Efficacy and safety of Privigen, a novel liquid intravenous immunoglobulin formulation, in adolescent and adult patients with chronic immune thrombocytopenic purpura.

Intravenous immunoglobulin (IVIG) has become a mainstay of treatment for acute and chronic immune thrombocytopenic purpura (ITP). The efficacy and safety of Privigen, a new, ready-to-use, 10% liquid human IgG formulation, was evaluated in this open-label, multicentre study. Privigen infusions (1 g/kg per day for 2 consecutive days, days 1 and 2) were given to 57 adolescent and adult patients with chronic ITP and platelet counts < or =20 x 10(9)/l. By day 7, 80.7% of patients (95% CI, 69.2, 89.3) achieved platelet counts of > or =50 x 10(9)/l. Correspondingly, haemorrhage number and severity were significantly reduced. Adverse events were generally mild or moderate and typical of underlying disease and IVIG treatment. Privigen was well tolerated - 104 of 114 infusions were performed at the maximum permitted infusion rate (4 mg/kg/min). Thus, in patients with chronic ITP, a two-day regimen of Privigen was effective in increasing platelet count, reducing bleeding events and was well tolerated.

Red cell damage after pumping by two infusion control devices (Arcomed VP 7000 and IVAC 572).

The aim of this study was to assess the performance in terms of red cell damage of two peristaltic volumetric infusion pumps - the Alaris IVAC 572 (San Diego, CA, USA) and Arcomed Volumed VP7000 (Regensdorf, Switzerland). Various infusion pumps are available to transfuse blood at a predetermined rate. It is recommended that each machine should be individually assessed. This experiment used six units of single-donor-transfusable packed red cells and ran each unit through both pumps. This was carried out at 9, 28 and 35 days post-donation at rates from 2 to 150 mL h(-1). Post-pumping samples from these experiments, and a pre-pumping sample in each case, were analysed for levels of potassium and free haemoglobin (Hb). They were also examined microscopically for evidence of cell damage. Potassium levels showed no significant change with pumping on any occasion, but rose significantly as the samples aged. Free Hb showed some variation, but the only consistent finding was a similar rise in value with increasing pack age. Microscopic examination revealed no cell damage under any condition. Both pumps performed to an acceptable level and appear safe to be used for red cell transfusion.

An acute haemolytic transfusion reaction caused by anti-Wr.

The Wright (Wr(a)) antigen is found on the red blood cells of approximately 1 : 1000 Caucasians. Anti-Wr(a) has been reported to be present in 1 : 25 to 1 : 100 healthy blood donors and an even higher proportion of hospital patients. Incompatibility due to anti-Wr(a) might therefore be expected to occur in approximately 1 in 50,000 blood transfusions. Reports of haemolytic transfusion reactions (HTR) and haemolytic disease of the newborn due to anti-Wr(a) are, however, rare. We report an acute HTR due to anti-Wr(a) in a 58-year-old man with myelodysplastic syndrome associated with rigors, shortness of breath and a significant rise in serum bilirubin from 16 micromol L(-1) pretransfusion to 110 micromol L(-1) immediately afterwards. This was accompanied by the appearance of bilirubin and urobilinogen in his urine and a fall in haemoglobin of nearly 2 g dL(-1) following the transfusion. Anti-Wr(a) was the only antibody implicated. When tested against the recipients plasma, Wr(a+) panel cells and the transfused unit responsible for the reaction were 2-3+ by indirect antiglobulin test (IAT) and the donation typed as Wr(a+). The recipient had the common Wr(a-) phenotype. The reaction resulted in the patient being admitted to hospital for 2 days. The increasing use of electronic issue may result in more frequent reports of reactions due to anti-Wr(a) using current screening cells.

Misdiagnosis of hereditary angio-oedema type 1 and type 2.

