reagents, 10.4% deviation was reduced to 1.1% with both procedures; 4.9% deviation was reduced to 0.5% with bovine/combined reagents with local ISI calibrations and to 2.9% with the PT/INR Line. Mean INR dispersion was reduced with all thromboplastins and automated systems using the PT/INR Line.The procedure using the PT/INR Line provides reliable INR derivation without the need for WHO ISI calibration across the range of locally used commercial thromboplastins and automated PT systems included in two independent international studies.? 2010 International Society on Thrombosis and Haemostasis.
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- 2011
3. Aortic aneurysms and consumptive coagulopathy
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Ludlam Ca and Micallef-Eynaud Pd
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Male ,medicine.medical_specialty ,Aortic aneurysm ,Consumptive Coagulopathy ,medicine ,Humans ,cardiovascular diseases ,Thrombus ,education ,Aged ,Ultrasonography ,Aged, 80 and over ,education.field_of_study ,Heparin ,business.industry ,Warfarin ,Fibrinogen ,Hematology ,General Medicine ,Disseminated Intravascular Coagulation ,medicine.disease ,Thrombocytopenia ,Aortic Aneurysm ,Surgery ,Prothrombin Time ,cardiovascular system ,Coagulation screen ,Female ,Partial Thromboplastin Time ,Blood Coagulation Tests ,business ,medicine.drug - Abstract
We describe three cases of consumptive coagulopathy caused by extensive thrombus formation in otherwise 'uncomplicated' aortic aneurysms. These cases demonstrate the importance of performing a coagulation screen in any patient presenting with thrombocytopenia who may have an aortic aneurysm. Effective therapy with low-dose heparin was demonstrated with subsequent haemostasis being maintained with warfarin.
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- 1991
4. Concurrent evolution of human immunodeficiency virus type 1 in patients infected from the same source:Rate of sequence change and low frequency of inactivating mutations
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BALFE, P, SIMMONDS, P, LUDLAM, CA, BISHOP, JO, and Leigh Brown, AJ
- Abstract
Direct sequencing of segments of the envelope gene of human immunodeficiency virus type 1 proviruses in peripheral blood mononuclear cells has revealed that a cohort of hemophiliacs who were infected after exposure to a single common batch of factor VIII share closely related virus strains. Seventy-four sequences extending from hypervariable regions V4 through V5 from nine patients yielded a mean intrapatient nucleotide distance of 5.5%, while a mean of 4.2% was observed in 39 sequences of the V3 loop (six patients). Phylogenetic analysis revealed that sequences of six Edinburgh patients were particularly closely related and those from a patient infected in the United States were very distinct. The mean nucleotide distance among these six was 8.3%, while the mean distance from the U.S.-derived sequences was 25.5% in the V4-V5 region. The rate of sequence change across this patient group has been estimated to be 0.4% per year in the V4-V5 region and 0.5% per year in the V3 region, with at least a twofold range across patients. Only two inactivating nucleotide substitutions have been observed in a total of 42 kb of sequence obtained from the env and gag genes during this study.
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- 1990
5. Acute Systemic Inflammation Enhances Tissue Plasminogen Activator Release in Man
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Chia, S, primary, Reid, K, additional, Dawson, P, additional, Ludlam, CA, additional, Fox, KAA, additional, and Newby, DE, additional
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- 2002
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6. Endothelial Dysfunction and Impaired Endogenous Fibrinolysis Do Not Contribute to Acute Stent Thrombosis or In-stent Restenosis
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Chia, S, primary, Megson, EL, additional, Harding, SA, additional, Ludlam, CA, additional, Fox, KAA, additional, Boon, NA, additional, and New, DE, additional
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- 2002
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7. Detection of a novel DNA virus (TT virus) in blood donors and blood products
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Simmonds, P, primary, Davidson, F, additional, Lycett, C, additional, Prescott, LE, additional, MacDonald, DM, additional, Ellender, J, additional, Yap, PL, additional, Haydon, GH, additional, Gillon, J, additional, Jarvis, LM, additional, and Ludlam, CA, additional
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- 1998
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8. New-variant Creutzfeldt-Jakob disease and treatment of haemophilia
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Ludlam, CA, primary
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- 1998
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9. Investigation of the relative infectivity and pathogenicity of different hepatitis C virus genotypes in hemophiliacs
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Jarvis, LM, primary, Ludlam, CA, additional, Ellender, JA, additional, Nemes, L, additional, Field, SP, additional, Song, E, additional, Chuansumrit, A, additional, Preston, FE, additional, and Simmonds, P, additional
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- 1996
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10. Interferon treatment for chronic hepatitis C infection in hemophiliacs-- influence of virus load, genotype, and liver pathology on response
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Hanley, JP, primary, Jarvis, LM, additional, Andrew, J, additional, Dennis, R, additional, Hayes, PC, additional, Piris, J, additional, Lee, R, additional, Simmonds, P, additional, and Ludlam, CA, additional
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- 1996
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11. Heterogeneity of hepatitis C virus genotypes in hemophilia: relationship with chronic liver disease
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Preston, FE, primary, Jarvis, LM, additional, Makris, M, additional, Philp, L, additional, Underwood, JC, additional, Ludlam, CA, additional, and Simmonds, P, additional
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- 1995
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12. Use of porcine factor VIII in the treatment of patients with acquired hemophilia
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Morrison, AE, primary, Ludlam, CA, additional, and Kessler, C, additional
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- 1993
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13. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.
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Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM, Wright, Rohana J, Newby, David E, Stirling, David, Ludlam, Christopher A, Macdonald, Ian A, and Frier, Brian M
- Abstract
Objective: To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes.Research Design and Methods: We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry.Results: In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (PConclusions: Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury. [ABSTRACT FROM AUTHOR] - Published
- 2010
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14. Vascular dysfunction in chronic obstructive pulmonary disease.
