Publications by authors named "Kiran Parmar"

24 Publications

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Coagulation derangement and risk factors for valve thrombosis following transcatheter aortic valve implantation.

Open Heart 2021 Jun;8(1)

Cardiovascular Division, School of Life Science and Medicine, King's College London, London, UK.

Aims: Durability of transcatheter aortic valve implantation (TAVI) is key to its expansion. We sought to identify incidence of valve thrombosis and predictors of valve thrombosis in our single centre with associated coagulation testing pre-TAVI and post-TAVI.

Methods And Results: This single-centre observational study comprised patients undergoing transfemoral TAVI discussed in the Heart Team meeting . Patients were followed up with echocardiography at 120 days to identify incidence of elevated transvalvular gradient and multivariable analysis was performed to identify factors associated with an increased odds of developing valve thrombosis. In addition, 11 patients underwent baseline, day 1 and day 120 post-TAVI coagulation testing. Between August 2017 and August 2019, 437 consecutive patients underwent transfemoral TAVI. Of these patients, 207/437 (47.4%) had 3-month follow-up echo data available and were analysed. Of these patients, 26/207 (12.6%) had elevated transvalvular gradients. These patients tended to be younger (80±14 vs 83±6 years; p=0.047) with a lower ejection fraction (49±13 vs 54%±11%; p=0.021), with a greater proportion of the population experiencing atrial fibrillation (14/21, 54% vs 68/181, 38%; p=0.067). Following multivariable analysis, there remained a trend towards higher eccentricity index associated with elevated gradients. Baseline (pre-TAVI) elevation of thrombin antithrombin levels (56±63; reference range 1.0-4.1 ng/L) and PF 1+2 (791±632; reference range 69-229 ng/mL) normalised at 120 days post-TAVI CONCLUSION: This study demonstrated that in the cohort of patients undergoing transfemoral TAVI in our centre: younger age, poor ejection fraction, atrial fibrillation and increased baseline eccentricity of the aortic valve annulus were present to a greater extent in patients exhibiting elevated transvalvular gradients at 3-month follow-up. Further work is required to delineate the extent of coagulation derangement and confirm predictors of thrombosis.
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http://dx.doi.org/10.1136/openhrt-2020-001496DOI Listing
June 2021

Degradation of the Endothelial Glycocalyx Contributes to Metabolic Acidosis in Children Following Cardiopulmonary Bypass Surgery.

Pediatr Crit Care Med 2021 May 4. Epub 2021 May 4.

Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, United Kingdom. Thrombosis and Vascular Biology Research Group, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Institute of Women and Children's Health, King's College London, St Thomas' Hospital, London, United Kingdom. Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. Department of Intensive Care, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

Objectives: Cardiopulmonary bypass surgery is complicated by metabolic acidosis, microvascular dysfunction, and capillary leak. The glycocalyx-a layer of proteins and sugars lining the vascular endothelium-is degraded during cardiopulmonary bypass. We aimed to describe the kinetics of glycocalyx degradation during and following cardiopulmonary bypass. We hypothesized that cleavage of negatively charged fragments of the glycocalyx would directly induce metabolic acidosis through changes in the strong ion gap (defined using Stewart's physicochemical approach to acid-base chemistry). We also investigated whether glycocalyx degradation was associated with failure of endothelial function and cardiovascular dysfunction.

Design: Single-center prospective cohort study.

Setting: Twenty-two bed surgical/medical PICU.

Patients: Twenty-seven term infants and children requiring cardiopulmonary bypass surgery for the correction/palliation of congenital heart disease.

Interventions: None.

Measurements And Main Results: We recruited 27 patients, 5 days to 57 months old. We prospectively sampled plasma prior to, during, and following cardiopulmonary bypass at predefined time points. We measured plasma concentrations of interleukin-6 (inflammatory marker), heparan sulfate (negatively charged glycocalyx glycosaminoglycan), and syndecan-1 (neutrally charged glycocalyx protein). We defined the following outcome measures: metabolic acidosis (strong ion gap), renal dysfunction (fold change in creatinine), capillary leak (fluid bolus volume), cardiovascular dysfunction (Vasoactive Inotropic Score), and length of ventilation. In linear regression models, maximum measured heparan sulfate concentration (negatively charged) was associated with metabolic acidosis (p = 0.016), renal dysfunction (p = 0.009), and length of ventilation (p = 0.047). In contrast, maximum measured syndecan-1 concentration (neutrally charged) was not associated with these clinical endpoints (p > 0.30 for all).

Conclusions: Our data show that metabolic acidosis (increased strong ion gap) is associated with plasma concentration of heparan sulfate, a negatively charged glycosaminoglycan cleaved from the endothelial glycocalyx during cardiopulmonary bypass. In addition, cleavage of heparan sulfate was associated with renal dysfunction, capillary leak, and global markers of cardiovascular dysfunction. These data highlight the importance of designing translational therapies to protect the glycocalyx in cardiopulmonary bypass.
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http://dx.doi.org/10.1097/PCC.0000000000002746DOI Listing
May 2021

Individualized, Intraoperative Dosing of Fibrinogen Concentrate for the Prevention of Bleeding in Neonatal and Infant Cardiac Surgery Using Cardiopulmonary Bypass (FIBCON): A Phase 1b/2a Randomized Controlled Trial.

Circ Cardiovasc Interv 2020 12 20;13(12):e009465. Epub 2020 Nov 20.

Department of Paediatric Intensive Care, Evelina London Children's Hospital, United Kingdom (K.S., J.H., A.G.N., S.M.T.).

Background: Mediastinal bleeding is common following pediatric cardiopulmonary bypass surgery for congenital heart disease. Fibrinogen concentrate (FC) represents a potential therapy for preventing bleeding.

