Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety.

From 1997, plasma-derived C1-inhibitor concentrate (Cetor®) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

Haemovigilance: an effective tool for improving transfusion practice.

Haemovigilance is a tool to improve the quality of the blood transfusion chain, primarily focusing on safety. In this review we discuss the history and present state of this relatively new branch of transfusion medicine as well as some developments that we foresee in the near future. The top 10 results and conclusions are: (1) Haemovigilance systems have shown that blood transfusion is relatively safe compared with the use of medicinal drugs and that at least in Europe blood components have reached a high safety standard. (2) The majority of the serious adverse reactions and events occur in the hospital. (3) The majority of preventable adverse reactions are due to clerical errors. (4) Some adverse reactions such as anaphylactic reactions often are not avoidable and therefore have to be considered as an inherent risk of blood transfusion. (5) Well-functioning haemovigilance systems have not only indicated how safety should be improved, but also documented the success of various measures. (6) The type of organisation of a haemovigilance system is of relative value, and different systems may have the same outcome. (7) International collaboration has been extremely useful. (8) Haemovigilance systems may be used for the vigilance and surveillance of alternatives for allogeneic blood transfusion such as cell savers. (9) Haemovigilance systems and officers may be used to improve the quality of aspects of blood transfusion other than safety, such as appropriate use. (10) Haemovigilance systems will be of benefit also for vigilance and surveillance of the treatment with other human products such as cells, tissues and organs.

Efficacy and safety of a nanofiltered liquid intravenous immunoglobulin product in patients with primary immunodeficiency and idiopathic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: In the production process of a new 5% liquid intravenous immunoglobulin (IVIG-L) product (Nanogam(®) ), a combined pepsin/pH 4·4 treatment/15-nm filtration (pH 4·4/15NF) step and a solvent-detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. MATERIALS AND METHODS: Efficacy, including pharmacokinetics, of IVIG-L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long-term follow-up study (mean 2·2 years, n=17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG-L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. RESULTS: In PID patients treated with IVIG-L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short-term and long-term follow-up. Pharmacokinetic studies resulted in an IgG half-life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG-L, and 20/24 patients responded with a platelet count >50 × 10(9) /l (83·3%) within 1 week. IVIG-L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. CONCLUSIONS: In clinical studies, IVIG-L (Nanogam®) demonstrated to be efficacious, well tolerated and safe.

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study.

BACKGROUND: Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). METHODS: Forty patients [with international normalized ratio (INR)≥ 2·1] assigned semi-urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR ( ≤ 1·5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high ( ≥ 1·5). RESULTS: Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0·007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1·6 (1·2-2·2) with PCC vs. 2·3 (1·5-3·5) with FFP; 1 h after CPB both groups reached similar values [1·6 (1·3-2·2) with PCC and 1·7 (1·3-2·7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0·001). Both groups differed significantly on the course of factor II (P = 0·0023) and factor X (P = 0·008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. CONCLUSION: PCC reverses anticoagulation safely, faster and with less bleeding than FFP.

Is haemovigilance improving transfusion practice?--The european experience.

Improving transfusion practice for a donor means a safer donation process and maximal use of the donation. From the clinical perspective, it includes the production of the right type of blood component of adequate quality, administered at the right dose at the right moment to the right patient in order to obtain the expected or anticipated effect in absence of harm. Transfusion practice involves not only the complete blood chain, i.e. from the donation to clinical usage, but also the input from the competent authority that bears responsibility for the concepts of improving health care practice. In Europe, experience has shown that haemovigilance offers an effective tool in improving transfusion practice.

Emergency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium.

OBJECTIVE: To corroborate results obtained in The Netherlands with PPSB-SD, showing a safe acute reversal of anticoagulation within 15 minutes of administration. MATERIAL AND METHODS: PPSB-SD is a concentrate prothrombin complex containing a relatively constant high level of vitamin K-dependant coagulation factors II, VII, IX and X. PPSB-SD was administered to 14 patients treated with oral anticoagulants, according the patient's weight, the initial and the target INR (< 2.0 for moderate haemorrhage and abdominal surgery, or < 1.5 for severe haemorrhage and cardio-vascular interventions). INR values were measured with the Coagucheck Pro (Roche Diagnostics) upon admission and at 15 minutes, 1, 3 and 5 hours after treatment, and confirmed by the hospitals' laboratory. RESULTS: Within 15 minutes 11 patients out of 12 reached their INR target (data were missing for 2 patients). INR decreased rapidly, then remained stable for the next 5 hours. All patients had a favourable outcome: bleeding was stopped and no haemorrhage occurred during surgery. Only one adverse event was reported, but it was not related to the PPSB-SD treatment. No sign of disseminated intravascular coagulation was observed during this study. The administration of PPSB-SD along with vitamin K and dosed according to body weight and initial and target INR allowed for optimal reversal of anticoagulation, as no second infusion was necessary. The recommended dosing worked also very well for patients with high initial INR (9.2 to 22.8) who were brought down to normal values (0.9 to 1.1) within 15 minutes. CONCLUSION: PPSB-SD can safely be used for the rapid reversal of anticoagulation as needed in emergency situations.