BACKGROUND: Hereditary angio-oedema is a rare, life-threatening, autosomal dominant condition caused by deficiency (type 1) or dysfunction (type 2) of complement C1 inhibitor. Serological assays to measure C1 inhibitor concentration and function are widely available. However, expert interpretation may not be. OBJECTIVE: To review all cases within three NHS Trusts with a putative diagnosis of hereditary angio-oedema. METHOD: Review of laboratory results and clinical notes of 44 cases of presumed hereditary angio-oedema. RESULTS: Audit revealed that 11 of 42 (26%) cases had been incorrectly considered to have a diagnosis of hereditary angio-oedema. Two of 44 had insufficient data to assess. All 11 had low functional C1 inhibitor recorded at presentation. RESULTS: available in these 11 cases at the time of diagnosis showed a normal or borderline C4 level (>or= 50% of mean normal, in contrast to hereditary angio-oedema, where C4 was less than 40% of mean normal) indicating that the low C1 inhibitor levels were a result of sample decay. Cases incorrectly diagnosed were predominantly female and had a mean age at presentation of 40 years (compared with 22 years for type 1 hereditary angio-oedema). Six of the 11 cases were offered C1 inhibitor concentrate (pooled plasma product) as treatment. CONCLUSION: We recommend that all suspected cases of hereditary angio-oedema are reviewed, that specialist advice is sought before making the diagnosis and that the diagnosis is only made after initial abnormal serology is confirmed on a second sample.

Efficacy, tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies.

BACKGROUND AND OBJECTIVES: A nanofiltration step with the capacity to reduce blood-borne pathogens was introduced into the manufacturing process of intravenous immunoglobulin (IVIG). In order to demonstrate the efficacy, safety and pharmacokinetics of the modified product, we conducted Phase II/III studies comparing the nanofiltered IVIG (IVIG-N) with its parent product, Sandoglobulin, in patients with chronic immune thrombocytopenic purpura (ITP) and primary immunodeficiencies (PID). MATERIALS AND METHODS: Patients with ITP (n = 27) with platelet counts of < 20 x 10(9)/l were treated with Sandoglobulin or IVIG-N infusions at a dose of 0.4 g/kg body weight on five consecutive days. The primary efficacy end-point was the number of patients with an increase in platelet counts to > 50 x 10(9)/l. Secondary end-points were time to and duration of response, and regression of bleeding. Patients with PID (n = 36) were treated for 6 months with Sandoglobulin or IVIG-N at doses of 0.2-0.8 g/kg, infused at 3- or 4-week intervals. The primary end-point was the number of days absent from school/work. Secondary end-points were hospitalization, use of antibiotics and feeling of well-being. In both studies, tolerability was assessed by recording of adverse events and laboratory determinations. Viral safety was ascertained by serology supplemented with nucleic acid detection methods. Pharmacokinetics were analysed in patients with PID using serum concentration-time data for immunoglobulin G (IgG), and IgG antibodies to hepatitis B surface antigen (anti-HBsAg). RESULTS: In the ITP study, the primary end-point was met by 12/16 patients on IVIG-N and by 10/10 patients on Sandoglobulin (P = 0.123). A shift towards lesser bleeding intensity was seen in both groups. In the PID study, seven of 18 patients on IVIG-N and six of 16 patients on Sandoglobulin missed days at work/school, with monthly mean absences of 0.4 and 0.5 days (P = 0.805). The feeling of well-being was comparable in both groups. In the ITP study, adverse events with a causal relationship to medication were suspected in six patients on IVIG-N and in seven on Sandoglobulin. In the PID study, three patients on IVIG-N and two on Sandoglobulin experienced possible drug-related adverse events. In both studies, serological and polymerase chain reaction (PCR) tests gave evidence for virus safety. Pharmacokinetics showed constant peak and trough serum IgG levels in all patients, indicating almost steady-state conditions for both formulations. The overall half-life (t1/2) for total IgG was 33 +/- 17 days in the IVIG-N arm and 25 +/- 16 days in the Sandoglobulin arm; for anti-HBsAg t1/2, values were 17 +/- 7 and 17 +/- 9 days, respectively. CONCLUSIONS: IVIG-N is efficacious, well tolerated and safe in patients with ITP and PID. Its pharmacokinetic properties were comparable to those of Sandoglobulin.

Haemostatic and fibrinolytic responses to bone marrow transplantation.

Thrombin and plasmin activation markers were serially measured in 80 patients undergoing bone marrow transplantation (BMT). There were prothrombotic and fibrinolytic responses observed during autograft and allograft BMTs. Thrombin-antithrombin and prothrombin fragment F1+2 levels increased from day -7 to -3 (P<0.0001) from 3.7 to 7 ng/ml and 1.2 to 1.63 nmol/l, respectively. A rise in plasmin-antiplasmin levels occurred between days 4 and 14 (P< 0.0004), from 393 ng/ml on day -7 to a peak of 795 ng/ml on day 11. No correlation between reduced protein C levels post-BMT and a prothrombotic state was observed.

