Thrombin Generation Is Normal in Most Patients with Cirrhosis despite a Prolonged INR.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1826-1826
Author(s):  
Alexander Gatt ◽  
Anne Riddell ◽  
Vincenza Calvaruso ◽  
Michael Makris ◽  
Edward Tuddenham ◽  
...  
Keyword(s):  
Liver Disease ◽  
Tissue Factor ◽  
Patient Group ◽  
Protein C ◽  
Thrombin Generation ◽  
Control Sample ◽  
Normal Subjects ◽  
Sensitivity Index ◽  
Clotting Factors ◽  
The Mean

Abstract Introduction: Advanced liver disease is associated with prolongation of the prothrombin time (PT). In order to decrease the inter-laboratory variability of PT measurement, the international normalised ratio (INR) calculated as the ratio of patient’s PT to a normal (control) sample, raised to the power of the international sensitivity index (ISI) of the particular thromboplastin used was developed. However, the ISI is derived from PT results of patients on warfarin and results cannot be extrapolated to liver patients. Despite this, the INR is still commonly performed to assess bleeding risk in patients with liver disease worldwide. Furthermore the INR is only affected by factors I, II, V, VII, and X and is not influenced by other factors such as factor VIII which is usually raised in hepatic cirrhosis. Recently it has been reportd that thrombomodulin addition (to take into account the protein C pathway) normalises thrombin generation (TG)1 despite these patients having a low TG if thrombomodulin is not used. Aim: We speculated that TG, which is a global assay of coagulation and sensitive to all coagulation factors, when triggered by a low tissue factor (TF) concentration might not correlate with the INR in patients with liver disease and that contact inhibition with corn trypsin inhibitor (CTI) might better reflect the coagulation potential in this patient group. Results: 73 unselected patients with liver cirrhosis due to various diseases and 25 normal subjects were studied. INR and TG using the calibrated automated thrombogram (CAT) at 1pM tissue factor (TF) with CTI, 5pM without CTI and with and without Protac (a Protein C activator) were performed using platelet poor plasma (PPP). The INR range was 0.8–4.0 (mean 1.6). At 5pM TF without Protac, the patient group had a significantly lower endogenous thrombin potential (ETP) than the controls (mean ETP difference 752nM/min; P <0.0001). With Protac, no significant differences could be detected between the 2 groups. However, if the ETP without Protac was divided by the ETP with Protac x 100, the liver group showed more resistance to PC activation (mean % difference 25.4; P 0.0002). At 1pM TF, the mean ETP in the cirrhosis cohort was slightly lower than the normal group (difference between means 216nM/min; P 0.03). However, only 7 (9.6%) patients had ETP values less than the normal range (mean±2SD). No correlation was found between the ETP at 1pM and the INR. The mean FVIII:C was raised at 185.6 (78–420U/dl). Conclusion: TG measured at low TF with CTI is normal in the majority of patients with cirrhosis. These patients are also more resistant to PC activation and have supranormal FVIII:C. Thus most patients have a normal or high thrombin potential despite an abnormal INR. These findings have important implications as in the absence of bleeding, “prophylactic” plasma and clotting factors are unnecessary.

Procoagulant Status In Patients With Immune Thrombocytopenia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3528-3528 ◽  
Author(s):  
Ihosvany Fernández Bello ◽  
Mayte Álvarez Román ◽  
Elena G. Arias Salgado ◽  
Monica Martin Salces ◽  
Miguel Canales ◽  
...  
Keyword(s):  
The Netherlands ◽  
Tissue Factor ◽  
Protein C ◽  
Thrombin Generation ◽  
Red Cells ◽  
Procoagulant Activity ◽  
Platelet Counts ◽  
Significant Difference ◽  
The Mean ◽  
Spearman Test

