A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor

Bypass agents are the common treatment for haemophilia patients who develop inhibitory antibodies. Laboratory assessment of the efficacy of bypassing agent therapy is a challenge. In the present work we modified the conditions triggering thrombin generation (TG) assay in order to find the most sensitive assay for detection of rFVIIa and its analogue NN1731 in haemophilic plasma. TG was measured in samples of normal plasma, plasma of haemophilia patient with inhibitors, as well as haemophilia induced plasma. Recalcification-induced TG was compared to tissue factor (TF) -induced TG in the presence and absence of rFVIIa and NN1731. Recalcification-induced TG (without TF) in haemophilic plasma yielded baseline flat curves, with increased TG as a consequence of spiking the plasma rFVIIa. Using our system, we observed both dose-dependence and time-dependence of rFVIIa effect on TG. Elevated concentrations of TF mask the difference between rFVIIa-treated and non-treated haemophilic plasma. NN1731 yielded normalisation of recalcification-induced TG curves (without TF) which may reflect high potency. In conclusion, we suggest that triggering TG by recalcification-only may be the most sensitive assay for determining the impact of bypassing agents in haemophilic plasma, and may serve as a caution surrogate safety marker in future studies.     

Clinical trial: evaluation of a clinical decision-support model for upper abdominal complaints in primary-care practice

Background: Gastro-oesophageal reflux disease (GERD) and dyspepsia affect 25-40% of the general population. In the absence of alarm symptoms, the current recommended policy in young dyspeptic patients is a 'test and treat' strategy for Helicobacter pylori; in GERD patients, a therapeutic trial with proton pump inhibitors is the treatment of choice. AIM: To create a short and simple clinical algorithm, for the diagnosis and treatment of patients with upper gastrointestinal complaints. METHODS: The clinical usefulness and cost-effectiveness of the new algorithm were evaluated in a controlled clinical trial, held in primary-care clinics in Israel. Clinical and economical treatment outcomes were evaluated after 1, 3 and 6 months comparing doctors who used the algorithm (cases) vs. those who did not (controls). RESULTS: 78 cases and 54 controls completed the 6 months of follow up. The improvement in symptom severity and quality of life was greater in the cases than in the controls (P < 0.05). General practitioner clinics visits (P = 0.04), gastroenterology clinics visits (P = 0.02) and medication costs (P = 0.004) were all significantly reduced among cases. Controls underwent also more imaging tests (computerized tomography, ultrasound and X-ray) and endoscopies. The average cost for 6 months' treatment and follow-up was $US 199 for cases compared with an average of $US 336 in the control group. CONCLUSION: The use of a clinical decision-support tool can facilitate and promote the implementation of management guidelines by general practitioners. The short algorithm presented in the study was found to be useful and easy to apply in clinical practice. Its effectiveness can be further increased by implementing it in computerized medical systems.     

Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII

The administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factor VII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion,aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.     

Thrombophilia does not increase risk for neonatal complications in preterm infants

The association between thrombophilia and neonatal complications was evaluated in a single-center prospective study. Prevalence of genetic prothrombotic markers (FVL, MTHFR, FIIG20210A) and levels of plasma homocysteine were assayed in 166 premature (mean gestational age: 30.9+/-2.3 weeks) and low birth weight (mean weight: 1327+/-319 grams) infants. The incidence of any neonatal complications was compared in infants with and without thrombophilia. A total of 38 infants were defined as "thrombophilic" due to heterozygous FVL (n=4) and/or FIIG20210A (n=8, including one case of combination with FVL) or homozygous 677T MTHFR (n=22) or homocysteine plasma levels above 15 micro mole/liter. Neonatal complications included: small for gestational age (28.8%), respiratory distress syndrome (51.8%), broncho-pulmonary dysplasia (10.2%), patent ductus arteriosus (12.7%), intraventricular hemorrhage (17%), periventricular leucomalacia (8.4%), retinopathy of prematurity (15.1%) and necrotizing enterocolitis in 1.2% of infants. No thrombosis was documented. The prevalence of perinatal complications and the severity of diseases were similar among infants with or without thrombophilia (p = 0.564). Our data suggest that preterm infants with thrombophilia are not at increased risk for developing neonatal complications.     

Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma.

PURPOSE: To report our experience with recombinant activated factor VII (rFVIIa) to control hemorrhage in trauma patients with profound multifactorial coagulopathy. rFVIIa forms a complex with tissue factor exposed at sites of tissue damage and induces activation of coagulation limited to the site of injury. It is approved for use in hemophilia patients, however, its use in trauma is still controversial due to the theoretical risk of thromboembolic complications. CLINICAL FEATURES: Nineteen critically ill, multi-transfused patents with trauma (ten blunt and nine penetrating), aged 25 + 17 yr,were treated with rFVIIa after all conventional hemostatic measures had failed. After one to three doses of rFVIIa, hemorrhaging ceased within minutes in 15/19 (78.9%) patients. The total dose of rFVIIa required to control bleeding was 195 +/- 112.7 microg x kg(-1). Shortening of prothrombin time and partial thromboplastin time was observed within 15-30 min from 22.7 +/- 7.9 to 10.4 +/- 2.6 sec and 71 +/- 38.9 to 42.2 +/- 24 sec respectively, (P < 0.05). Transfusion requirements decreased from 30 +/- 18.3 units used within 5.6 +/- 3.4 hr of admission to 2.8 +/- 2.5 within the following 24 hr (P < 0.05). One patient developed clinical deep vein thrombosis. No systemic activation of coagulation was observed clinically. Thirteen patients (68.4%) survived and recovered. Four patents did not respond to rFVIIa treatment and exsanguinated within 24 hr. Two patients died after one week, one from sepsis and one from multi-organ failure. CONCLUSIONS: rFVIIa is a promising adjunctive hemostatic treatment for trauma patients suffering from massive bleeding. Controlled trials are warranted to evaluate the safety and efficacy of this drug.     

Infantile Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) in childhood is a benign disease, as only 10% to 20% of (he patients have a chronic course. A retrospective study of 57 ITP patients ranging in age from four months to two years revealed that 30% of them proceeded to chronicity. Unlike ITP in the general pediatric population, chronic infantile ITP was characterized by male predominance, a high frequency of preceding viral infections, and lack of responsiveness to any of the known modalities of treatment.     

Analysis of heart rate and respiratory patterns in sudden infant death syndrome victims and control infants

Retrospective analyses of patterns of breathing and heart rate variability obtained by visual inspection and spectral analysis of ECG and respiratory activity have provided markers associated with subsequent death in a referred population of infants at high risk for sudden infant death syndrome (SIDS). Such markers include breathing patterns characterized by excessive apneic pauses and periodic breathing, heart rate spectra characterized by increased low frequency oscillations, and respiratory activity spectra characterized by a widened "bandwidth" during regular breathing. To test whether such measurements could distinguish SIDS cases and randomly selected controls from a population study the data from 10 cases and 100 age-matched control subjects were analyzed blind. The code was disclosed after completion of the analysis. We found that none of the markers served to distinguish the SIDS cases from the controls in the population at large. This observation may indicate important physiological differences between infants destined to die in the referred high risk population and infants who die of SIDS at large. The possible reasons for our inability to identify the group of SIDS in the general population, as compared to the group of deaths in the referred high risk group are: (1) different disease processes in the two groups, (2) difference responses to the same disease process in the two groups, (3) a response reflecting the psychosocial setting of the referred high risk population, (4) methodological differences between this and previous studies. We conclude that these markers are not of value in screening the population at large.