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Maclay JD, McAllister DA, Mills NL, Paterson FP, Ludlam CA, Drost EM, Newby DE, Macnee W, Maclay, John D, McAllister, David A, Mills, Nicholas L, Paterson, Finny P, Ludlam, Christopher A, Drost, Ellen M, Newby, David E, and Macnee, William
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Rationale: Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), which may in part be attributable to abnormalities of systemic vascular function. It is unclear whether such associations relate to the presence of COPD or prior smoking habit.Objectives: To undertake a comprehensive assessment of vascular function in patients with COPD and healthy control subjects matched for smoking history.Methods: Eighteen men with COPD were compared with 17 healthy male control subjects matched for age and lifetime cigarette smoke exposure. Participants were free from clinically evident cardiovascular disease.Measurements and Main Results: Pulse wave velocity and pulse wave analysis were measured via applanation tonometry at carotid, radial, and femoral arteries. Blood flow was measured in both forearms using venous occlusion plethysmography during intrabrachial infusion of endothelium-dependent vasodilators (bradykinin, 100-1,000 pmol/min; acetylcholine, 5-20 microg/min) and endothelium-independent vasodilators (sodium nitroprusside, 2-8 microg/min; verapamil, 10-100 microg/min). Tissue plasminogen activator (t-PA) was measured in venous plasma before and during bradykinin infusions. Patients with COPD have greater arterial stiffness (pulse wave velocity, 11 +/- 2 vs. 9 +/- 2 m/s; P = 0.003; augmentation index, 27 +/- 10 vs. 21 +/- 6%; P = 0.028), but there were no differences in endothelium-dependent and -independent vasomotor function or bradykinin-induced endothelial t-PA release (P > 0.05 for all).Conclusions: COPD is associated with increased arterial stiffness independent of cigarette smoke exposure. However, this abnormality is not explained by systemic endothelial dysfunction. Increased arterial stiffness may represent the mechanistic link between COPD and the increased risk for cardiovascular disease associated with this condition. [ABSTRACT FROM AUTHOR]- Published
- 2009
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15. Hepatitis C and sequencing in blood products, haemophiliacs and drug users
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Ludlam, CA, primary
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- 1991
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16. Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans.
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Gudmundsdóttir IJ, Megson IL, Kell JS, Ludlam CA, Fox KA, Webb DJ, and Newby DE
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- 2006
17. Clinical perspectives of emerging pathogens in bleeding disorders.
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Ludlam CA, Powderly WG, Bozzette S, Diamond M, Koerper MA, Kulkarni R, Ritchie B, Siegel J, Simmonds P, Stanley S, Tapper ML, von Depka M, Ludlam, Christopher A, Powderly, William G, Bozzette, Samuel, Diamond, Michael, Koerper, Marion A, Kulkarni, Roshni, Ritchie, Bruce, and Siegel, Jamie
- Abstract
As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma. [ABSTRACT FROM AUTHOR]
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- 2006
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18. The procoagulant potential of environmental particles (PM10)
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Gilmour PS, Morrison ER, Vickers MA, Ford I, Ludlam CA, Greaves M, Donaldson K, and MacNee W
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BACKGROUND AND AIMS: Epidemiology studies have shown that cardiovascular (CV) disease is primarily responsible for the mortality associated with increased pulmonary environmental particle (PM10) exposure. The mechanisms involved in PM10 mediated CV effects are unknown although changes in plasma viscosity and in the homoeostasis of blood coagulation have been implicated. It was hypothesised that PM10 exposure would result in an inflammatory response and enhance the activation of the extrinsic coagulation mechanisms in pulmonary and vascular cells in culture. METHODS: Primary human monocyte derived macrophages and human umbilical cord vein endothelial, human alveolar type II epithelial (A549), and human bronchial epithelial (16HBE) cells were tested for their inflammatory and procoagulant response to PM10 exposure. IL-8, tissue factor (TF), and tissue plasminogen activator (tPA) gene expression and protein release, and coagulation enhancing ability of culture media were determined 6 and 24 hours following exposure. RESULTS: The culture media from macrophages and 16HBE bronchial epithelial cells, but not A549 cells, exposed to PM10 had an enhanced ability to cause clotting. Furthermore, H2O2 also increased the clotting activity. Apoptosis was significantly increased in macrophages exposed to PM10 and LPS as shown by annexin V binding. TF gene expression was enhanced in macrophages exposed to PM10, and HUVEC tissue factor and tPA gene and protein expression were inhibited. CONCLUSIONS: These data indicate that PM10 has the ability to alter macrophage, epithelial, and endothelial cell function to favour blood coagulation via activation of the extrinsic pathway and inhibition of fibrinolysis pathways. [ABSTRACT FROM AUTHOR]
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- 2005
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19. Common Peroneal Nerve Entrapment in a Hemophiliac
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Large Df, Ludlam Ca, and Macnicol Mf
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business.industry ,technology, industry, and agriculture ,Common peroneal nerve entrapment ,MUSCLE HEMATOMA ,General Medicine ,Anatomy ,medicine.disease ,Nerve entrapment ,Nerve compression syndrome ,stomatognathic diseases ,Hematoma ,Medicine ,Orthopedics and Sports Medicine ,Surgery ,Fibula ,business ,Common peroneal nerve - Abstract
Traumatic neuropathies of the common peroneal nerve at the head of the fibula are relatively common, but nerve entrapment at this site is rarely encountered. A 55-year-old man with hemophilia A in whom common peroneal nerve entrapment occurred secondary to a probable muscle hematoma is described.
- Published
- 1983
20. Treatment of haemophilia.
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Ludlam, Christopher A. and Ludlam, CA
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HEMOPHILIA treatment , *HIV infections , *HEMOPHILIA in children , *THERAPEUTICS - Abstract
Discusses treatment options for hemophilia. Recombinant concentrates; Prophylactic therapy in children; Continuous infusion; Inhibitors; Treatment of acquired hemophilia; Infection with HIV and/or HCV.