Abstract Introduction Immune thrombocytopaenia (ITP) is an acquired immune-mediated disorder characterized by mild to severe thrombocytopaenia caused by autoantibodies against platelet proteins. Bleeding risk in patients with ITP is increased with platelet counts less than 20 or 30 x 109/L. However, patients with ITP often have few bleeding symptoms despite very low platelet counts suggesting the existence of compensatory mechanisms. Moreover, an increased risk for thrombosis in patients with ITP has been described (Nørgaard M, 2012). It has been recently reported that increased production of platelet- and red cells-derived microparticles (MP) might be one of the causes of increased thrombotic risk in ITP patients (Sewify, 2013). Objective The aim of this study was to evaluate the microparticle-associated and plasma procoagulant activities in ITP patients with thrombocytopaenia. Methods Sixty-eight patients with chronic ITP and platelet count less than 50 x 109/L and twenty-two healthy controls were included. Platelet counts were determined with a Coulter Ac. T Diff cell counter (Beckman Coulter, Madrid, Spain). Citrated blood was centrifuged at 1,500 g for 15 min at 23°C. Platelet-poor plasma obtained was additionally centrifuged twice at 23°C (15 min at 1,500 g, and 2 min at 13,000 g) and aliquots were stored at -70ºC until analysis. Phosphatidylserine-MP (Ph-MP) and tissue factor-MP (TF-MP) dependent procoagulant activities were determined with the ZYMUPHEN kits (Hyphen BioMed, Neuville sur Oise, France) following the manufacturer’s instructions. Plasma thrombin generation was measured using the Calibrated Automated Thrombogram (CAT) test as described by Hemker et al (2000) at a final concentration of 1 pM tissue factor and 4 μM phospholipids (PPP-Reagent LOW, Thrombinoscope BV, Maastricht, The Netherlands). We evaluated the endogenous thrombin potential (ETP, the total amount of thrombin generated over time); the lag time (the time to the beginning of the explosive burst of thrombin generation); the peak height of the curve (the maximum thrombin concentration produced); and the time to the peak. To test resistance to protein C, CAT experiments were performed without and with the addition of thrombomodulin (TM) (PPP and PPP with thrombomodulin reagents, Thrombinoscope BV, Maastricht, The Netherlands). Results were expressed as the ratio [(ETP with TM)/(ETP without ETP)]x100. Results were expressed as mean±SD. Comparisons of quantitative variables were made with Mann-Whitney test and correlations with Spearman test. Values of p≤0.05 were considered statistically significant. Results Ph-MP associated procoagulant capacity in ITP patients was higher than in controls (p<0.05) whereas MP-TF associated procoagulant activity was practically negligible in both groups. Plasma procoagulant activity was higher in ITP patients than in controls (ETP: 1604±616 nM x min in ITP patients and 1302±416, p=0.012 in controls; Peak: 328±123 nM in ITP patients and 203±74 nM in controls, p<0.001). We tested whether the higher procoagulant activity of plasma from ITP patients was due to a resistance to protein C. We observed that the mean Ratio value in ITP patients was slightly higher than the mean Ratio of controls (60±18 and 50±13 respectively, p=0.034). Despite this significant difference in the Ratio, no correlation was found between this value and the CAT parameters. Conclusion ITP patients with thrombocytopaenia had a higher Ph-MP associated and plasma procoagulant activity than controls. The fact that the increased MP-procoagulant activity was not accompanied by a higher TF-MP associated procoagulant activity brings further support to the previous observation that MPs in ITP patients are from platelets and red cells, as both cells express very low levels of TF (Sewify, 2013). Regarding the increased plasma procoagulant capacity observed in ITP patients, our results suggest that resistance to protein C does not seem to be the main mechanism involved. References • Nørgaard M. Thromb Res. 2012;130 Suppl 1:S74-75. • Sewify EM, et al. Thromb Res. 2013;131:e59-63. Hemker HC, et al. Thromb Haemost 2000;83:589-9. Disclosures: No relevant conflicts of interest to declare.

