The association between cytomegalovirus immune globulin and long-term recipient and graft survival following liver transplantation.

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and long-term clinical outcomes has not been well defined. We examined the association between CMVIG and long-term recipient and graft survival in liver transplant recipients. Data were from the Scientific Registry of Transplant Recipients and included recipients transplanted between January 1995 and October 2008; follow-up was through March 2009. All recipients≤80 years of age with primary, single-organ liver transplants, given CMVIG with (n=2350) or without antivirals (n=455), antivirals without CMVIG (n = 32,939), or no CMV prophylaxis (n=28,508) before discharge were included. Kaplan-Meier analysis was used to examine rates of acute rejection (AR), graft loss, and death, over 7 years post transplantation. The adjusted risk of AR, graft loss, and death associated with CMVIG with and without antivirals vs. no prophylaxis was estimated using the Cox proportional hazards regression. In the univariate analysis, CMVIG, with and without antivirals, was associated with increased AR rates, but decreased mortality; CMVIG with antivirals was also associated with decreased graft loss compared with no prophylaxis. From the multivariable model, CMVIG with antivirals was associated with increased risk for AR, but decreased risk for graft loss and death; after adjustment, the association between CMVIG alone and mortality was not significant. CMVIG with antivirals is associated with increased risk of AR but greater long-term patient and graft survival after liver transplantation.

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.

Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.

Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery, and safety in patients with hemophilia B.

Highly purified factor IX, produced by a monoclonal antibody immunoaffinity technique, contains a high concentration of factor IX with negligible amounts of other vitamin K-dependent coagulation factors. When infused in patients with hemophilia B, monoclonal factor IX concentrate yielded a mean half-life of 34.6 +/- 13.1 (+/- SD) hours and in vivo recovery of 0.67 +/- 0.14 U/dL rise per each U/kg of factor IX infused. Unlike prothrombin complex concentrate (PCC) infusion, monoclonal IX infusion was not associated with rises in factors II, VII, and X, but achieved in vivo recovery and half-life at least comparable to PCC. Long-term use of monoclonal IX as a home-care product provided excellent response in the control of bleeding episodes and was equivalent to previous patient experience with PCC. The results indicate that monoclonal IX concentrate raises factor IX levels effectively, while avoiding extraneous thrombogenic components.

Variability of in vivo recovery of factor IX after infusion of monoclonal antibody purified factor IX concentrates in patients with hemophilia B. The Mononine Study Group.

Monoclonal antibody purified factor IX concentrate, Mononine (Armour Pharmaceutical Company, Kankakee, Illinois, USA), is a recently developed replacement factor concentrate for the treatment of patients with hemophilia B. The pharmacokinetic properties of monoclonal antibody purified factor IX concentrate (MAb Factor IX concentrate) have been evaluated in only small samples of patients, and little is known about those factors that might influenced in vivo recovery of factor IX after infusion is a larger patient population. In vivo recovery of factor IX was therefore evaluated for 80 different indications in 72 patients who received MAb Factor IX concentrate for the management of spontaneous or trauma-induced bleeding, or as prophylaxis with surgery. The average recovery after infusions for presurgical pharmacokinetic analysis (mean +/- standard deviation) was 1.28 +/- 0.56 U/dl rise per U/kg infused (range 0.41-2.80), and the average recovery after all infusions for treatment was 1.23 +/- 0.49 U/dl rise per U/kg infused (range - 0.35-2.92). Recovery values for multiple MAb Factor IX doses in a given patient were also variable; the average recovery was 1.22 +/- 0.53 U/dl rise per U/kg given, and standard deviations ranged from 0.03 to 1.26. Patient age, weight, and MAb Factor IX concentrate dose minimally but significantly influenced factor IX recovery. There was no significant effect of either race, history of previous thrombotic complications during treatment with other replacement factor concentrates, or bleeding state on recovery. All of the patients treated with this preparation experienced excellent hemostasis, and no thrombotic complications were observed.

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Orthostatic changes in normovolemic children: an analysis of the "tilt test".

Orthostatic changes in pulse rate and blood pressure were assessed on 455 normovolemic children between 4 and 17 years of age who visited emergency departments with a variety of complaints. Blood pressures and pulse rates were measured in the upper extremity with the patient supine, sitting, and standing. The postural changes in pulse rate and blood pressure for age groups 4 to 9 years, 10 to 13 years, and 14 to 18 years were computed, and statistical analyses were performed to identify factors predisposing to changes in pulse rate and blood pressure. In all categories of chief complaint, comparable numbers (average 25.4%) of patients had an increase in pulse rate of greater than 20 beats/min. An average of 10.7% of children in each category had a fall in systolic blood pressure greater than 20 torr. Only increasing body temperature, especially in the youngest children, and diarrhea, particularly if more than 12 hours in duration, predisposed to having a "positive tilt test" using these criteria. The "tilt test" for assessing orthostatic hypotension is of little value in assessing normovolemic children presenting for acute care. A positive test result is very nonspecific.

