Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System.

AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors.

Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.

Treatment of murine testicular leukemia.

The murine leukemia P388 is being evaluated as a potential model for testicular leukemia since this tumor is responsive to most of the drugs used to treat childhood acute lymphocytic leukemia. Infiltration of P388 cells into testes occurs, but the tumor cells plateau at about 10(5) to 10(6) cells/testes, a number inadequate to produce macroscopic disease. Therefore, disease could be evaluated only by bioassay, i.e., suspending and implanting the testes into recipient mice. In advanced disease (at plateau), the tumor cells are responsive to Adriamycin; when the tumor cells are proliferating in testes, they respond to treatment with Adriamycin, methotrexate, and vincristine. Therefore, in this model, the testicular leukemia cells do not appear to reside in a pharmacological sanctuary.

Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery.

Recombinant factor VIIa (rFVIIa: NovoSeven; Novo Nordisk) has proven efficacy in the treatment of haemophilic patients with inhibitors. This prospective, double-blind study compared rFVIIa (35 vs. 90 microg/kg) in the initiation and maintenance of haemostasis during and after elective surgery. Patients with inhibitors (FVIII, n = 26; FIX, n = 3) received rFVIIa immediately prior to incision; intraoperatively as needed; every 2 h for the first 48 h; and every 2-6 h for the following 3 days. Haemostasis was evaluated during surgery, at 0, 8, 24 and 48 h and 3, 4 and 5 days after wound closure. After day 5, open-label rFVIIa (90 microg/kg) was available for maintenance. Intraoperative haemostasis was achieved in 28/29 patients. All high-dose patients and 12/15 low dose patients had satisfactory haemostasis during the first 48 h. Twenty-three patients (13/14 high dose) successfully completed the study. Although the 35 microg/kg dose is probably sub-optimal for post-operative management, at least in major procedures, rFVIIa 90 microg/kg is an effective first-line option in surgery for patients with inhibitors.

Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors.

OBJECTIVE: To assess the safety and efficacy of a fixed dose of recombinant activated factor VII (rFVIIa; NovoSeven) in the home setting for mild to moderately severe joint, muscle; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors. DESIGN: Multicentre, open-label, single arm, phase III study of one year duration. METHODS; Patients or their caregivers administered up to three doses of rFVIIa (90 microg/kg i.v.) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode. Once the subject considered that rFVIIa had been "effective" with regard to haemostasis (after 1-3 injections), one further (maintenance) dose of rFVIIa was administered. RESULTS: Of 60 patients enrolled, 56 experienced at least one bleed, and 46 completed the one year study. 614 of 877 bleeds (70%) were evaluable according to protocol definitions. Haemostasis was rated as "effective" in 92% (566/614) of evaluable bleeds after a mean of 2.2 injections. For successfully treated episodes, the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h (mean+/-SD). Twenty-four hours after initial successful response, haemostasis was reported as having been maintained in 95% of cases. Efficacy was comparable for muscle, joint and target joint, and mucocutaneous bleeding episodes. In an intent-to-treat analysis of all 877 bleeding events, efficacy outcomes were equivalent to the evaluable bleeds, with an effective response in 88% of treated episodes. Treatment-related adverse events occurred in 32 (3% of all) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50% (18/32) of these events. A single episode of superficial thrombophlebitis was the only thrombotic complication encountered, and there were no patient withdrawals due to adverse events. Development of FVII(a) antibodies could not be detected, and hypersensitivity reactions to rFVIIa were not reported. CONCLUSION: rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors.

History of plasma-product safety.