Methods: We performed a single-center, phase 1b/2a, randomized controlled trial on infants 2.5 to 12 kg undergoing cardiopulmonary bypass surgery, aimed at (1) demonstrating the feasibility of an intraoperative point-of-care test, rotational thromboelastometry, to screen out patients at low risk of postoperative bleeding and then guide individualized FC dosing in high-risk patients and (2) determining the dose, safety, and efficacy of intraoperative FC supplementation. Screening occurred intraoperatively 1-hour before bypass separation using the rotational thromboelastometry variable fibrinogen thromboelastometry maximum clot firmness (FibTEM-MCF; fibrinogen contribution to clot firmness). If FibTEM-MCF ≥7 mm, patients entered the monitoring cohort. If FibTEM-MCF ≤6 mm, patients were randomized to receive FC/placebo (2:1 ratio). Individualized FC dose calculation included weight, bypass circuit volume, hematocrit, and intraoperative measured and desired FibTEM-MCF. The coprimary outcomes, measured 5 minutes post-FC administration were FibTEM-MCF (desired range, 8-13 mm) and fibrinogen levels (desired range, 1.5-2.5 g/L). Secondary outcomes were thrombosis and thrombosis-related major complications and postoperative 24-hour mediastinal blood loss.

Results: We enrolled 111 patients (cohort, n=21; FC, n=60; placebo, n=30); mean (SD) age, 6.4 months (5.8); weight, 5.9 kg (2.0). Intraoperative rotational thromboelastometry screening effectively excluded low-risk patients, in that none in the cohort arm (FibTEM-MCF, ≥7 mm) demonstrated clinically significant early postoperative bleeding (>10 mL/kg per 4 hours). Among randomized patients, the median (range) FC administered dose was 114 mg/kg (51-218). Fibrinogen levels increased from a mean (SD) of 0.91 (0.22) to 1.7 g/L (0.41). The postdose fibrinogen range was 1.2 to 3.3 g/L (72% within the desired range). The corresponding FibTEM-MCF values were as follows: pre-dose, 5.3 mm (1.9); post-dose, 13 mm (3.2). Ten patients (8 FC and 2 placebo) exhibited 12 possible thromboses; none were clearly related to FC. There was an overall difference in mean (SD) 24-hour mediastinal drain loss: cohort, 12.6 mL/kg (6.4); FC, 11.6 mL/kg (5.2); placebo, 17.1 mL/kg (14.3; ANOVA =0.02).

Conclusions: Intraoperative, individualized dosing of FC appears feasible. The need for individualized dosing is supported by the finding that a 4-fold variation in FC dose is required to achieve therapeutic fibrinogen levels. Registration: URL: https://eudract.ema.europa.eu/; Unique identifier: 2013-003532-68. URL: https://www.isrctn.com/; Unique identifier: 50553029.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009465DOI Listing
December 2020

A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield.

Transfusion 2020 Jun 1;60 Suppl 3:S52-S61. Epub 2020 Jun 1.

St Thomas' Hospital, Thrombosis & Haemophilia Centre & Thrombosis and Vascular Biology Group, London, UK.

Background: Acute trauma coagulopathy (ATC) after military trauma has not been comprehensively studied. ATC is defined as a prolonged prothrombin time ratio (PTr) or reduced clot amplitude (A5) in viscoelastic testing. Compared to civilian trauma, military trauma has more injuries from explosions and gunshot wounds (GSWs), potentially leading to a different pathophysiology for traumatic coagulopathy. This study aimed to characterize military ATC on admission to a military hospital in Afghanistan and to explore any differences due to the mechanism of injury.

Methods: Severely injured military casualties were enrolled in the study. Blood samples were taken on admission and after routine testing, waste plasma was prepared, frozen, and transported to the United Kingdom for in-depth hemostatic analysis.

Results: Seventy-seven percent of casualties had ATC defined by a PTr greater than 1.2 and 19% when defined by rotational thromboelastometry (ROTEM) A5 less than 36 mm. Coagulation factor depletion correlated with degree of shock, particularly factor V (p < 0.01), factor X (p < 0.01), and fibrinogen levels (p < 0.01). Thrombin generation was well preserved. Fibrinolytic biomarkers were raised correlating with the degree of shock (p < 0.01), and 8% of casualties had hyperfibrinolysis on ROTEM analysis. Plasmin-antiplasmin complexes (p < 0.01) and d-dimer levels (p = 0.01) were higher and clot firmness lower (p = 0.02) in those injured by explosion compared to GSW's.

Conclusions: ATC was present and correlated with shock, similar to civilian trauma. Thrombin generation remained adequate. Fibrinogen and factor V levels were disproportionately low but still sufficient to allow clot formation. Fibrinolysis is a key feature, probably due to a tissue plasminogen activator surge at the time of injury. Blast injuries are associated with a greater activation of fibrinolysis than GSWs.
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http://dx.doi.org/10.1111/trf.15658DOI Listing
June 2020

Alterations in fibrin formation and fibrinolysis in early onset-preeclampsia: Association with disease severity.

Eur J Obstet Gynecol Reprod Biol 2019 Oct 25;241:19-23. Epub 2019 Jul 25.

Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland; SPHERE Research Group, Conway Institute, University College Dublin, Ireland; The Rotunda Hospital, Parnell Square, Dublin, Ireland; Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland; School of Medicine, University College Dublin, Ireland. Electronic address:

Objective: ; Early-onset preeclampsia is a rare pregnancy-specific disorder associated with significantly increased maternal and fetal morbidity and mortality. Whilst it is known that even normotensive pregnancies are associated with changes in clot formation and dissolution, the nature of how these changes differ in those with early onset preeclampsia has not been well established. We sought to evaluate parameters of fibrin formation and fibrinolysis in individuals with early onset preeclampsia in comparison to both pregnant and non-pregnant controls. Furthermore, such parameters were correlated with markers of disease severity in this patient cohort, including the presence of multiorgan involvement, the rate of disease progression and the extent of the anti-angiogenic state in this condition.