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- 1998
21. Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers smoking, thrombin, and vascular responses in vivo.
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Lang NN, Gumundsdóttir IJ, Boon NA, Ludlam CA, Fox KA, and Newby DE
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- 2008
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22. The EAHAD blood coagulation factor VII variant database.
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Giansily-Blaizot M, Rallapalli PM, Perkins SJ, Kemball-Cook G, Hampshire DJ, Gomez K, Ludlam CA, and McVey JH
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- Gene Frequency, Genetic Variation, Humans, Mutation, Protein Structure, Secondary, Databases, Genetic, Factor VII genetics
- Abstract
Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus-specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross-species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)
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- 2020
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23. The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers.
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McVey JH, Rallapalli PM, Kemball-Cook G, Hampshire DJ, Giansily-Blaizot M, Gomez K, Perkins SJ, and Ludlam CA
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- Biomedical Research, Databases, Factual, Europe, Humans, Hemophilia A epidemiology, Hemostasis physiology
- Abstract
Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity., Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders., Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF)., Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
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- 2020
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24. Hepatitis C infection and outcomes in the Scottish haemophilia population.
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Khan MM, Tait RC, Kerr R, Ludlam CA, Lowe GD, Murray W, and Watson HG
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- Adult, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular therapy, Coagulants adverse effects, Cohort Studies, Drug Therapy, Combination, Female, Genotype, Hepacivirus genetics, Hepatitis C epidemiology, Hepatitis C etiology, Humans, Liver pathology, Liver Failure epidemiology, Liver Failure therapy, Liver Neoplasms epidemiology, Liver Neoplasms therapy, Liver Transplantation, Male, Middle Aged, Scotland, Treatment Outcome, White People, Antiviral Agents therapeutic use, Blood Coagulation Disorders, Inherited drug therapy, Coagulants therapeutic use, Hepatitis C drug therapy
- Abstract
Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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25. Endogenous tissue plasminogen activator enhances fibrinolysis and limits thrombus formation in a clinical model of thrombosis.
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Lucking AJ, Gibson KR, Paterson EE, Faratian D, Ludlam CA, Boon NA, Fox KA, and Newby DE
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- Adolescent, Adult, Angiotensin-Converting Enzyme Inhibitors pharmacology, Bradykinin pharmacology, Cross-Over Studies, Double-Blind Method, Endothelium, Vascular physiology, Humans, Fibrinolysis, Thrombosis etiology, Tissue Plasminogen Activator physiology
- Abstract
Objective: Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation., Approach and Results: Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions (P<0.001 for all). Intra-arterial bradykinin increased plasma t-PA concentrations in the chamber effluent (P<0.01 for all versus saline) that was quadrupled in the presence of enalapril (P<0.0001 versus placebo). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07)., Conclusions: Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.
- Published
- 2013
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26. Guidelines for the management of hemophilia.
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Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, and Street A
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- Comprehensive Health Care organization & administration, Delivery of Health Care organization & administration, Hemophilia A diagnosis, Humans, Pain Management, Blood Coagulation Factors therapeutic use, Hemophilia A therapy, Hemorrhage prevention & control, Hemostatics therapeutic use
- Abstract
Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2013
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27. Plasma microparticles are not elevated in fresh plasma from patients with gynaecological malignancy--an observational study.
- Author
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Zahra S, Anderson JA, Stirling D, and Ludlam CA
- Subjects
- Antithrombin III metabolism, Case-Control Studies, Cell-Derived Microparticles pathology, Female, Fibrin Fibrinogen Degradation Products metabolism, Flow Cytometry, Genital Neoplasms, Female pathology, Humans, Peptide Fragments metabolism, Peptide Hydrolases metabolism, Protein Precursors metabolism, Prothrombin metabolism, Thrombin metabolism, Cell-Derived Microparticles metabolism, Genital Neoplasms, Female blood
- Abstract
Objectives: Gynaecological cancer is common. It is highly amenable to effective treatment, but thrombosis remains a common complication. There is controversy about whether microparticles (MPs), particularly tissue factor (TF) positive MPs, are increased in patients with malignancy and/or thrombosis. We therefore set out to investigate the relationship between MPs of different cellular origins, in patients with gynaecological malignancy. We hypothesised that patients with gynaecological malignancy have increased numbers of MPs. We measured MPs released by different cell types in these patients, and correlated the results with measures of haemostatic activation., Methods: We measured the number of platelet-derived MPs (PMPs), endothelial cell-derived MPs (EMPs), leucocyte-derived MPs (LMPs), TF+ve MPs and annexin V (AV) binding MPs in fresh plasma by flow cytometry in patients with gynaecological malignancy and a control group. We also measured D-dimers, prothrombin fragments 1 and 2 (PF1&2) and thrombin-antithrombin (TAT) complexes as indirect markers of haemostatic activation., Results: The number of MPs (from all cell types) was similar in the two patient groups, with no significant differences. The number of circulating TF+ve MPs was also similar between the two groups. D-dimers (p<0.001) and PF1&2 (p=0.009) were significantly higher in the malignant group reflecting haemostatic activation, but there was no correlation between the level of D-dimers, PF1&2 and TAT and MP numbers., Conclusion: Using fresh samples, MPs were not significantly increased in patients with gynaecological malignancy. There was, however, evidence of haemostatic activation in the patients with malignancy, but no correlation between the number of MPs and haemostatic activation., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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28. Microparticles, malignancy and thrombosis.