Parenteral glutamine protects hepatic function during bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). The major pathological changes are seen in centrilobular (zone 3) hepatocytes and adjacent endothelium. Glutathione (GSH) becomes depleted following chemotherapy and experimental evidence suggests reduced levels predispose to centrilobular hepatocyte and endothelial cell injury. Animal studies have shown that glutamine infusions can maintain GSH levels and protect against free radical injury. We have prospectively studied the effect of glutamine supplementation during BMT. Thirty-four patients undergoing BMT were randomised to receive either glycl-L-glutamine (n = 18) or an isonitrogenous mixture of non-essential amino acids (n = 16). Glutamine was shown to significantly preserve protein C (days +4 and +7, P < 0.05) and albumin levels (days 0 and +4, P < 0.02). Markers of thrombin and plasmin generation (thrombin-antithrombin, prothrombin fragment F1+2 and plasmin-antiplasmin levels) were not significantly changed between the two groups. These findings suggest that glutamine preserves hepatic function but does not alter thrombin or plasmin generation during BMT. Previous studies have shown reductions in protein C, albumin, factor X and factor VII levels post BMT. Falling protein C levels have been shown to be predictive of severe VOD. These data suggest a role for glutamine in the protection of hepatic function following BMT.

Trisomy 12 is a Rare Event in Cases of CLL with Typical Immunophenotype and Morphology.

131 patients with lymphoproliferative disorders were classified as having typical Chromic Lymphocytic Leukaemia [CLL], atypical CLL, Chromic Lymphocytic Leukaemia/Prolymphocytic Leukaemia [CLL/PL] or Non-Hodgkin's Lymphoma [NHL] using immunophenotyping and morphology. The incidence of trisomy 12 (+12) in each of the groups was ascertained using fluorescent in situ hybridization. Trisomy 12 was found to be rare in the typical CLL group (<3%) and more common in the atypical CLL (22%), CLL/PL (40%) and NHL (43%) categories. The low incidence of +12 in the typical CLL group is most likely due to our adherence to strict inclusion criteria to ensure other similar lymphoproliferative disorders, with a high incidence of +12, were excluded. This approach leads to more homogeneous disease categories and consequently may help to resolve issues such as the impact on survival of +12 in CLL.

Is transdermal nicotine associated with cardiovascular risk?

We had the unique opportunity to study the effects of transdermal nicotine on markers of haemostasis and serum lipids in patients with ulcerative colitis; all were non-smokers and were given transdermal nicotine to assess its value in maintenance therapy for colitis. In a controlled double-blind trial, 45 patients with ulcerative colitis in remission on 5-aminosalicylic acid, were randomly allocated to receive transdermal nicotine (20) or placebo (25) patches. Markers of haemostasis, including platelet activation (platelet volume and surface expression of P selectin), endothelial damage (plasma von Willebrand factor antigen) and plasma fibrinogen were measured at the beginning and after 12 weeks of treatment. The white cell count and serum lipids were also measured. Nicotine significantly lowered plasma fibrinogen but did not affect markers of platelet activation, endothelial damage, white cell count and serum lipids. The possibility that transdermal nicotine may beneficially influence cardiovascular risk factors warrants further exploration.

Serum erythropoietin during autologous bone marrow transplantation: relationship to measures of erythroid activity.

Marked elevation of serum erythropoietin (sEPO) occurs following high dose chemotherapy for malignant disease. It has been proposed that the subsequent fall in sEPO constitutes a relative erythropoietin (EPO) deficiency, prompting trials of recombinant EPO to reduce red cell transfusion during chemotherapy. We have investigated these phenomena by serial estimations of reticulocytes and sEPO in 11 autologous marrow transplant recipients. sEPO reached two to five times baseline 0 to 5 days after transplant but the inverse relationship between sEPO and haematocrit was maintained. Observed to expected log sEPO (Epo ratio) rose and fell in parallel with sEPO, remaining greater than 1.0 throughout. A progressive fall in reticulocyte count during chemotherapy was followed by an increase during engraftment. The strong inverse relationships between reticulocytes and Epo ratio in the 10 days after initiating chemotherapy support the hypothesis that loss of EPO-receptor bearing erythroid precursors allows a rise in sEPO during chemotherapy. The elevation of Epo ratio levels during engraftment indicates that it is the availability of EPO-sensitive progenitors, rather than the supply of EPO, that limits the rate of resumption of erythropoiesis after high-dose chemotherapy.

The effects of time from venepuncture and choice of anticoagulant on mean platelet volume estimations.