Study Design: ; Patients with early onset preeclampsia (N = 20) and both pregnant (N = 16) and non -pregnant (N = 16) controls were recruited from the cohort at a large urban maternity hospital which saw over 15,000 deliveries during the study period. Platelet poor plasma was prepared from collected whole blood and analysed for parameters of fibrin formation and fibrinolysis (lagtime to and rate of fibrin formation; PAI-1; PAI-2; D-dimer; plasmin-antiplasmin; tPA) in addition to markers of angiogenesis (sFLT-1; Endoglin) using commercially available specific immunoassays.

Results: ; The maximum rate of fibrin formation as well as PAI-1, PAI-2 and D-dimer levels were all significantly increased in those with early onset preeclampsia and pregnant controls when compared to non-pregnant controls without significant differences between the 2 former groups. Plasmin-antiplasmin levels were significantly reduced in a similar manner. tPA levels were significantly elevated in EOP compared to both pregnant and non-pregnant controls. EOP was associated with significantly increased anti-angiogenic factors (sFLT-1; Endoglin) when compared to both pregnant and non-pregnant controls.

Conclusion: ; Markers of fibrin formation and fibrinolysis are significantly alerted in early onset preeclampsia; furthermore, certain markers correlate with disease severity in this patient cohort.
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http://dx.doi.org/10.1016/j.ejogrb.2019.07.035DOI Listing
October 2019

Haemostatic Changes in Five Patients Infected with Ebola Virus.

Viruses 2019 07 15;11(7). Epub 2019 Jul 15.

Chemical Biological & Radiological Division, Dstl, Porton Down SP4 0JQ, UK.

Knowledge on haemostatic changes in humans infected with Ebola virus is limited due to safety concerns and access to patient samples. Ethical approval was obtained to collect plasma samples from patients in Sierra Leone infected with Ebola virus over time and samples were analysed for clotting time, fibrinogen, and D-dimer levels. Plasma from healthy volunteers was also collected by two methods to determine effect of centrifugation on test results as blood collected in Sierra Leone was not centrifuged. Collecting plasma without centrifugation only affected D-dimer values. Patients with Ebola virus disease had higher PT and APTT and D-dimer values than healthy humans with plasma collected in the same manner. Fibrinogen levels in patients with Ebola virus disease were normal or lower than values measured in healthy people. Clotting times and D-dimer levels were elevated during infection with Ebola virus but return to normal over time in patients that survived and therefore could be considered prognostic. Informative data can be obtained from plasma collected without centrifugation which could improve patient monitoring in hazardous environments.
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http://dx.doi.org/10.3390/v11070647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669445PMC
July 2019

Rotational thromboelastometry alongside conventional coagulation testing in patients with Crimean-Congo haemorrhagic fever: an observational cohort study.

Lancet Infect Dis 2019 08 28;19(8):862-871. Epub 2019 Jun 28.

Haemostasis Research Unit, Guy's and St Thomas' Foundation Trust, London, UK.

Background: Data describing the coagulopathy of Crimean-Congo haemorrhagic fever are scarce. We did rotational thromboelastometry (ROTEM) and conventional coagulation testing in patients with Crimean-Congo haemorrhagic fever to increase our understanding of the coagulopathy of this infectious disease.

Methods: We did a prospective observational cohort study of adults aged 18 years and older and admitted to hospitals with PCR-confirmed Crimean-Congo haemorrhagic fever in Samsun and Tokat, Turkey. Demographic, clinical, and laboratory data were collected and blood samples for ROTEM analysis and coagulation testing were drawn at admission and during hospital admission and convalescence (up to 30 days after onset of illness). For the ROTEM analysis we recorded the following extrinsically activated ROTEM (EXTEM S) variables, with normal ranges indicated: clotting time (38-79 s), clot formation time (34-159 s), amplitude at 10 min after clotting time (43-65 mm), maximum clot firmness (50-72 mm), and maximum lysis (>15% at 1 h). The following fibrin-specific ROTEM (FIBTEM S) variables were also recorded: amplitude at 10 min after clotting time (normal range 7-23 mm) and maximum clot firmness (9-25 mm). Disease severity was assessed by Swanepoel criteria, severity grading score (SGS), and the severity scoring index (SSI), with mild disease defined as meeting no Swanepoel criteria, graded mild by SSI, and graded low risk by SGS.

Findings: Between May 27, 2015, and Aug 2, 2015, 65 patients with confirmed Crimean-Congo haemorrhagic fever were recruited and had blood taken at 110 time points. Most were male (40 [62%] of 65) with mild disease (49 [75%] of 65). Haemorrhage occurred in 13 (20%; 95% CI 11·1-31·8) of 65 patients and 23 (35%) of 65 received blood products (15 received fresh frozen plasma and eight received red blood cell concentrates), and 21 patients received platelet transfusions. At admission, the following EXTEM S variables differed significantly between mild cases and moderate to severe cases: median clotting time 56 s (range 42-81; IQR 48-64) versus 69 s (range 48-164; IQR 54-75; p=0·01); mean amplitude at 10 min after clotting time 45·1 mm (SD 7·0) versus 33·9 mm (SD 8·6; p<0·0001); median clot formation time 147 s (range 72-255; IQR 101-171) versus 197 s (range 98-418; IQR 156-296; p=0·006); and maximum clot firmness 54·4 mm (SD 7·2) versus 45·1 mm (SD 12·5; p=0·003). The EXTEM S variables were compared at different time points; maximum clot firmness (p=0·024) and amplitude at 10 min after clotting time (p=0·090) were lowest on days 4-6 of illness. We found no significant differences in FIBTEM variables between mild and moderate to severe cases (median amplitude at 10 min, 13 mm [range 8-20; IQR 11-15] vs 12 mm [range 6-25; IQR 10-15; p=0·68]; and median maximum clot firmness, 15 mm [range 9-60; IQR 13-21] vs 17 mm [range 7-39; IQR 13-23; p=0·21]); and no hyperfibrinolysis (maximum lysis >15%).