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Zahra S, Anderson JA, Stirling D, and Ludlam CA
- Subjects
- Cell-Derived Microparticles immunology, Female, Humans, Immunophenotyping, Male, Neoplasms complications, Thrombosis etiology, Thrombosis immunology, Cell-Derived Microparticles physiology, Neoplasms physiopathology, Thrombosis physiopathology
- Abstract
Microparticles (MPs) are considered to be important biological effectors of several different physiological and pathological processes. There is increasing evidence of their role in haemostasis and thrombosis, and also of their importance in cancer cell survival, invasiveness and metastasis. The level of circulating MPs has been assessed in many different disease states, and there are reports that patients with malignancy and patients with thrombosis have increased levels of circulating MPs and MP-dependent thrombogenic potential. Research into the function and effect of MPs is currently hampered by a lack of standardization in the methods used to identify and quantify them. As these methods improve it is likely that MP assays will be of use both diagnostically and therapeutically in the future., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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29. EUHASS: The European Haemophilia Safety Surveillance system.
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Makris M, Calizzani G, Fischer K, Gilman EA, Hay CR, Lassila R, Lambert T, Ludlam CA, and Mannucci PM
- Subjects
- Blood Coagulation Disorders, Inherited drug therapy, Blood Coagulation Factors adverse effects, Databases, Factual, Europe, Humans, Prospective Studies, Recombinant Proteins adverse effects, Adverse Drug Reaction Reporting Systems ethics, Adverse Drug Reaction Reporting Systems organization & administration, Adverse Drug Reaction Reporting Systems statistics & numerical data, Hemophilia A drug therapy
- Abstract
Pharmacovigilance is an essential element of any drug treatment and considering the history of adverse events due to products used to treat inherited bleeding disorders, it should be an integral component of modern haemophilia treatment. Because inherited bleeding disorders and adverse events are rare, a multicentre, preferably multinational, adverse event reporting scheme for all clotting factor products is required. EUHASS is a European, prospective, multicentre adverse event reporting scheme in the field of inherited bleeding disorders., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
30. Biovigilance and pharmacovigilance for haemophilia.
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Weinstein M, Makris M, and Ludlam CA
- Subjects
- Europe, Global Health, Humans, North America, Product Surveillance, Postmarketing, Risk Management, Adverse Drug Reaction Reporting Systems standards, Blood Coagulation Factors adverse effects, Hemophilia A drug therapy
- Published
- 2010
- Full Text
- View/download PDF
31. Guideline for investigation and management of adults and children presenting with a thrombocytosis.
- Author
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Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M, Erber W, Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy C, Radia DH, Reilly JT, Van der Walt J, Wilkins B, and McMullin MF
- Subjects
- Adult, Algorithms, Child, Diagnosis, Differential, Evidence-Based Medicine methods, Humans, Myelodysplastic Syndromes diagnosis, Myelodysplastic-Myeloproliferative Diseases diagnosis, Myeloproliferative Disorders diagnosis, Risk Assessment methods, Thrombocythemia, Essential diagnosis, Thrombocythemia, Essential therapy, Thrombocytosis etiology, Thrombocytosis therapy, Thrombocytosis diagnosis
- Published
- 2010
- Full Text
- View/download PDF
32. Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.
- Author
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Giangrande PL, Wilde JT, Madan B, Ludlam CA, Tuddenham EG, Goddard NJ, Dolan G, and Ingerslev J
- Subjects
- Adolescent, Adult, Aged, Blood Loss, Surgical prevention & control, Child, Child, Preschool, Clinical Protocols, Elective Surgical Procedures, Hemophilia A complications, Humans, Middle Aged, Orthopedic Procedures adverse effects, Treatment Outcome, Young Adult, Consensus Development Conferences as Topic, Factor VIIa therapeutic use, Hemophilia A drug therapy, Joint Diseases surgery, Postoperative Hemorrhage prevention & control, Recombinant Proteins therapeutic use
- Abstract
Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.
- Published
- 2009
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33. European curriculum for thrombosis and haemostasis.
- Author
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Astermark J, Negrier C, Hermans C, Holme PA, Klamroth R, Kotsi P, de Moerloose P, Pasi J, Rocino A, von Depka M, Windyga J, and Ludlam CA
- Subjects
- Blood Coagulation Disorders, Inherited therapy, Clinical Competence, Europe, Hematology standards, Humans, Curriculum, Education, Medical, Graduate methods, Hematology education, Hemostatic Techniques standards, Thrombosis therapy
- Published
- 2009
- Full Text
- View/download PDF
34. Acute endothelial tissue plasminogen activator release in pregnancy.
- Author
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Robb AO, Mills NL, Din JN, Cameron S, Ludlam CA, Newby DE, and Denison FC
- Subjects
- Bradykinin pharmacology, Case-Control Studies, Endothelium, Female, Fibrinolysis, Gravidity, Humans, Pregnancy, Pregnancy Trimester, Third, Regional Blood Flow, Thrombosis etiology, Plasminogen Activator Inhibitor 1 blood, Tissue Plasminogen Activator metabolism
- Abstract
Objective: Pregnancy is associated with marked changes in vascular physiology and an increased risk of thrombosis. The aim of the study was to assess the effect of pregnancy on the acute release of tissue plasminogen activator (t-PA) from the endothelium., Methods and Results: Ten primigravida pregnant women were recruited in the third trimester of pregnancy (week 36 +/- 1) and compared with 20 age-matched non-pregnant women (day 9.8 +/- 0.3 of menstrual cycle). Blood flow and plasma fibrinolytic factors were measured in both forearms by venous occlusion plethysmography and blood sampling, respectively, during unilateral brachial artery infusions of bradykinin (100-1000 pmol min(-1)). Pregnant women had higher plasma plasminogen activator inhibitor type 1 (PAI-1) antigen concentrations (77.1 +/- 12.4 vs. 21.5 +/- 9.8 ng mL(-1); P = 0.004) that resulted in lower basal t-PA/PAI-1 ratios (0.2 +/- 0.1 vs. 0.6 +/- 0.1; P = 0.02) and plasma t-PA activity concentrations (0.17 +/- 0.02 vs. 0.58 +/- 0.06 IU mL(-1); P < 0.0004). In both groups, bradykinin caused dose-dependent increases in blood flow and local release of plasma t-PA antigen and activity (P < 0.005 for all). Both the plasma t-PA/PAI-1 ratios and the net release of active t-PA were markedly reduced in pregnant women (P < 0.05 for both). Area under the curve for net active t-PA release was reduced by 36%., Conclusions: Pregnancy is associated with major perturbations of endogenous fibrinolytic capacity with an overwhelming increase in plasma PAI-1 concentrations and an inadequate release of active t-PA. These prothrombotic effects may, in part, explain the increased risk of arterial and venous thrombosis in pregnant women.