The Mean Platelet Volume (MPV) is a readily measured parameter using modern automated cell counters. Despite studies which indicate that MPV may be altered in various disease states, its widespread application has been hindered by its known dependence on factors such as time from venepuncture, choice of anticoagulant and sample storage temperature. In this report we describe the changes in MPV measured on a Technicon H1 analyser with time from sampling using two different anticoagulants under clinical laboratory conditions. Small changes in MPV with time were seen in both anticoagulants. These were statistically significant by Student's paired t-test but, on analysis of variance, were not significant compared with the variation in MPV between individuals. The well-documented effects of time, temperature and anticoagulant on MPV need not interfere with the interpretation of a result from a sample dealt with under similar conditions to those applying in this study.

Obstetric management in von Willebrand's disease: a report of 24 pregnancies and a reivesw of the literature.

The case records of 13 patients (24 pregnancies) with von Willebrand's disease (vWD) were studies rettospectively. The overall incidence of primary and secondary post-partum haemorrhage (PPH) was 15.8% and 25% respectively, all primary PPH occurring in tyre 2 discase (3/14 deliveries, 21.4%). The risk of primary PPH in type 2 patients who did not receive prophylactic factor VIII was 37.5% (3/8 deliveries). Factor VIII coagulant activity (VIII:C) and von Willebrand factor antigen (vWF:Ag) rose above bascline values by a factor of at least 1.5 during the pregnancy in most case. More severely affected patients were less likely to benefit significatntly. A baseline VIII:C of <15 iu/dl (4/14 cases) was predictive of a third trimester level of <15 iu/dl. Improvements in the von Willebrand factor activity were less marked. The baseline von Willebrand factor activity was <15 iu/dl in all patients with serial data, none of whom achieved a third-trimester von Willebrand factor activity of >50 iu/dl. The bleeding times were unaltered significantly in all but one of the cases, reflecting a general failure of the primary haemostatic defect to improve with pregnancy. The findings demonstrate that coagulation parameters do not universally improve in pregnancy in vWD, especially when preconception levels are low. The risk of primary PPH is generally higher in type 2 diseases. The level of factor VIII:C is not a good predictor of the risk of primary PPH in type 2 patients. Secondary PPH is a significatnt risk in both type 1 and type 2 patients.

Epstein-Barr virus-associated haemophagocytic syndrome in a patient with juvenile chronic arthritis.

We describe a case of reactive haemophagocytic syndrome (RHS) in a patient with previous polyarticular juvenile chronic arthritis (JCA). This is the first reported association of these conditions and may be indicative of defective immunological responses to viral infections in this form of JCA.

C-anaphase in a case of acute nonlymphocytic leukemia.

C-anaphase was seen in approximately 50% of bone marrow cells from a patient with acute nonlymphocytic leukemia (ANLL). The abnormality acting as a marker for the disease, being present at diagnosis, disappearing during remission and returning at relapse.

Evaluation of erythropoiesis after bone marrow transplantation: quantitative reticulocyte counting.

Erythroid regeneration is an important and separate element in the engraftment process in allogeneic and autologous bone marrow transplantation (alloBMT, autoBMT). Qualitative visual reticulocyte counting has proved inadequate in the evaluation of erythropoiesis after BMT but automated flow cytometry now allows the reliable quantitation of reticulocytes even to very low levels. Reticulocyte counts and highly fluorescent reticulocyte (HFR) counts (very early reticulocytes) were estimated daily in recipients of 22 autoBMT and 14 alloBMT using a Sysmex R-1000 automated reticulocyte counter. Marrow ablation caused an immediate and rapid fall in both the reticulocyte count and the HFR. Measurable numbers of reticulocytes persisted throughout the hypoplastic period, but HFR fell to zero in the majority of both the autoBMT and alloBMT. HFR rose significantly after a median time of 14 d post-autoBMT, and 12 d post-alloBMT. Attainment of 15 x 10(9)/l reticulocytes and 0.5 x 10(9)/l HFR at day 21 post-transplant was associated with ultimate engraftment in 100% cases. Inadequate engraftment was seen in the majority of patients whose responses fell below these levels. Graft-versus-host disease was associated with a transient slight reduction in reticulocyte count. Neither episodes of infection nor blood transfusions had any significant impact on trends of reticulocytes or HFR. Automated flow cytometric reticulocyte counting has been shown to provide an accessible measure of erythroid activity which may be of predictive value in the management of patients following bone marrow transplantation.