Interpretation: Coagulopathy of Crimean-Congo haemorrhagic fever is related to defects in clot development and stabilisation that are more marked in severe disease than in mild disease. The combination of normal and slightly deranged coagulation screens and FIBTEM results with the absence of hyperfibrinolysis suggests that the coagulopathy of Crimean-Congo haemorrhagic fever relates to platelet dysfunction.

Funding: Wellcome Trust, UK Ministry of Defence, and National Institute for Health Research Health Protection Research Unit.
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http://dx.doi.org/10.1016/S1473-3099(19)30112-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641897PMC
August 2019

A comparison of haemostatic biomarkers during low-risk patients undergoing cardiopulmonary bypass using either conventional centrifugal cell salvage or the HemoSep device.

Perfusion 2019 01 1;34(1):76-83. Epub 2018 Aug 1.

5 Cardiothoracic Surgery/Cardiac Surgical Research, The Rayne Institute, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, UK.

Background: Cardiac surgery using cardiopulmonary bypass (CPB) is associated with a coagulopathy due to haemodilution, thrombocytopenia and platelet dysfunction and the activation of coagulation and fibrinolysis, despite the use of large doses of unfractionated heparin. Conventional red cell salvage may exacerbate post-operative bleeding as plasma containing haemostatic factors is discarded. We hypothesized that a novel cell salvage device (HemoSep) may attenuate haemostatic changes associated with red cell salvage. We studied haemostatic markers following autologous transfusion from conventional cell salvage or the HemoSep device.

Methods: This randomised, controlled trial compared haemostatic markers in patients undergoing coronary artery bypass grafting or aortic valve replacement who received autologous blood returned from cell salvage (control) or HemoSep (study). Blood samples were taken pre-operatively, end of CPB, post-transfusion of salvaged blood and 3 hours post-operatively and analysed for full blood count (FBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer and endogenous thrombin potential (ETP).

Results: Fifty-four patients were recruited (n=28 control, n=26 study). Processed blood volume for transfusion was significantly (p<0.001) higher in the HemoSep group. In the HemoSep group, the PT was shorter (18.7±0.3 vs 19.9±0.3 sec; p<0.05) post-operatively and the aPTT was longer (48.6±3.8 vs 37.3±1.0 sec; p<0.01) following autologous transfusion. In the control group, D-dimer and ETP levels were higher (1903±424 vs.1088±151; p<0.05 and 739±46 vs. 394±60; p<0.001, respectively) following autologous transfusion.

Conclusions: Although centrifuged cell salvage is known to adequately haemoconcentrate and remove unwanted substrates and bacteriological contamination, the process can exacerbate coagulopathy. The HemoSep device demonstrated some increase in haemostatic markers when used in low-risk cardiac surgery patients.
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http://dx.doi.org/10.1177/0267659118789051DOI Listing
January 2019

The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium.

Br J Haematol 2018 03 23;180(5):694-704. Epub 2018 Jan 23.

School of Health and Related Research, University of Sheffield, Sheffield, UK.

This study aimed to estimate the diagnostic utility of biomarkers for suspected venous thromboembolism (VTE) in pregnancy and the puerperium. Research nurses/midwives collected blood samples from 310 pregnant/postpartum women with suspected pulmonary emboli (PE) and 18 with diagnosed deep vein thrombosis (DVT). VTE was diagnosed using imaging, treatment and adverse outcome data. Primary analysis was limited to women with conclusive imaging (36 with VTE, 247 without). The area under the curve (AUC) for each biomarker was: activated partial thromboplastin time 0·669 (95% confidence interval 0·570-0·768), B-type natriuretic peptide 0·549 (0·453-0·645), C-reactive protein 0·542 (0·445-0·639), Clauss fibrinogen 0·589 (0·476-0·701), D-Dimer (by enzyme-linked immunosorbent assay) 0·668 (0·561-0·776), near-patient D-Dimer 0·651 (0·545-0·758), mid-regional pro-atrial natriuretic peptide 0·524 (0·418-0·630), prothrombin fragment 1 + 2 0·562 (0·462-0·661), plasmin-antiplasmin complexes 0·639 (0·536-0·742), prothombin time 0·613 (0·508-0·718), thrombin generation lag time 0·702 (0·598-0·806), thrombin generation endogenous potential 0·559 (0·437-0·681), thrombin generation peak 0·596 (0·478-0·715), thrombin generation time to peak 0·655 (0·541-0·769), soluble tissue factor 0·531 (0·424-0·638) and serum troponin 0·597 (0·499-0·695). No diagnostically useful threshold for diagnosing or ruling out VTE was identified. In pregnancy and the puerperium, conventional and candidate biomarkers have no utility either for their negative or positive predictive value in the diagnosis of VTE.
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http://dx.doi.org/10.1111/bjh.15102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887890PMC
March 2018

The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies.

Rheumatology (Oxford) 2018 01;57(1):120-124

Thrombosis & Haemophilia Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Objectives: HCQ has been described as having a beneficial effect in patients with APS but its mechanism of action is unclear. We hypothesized that HCQ may have effects on subnormal angiogenesis, inflammation and haemostatic biomarkers seen in APS. The aim of our study was to assess laboratory markers [annexin A5 (AnxA5) anticoagulant activity, tissue factor (TF) levels, thromboelastography (TEG), CRP, Bb, C3a and VEGF] in HCQ-naïve patients with aPL at baseline and after commencing HCQ.

Methods: Twenty-two patients with aPL [20 female, 2 male, median age 55 (range 18-70) years] had blood taken pre- and 3 months after starting HCQ 200 mg daily.