- Published
- 2009
- Full Text
- View/download PDF
35. An update on the assessment and management of the risk of transmission of variant Creutzfeldt-Jakob disease by blood and plasma products.
- Author
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Turner ML and Ludlam CA
- Subjects
- Animals, Blood Component Transfusion adverse effects, Consumer Product Safety, Creutzfeldt-Jakob Syndrome prevention & control, Humans, PrPSc Proteins analysis, Risk Assessment methods, Risk Management methods, Creutzfeldt-Jakob Syndrome transmission, Public Health, Transfusion Reaction
- Abstract
There have been four highly probable instances of variant Creutzfeldt-Jakob disease (vCJD) transmission by non-leucocyte depleted red cell concentrates and it is now clear that the infectious agent is transmissible by blood components. To date there in no reported evidence that the infectious agent has been transmitted by fractionated plasma products, e.g. factor VIII concentrate. This review outlines current and potential risk management strategies including donor deferral criteria, the potential for donor screening, blood component processing and prion reduction filters, plasma product manufacture and the difficulties in identification and notification of those considered 'at risk of vCJD for public health purposes'.
- Published
- 2009
- Full Text
- View/download PDF
36. Less severe bleeding in hemophilia B than in hemophilia A.
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Lowe GD and Ludlam CA
- Subjects
- Hemorrhage etiology, Humans, Severity of Illness Index, Hemophilia A pathology, Hemophilia B pathology, Hemorrhage diagnosis
- Published
- 2008
- Full Text
- View/download PDF
37. Vascular B1 kinin receptors in patients with congestive heart failure.
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Lang NN, Cruden NL, Tse GH, Bloomfield P, Ludlam CA, Fox KA, and Newby DE
- Subjects
- Adult, Aged, Angiotensin-Converting Enzyme Inhibitors administration & dosage, Angiotensin-Converting Enzyme Inhibitors adverse effects, Bradykinin analogs & derivatives, Bradykinin pharmacology, Bradykinin B1 Receptor Antagonists, Bradykinin B2 Receptor Antagonists, Cross-Over Studies, Double-Blind Method, Female, Heart Failure metabolism, Heart Failure physiopathology, Humans, Infusions, Intra-Arterial, Kallidin analogs & derivatives, Kallidin pharmacology, Middle Aged, Nitroprusside pharmacology, Receptor, Bradykinin B1 agonists, Receptor, Bradykinin B2 physiology, Regional Blood Flow drug effects, Tissue Plasminogen Activator blood, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Blood Pressure drug effects, Heart Failure drug therapy, Receptor, Bradykinin B1 physiology, Vasodilation drug effects
- Abstract
Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.
- Published
- 2008
- Full Text
- View/download PDF
38. Linking the world with training and research for improving haemophilia care.
- Author
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Srivastava A, Hoots WK, Soucie JM, and Ludlam CA
- Subjects
- Congresses as Topic, Delivery of Health Care trends, Education, Medical, Continuing trends, Hemophilia A epidemiology, Humans, Multicenter Studies as Topic, Quality of Life psychology, World Health Organization organization & administration, Biomedical Research trends, Delivery of Health Care standards, Education, Medical, Continuing standards, Hemophilia A therapy
- Published
- 2008
- Full Text
- View/download PDF
39. Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans.
- Author
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Gudmundsdóttir IJ, Lang NN, Boon NA, Ludlam CA, Webb DJ, Fox KA, and Newby DE
- Subjects
- Adult, Epoprostenol metabolism, Female, Humans, Male, Nitric Oxide metabolism, Pilot Projects, Platelet Activation, Potassium Channels, Calcium-Activated metabolism, Tissue Plasminogen Activator metabolism, Vasoconstriction, Vasodilation, Atherosclerosis physiopathology, Endothelium, Vascular physiopathology, Receptor, PAR-1 metabolism, Receptors, Thrombin metabolism, Thrombin metabolism
- Abstract
Objectives: The purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1 (PAR-1) activation in vivo in man., Background: Thrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man., Methods: Dorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the "NO clamp" (L-N(G)-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively., Results: Endothelial denudation did not affect PAR-1-evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition., Conclusions: Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.
- Published
- 2008
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- View/download PDF
40. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV.
- Author
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Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, Lee CA, Ludlam CA, and Williams M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Creutzfeldt-Jakob Syndrome complications, Creutzfeldt-Jakob Syndrome mortality, Follow-Up Studies, Hemophilia A complications, Hemophilia B complications, Hemorrhage complications, Hemorrhage mortality, Hodgkin Disease complications, Hodgkin Disease mortality, Humans, Infant, Infant, Newborn, Liver Diseases complications, Liver Diseases mortality, Male, Middle Aged, Myocardial Ischemia complications, Myocardial Ischemia mortality, Retrospective Studies, United Kingdom, HIV Infections, Hemophilia A mortality, Hemophilia B mortality, Life Expectancy
- Abstract
Since the 1970s, mortality in the hemophilia population has been dominated by human immunodeficiency virus (HIV) and few reports have described mortality in uninfected individuals. This study presents mortality in 6018 people with hemophilia A or B in the United Kingdom during 1977 to 1998 who were not infected with HIV, with follow-up until January 1, 2000. Given disease severity and factor inhibitor status, all-cause mortality did not differ significantly between hemophilia A and hemophilia B. In severe hemophilia, all-cause mortality did not change significantly during 1977 to 1999. During this period, it exceeded mortality in the general population by a factor of 2.69 (95% confidence interval [CI]: 2.37-3.05), and median life expectancy in severe hemophilia was 63 years. In moderate/mild hemophilia, all-cause mortality did not change significantly during 1985 to 1999, and median life expectancy was 75 years. Compared with mortality in the general population, mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischemic heart disease it was lower, at only 62% (95% CI: 51%-76%) of general population rates, and for 14 other specific causes it did not differ significantly from general population rates. There was no evidence of any death from variant Creutzfeldt-Jakob disease or from conditions that could be confused with it.