High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, crossover study.

We discontinued high-dose intravenous immunoglobulin treatment (IVIg) in 7 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who seemed to have responded to IVIg. After discontinuation of treatment, all 7 patients deteriorated. We then randomized the patients to IVIg or placebo (albumin) treatment in a double-blind crossover study. The clinical condition of all patients improved after IVIg and did not improve after placebo treatment. The mean time lapse from the end of the trial treatment to the occurrence of deterioration was 6.4 weeks after treatment with IVIg and 1.3 weeks after treatment with placebo. This selected group of patients with CIDP had a beneficial response to IVIg.

PPSB as first choice treatment in the reversal of oral anticoagulant therapy.

In the treatment of reversal of oral anticoagulant therapy, a number of treatment modalities is available and depends on the severity of the clinical situation and the degree of the coagulopathy. FFP and PPSB (PCC) are commonly used in the treatment and/or in combination with cessation of oral anticoagulant therapy and administration of Vitamin K. The double viral inactivated plasma product PPSB-SD is the first choice treatment in this indication because of the relatively constant, high concentrated level of the Vitamin K dependent coagulation factors II, VII, IX and X, compared to FFP.

Prevention of transmission of HIV by organ and tissue transplantation. HIV testing protocol and a proposal for recommendations concerning donor selection.

Human immunodeficiency virus (HIV) can be transmitted by solid organ and some forms of tissue transplantation. Although routine screening of organ and tissue donors for anti-HIV antibodies was implemented in most Western European countries and North America in 1985, several recent case reports indicate that a definite, albeit very small, risk of HIV transmission still remains. The screening tests that are currently used cannot rule out a false-negative test result occurring during the window period. Moreover, massive transfusion of the donor during the donor procedure may result in an undetectable anti-HIV antibody titer (by dilution of donor blood) that consequently leads to a false-negative test result. These risks of HIV transmission via transplantation and important issues in HIV testing are discussed in detail. Furthermore, several recommendations for the prevention of transmission and a protocol for HIV testing for both organ and tissue donation are presented. These may serve as intermediary guidelines until official ones, such as already exist for blood donation, are defined by the transplantation communities. The exclusion of donors whose behavior may place potential recipients at risk for HIV infection is essential. A thorough heteroanamnesis of the donor's next of kin during the donor procedure should provide sufficient information about donor history to enable a decision to be made in this respect. Special attention is given to the question of whether the existing donor selection criteria for blood donation should be applied in a similar way to organ donation since the strict application of selection criteria may limit the number of available donor organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study.

Patients with a clinical diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were randomised in a double-blind, placebo-controlled multicentre trial to investigate whether high-dose intravenous immunoglobulin treatment (IVIg) for 5 consecutive days has a beneficial effect. Fifteen patients were randomised to IVIg and 13 to placebo. In the IVIg treatment group 4 patients improved and 3 patients in the placebo group. The degree of improvement of the patients in the IVIg treatment group was no different from the patients in the placebo group. Electrophysiological studies did not show significant differences between the groups. Since a previously performed cross-over trial showed that a selected group of CIDP patients responded better to IVIg than to placebo, it is concluded that we need better criteria to select CIDP patients for treatment with IVIg.

High-dose intravenous immunoglobulin treatment in cryptogenic West and Lennox-Gastaut syndrome; an add-on study.

In an add-on pilot study, a group of 15 children with cryptogenic and intractable West syndrome (3) and Lennox-Gastaut syndrome (12) received intravenous immunoglobulin (IVIg, 0.4 g/kg body weight per day for 5 consecutive days, followed by the same dose once every 2 weeks for 3 months). Five patients had been treated previously with ACTH without success. The reduction in clinical seizures averaged 70%. Electroencephalographic (EEG) recordings revealed a mean reduction in epileptic discharges of 40%. In all 15 patients, acceleration of EEG background activity occurred, and psychomotor development improved. Prior to IVIg administration, CSF examinations were normal. After IVIg administration, the serum total IgG concentration increased by an average of 76%, and the CSF IgG concentration by 44%. According to our data, IVIg crosses the blood-CSF barrier, and might be effective in the treatment of West syndrome and Lennox-Gastaut syndrome. We suggest it should be considered when other treatments, such as ACTH, have failed.

A dysbalanced immune system in cryptogenic Lennox-Gastaut syndrome.

In children with cryptogenic Lennox-Gastaut syndrome we found a functionally impaired humoral immune response to a primary antigen (haemocyanin), despite signs of a triggered immune system consisting of elevated IgG concentrations. This combination of immunological findings, considered to be the expression of a dysbalanced-triggered as well as functionally impaired-immune system, has also been described in an auto-immune disease like systemic lupus erythaematodes in humans, and in genetically epilepsy-prone rats. The interactions between the immune system and the nervous system in Lennox-Gastaut syndrome will be discussed.