Results: Soluble TF levels were significantly reduced comparing baseline and 3 months after HCQ commencement [401.8 (152.8) vs 300.9 (108) pg/ml (P = 0.010)]. No significant changes were found in the following [reported as pre- and post-HCQ commencement, mean (s.d.)]: AnxA5 anticoagulant ratio [187.1 (29.5) vs 193 (31) (P = 0.157)], anti-domain1 β2 glycoprotein1 IgG activity [1.8 (2) vs 1.2 (1.4) μg/ml (P = 0.105)], complement C3a-des-Arg [147.8 (84.5) vs 154.4 (88.1) ng/ml (P = 0.905)], complement Bb [1.3 (0.7) vs 1.1 (0.7) μg/ml (P = 0.422)], VEGF [68.8 (40) vs 59.4 (19.6) pg/ml (P = 0.454)] and CRP [7 (3.5) vs 7 (3.9) μg/ml (P = 0.917)]. TEG results including TEG reaction time, achievement of clot firmness, TEG maximum amplitude and TEG percentage lysis 30 and 60 min after maximum amplitude showed no significant difference.

Conclusion: HCQ significantly reduced soluble TF levels in patients with aPL. No significant change was observed in AnxA5 activity, anti-domain 1 IgG activity, TEG, CRP, complement Bb and C3a-des-Arg, and VEGF. Further studies of a larger patient cohort are needed.
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http://dx.doi.org/10.1093/rheumatology/kex378DOI Listing
January 2018

The utility of thromboelastography and thrombin generation in assessing the prothrombotic state of adults with sickle cell disease.

Thromb Res 2017 Oct 6;158:113-120. Epub 2017 Sep 6.

Department of Haematology, Guy's and St Thomas' Hospital, Westminster Bridge Road, Lambeth, London SE1 7EH, United Kingdom; Thrombosis and Vascular Biology Group Laboratory, Rayne Institute, Kings College London, 4th Floor Lambeth Wing, St Thomas' Hospital, Westminster Bridge Road, Lambeth, London SE1 7EH, United Kingdom. Electronic address:

Introduction: Previous studies have suggested a chronic hypercoagulable state in SCD, and that thrombosis also plays a role in the pathophysiology of sickle cell vaso-occlusive pain crises (VOC). Studies looking at thrombin generation have produced conflicting results. In this study we aimed to assess and compare whole blood thromboelastography (TEG) and plasma Calibrated Automated Thrombogram (CAT) in SCD versus healthy controls and in four different SCD subgroups.

Materials And Methods: In this prospective observational study, TEG and 1pM TF activated CAT assays were performed in citrated blood samples from 77 adult (18-66years old) SCD patients (HbSS and HbSB) and 22 healthy (HbAA) ethnically-matched controls.

Results And Conclusions: SCD was associated with a prothrombotic state in all TEG parameters. CAT results showed that the upslope of the CAT in SCD displayed a hypercoagulable state with shorter time to peak and higher velocity index, but the downslope was also faster leading to an overall lower endogenous thrombin potential (ETP) compared to healthy controls. TEG subgroup analyses showed that during VOC the prothrombotic state is greater compared to patients on disease ameliorating therapy. CAT did not display statistically significant differences between the SCD subgroups. This study shows that the prothrombotic state in SCD is best displayed with TEG, and suggests the hypercoagulable changes of SCD rely at least in part in the cellular components of blood, which can only be detected in whole blood assays.
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http://dx.doi.org/10.1016/j.thromres.2017.08.020DOI Listing
October 2017

An in vitro study of the effects of t-PA and tranexamic acid on whole blood coagulation and fibrinolysis.

J Clin Pathol 2017 Feb 21;70(2):154-161. Epub 2016 Jul 21.

Department of Thrombosis and Vascular Biology, Rayne Institute, London, UK.

Aims: Acute traumatic coagulopathy is characterised by fibrinolysis and low fibrinogen. It is unclear how much fibrinogenolysis contributes to reduce fibrinogen levels. The study aim was to: investigate in vitro the effects of tissue-plasminogen activator (t-PA) and tranexamic acid (TXA) on coagulation and fibrinolysis.

Methods: Whole blood was spiked with varying t-PA concentrations. Clauss fibrinogen levels and thrombelastography (TEG, Haemonetics) were performed, including functional fibrinogen level (FLEV). TXA effects were assessed using four TXA concentrations. Recorded parameters from kaolin activated TEG included maximal amplitude (MA), clot strength (G), percentage lysis (LY). Plasmin-antiplasmin complex (PAP), endogenous thrombin potential (ETP), prothrombin fragment 1+2 (PF1+2), factor V and factor VIII levels were all measured.

Results: t-PA induced fibrinolysis: it increased PAP and LY, but decreased MA and G. t-PA induced fibrinogenolysis, with a concentration-dependant decrease in fibrinogen from 2.7 (2.6-3.1) to 0.8 (0.8-0.9) g/L with 60 nM t-PA. FLEV and fibrinogen levels were well correlated. High t-PA doses increased PF1+2, decreased ETP of 19% and FVIII of 63% but not FV. TXA had no effect on plasmin generation as evidenced by no change in PAP. It corrected LY, MA and G and partly protected fibrinogen against fibrinogenolysis: 0.03 mg/mL TXA reduced the fibrinogen fall induced by t-PA 20 nM from 43% to 14%. TXA halved the FVIII fall and increased ETP.

Conclusions: t-PA induced plasminogen activation and fibrinogenolysis in a concentration-dependant manner. TXA did not affect plasmin activation but reduced fibrinogenolysis. These results suggest that TXA given early in bleeding patients may prevent fibrinogenolysis.
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http://dx.doi.org/10.1136/jclinpath-2016-203854DOI Listing
February 2017

Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.

J Pathol 2016 09;240(1):61-71

Division of Transplantation Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.4754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996338PMC
September 2016

An observational study of haemostatic changes, leptin and soluble endoglin during pregnancy in women with different BMIs.

Blood Coagul Fibrinolysis 2017 Jan;28(1):50-55

aDepartment of Anaesthesia, Royal Gwent Hospital, Newport bAcademic department of Anaesthesia, Critical Care and Resuscitation, Heart of England NHS Foundation Trust, Birmingham cDepartment of Thrombosis & Haemostasis, King's College and Thrombosis & Haemophilia Centre, Guy's & St Thomas' NHS Trust, London, United Kingdom dShanghai Institute of Planned Parenthood Research, Shanghai, China ePerioperative, Critical Care and Trauma Trials Group, School of Clinical and Experimental Medicine, University of Birmingham, United Kingdom.

Obesity increases the risk of venous thromboembolism (VTE) in pregnancy. The pathogenesis is hypothesized to be because of multiple factors including prothrombotic changes, but there has been minimal haemostatic research looking at the combined state of obesity and pregnancy. We aimed to determine whether variation in BMI in the third trimester of pregnancy was associated with prothrombotic changes. We recruited 110 women into four groups depending on their BMI at first antenatal appointment: normal, overweight, obese and morbidly obese. Women with increased risk of VTE, and/or receiving thromboprophylaxis, and/or more than 35 years and those in labour were excluded. Thromboelastography, platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, prothrombin fragment 1 + 2, free and total protein S, plasminogen activator inhibitor type 1, tissue plasminogen activator antigen, D-dimers, soluble endoglin and leptin levels were measured. There were no significant differences in haemostatic measures with changing BMI. There was a positive correlation between BMI and both platelet count (correlation coefficient r = 0.214, P = 0.036) and leptin (r = 0.435, P < 0.001), but only leptin had a significant association with BMI once adjusted for age, gestation and parity. Despite recruitment into the morbidly obese group being suboptimal, these findings suggest that in pregnancy, the increased risk of VTE seen in obese mothers is not mediated through increased prothrombotic changes, and thus the increased risk of VTE in obese pregnant women may be because of other mechanisms, for example endothelial dysfunction, inflammation and venous stasis.
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http://dx.doi.org/10.1097/MBC.0000000000000535DOI Listing
January 2017

A symbiotic approach to mentoring future academics.

Clin Teach 2013 Oct;10(5):337-8

Department of Medicine & Social Care Education, University of Leicester, UK.

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http://dx.doi.org/10.1111/tct.12042DOI Listing
October 2013

Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome.

Thromb Haemost 2012 Mar 11;107(3):423-9. Epub 2012 Jan 11.

Guy’s and St.Thomas’ NHS Foundation Trust, London, UK.

The antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Increased complement activation has been implicated in the pathogenesis of APS in animal models. It was our objective to evaluate complement activation in patients with aPL or primary antiphospholipid syndrome (PAPS). We measured complement activation products, fragments Bb and C3a-desArg by ELISA in 186 aPL/PAPS patients and 30 healthy controls. All patients with aPL had significantly increased levels of complement activation products. Fragment Bb levels (mean, 95% CI); (thrombotic APS 0.54 units/ml, 0.31-0.83, obstetric APS 0.60 units/ml,0.39-1.02, isolated aPL 0.48 units/ml, 0.29-0.85, overall 0.39 units/ml, 0.33-0.47) and C3a-desArg levels (mean, 95% CI): (thrombotic APS 261 ng/ml, 219-311, obstetric APS 308 ng/ml, 243-391, isolated aPL 258 ng/ml, 193-337, overall 225 ng/ml, 202-251) were significantly higher compared to controls (fragment Bb 0.06 units/ml, 0.03-0.11, C3a-desArg 69 ng/ml, 50-92). There were correlations between Fragment Bb and C3a-desArg levels in all patients with aPL. Receiver operator characteristic (ROC) analysis showed increased fragment Bb and C3a-desArg levels had strong associations with the presence of persistent lupus anticoagulant (area under ROC: Bb 0.89, and C3a-desArg 0.90), dual and triple aPL positivity (Bb 0.71-0.82, C3a-desArg 0.71-0.80) but not with high titre anti-cardiolipin antibodies (Bb 0.62, C3a-desArg 0.65), or anti β2-glycoprotein 1 antibodies (Bb 0.66, C3a-desArg 0.67). Complement activation is present in all patient groups within this large cohort of patients aPL. This suggests it may have a major role in the pathogenesis of APS and merits further study.
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http://dx.doi.org/10.1160/TH11-08-0554DOI Listing
March 2012

Quantification of forces required for stabbing with screwdrivers and other blunter instruments.

Int J Legal Med 2012 Jan 5;126(1):43-53. Epub 2011 Apr 5.

East Midlands Forensic Pathology Unit, University of Leicester, Leicester Royal Infirmary, Leicester, UK.

In the UK, stabbing is the most common cause of homicide. The weapons used include knives, swords, screwdrivers and glass shards. Quantifying the exact force used in a stabbing incident is considered to be a difficult area due to the large number of variables present, such as sharpness of weapon, angle of attack and relative movements of the people involved. Having quantifiable data would allow a forensic pathologist to make a more informed decision when it comes to answering the commonly posed question in court "what was the degree of force involved in the stabbing incident?" The answer to this question is considered significant in determining an alleged assailant's intent to cause harm. This paper presents results of the first detailed study relating geometry of screwdrivers to the forces required for penetration. Additionally, a range of other blunt weapons such as pens and chisels have also been studied. A silicone rubber-foam analogue has been used as the main skin simulant owing to it having similar mechanical properties to that of human skin and giving highly repeatable results. Different screwdrivers of varying shape and size have been tested (i.e. slotted, Phillips, posidriv and Torx), along with other implements including chisels and pens. The weapon geometry was characterised and related to the peak force required for penetration. Our results show that there is a direct correlation between the cross-sectional area of a screwdriver head and the amount of force required for penetration. Screwdrivers with larger cross-sectional areas require a significantly greater force to penetrate (forces in the region of 100-120 N) but "sharper" slotted screwdrivers penetrate with much lower forces (~30 N). The forces required for penetrating the rubber-foam analogue with screwdrivers are higher than for "sharp" knives, but in some cases similar to the forces required for stabbing with "blunt" knives. For the other weapons such as chisels and biros, the force required for penetration was again high and there was found to be a good relationship between area of the implement making contact and penetration force.
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http://dx.doi.org/10.1007/s00414-011-0562-9DOI Listing
January 2012

The relationship among thromboelastography, hemostatic variables, and bleeding after cardiopulmonary bypass surgery in children.

Anesth Analg 2010 Apr 8;110(4):995-1002. Epub 2010 Feb 8.

Paediatric Intensive Care Unit, Evelina Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London SE1 7EH, UK.

Background: Mediastinal bleeding is common after pediatric cardiopulmonary bypass (CPB) surgery. Thromboelastography (TEG) may predict bleeding and provide insight into likely mechanisms. We aimed to (a) compare perioperative temporal profiles of TEG and laboratory hemostatic variables between patients with significant hemorrhage (BLEED) and those without (CONTROL), (b) investigate the relationship between TEG variables and routine hemostatic variables, and (c) develop a model for prediction of bleeding.

Methods: TEG and laboratory hemostatic variables were measured prospectively at 8 predefined times for 50 children weighing <20 kg undergoing CPB.

Results: Patients who bled demonstrated different TEG profiles than those who did not. This was most apparent after protamine administration and was partly attributable to inadequate heparin reversal, but was also associated with a significantly lower nadir in mean (sd) fibrinogen for the BLEED group compared with CONTROL group: 0.44 (0.18) and 0.71 (0.40) g/L, respectively (P = 0.01). Significant nonlinear relationships were found between the majority of TEG and laboratory hemostatic variables. The strongest relationship was between the maximal amplitude and the platelet-fibrinogen product (logarithmic r(2) = 0.71). Clot strength decreased rapidly when (a) fibrinogen concentration was <1 g/L, (b) platelets were <120 x 10(9)/L, and (c) platelet-fibrinogen product was <100. A 2-variable model including the activated partial thromboplastin time at induction of anesthesia and TEG mean amplitude postprotamine discriminated well for subsequent bleeding (C statistic 0.859).

Conclusions: Hypofibrinogenemia and inadequate heparin reversal are 2 important factors contributing to clot strength and perioperative hemorrhage after pediatric CPB. TEG may be a useful tool for predicting and guiding early treatment of mediastinal bleeding in this group.
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http://dx.doi.org/10.1213/ANE.0b013e3181cd6d20DOI Listing
April 2010

The utility of the Taipan snake venom assay in assessing lupus anticoagulant status in individuals receiving or not receiving an oral vitamin K antagonist.

Blood Coagul Fibrinolysis 2009 Jun;20(4):271-5

Thrombosis and Vascular Biology Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK.

The objective of the present study was to evaluate the Taipan snake venom time (TSVT) assay in the detection of lupus anticoagulant in patients receiving or not receiving oral vitamin K antagonists. Blood samples were collected from individuals requiring investigation for the presence of a lupus anticoagulant. The TSVT test was run in parallel with the dilute Russell viper venom time (dRVVT) assay and anticardiolipin antibody assays. Results were assessed by Bayesian statistics. Two thousand and five plasma samples were obtained from 1335 individuals. One thousand, one hundred and eleven individuals were not receiving oral vitamin K antagonists; of these, 451 had a lupus anticoagulant by conventional testing, and the TSVT showed a sensitivity of 22%, specificity of 98%, positive predictive value of 80%, negative predictive value of 78%, positive likelihood ratio of 12.3 and a negative likelihood ratio of 0.790. Two hundred and ten of the 224 patients receiving oral vitamin K antagonists were known to have a persistent lupus anticoagulant prior to oral anticoagulation. In this setting, TSVT had a sensitivity of 39% and specificity of 93%, but the dRVVT had a 50% false-positive rate, which meant that despite having a higher sensitivity at 61% than the TSVT, its specificity was only 53%. TSVT is a specific but insensitive assay for the lupus anticoagulant in individuals not receiving oral vitamin K antagonists, when assessed against the dRVVT as the gold standard. It can be argued that despite the TSVT's poor sensitivity in patients taking oral vitamin K antagonists, its high specificity and positive predictive value make it a preferable assay to the dRVVT to diagnose lupus anticoagulant in this group.
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http://dx.doi.org/10.1097/mbc.0b013e3283256037DOI Listing
June 2009

Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid (CC-4047) and their relationship with venous thrombosis.

Eur J Haematol 2005 Apr;74(4):293-6

Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK.

We evaluated the serum/plasma levels of cytokines [interleukin (IL)-6, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta2] and markers of coagulation, fibrinolysis, endothelial and platelet activation during the first 4 wk of treatment with the thalidomide analogue Actimid (CC-4047) in 15 patients with relapsed/refractory myeloma. There was evidence of activation of endothelium (soluble vascular cell adhesion molecule, sVCAM), coagulation (prothrombin fragment 1 + 2, PF1 + 2) and fibrinolysis (D-dimers) but no evidence of platelet activation or endothelial cell damage in myeloma patients. These parameters were not affected by the use of CC-4047. Three of four patients with baseline D-dimers levels >500 microg/L subsequently developed deep vein thrombosis (DVT). The hypothesis that D-dimer level >500 microg/L may predict for those patients most at risk of thromboembolism with multiple myeloma undergoing treatment is worthy of further study.
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http://dx.doi.org/10.1111/j.1600-0609.2004.00393.xDOI Listing
April 2005

The relationship between acute ischaemic stroke and plasma D-dimer levels in patients developing neither venous thromboembolism nor major intercurrent illness.