- Published
- 2007
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41. Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease.
- Author
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Robinson SD, Ludlam CA, Boon NA, and Newby DE
- Subjects
- Analysis of Variance, Biomarkers analysis, Cohort Studies, Coronary Angiography, Coronary Disease diagnostic imaging, Coronary Disease mortality, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Infusions, Intra-Arterial, Male, Plasminogen Activator Inhibitor 1 analysis, Predictive Value of Tests, Probability, Prospective Studies, Severity of Illness Index, Survival Analysis, Tissue Plasminogen Activator analysis, Treatment Outcome, Coronary Disease drug therapy, Plasminogen Activator Inhibitor 1 metabolism, Substance P administration & dosage, Tissue Plasminogen Activator metabolism
- Abstract
Objective: The endothelium-derived fibrinolytic factor tissue plasminogen activator (t-PA) is a major determinant of vessel patency after coronary plaque rupture and thrombosis. We assessed whether endothelial fibrinolytic capacity predicts atherothrombotic events in patients with coronary heart disease., Methods and Results: Plasma t-PA and plasminogen activator inhibitor (PAI)-1 concentrations were measured during intrabrachial substance P infusion in 98 patients with angiographically proven stable coronary heart disease. Forearm blood flow was measured during infusion of substance P and sodium nitroprusside. Cardiovascular events (cardiovascular death, myocardial infarction [MI], ischemic stroke [CVA], and emergency hospitalization for unstable angina) were determined during 42 months of follow-up. Patients experiencing a cardiovascular event (n=19) had similar baseline characteristics to those free of events. Substance P caused a dose-dependent increase in plasma t-PA concentrations (P<0.001). However, net t-PA release was 72% lower in the patients who experienced death, MI, or CVA, and 48% lower in those who suffered death, MI, CVA or hospitalization for unstable angina (P<0.05). Major adverse cardiovascular events were most frequent in those with the lowest fibrinolytic capacity (P=0.03 for trend); patients with the lowest quartile of t-PA release had the highest rate of adverse events (P=0.01)., Conclusion: Endothelial fibrinolytic capacity, as measured by stimulated t-PA release, predicts the future risk of adverse cardiovascular events in patients with coronary heart disease. We suggest that endothelial fibrinolytic capacity is a powerful novel determinant of cardiovascular risk.
- Published
- 2007
- Full Text
- View/download PDF
42. Plasma microparticles and vascular disorders.
- Author
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Lynch SF and Ludlam CA
- Subjects
- Blood Coagulation Factors metabolism, Endothelium, Vascular pathology, Humans, Leukocytes pathology, Phospholipids metabolism, Plasma, Platelet Activation, Signal Transduction physiology, Vascular Diseases pathology, Vascular Diseases blood
- Abstract
Microparticles are circulating, phospholipid rich, submicron particles released from the membranes of endothelial cells, platelets, leucocytes and erythrocytes. Investigation into their biological activity has revealed diverse actions in coagulation, cell signalling and cellular interactions. These actions are mediated through their phospholipid rich surfaces and the expression of cell surface molecules which reflect their cell of origin and its state of activation. Microparticle numbers are reported to be elevated in a number of conditions where vascular dysfunction and inflammation are important pathophysiological mechanisms, for example coronary artery disease or thrombotic microangiopathies. Currently, there are a variety of different methods used for the quantitation of circulating microparticles; however with standardisation their assessment may prove to be of clinical value, reflecting the state of the vasculature. Knowledge of the functional properties of microparticles will contribute to our understanding of the mechanisms underlying vascular dysfunction and prothrombotic states.
- Published
- 2007
- Full Text
- View/download PDF
43. Tissue plasminogen activator genetic polymorphisms do not influence tissue plasminogen activator release in patients with coronary heart disease.
- Author
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Robinson SD, Ludlam CA, Boon NA, and Newby DE
- Subjects
- Aged, Female, Fibrinolysis genetics, Gene Deletion, Genotype, Humans, Male, Middle Aged, Nitroprusside pharmacology, Substance P pharmacology, Tissue Plasminogen Activator physiology, Coronary Disease genetics, Coronary Disease pathology, Polymorphism, Genetic, Tissue Plasminogen Activator genetics, Tissue Plasminogen Activator metabolism
- Abstract
Objectives: To determine if polymorphisms of the tissue plasminogen activator (t-PA) gene influence acute endogenous t-PA release in patients with coronary heart disease (CHD)., Methods: Forearm blood flow and plasma t-PA concentrations were measured in response to intra-brachial infusion of substance P and sodium nitroprusside in 96 patients with stable CHD. Genotyping was performed using a Taqman polymerase chain reaction assay specifically designed to detect the polymorphisms of interest: (i) Alu-repeat insertion/deletion sequence; (ii) C-->T substitution in an upstream enhancer region (-7351 C/T); (iii) T-->C in exon 6 (20 099 T/C); and (iv) T-->A (27 445 T/A) in intron 10., Results: Substance P and sodium nitroprusside caused dose-dependent increases in forearm blood flow in all patients (P < 0.001 for all) that were independent of the four genetic polymorphisms. Similarly, there were no differences in basal plasma t-PA antigen concentrations or net t-PA release between genotypes. Compared to non-smokers, smokers exhibited impaired substance P-induced vasodilatation (P < 0.001) and t-PA release (P = 0.05)., Conclusions: Despite confirming our previous findings in cigarette smokers, we have found no effect of polymorphisms of the t-PA gene on two complementary aspects of endothelial function. We conclude that genetic variation of the t-PA locus is unlikely to have a major influence on acute t-PA release in subjects with established CHD.