Combined iron deficiency and lead poisoning in children. Effect on FEP levels.

Concern for the concomitant occurrence of iron deficiency and elevated blood lead in children is raised by animal studies documenting increased gastrointestinal lead absorption in the presence of iron deficiency. An elevation in free erythrocyte protoporphyrin (FEP) above 35 mg/dl is seen with both iron deficiency and lead toxicity. To determine whether the degree of elevation in FEP is useful in predicting which children with elevated blood lead levels have concomitant iron deficiency, 109 children suspected of having an elevated lead burden were studied. A complete blood count, reticulocyte count, FEP, lead, and ferritin were measured on each child. The effect of the independent variables, lead and iron status, both alone and in combination, on the dependent variable, FEP, was analyzed through a linear regression model. Lead status alone accounted for 42 percent of the explained variance in FEP, and the lead-iron interaction increased the explained variance by only an additional 1 percent. Screening for iron deficiency in children with elevated blood lead should continue to be based on dietary and socioeconomic risk factors and not on degree of elevation in FEP.

Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records.

BACKGROUND: Delayed correction of blood clotting times as measured by the International Normalized Ratio (INR) is associated with adverse outcomes among certain patients with warfarin-related major bleeding. However, there are limited data on the association between INR correction and mortality. OBJECTIVE: To assess factors associated with 30-day mortality and time to death in patients receiving fresh frozen plasma (FFP) for warfarin-associated major bleeding. METHODS: A retrospective database analysis was undertaken with electronic health record data from a large integrated health system. Patients met the following criteria: major hemorrhage diagnosis; INR ≥ 2 on the day before or day of receipt of FFP; and prescription fill for warfarin within 90 days. INR correction (defined as INR ≤ 1.3) was evaluated at the last available test 1 day following the start of FFP administration. Kaplan-Meier curves and Cox proportional hazards models were constructed to assess mortality. RESULTS: Four hundred and five patients met the selection criteria (mean age of 75 years, 54% male), and 67% remained uncorrected at 1 day following the start of FFP administration. Among all patients, 11% died within 30 days of hospital admission. An uncorrected INR was not associated with a higher risk of 30-day mortality for patients overall, but was statistically significant for the subgroup with intracranial hemorrhage (ICH) (adjusted odds ratio 2.55; 95% confidence interval 1.04-6.28). CONCLUSIONS: Among the subgroup of major bleeding patients with warfarin-associated ICH, those not correcting to either INR ≤ 1.3 or INR ≤ 1.5 with the use of FFP have an increased rate of mortality at 30 days.

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Blister cells in children with sickle hemoglobinopathies.

The presence of blister cells in the peripheral blood of patients with sickle hemoglobinopathies was investigated to assess whether their presence was predictive of the patients' clinical state and would be diagnostically useful. Peripheral blood smears (PBS) were examined from 23 children with sickle hemoglobinopathies, 20 children with iron deficiency, and 29 healthy control children. The number of blister cells per 1,000 red blood cells was then correlated with the child's health state: well, minor illness, and illness requiring hospitalization. The presence or number of blister cells was found to be unreliable to predict the state of health or the cause of a pulmonary insult in children with sickle hemoglobinopathies.

Psychogenic intractable sneezing in children.

Four preadolescent children had paroxysms of intractable sneezing. After days of hospitalization and numerous local and systemic drug treatments had failed, a psychogenic cause of their problem was entertained. This uncommon form of conversion reaction most often occurs between the ages of 9 and 15 years, and prognosis is good if the appropriate interventions are undertaken.

Concomitant treatment with factor IX concentrates and antifibrinolytics in hemophilia B.

Concomitant use of the monoclonal antibody-purified factor IX concentrate (Mononine, Armour Pharmaceutical Company, Collegeville, Pa.) and two antifibrinolytic agents, epsilon-aminocaproic acid (EACA; Amicar, Immunex, Seattle, Wash.) or tranexamic acid (AMCA; Cyklokapron, Kabi Pharmacia, Piscataway, N.J.) was examined for safety and efficacy in patients with hemophilia B. In a retrospective review of 19 patients treated with monoclonal antibody-purified factor IX and EACA on 35 occasions, bleeding was successfully controlled and no instances of clinical thrombotic complications were reported; one instance of urticaria resolved without additional treatment. The use of EACA or AMCA in combination with monoclonal antibody-purified factor IX was also examined prospectively in a study of 9 patients. Bleeding was effectively controlled and no thrombotic events were detected clinically with either antifibrinolytic agent. No significant changes in hematocrit or hemoglobin were detected, and there was no evidence of thrombosis as evaluated clinically and by sensitive molecular markers. It was concluded from both the retrospective and prospective data that monoclonal antibody-purified factor IX concentrate in combination with an antifibrinolytic agent does not activate the coagulation cascade and is a safe and effective treatment for prevention and control of oral bleeding in hemophilia B patients.