Recombinant Tissue Factor as Substitute for Conventional Thromboplastin in the Prothrombin Time Test

1992 ◽  
Vol 67 (01) ◽  
pp. 042-045 ◽  
Author(s):  
Armando Tripodi ◽  
Arnaldo Arbini ◽  
Veena Chantarangkul ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Prothrombin Time ◽  
Tissue Factor ◽  
Oral Anticoagulant Therapy ◽  
Clotting Factor ◽  
Rabbit Brain ◽  
Sensitivity Index ◽  
Clotting Factors ◽  
Wide Range ◽  
Reference Preparation ◽  
Time Test

SummaryRelipidated recombinant tissue factor (r-TF) has been assessed in comparison with conventional rabbit brain thromboplastin (Manchester Reagent) for its suitability for measurement of prothrombin time (PT). The International Sensitivity Index (ISI) of r-TF calibrated against the International Reference Preparation BCT/253 (human plain) was found to be 0.96 and 1.12 with instrumental and manual techniques. Our study of plasmas from patients with congenital deficiencies of clotting factors covering a wide range of severity demonstrates that r-TF is able to detect even minor deficiencies of factors involved in the extrinsic and common coagulation pathways. Patients with liver diseases were correctly diagnosed with a prevalence of abnormal results comparable for both reagents. Between-assay reproducibility expressed as coefficient of variation was 2.3 % and 3.9 % at normal and abnormal PT levels.In conclusion, our evaluation shows that relipidated r-TF possesses the necessary requisites of sensitivity, diagnostic accuracy and reproducibility which make it a suitable candidate for PT determination both for monitoring oral anticoagulant therapy and diagnosing congenital and acquired clotting factor deficiencies. Moreover, being a highly defined reagent it may constitute a step forward in the standardization of PT testing.

Phospholipid-bound Tissue Factor Modulates both Thrombin Generation and APC-mediated Factor Va Inactivation

1999 ◽  
Vol 82 (12) ◽  
pp. 1673-1679 ◽  
Author(s):  
Katalin Váradi ◽  
Jürgen Siekmann ◽  
Peter Turecek ◽  
H. Peter Schwarz ◽  
Victor Marder
Keyword(s):  
Tissue Factor ◽  
Surface Density ◽  
Protein C ◽  
Thrombin Generation ◽  
Feedback Inhibition ◽  
Activated Protein C ◽  
Reaction System ◽  
Inverse Correlation ◽  
High Concentration ◽  
Factor Va

SummaryHemostasis is initiated by tissue factor (TF) exposed on cellular phospholipid (PL) membranes, leading to thrombin generation. The binding of thrombin to thrombomodulin (TM), activates the protein C pathway, resulting in the inactivation of factors Va and VIIIa by activated protein C (APC) and a negative feedback effect on thrombin generation. A new assay system was developed for simultaneous measurement of thrombin and APC generation in defibrinated plasma induced by large unilamellar PL vesicles complexed with full-length recombinant TF (TF:PL). TF:PL preparations with a low TF concentration induced an initial rate of thrombin generation below 100 nM/min, and resulted in less thrombin formation in the presence of TM than in its absence. In contrast, TF:PL preparations with a high concentration of TF induced a higher rate of thrombin generation, and APC-mediated feedback inhibition did not occur, despite maximal APC generation. We used the same TF:PL surfaces to study factor Va inactivation by APC in a non-plasma reaction system, and found an inverse correlation between TF surface density and the rate of factor Va inactivation. This observation suggests a previously unrecognized hemostatic effect of TF, namely a non-enzymatic surface density-based inhibition of the anticoagulant effect of APC. In this model, high concentrations and surface density of TF exert complementary effects by promoting the regular procoagulant cascade and by inhibiting the protein C pathway, thereby maximizing hemostasis after vascular injury.