- Published
- 2006
- Full Text
- View/download PDF
44. Proposal to establish a European Association for Hemophilia and Allied Disorders.
- Author
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Ludlam CA and Mannucci PM
- Subjects
- Blood Coagulation Disorders, Financing, Organized, Humans, International Cooperation, Research economics, Societies, Workforce, Hemophilia A, Research trends
- Published
- 2006
- Full Text
- View/download PDF
45. Vascular and fibrinolytic effects of intra-arterial tumour necrosis factor-alpha in patients with coronary heart disease.
- Author
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Robinson SD, Dawson P, Ludlam CA, Boon NA, and Newby DE
- Subjects
- Acute Disease, Adult, Aged, C-Reactive Protein metabolism, Coronary Disease physiopathology, Cross-Over Studies, Cytokines blood, Double-Blind Method, Endothelium, Vascular physiopathology, Female, Forearm blood supply, Humans, Inflammation Mediators blood, Male, Middle Aged, Plasminogen Activator Inhibitor 1 blood, Regional Blood Flow, Tissue Plasminogen Activator blood, Vasculitis chemically induced, Vasculitis physiopathology, Vasodilation drug effects, Vasomotor System drug effects, Vasomotor System physiopathology, Coronary Disease blood, Fibrinolysis drug effects, Tumor Necrosis Factor-alpha pharmacology, Vasculitis blood
- Abstract
Elevated plasma t-PA (tissue plasminogen activator) and serum CRP (C-reactive protein) concentrations are associated with an adverse cardiovascular risk. In the present study, we investigated whether acute local inflammation causes vascular dysfunction and influences t-PA release in patients with stable coronary heart disease. Serum CRP, plasma t-PA and PAI-1 (plasminogen activator inhibitor type 1) concentrations were determined in 95 patients with stable coronary heart disease. A representative subpopulation of 12 male patients received an intra-brachial infusion of TNF-alpha (tumour necrosis factor-alpha) and saline placebo using a randomized double-blind cross-over study design. Forearm blood flow and plasma fibrinolytic and inflammatory variables were measured. Serum CRP concentrations correlated with plasma t-PA concentrations (r=0.37, P<0.001) and t-PA/PAI-1 ratio (r=-0.21, P<0.05). Intra-arterial TNF-alpha caused a rise in t-PA concentrations (P<0.001) without affecting blood flow or PAI-1 concentrations. TNF-alpha pretreatment impaired acetylcholine- and sodium nitroprusside-induced vasodilatation (P<0.001 for both) whilst doubling bradykinin-induced t-PA release (P=0.006). In patients with stable coronary heart disease, plasma fibrinolytic factors correlate with a systemic inflammatory marker and local vascular inflammation directly impairs vasomotor function whilst enhancing endothelial t-PA release. We suggest that the adverse prognosis associated with elevated plasma t-PA concentrations relates to the underlying causative association with vascular inflammation and injury.
- Published
- 2006
- Full Text
- View/download PDF
46. Phosphodiesterase type 5 inhibition does not reverse endothelial dysfunction in patients with coronary heart disease.
- Author
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Robinson SD, Ludlam CA, Boon NA, and Newby DE
- Subjects
- 3',5'-Cyclic-GMP Phosphodiesterases, Coronary Disease physiopathology, Cross-Over Studies, Cyclic Nucleotide Phosphodiesterases, Type 5, Double-Blind Method, Endothelium, Vascular physiopathology, Fibrinolysis drug effects, Forearm blood supply, Humans, Male, Middle Aged, Phosphoric Diester Hydrolases, Purines, Sildenafil Citrate, Sulfones, Tissue Plasminogen Activator metabolism, Coronary Disease drug therapy, Endothelium, Vascular drug effects, Phosphodiesterase Inhibitors therapeutic use, Piperazines therapeutic use
- Abstract
Objectives: To investigate whether sildenafil citrate, a selective phosphodiesterase type 5 inhibitor, may improve endothelial vasomotor and fibrinolytic function in patients with coronary heart disease., Design: Randomised double blind placebo controlled crossover study., Patients and Methods: 16 male patients with coronary heart disease and eight matched healthy men received intravenous sildenafil or placebo. Bilateral forearm blood flow and fibrinolytic parameters were measured by venous occlusion plethysmography and blood sampling in response to intrabrachial infusions of acetylcholine, substance P, sodium nitroprusside, and verapamil., Main Outcome Measures: Forearm blood flow and acute release of tissue plasminogen activator., Results: Mean arterial blood pressure fell during sildenafil infusion from a mean (SEM) of 92 (1) to 82 (1) mm Hg in patients and from 94 (1) to 82 (1) mm Hg in controls (p < 0.001 for both). Sildenafil increased endothelium independent vasodilatation with sodium nitroprusside (p < 0.05) but did not alter the blood flow response to acetylcholine or verapamil in patients or controls. Substance P caused a dose dependent increase in plasma tissue plasminogen activator antigen concentrations (p < 0.01) that was unaffected by sildenafil in either group., Conclusions: Sildenafil does not improve peripheral endothelium dependent vasomotor or fibrinolytic function in patients with coronary heart disease. Phosphodiesterase type 5 inhibitors are unlikely to reverse the generalised vascular dysfunction seen in patients with coronary heart disease.
- Published
- 2006
- Full Text
- View/download PDF
47. Plasma TAFI and soluble CD40 ligand do not predict reperfusion following thrombolysis for acute myocardial infarction.