Pediatric resident objectives for hematology/oncology.

Pediatric residents are exposed to a massive amount of scientific information and data from each pediatric subspecialty discipline. The residents may or may not know what is important and what is relevant from a general pediatrician's point of view. Educational objectives have been written by three pediatric hematologists/oncologists to guide the resident specifically as to the minimal expectations of knowledge and performance in this discipline. Other pediatric residency programs may wish to use the objectives as a starting point or an outline for their own objectives.

Safety of high doses of a monoclonal antibody-purified factor IX concentrate. The Mononine Study Group.

This report summarizes safety and efficacy information among patients treated with high doses (> 75 U/kg) of a monoclonal antibody-purified factor IX concentrate [coagulation factor IX (human) monoclonal antibody purified)] in two clinical trials. One hundred infusions of this factor IX concentrate at doses > 75 U/kg were administered to 35 patients, six of whom had experienced thrombotic complications during previous treatment with prothrombin complex concentrate. Hemostasis in all patients was rated as "excellent," and there were no thrombotic complications.

Optimal blood ordering for emergency department patients.

A lack of documented criteria for determining which emergency patients should have blood crossmatched for possible transfusion led us to review the records of all patients for whom blood was crossmatched in the emergency unit of our hospital in 1977. Of 378 patients who had blood crossmatched for 1,230 units, only 105 (28%) received blood transfusions (331 units total). Variables showing relationship to transfusion of blood were consolidated into four criteria: 1) shock; 2) hematocrit less than 30%; 3) observed blood loss of at least 500 ml or grossly visible gastrointestinal bleeding; and 4) emergency surgery with anticipated blood loss. Application of these criteria identified 55% of patients who did not receive transfusions and 41% of units unnecessarily crossmatched, while failing to identify only three patients received single-unit transfusions. Use of the criteria would have reduced the crossmatch/transfusion ration from 3.7:1 to 2.6:1.

Lack of immune response to mouse IgG in previously untreated haemophilia A and haemophilia B patients treated with monoclonal antibody purified factor VIII and factor IX preparations.

Immunoaffinity purification of factor VIII and factor IX results in the inclusion of trace quantities (50 ng 100 IU(-1) ) of mouse protein in the final product. It is possible that infusion of extremely low levels of proteins might induce human antimouse antibody (HAMA) responses. To test this possibility, IgG, IgM and IgE antibodies to mouse IgG were assessed in previously untreated haemophilia A and haemophilia B patients (n = 9 and n = 11, respectively) who received monoclonal antibody (MAb) purified factor VIII (Monoclate-P® Antihaemophilic Factor [Human] Centeon, King of Prussia, PA) or factor IX (Mononine® Coagulation Factor IX [Human] Centeon). HAMA were evaluated prior to and 2-42 months after initial treatment. IgE antibodies to mouse IgG were undetectable (< 19 ng ML(-1) ) at all time points. Antimouse IgG levels for Monoclate-P-treated patients averaged (mean±SD) 0.40±0.18 µg mL(-1) prior to treatment, and 0.64±0.43 µg mL(-1) at the time of last observation (P > 0.05, not significant [n.s.]). Respective values for antimouse IgM in these patients were 2.48±1.20 µg mL(-1) and 2.85±1.63 µg mL(-1) (P > 0.05, n.s.). Antimouse IgG levels for Mononine-treated patients averaged 0.48±0.52 µg mL(-1) prior to treatment, and 0.66±0.59 µg mL(-1) after 3 months of therapy (P > 0.05, n.s.). Respective values for antimouse IgM in these pa-tients were 1.94±1.52 µg mL(-1) and 1.77±0.99 µg mL(-1) (P > 0.05, n.s.). Lack of immunogenicity of traces of mouse protein in these preparations is supported in that none of the patients assessed developed anaphylactoid reactions during treatment.

Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures.

The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine® Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty (n= 12), gastrointestinal (GI) or rectal surgery (n= 6), synovectomy/osteotomy (n= 8), hernia repair (n= 4), central catheter insertion (n= 3), ENT surgery (n= 4), dental procedures (n= 14), biopsies (n= 2), gynaecological procedures (n= 4), ophthalmological surgery (n= 4), spinal surgery (n= 4), urogenital surgery (n= 2), other orthopaedic surgery (n= 4) or other miscellaneous procedures (n= 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates.