Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry.

OBJECTIVES: To establish whether reagent-supported thrombelastometry with the rotation thrombelastometry system (ROTEM) point-of-care device correlated with fibrinogen level in postpartum haemorrhages. DESIGN: Prospective observational study. POPULATION AND SETTING: Ninety-one women at the third trimester of pregnancy: 37 with postpartum haemorrhage (study group) and 54 without abnormal bleeding (control group). METHODS: Standard laboratory test results were compared with those obtained at bedside from the ROTEM with the FIBTEM test (54 tests in the control group and 51 in the study group). MAIN OUTCOME MEASURES: Analysis of correlations between fibrinogen levels and FIBTEM test results: clotting time (CT), clot amplitude at 5 and 15 minutes (CA5; CA15) and maximal amplitude [maximum clot firmness (MCF)]. RESULTS: Median fibrinogen level was significantly lower in the haemorrhage group than in the control group (3.4 and 5.1 g/l, respectively, P < 0.0001). Median CT was higher in the haemorrhage group than in the control group (P = 0.05). CA5, CA15 and MCF were significantly lower in the haemorrhage group than in controls (P < 0.0001) and strongly correlated with fibrinogen levels in both groups (r = 0.84-0.87, P < 0.0001). A cut-off value of CA5 at 5 mm and CA15 at 6 mm presented an excellent sensitivity (100% for both parameters) and a good specificity (respectively 85 and 88%) to detect fibrinogen levels <1.5 g/l in postpartum haemorrhage. Conclusions The early parameters obtained from the FIBTEM test correlated well with fibrinogen levels. ROTEM might be helpful in guiding fibrinogen transfusion during postpartum haemorrhage.

Pharmacokinetics, pharmacodynamics, and safety of a platelet GPIIb/IIIa antagonist, RGD891, following intravenous administration in healthy male volunteers.

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 microM)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (Vss, 23.0-25.9 L) and a short terminal t1/2 lambda z (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2 lambda z of 4.5 to 6.6 hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose-dependent and reversible manner. At the highest dose (60 micrograms/kg bolus dose + 336 micrograms/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studies.

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials.

OBJECTIVE: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. SUBJECTS AND METHODS: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5-97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. RESULTS: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5-97.5% interval for each laboratory parameter. CONCLUSION: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

Efficacy and safety of continuous infusion of Mononine during five surgical procedures in three hemophilic patients.

We report here five surgeries successfully performed with a continuous infusion of Mononine (Armour Pharmaceutical Company, Kankakee, IL) in three hemophilic B patients. Before surgery the patients received a bolus dose of 40 to 100 U/kg according to the type of surgery. This injection was followed by a continuous infusion of Mononine, with an infusion rate of 3.5-7 U/kg/hr in order to maintain a factor IX level between 50 and 100% during the whole surgery and the following 6 days. The infusion rate was further adjusted according to the type of surgery until hospital discharge. This method appears to be safe and efficient, since no abnormal bleeding occurred during surgery and none of the patients presented any thrombotic complication. However, this alternative to intermittent administration of factor IX should be standardized and precisely evaluated, regarding the level and the amount of factor IX required, and the cost of the infused material. In our hands, this cost was decreased by 30-40% compared to previous therapeutic schedules at our institution.

Detection of gram-negative bacteraemia in early sepsis by a quantitative chromogenic and kinetic endotoxin assay. The Study Group.

A kinetic chromogenic limulus test was carried out in order to investigate the possibility of a sensitive and specific detection of circulating endotoxin during the first 24 h of septic shock or severe sepsis in 76 patients. Two commercial kits, Whittaeker (W) and Chromogenix (C), were used. Blood culture was taken as a reference. At 1:10 plasma dilution (a currently used dilution in the end point limulus test) abnormal reaction kinetics were found in 13% and 41% of tests, for C and W respectively (P = 0.0008), resulting in unreliable results. Retesting plasma at a greater dilution, until the reaction kinetic was identical to calibration curve control values, gave similar results between the two kits and a better accuracy. Beyond a 0.5 EU mL-1 endotoxin level, the probability of Gram-negative bacteraemia was high (sensitivity = 0.53 and 0.47; specificity = 0.95 and 0.93 for C and W respectively). This kinetic limulus amoebocyte lysate (LAL) test may be useful in therapeutic decisions for treatment of endotoxaemia.

Prothrombin time sensitivity and specificity to mild clotting factor deficiencies of the extrinsic pathway: evaluation of eight commercial thromboplastins.

Prothrombin-time (PT) sensitivity and specificity to mild clotting factor II, V, VII and X deficiencies have rarely been studied. We therefore carried out a prospective study, in 350 patients, of eight commercial thromboplastins (CTs) in their ability to detect mild clotting factor deficiencies, notably in factor VII. In each patient the factor II, V, VII and X clotting activities and PT performed with each CT were determined. For each CT, PT sensitivity and specificity in detecting factor deficiencies below 0.5 U/ml or below 0.4 U/ml were determined at various PTs, and then Receiver Operator Characteristic curves constructed. At optimum PT threshold level (sensitivity = specificity), exactitude varied from 0.64 to 0.74 (p < 0.01) and from 0.67 to 0.81 (p < 0.0001) in detecting deficiencies below 0.5 and 0.4 U/ml respectively. In conclusion, this study shows the limits of the PT test as performed with 8 CTs in patients with mild clotting factor deficiencies. The impact of such differences in sensitivity and specificity on monitoring certain patients subjects to decrease in coagulation factor, and, in particular, of those under low dose oral anticoagulant, remains to be determined.

Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state.

This study explored the relationship between cytokines (TNF, IL-1, IL-6), coagulation and fibrinolytic factors in the early stage of sepsis syndrome and the relation between these factors with the severity of inflammatory illness as measured by the Simplified Acute Physiology Score (SAPS). Twenty-one normal controls were compared to 34 patients divided into three categories ranging from uncomplicated postoperative patients, to patients with severe infectious conditions including septic shock. A major hemostatic imbalance was demonstrated with particularly marked reduction in fibrinolytic activity [drop of antithrombin III (ATIII) and protein C with an increase of plasminogen activator inhibitor (PAI-1) levels] which were directly correlated with the severity of the inflammatory state. Both ATIII and PAI-1 levels were correlated with the levels of TNF and IL-6 and the severity of illness as measured by SAPS. We established an index, ATIII/PAI-1 antigen that is significantly different among the four groups (p < 0.001) and strongly correlated with the SAPS (p < 0.001). As PAI-1 could be secreted not only by TNF activating endothelial cells but also by hepatocytes activated by insulinemia, treatment of sepsis with cytokine-specific agents might be of limited effect.

[Occurrence of a circulating anticoagulant, factor V inhibitor after surgical intervention]. / Apparition d'un anticoagulant circulant antifacteur V après intervention chirurgicale.

A case is reported of an endogenous inhibitor to factor V occurring one month after subtotal gastrectomy and splenectomy, with peroperative radiotherapy, for gastric adenocarcinoma. Preoperative coagulation tests were normal: 31 s for activated kephalin time (control 31 s) and 93% for prothrombin level. There was a fall in this latter during the first three postoperative days. Four hundred ml plasma without cryoprotein were therefore given, bringing the coagulation tests back to the normal range. On day 25, a routine check showed an activated kephalin time of 71 s (control 31 s), a prothrombin level of 13% with a thrombin time of 18 s (control 18 s). There was no associated haemorrhagic diathesis. Measurement of all the individual coagulation factors showed that there was a fall in factor V level (0.05 IU.ml-1). A large amount of antifactor V antibody was then found (47 IU.ml-1). No treatment was undertaken, the patient being so well. Two months later, the antibody had disappeared. The usual circumstances in which this antibody can be seen and the management of the related severe haemorrhages are discussed.

[Therapeutic management of pregnancy complicated by congenital antithrombin III deficiency associated with pregnancy nephropathy]. / Conduite thérapeutique au cours d'une grossesse avec déficit congénital en antithrombine iii associée à une néphropathie gravidique.

Thrombo-embolic complications in pregnant women who have congenital antithrombin III deficiency are usually prevented by giving injections of sub-cutaneous heparin from the beginning to the end of pregnancy and with the administration of concentrated doses of antithrombin III (A.T. III) at delivery and in the following days. When we discovered a severe pre-eclampsia at the 28th week of pregnancy in a patient who had congenital deficiency of A.T. III and who had a past history of very severe thrombo-embolic complications we administered concentrated A.T. III as well as continuing the heparin treatment and anti-hypertensive treatment during the pregnancy. Severe fetal distress made us carry out a caesarean operation after 32 weeks of amenorrhoea. Delivery and the post-partum period were conducted without any complications. The newborn baby, who did not have congenital A.T. III deficiency, is very well.

[Assessment of the risk of postpartum thromboembolism by measuring antithrombin III levels. A false hope]. / Dépistage du risque thrombo-embolique du post-partum par le dosage de l'antithrombine III. Espoir déçu!

In order to predict better thrombo-embolic complications that sometimes occur after delivery, we studied the variations of antithrombin III levels (A.T. III) in 703 women, at the 8th month pregnancy (275 levels), on the first day (609 levels) and the 5th day (516 levels) after delivery. The average antithrombin III levels were respectively 90.8%, 83.4% and 98.7%. We found 120 levels (8.5%) lower than 80% (normal range for A.T. III = 80-120%), 107 of which on the first day after delivery were followed by a rapid increase to the normal range; these women however were satisfactory in the post-partum period. Therefore predicting thrombo-embolic complications in the post-partum period through A.T. III levels determination would seem to be pointless.

[Evaluation of the performance of the Coagulyzer II (Lancer)]. / Evaluation des performances du Coagulyzer II (Lancer).

The automation of equipment is essential in laboratories performing a large number of procedures with high precision. An evaluation of performance characteristics of a photoelectric automated coagulation instrument, the Coagulyzer II (Lancer) is reported and compared with performances of the Coag-a-pet 200.