The evolution of transfusion or infusion therapies for diseases requiring specific protein replacements (e.g., hemophilia A and B and severe combined immunodeficiency syndrome) was dramatic over the second half of the 20th century. Unfortunately, it was accompanied by extreme manifestations of transfusion-transmitted diseases, such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. The milestones of both the replacement therapies and the associated diseases are discussed in this presentation, which focuses on the technologic advances that resulted in even more "pure" replacement therapies for plasma-protein diseases. From donor screening to the development of viral attenuation techniques, every facet of production for these products was impacted by the exigent push for viral safety created by HIV and hepatitis. Almost invariably, this negatively affects total product yield. At the beginning of the 21st century, success in making plasma products safe from recognized and potential pathogens has dramatically increased societal pressures to produce a zero-risk, plasma-derived protein therapy. However, past improvements and low theoretic risks for future pathogen contamination have increased product cost. This is associated with a possible decrease in the overall supply of these plasma proteins because of the reduced numbers of acceptable donors and the loss of protein from expanded attenuation technology. These impacts and the role of dynamic societal and scientific pressures on these decision processes are discussed.

Safety issues affecting hemophilia products.

Clotting factor concentrates (CFCs) have evolved substantially toward both safety from pathogens and overall final purity of the products. The array of product types for both factor VIII and factor IX CFCs ranges from so-called intermediate purity (containing multiple plasma proteins), very high purity (containing chiefly the respective purified clotting protein plus an albumin stabilizer), and recombinant CFCs (with or without albumin stabilizers). Each is discussed in the context of theoretic safety, other possible effects on the host (eg, immunogenicity), and the niche that each occupies in the armamentarium for hemophilia therapy. The difficulty in applying a cost-efficacy model for making societal choices about appropriate product selection is discussed in the context of potential or emerging threats to CFC safety (e.g., variant Creutzfeldt-Jakob disease).

The Food and Drug Administration's perspective on plasma safety.

The balance between acceptable plasma-product safety and the demand for those products involves a finite (but very low) level of risk for transmitting infectious diseases. The Food and Drug Administration (FDA) has focused on the use of a triple safety net to provide safe plasma products. This safety net includes donor selection, plasma testing, and inventory hold (look back and retrieval). Although each part of this safety net contributes to reducing the overall viral load in plasma products, each part may not contribute equally to a safe product in all cases. Donor selection is not universally reliable, and plasma antibody testing can be negative for a disease during its seroconversion window period. However, inventory hold (especially for first-time donors) has added to the usefulness of the other safety-net components. This review article provides a brief overview of each safety component and subsequent related improvements, including advances in antibody testing for donor screening and the addition of PCR testing for donor minipools and viral inactivation procedures during plasma-product manufacturing. Dilemmas created by this safety approach are also discussed, including the debate over zero risk of product versus cost and the impact on donors when they test positive for the various diagnostic tests used. Other dilemmas include the decision to include or exclude currently used plasma tests with the advent of polymerase chain reaction (PCR) testing, expanded use of PCR to test for other plasma-transmitted diseases that impart limited risk to recipients, and the role of antigen/antibody interactions in plasma products, especially as the latter relate to plasma-pool and final-product testing.

Viral reduction techniques: types and purpose.

Viral reduction techniques help assure the highest level of plasma-product safety that is possible using today's technology. However, worldwide travel and changing demographics could bring new pathogens into focus and thus require plasma-product manufacturers to be continually vigilant in their efforts to refine current reduction techniques and develop and apply new methods. This review focuses on all the currently used viral reduction techniques, why viral reduction continues to be important (even with the use of polymerase chain reaction techniques to improve plasma screening), and possible future directions for viral reduction. When exploring current approaches, including heat treatment (especially pasteurization), solvent/detergent, pH changes, and ultrafiltration, this review also includes (where applicable) the negative impact of these techniques on product integrity and/or viruses not destroyed. Other techniques (eg, chromatography) and the fractionation steps relevant in the production of selected plasma products may also impart viral reduction and are briefly assessed. Relying on an extensive review of current online and printed literature, this article also discusses the current US and European guidelines and regulations that impact viral reduction techniques. This information includes emphasis on the recommendation to use at least 2 reduction techniques (each with a different mode of action) for each plasma product so as to substantially reduce both enveloped and nonenveloped viruses. The approach to validation studies and results from specific studies are reviewed, and future approaches for viral reduction are described.