- Author
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Cruden NL, Graham C, Harding SA, Ludlam CA, Fox KA, and Newby DE
- Subjects
- Adult, Aged, Aged, 80 and over, C-Reactive Protein metabolism, Female, Humans, Male, Middle Aged, Plasminogen Activator Inhibitor 1 blood, Solubility, Time Factors, Tissue Plasminogen Activator blood, CD40 Ligand blood, Carboxypeptidase B2 blood, Myocardial Infarction blood, Myocardial Reperfusion, Thrombolytic Therapy
- Abstract
Introduction: Thrombolytic therapy fails to achieve reperfusion in almost a third of patients with acute myocardial infarction. Thrombin activatable fibrinolysis inhibitor (TAFI) and soluble CD40 ligand (sCD40L) are novel endogenous fibrinolytic and atherothrombotic factors that determine clot stability. We investigated whether admission plasma thrombin activatable fibrinolysis inhibitor (TAFI) and soluble CD40 ligand (sCD40L) concentrations predicted reperfusion following thrombolytic therapy in patients with acute myocardial infarction., Materials and Methods: Prior to administration of thrombolytic therapy, venous blood was collected from 110 patients presenting with acute ST segment elevation myocardial infarction and plasma assayed for tissue plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor type-1 antigen (PAI-1), TAFI antigen and activity, C-reactive protein (CRP) and sCD40L concentrations. Reperfusion was determined using continuous ST segment monitoring., Results: Reperfusion occurred in 77 (70%) patients with a mean treatment to reperfusion time of 83 +/- 46 min. Peak creatine kinase was significantly lower in patients who reperfused (1578 +/- 1199 versus 2200 +/- 1744 U/L; P < 0.05) and correlated with time to reperfusion (r = 0.44 [95% CI: 0.23 - 0.61], P = 0.0001). There was a modest correlation between plasma TAFI antigen and activity (r = 0.3 [95% CI: 0.04 - 0.53]; P < 0.05). There were no significant associations between coronary reperfusion and plasma concentrations of t-PA, PAI-1, TAFI, CRP or sCD40L., Conclusions: Systemic plasma TAFI, sCD40L and CRP concentrations do not predict reperfusion in patients receiving thrombolytic therapy for acute ST elevation myocardial infarction.
- Published
- 2006
- Full Text
- View/download PDF
48. Managing the risk of transmission of variant Creutzfeldt Jakob disease by blood products.
- Author
-
Ludlam CA and Turner ML
- Subjects
- Animals, Blood microbiology, Blood Donors, Blood Transfusion methods, Creutzfeldt-Jakob Syndrome prevention & control, Disease Transmission, Infectious prevention & control, Humans, Prion Diseases transmission, Creutzfeldt-Jakob Syndrome transmission, Transfusion Reaction
- Abstract
Whereas plasma-derived clotting factor concentrates now have a very good safety record for not being infectious for lipid enveloped viruses, concern has arisen about the possibility that prion diseases might be transmitted by blood products. There is epidemiological evidence that classical sporadic Creutzfeld Jakob disease (CJD) is not transmitted by blood transfusion. There is now good evidence that the abnormal prion associated with variant CJD can be transmitted by transfusion of fresh blood components and infect recipients. To reduce the risk of the pathological prion in the UK infecting recipients of clotting factor concentrates, these are now only manufactured from imported plasma collected from countries where there has not been bovine spongiform encephalopathy (BSE) in cattle and the risk of variant CJD in the population is, therefore, considered negligible. The safety of these concentrates is also enhanced because prion protein is, to an appreciable extent, excluded by the manufacturing process from the final product. To help reduce the chance of prion transmission by fresh blood products, donations are leucodepleted, there is increasing use of imported fresh frozen plasma (especially for treating children) and potential donors, who have been recipients of blood since 1980 (the beginning of the BSE epidemic in cattle) are deferred.
- Published
- 2006
- Full Text
- View/download PDF
49. Management of acquired von Willebrand's syndrome in a patient requiring major surgery.
- Author
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Maddox JM, Anderson JA, Plews D, and Ludlam CA
- Subjects
- Blood Loss, Surgical prevention & control, Carcinoma, Transitional Cell complications, Factor VIII therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Male, Middle Aged, Plasma Exchange methods, Treatment Outcome, Urinary Bladder Neoplasms complications, von Willebrand Factor therapeutic use, Carcinoma, Transitional Cell surgery, Urinary Bladder Neoplasms surgery, von Willebrand Diseases drug therapy
- Abstract
We present the case of a patient with acquired von Willebrand's syndrome and a monoclonal gammopathy of undetermined significance who required cystectomy for relapsed transitional cell carcinoma (TCC) of the bladder. We demonstrated that infused von Willebrand factor (VWF) containing factor VIII concentrates had an unacceptably short half-life, but that this was significantly prolonged following combined therapy with plasma exchange and intravenous immunoglobulin (IVIgG). This approach was successfully utilized peri-operatively, with the total surgical blood loss less than would be expected even for a haemostatically normal patient. Trough VWF antigen and Ristocetin co-factor activity levels fell on the second postoperative day and we therefore administered further IVIgG. Levels again fell on the fifth postoperative day with the development of a Staphylococcus aureus septicaemia. At this point bleeding occurred from a surgical drain site requiring 'factor VIII inhibitor bypass activity' to secure haemostasis while further plasma exchange and IVIgG were administered. Now 5 years later, there is no evidence of recurrence of the TCC or progression of the monoclonal gammopathy.
- Published
- 2005
- Full Text
- View/download PDF
50. Inhibition of thrombin activatable fibrinolysis inhibitor augments fibrinolysis in human whole blood.
- Author
-
Cruden NL, Lawes L, Masson P, Robinson SD, Ludlam CA, and Newby DE
- Subjects
- Adult, Humans, Male, Plant Proteins pharmacology, Protease Inhibitors, Thrombelastography, Tissue Plasminogen Activator pharmacology, Carboxypeptidase B2 antagonists & inhibitors, Fibrinolysis drug effects
- Published
- 2005
- Full Text
- View/download PDF
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