Increase of plasma proapolipoprotein A-I in patients with liver cirrhosis and its relationship to circulating high-density lipoproteins 2 and 3

1993 ◽  
Vol 39 (1) ◽  
pp. 60-65 ◽  
Author(s):  
T Suehiro ◽  
M Yamamoto ◽  
K Yoshida ◽  
F Ohno
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Density Lipoprotein ◽  
Normal Subjects ◽  
High Density ◽  
High Density Lipoproteins ◽  
Enzyme Linked Immunosorbent Assay ◽  
Converting Enzyme ◽  
Sandwich Method ◽  
The Mean

Abstract We determine the concentration of proapolipoprotein (proapo) A-I and its ratio with total apolipoprotein (apo) A-I (proapo A-I/total apo A-I) in plasma of patients with liver disease; we used a noncompetitive sandwich method, an enzyme-linked immunosorbent assay. The mean (SD) proapo A-I concentrations in patients with decompensated or compensated liver cirrhosis were higher than in normal subjects: 88 (25), 105 (36), and 69 (25) mg/L, respectively. The mean (SD) ratio (expressed as %) for each of these types of liver cirrhosis was also higher than in normal subjects: 10.0 (3.5), 10.2 (3.9), and 4.6 (1.6), respectively. In the patients, the proapo A-I concentration was positively correlated with the concentration of high-density lipoprotein subtype 2 cholesterol (HDL2-C) (r = 0.736), and the proapo A-I/total apo A-I ratio was correlated inversely with the HDL3-C concentration (r = -0.609). The activity of proapo A-I converting enzyme in patients with liver cirrhosis (62 +/- 30 nmol/h per liter) was significantly (P &lt; 0.01) lower than that in normal subjects (172 +/- 55 nmol/h per liter). The increases of the plasma proapo A-I concentration and ratio in patients with liver cirrhosis may be caused by a decreased production of the converting enzyme in the liver. The increase of plasma proapo A-I may thus also affect the circulating HDL subtypes.

In vitro effects of human neutrophil cathepsin G on thrombin generation: Both acceleration and decreased potential

2010 ◽  
Vol 104 (09) ◽  
pp. 514-522 ◽  
Author(s):  
Thomas Lecompte ◽  
Agnès Tournier ◽  
Lise Morlon ◽  
Monique Marchand-Arvier ◽  
Claude Vigneron ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Time Course ◽  
Anticoagulant Activity ◽  
Cathepsin G ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Factor V ◽  
Clotting Factors

SummaryCathepsin G (Cath G), a serine-protease found in neutrophils, has been reported to have effects that could either facilitate or impede coagulation. Thrombin generation (CAT method) was chosen to study its overall effect on the process, at a plasma concentration (240 nM) observed after neutrophil activation. Coagulation was triggered by tissue factor in the presence of platelets or phospholipid vesicles. To help identify potential targets of Cath G, plasma depleted of clotting factors or of inhibitors was used. Cath G induced a puzzling combination of two diverging effects of varying intensities depending on the phospholipid surface provided: accelerating the process under the three conditions (shortened clotting time by up to 30%), and impeding the process during the same thrombin generation time-course since thrombin peak and ETP (total thrombin potential) were decreased, up to 45% and 12%, respectively, suggestive of deficient prothrombinase. This is consistent with Cath G working on at least two targets in the coagulation cascade. Our data indicate that coagulation acceleration can be attributed neither to platelet activation and nor to activation of a clotting factor. When TFPI (tissue factor pathway inhibitor) was absent, no effect on lag time was observed and the anticoagulant activity of TFPI was decreased in the presence of Cath G. Consistent with the literature and the hypothesis of deficient prothrombinase, experiments using Russel’s Viper Venom indicate that the anticoagulant effect can be attributed to a deleterious effect on factor V. The clinical relevance of these findings deserves to be studied.