The impact of Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease on plasma safety.

Although the true risk of transmitting (classical) Creutzfeld-Jakob Disease (CJD) and variant CJD (vCJD) via transfusion is likely very minimal, a review of prions and the impact of these associated prion diseases is timely because of their current effect on safety policies in the blood-plasma industry. Various types of human and animal prion diseases are outlined and reviewed, with emphasis on the importance of cross-species transmission as is relevant for vCJD. Review of the prion theory focuses on the relationship of prions to disease pathophysiology, prion resistance to protein modification, and potential prion transmission. Causes (with emphasis on iatrogenic CJD) and diagnosis of clinical CJD are described and contrasted with the same for vCJD. The origin of vCJD, the pathophysiologic questions surrounding this condition, and the latest diagnostic tests and research are also reviewed. Comparison of transmission feasibility versus actual transmission of CJD or vCJD by blood or blood products is then explored. Reasons for the discrepancy between theoretic and actual transmission for CJD and the body of evidence provided by look-back studies are examined. When compared with CJD, reasons are provided for the higher theoretic risk of transmitting vCJD by blood products. Studies evaluating transmission by blood products in animals are considered. Transfusion practices that include European and US criteria to prevent vCJD through blood products are reviewed. This includes the debate surrounding product leukoreduction, deferral of donors at high risk either for exposure to vCJD or for contracting CJD, targeted elimination of donor plasma, and how some policies may have contributed to product shortages.

Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury.

To try to define the significance of disseminated intravascular coagulation (DIC) in head-injured patients, we correlated clinical, laboratory, and pathological findings in 16 patients with head injury as their main problem who had DIC, who died within 4 days of injury, and who were examined postmortem. Patients were ranked according to the number of abnormal laboratory screening tests for DIC and the severity of these abnormalities. The most frequently abnormal laboratory tests were the fibrinogen degradation products and fibrinogen, followed in order by the activated partial thromboplastin time, prothrombin time, and thrombin time. The platelet count was the least abnormal value. The patients with the fewest abnormalities had the least abnormal computed tomographic scans. Autopsy reports revealed necrosis and bleeding in the brain and in a number of other organs, particularly the lungs. Microthrombi were not reported in the original autopsy reports. However, when these cases were reevaluated and their slides were stained with an immunoperoxidase technique using rabbit anti-human fibrinogen antiserum, microthrombi were seen frequently. Large microthrombi were more common in patients who had died within less than 24 hours, suggesting a relationship to death or to less time for lysis. In order of frequency, the brain/spinal cord, liver, lungs, kidneys, and pancreas were most commonly affected, and the liver, pituitary gland, pancreas, thymus, brain/spinal cord, large intestine, kidneys, and lungs had the greatest density of microthrombi. Pulmonary dysfunction had been a frequent problem in these patients, which may have been related to the high incidence of microthrombi and bleeding found in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Comprehensive care for patients with hemophilia: an expanded role in reducing risk for human immunodeficiency virus.

Hemophilia is an inherited coagulation disease that affects approximately 1 in 5,000 to 10,000 males worldwide. Chronic joint disease and other long-term complications of recurrent bleeding persist in patients with hemophilia despite improved and more available clotting protein concentrates. The best care can be provided to patients who are followed regularly in specialized treatment centers. Services of every "comprehensive" hemophilia treatment center (HTC) have expanded since previous treatment with clotting factor concentrates infected many hemophilics with the human immunodeficiency virus (HIV). Each HTC offers therapeutic, educational, and counseling expertise in care for the complications of HIV. A nationwide network of specialists now provides care for patients with hemophilia and related congenital abnormalities. In Region VI (Texas, Oklahoma, and Arkansas), the treatment centers and their affiliates provide medical, psychosocial, orthopedic/physical therapy, dental, and case management services. Extramural funded research programs provide care and laboratory testing at no cost to individual subjects.