Blood Coagul Fibrinolysis 2003 Oct;14(7):639-45

Department of Elderly Care, Guy's & St Thomas' Hospital Trust, London.

The true relationship between plasma D-dimers and acute ischaemic stroke (AIS) is uncertain as previous studies investigating this have not screened for subclinical deep vein thrombosis. We addressed this as part of a study in which we screened AIS patients for venous thromboembolism (VTE). We also assessed the performance characteristics of two D-dimer assays as exclusionary tests for VTE in these patients. One hundred and two unselected AIS patients were screened for VTE using magnetic resonance direct thrombus imaging. D-dimers were analysed on days 2, 9, 14 and 21 using the VIDAS immunofluorescent assay (cut-off >or= 500 ng/ml) and the IL test D-dimer immunoturbidimetric assay (cut-off >or= 255 ng/ml). The relationship between D-dimers and AIS was examined in 52 patients neither developing VTE nor intercurrent illness. D-dimers were elevated throughout the study. Median values at the four time points were 652, 692, 737 and 686 ng/ml (VIDAS assay) and 260.5, 268.5, 273 and 283 ng/ml (IL assay). D-dimers were higher in patients aged older than 70 years, with severe stroke or with total anterior circulation infarcts: only age older than 70 years was significantly associated with D-dimer values greater than the median on univariate and multivariable analysis. Both assays were 100% sensitive for VTE. Specificities were 30% (VIDAS assay) and 34% (IL assay). Specificity was adversely affected by age older than 70 and severe versus non-severe stroke. D-dimers are elevated in the first 3 weeks post-AIS after eliminating the confounding effect of subclinical deep vein thrombosis. The VIDAS and IL assays remained sensitive tests for VTE but the specificity was low, limiting their exclusionary efficiency in these patients.
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http://dx.doi.org/10.1097/00001721-200310000-00004DOI Listing
October 2003

Longitudinal evaluation of markers of endothelial cell dysfunction and hemostasis in treated antiphospholipid syndrome and in healthy pregnancy.

Am J Obstet Gynecol 2003 Feb;188(2):454-60

Departments of Maternal and Fetal Research Unit Women's Health, Guy's, King's and St Thomas' School of Medicine, King's College, London, United Kingdom.

Objective: The purpose of this study was to determine whether primary antiphospholipid syndrome pregnancies are associated with endothelial cell activation in the maternal circulation.

Study Design: Markers of endothelial cell activation were measured every 4 weeks during pregnancy in the blood of 23 women with primary antiphospholipid syndrome and 19 control subjects. All women with antiphospholipid syndrome received anticoagulant treatment. Plasma concentrations of plasminogen activator inhibitor type 1, tissue plasminogen activator, soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and soluble thrombomodulin were determined by enzyme-linked immunoassay. Concentrations of prothrombin fragments 1+2 and D-dimers were also determined.

Results: Three antiphospholipid syndrome pregnancies (13%) were complicated by intrauterine growth restriction and preeclampsia; one antiphospholipid syndrome pregnancy (4%) was complicated by preterm rupture of membranes. Six women with antiphospholipid syndrome (26%) had thrombotic events. Differences in concentrations of endothelial cell activation markers between antiphospholipid syndrome and control pregnancies were not significant.

Conclusion: Despite poorer pregnancy outcome, there was no evidence of greater endothelial cell activation in antiphospholipid syndrome pregnancies that were treated.
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http://dx.doi.org/10.1067/mob.2003.14DOI Listing
February 2003

Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis.

Brain 2003 Feb;126(Pt 2):424-32

Department of Clinical Neurosciences, St George's Hospital Medical School, London, UK.

Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P
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http://dx.doi.org/10.1093/brain/awg040DOI Listing
February 2003

Clinical impact of endoscopic ultrasound-guided fine needle aspiration of celiac axis lymph nodes (M1a disease) in esophageal cancer.

Ann Thorac Surg 2002 Mar;73(3):916-20; discussion 920-1

Department of Surgery, University of Texas Medical Branch at Galveston, USA.

Background: The purpose of this study was to determine how endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) with a histology confirmed biopsy protocol impacted on staging and managing esophageal carcinoma in terms of resectability and neoadjuvant therapy (chemotherapy and radiation therapy).

Methods: The records of 40 consecutive patients diagnosed with esophageal cancer referred for EUS staging were reviewed. Computed tomography (CT) scan then EUS imaging and EUS-guided FNA staging, including involvement of celiac node (M1a stage), surgical pathology, and subsequent treatment were correlated. Through-the-scope balloons were used for dilatation when needed to examine the celiac nodes.

Results: All 40 patients followed the protocol and were successfully imaged by EUS. Sixteen of the 40 required esophageal dilatation using the through-the-scope balloon. No complications were observed from esophageal dilatation for EUS. Twenty-three (58%) met the criteria for EUS-guided FNA biopsy from a total of 40 EUS imaging procedures. Twenty (87%) of the 23 EUS-guided FNA were directed toward the celiac nodes; 18 (90%) of the 20 were positive for malignancy and were treated by chemoradiation therapy and 2 (10%) FNA were negative for malignancy and were treated by surgical resection. The CT scan was able to detect only 6 (30%) of 20 cases of suspicious celiac lymph nodes, of which 5 (83%) were positive for malignancy by FNA.

Conclusions: EUS-guided FNA of celiac nodes (20 patients) directed management in all patients biopsied. EUS-guided FNA is superior to CT scan for diagnosing M1a disease. Protocol-directed EUS-guided FNA is a pivotal study when used in conjunction with stage-oriented treatment protocols for esophageal carcinoma.
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http://dx.doi.org/10.1016/s0003-4975(01)03560-3DOI Listing
March 2002