scholarly journals Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation

Blood ◽  
1982 ◽  
Vol 60 (1) ◽  
pp. 261-264 ◽  
Author(s):  
JH Griffin ◽  
DF Mosher ◽  
TS Zimmerman ◽  
AJ Kleiss
Keyword(s):  
Liver Disease ◽  
Serine Protease ◽  
Vitamin K ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation System ◽  
Antigen Concentration ◽  
Intravascular Coagulation ◽  
The Mean

Abstract Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as evidenced by positive FDP (greater than micrograms/ml). Plasma protein C was 4 micrograms/ml in normals and was significantly depressed (less than 2 SD below the mean of normals) in 19 of the 38 patients. Of 15 patients with suspected intravascular coagulation but normal FDP, protein C was decreased in 5 individuals; 3 of these 5 patients had liver disease. Based on these results, we suggest that extensive activation of the coagulation system in vivo causes a significant consumption of protein C, presumably due to its activation by thrombin and subsequent clearance.

scholarly journals Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1580-1586
Author(s):  
JP Miletich ◽  
GJ Jr Broze
Keyword(s):  
Vitamin K ◽  
Plasma Protein ◽  
Total Protein ◽  
Protein C ◽  
Warfarin Therapy ◽  
Normal Subjects ◽  
Plasma Vitamin ◽  
Protein Z ◽  
The Mean ◽  
Log Normal

In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.

scholarly journals Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1580-1586 ◽  
Author(s):  
JP Miletich ◽  
GJ Jr Broze
Keyword(s):  
Vitamin K ◽  
Plasma Protein ◽  
Total Protein ◽  
Protein C ◽  
Warfarin Therapy ◽  
Normal Subjects ◽  
Plasma Vitamin ◽  
Protein Z ◽  
The Mean ◽  
Log Normal

Abstract In contrast to the other well-studied vitamin K-dependent proteins that circulate in plasma, protein Z antigen is much more variable. The concentration in plasmas collected in EDTA from 455 normal, healthy donors is normally distributed with a mean of 2.9 micrograms/mL (46 nmol/L) and a SD of 1.0 microgram/mL (95% interval of 32% to 168% of the mean). No significant correlation to age or sex could be detected. In comparison, the concentration of protein C antigen measured with the same type of assay on the same 455 samples has a log normal distribution with a mean of 4.0 micrograms/mL (65 nmol/L) and a 95% interval of 70% to 138% of the mean. Also in marked contrast to other plasma vitamin K-dependent proteins, the total protein Z antigen level is extremely low in patients on stable warfarin therapy (range 1% to 16% of normal). Moreover, even though greater than 95% of the antigen in normal plasmas adsorbs to barium citrate (a crude reflection of the presence of gamma-carboxyglutamic acid (Gla) residues), in the patients taking warfarin almost all of the small amount of the antigen failed to adsorb, suggesting that virtually no protein Z had its full complement of Gla residues. Total protein C antigen in the same 25 patients averaged 53% of normal (34% to 72%) and 54% (average) of the total remaining antigen still adsorbed to barium citrate. The concentration of protein Z antigen in the plasma of a normal individual given a loading dose of warfarin fell at an initial rate of approximately 20% a day, indicating a plasma half-life (t1/2) of 2 to 3 days.

Haemostasis Change in Intensive Care Patients with Severe Sepsis and Patients with Organ Failure without Sepsis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1233-1233
Author(s):  
Patrick Van Dreden ◽  
Barry John Woodhams ◽  
Bernard Lenormand ◽  
Marc Vasse
Keyword(s):  
Severe Sepsis ◽  
Intensive Care ◽  
Organ Failure ◽  
Healthy Subjects ◽  
Protein C ◽  
Thrombin Generation ◽  
Protein S ◽  
Healthy Controls ◽  
Coagulation Abnormalities ◽  
The Mean

Abstract Abstract 1233 Introduction: Despite recent advances in understanding the pathophysiology of sepsis, multiple organ failure remains one of the leading causes of death in intensive care units (ICUs). A wide range of coagulation abnormalities have been observed in patients diagnosed with severe sepsis (SS). Its magnitude in relationship to organ failure without sepsis is less well documented. In this study, we examined and compared the results of plasma levels of coagulation tests and thrombin generation (calibrated automated thrombography (CAT) in patients with sepsis, patients with organ failure (OF) without sepsis and controls. We investigated whether the CAT and procoagulant phospholipids would be good prognostic markers and whether these markers would show a significant correlation with coagulation disorders. Patients and Methods: 21 patients with severe sepsis, 24 non-sepsis patients with organ failure were compared with 30 healthy subjects as controls. The delay between the onset of SS or OF and blood sampling was less than 12 hours. Analytical determinations of prothrombin time, activated partial thromboplastin time, and the levels of factors V,VII,VIII,X antithrombin, fibrinogen, protein C, protein S, D-Dimers were analysed using the STA-R analyser (Diagnostica Stago, France), Tissue factor activity (TFa) and thrombomodulin activity (TMa) were measured with two home-test. Free tissue factor pathway inhibitor (fTFPI), Soluble endothelial protein C receptor (sEPCR), and soluble thrombomodulin antigen were measured by ELISA assays (Diagnostica Stago, France). CAT was performed on PPP using PPP-reagent 5pM (Thrombinoscope, The Netherlands). Procoagulant phospholipids (PPL) were evaluated using the STA Procoag PPL assay (Diagnostica Stago, France). Results: The mean levels of factors V, VII, X, antithrombin, protein S, protein C, sEPCR were decreased in both SS and OF (p<0.001) compared with controls. Protein S, factor VII and X were significantly lower in the SS group than in the OF group (p<0.05). Factor VIII, D-Di, and fibrinogen level were increased in SS and OF groups (p<0.001). Activity and antigen thrombomodulin were significantly higher in SS and OF groups (p<0.01) than in healthy subjects, with no difference between patients groups. TFa was strongly increased in SS and OF (p<0.001) and not compensated by any increase in TFPI. We also observed that TF/fTFPI ratio were significantly increased in the SS and OF groups (p<0.001). Elevated thrombin generation was observed in patients with SS and OF. In particular lag-time and time to peak were prolonged (p<0.05), peak thrombin was significantly decreased only in SS group. However the mean total amount of thrombin generated in the groups of patients by endogenous Thrombin Potential (ETP) was equivalent to healthy controls. Procoagulant phospholipids were significantly higher in SS and OF groups than controls (p<0.001 and p<0.05 respectively). Non-surviving patients showed higher ETP, D-Di, TFa, PPL than survivors in both groups (p<0.05). No difference in fTFPI levels were observed between patients with negative outcome and survivors in the two groups of patients. IL-6 levels as inflammatory status were higher in SS and OF than in healthy controls, with a more pronounced increase in SS group. The levels of IL-6 were more important in non-survivors compared with survivors (p<0.05). Conclusion: This study suggests that severe septic and non septic patients with organ failure have similar coagulation abnormalities independently of the triggering event. Marked TFa generation was not adequately balanced by TFPI and inflammation may synergistically play a role in the pathogenesis of OF and death. Thrombin generation results showed that while the total amount of thrombin generated (ETP) was unchanged the initiation of thrombin generation was delayed and peak thrombin was reduced. This could be explained by the decreased levels of FVII, X, II causing a delay in the generation of thrombin. PPL and TGT may be useful in determining clinical outcome in patients and perhaps as a predictive parameter for an increased risk of bleeding or thrombotic complications in these patients. Their role to develop useful new markers in the management of patients remains to be defined. Disclosures: Van Dreden: Diagnostica Stago: Employment. Woodhams:Diagnostica Stago: Employment. Lenormand:Hospital: Employment. Vasse:hospital: Employment.

Sign in / Sign up

Export Citation Format

Share Document