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.

Placenta praevia, placental abruption and amphetamine use in pregnancy: a case study.

UNLABELLED: Pregnant women who misuse alcohol or substances often develop obstetric conditions that further complicate their pregnancy. This case study reflects on the maternity care provided for a woman who continued to use amphetamines during her pregnancy; and who was diagnosed with placenta praevia and subsequently suffered a placental abruption. Alcohol and substance misuse in pregnancy is currently escalating, increasing the risk in maternal and neonatal morbidity and mortality. Midwives must be confident in the advice and care they provide in order to reduce the risks caused by substance misuse, and be able to support this with evidence-based care. PURPOSE: The purpose of this case study is to discuss the obstetric condition involved with placenta praevia with the occurrence of a placental abruption in a woman who uses amphetamines during pregnancy; and the midwifery and obstetric care involved. INTEREST/RELEVANCE/CONGRUENCY: It will highlight the importance of evidence-based care in high risk obstetrics. CONTENT: (1) Case summary; (2) discussion; (3) risk factors; screening, diagnosis and management; foetal and neonatal monitoring; postnatal management, and trauma informed care. CONCLUSION: It was shown with planning, understanding, communication, and vigilance, the care of an amphetamine using pregnant woman with a diagnosis of placenta praevia and abruption can be successfully accomplished. The management of the woman discussed in this case study was within the recommendations currently available in the literature.

Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project.

Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0-2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy-five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C-section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra- and extra-cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence-based recommendations for their management.

Septic arthritis in males with haemophilia.

We used data collected as part of the Universal Data Collection (UDC) surveillance project in haemophilia treatment centers (HTC) to study the incidence, risk factors and impact of septic arthritis among males with haemophilia. Patients participating in UDC on two or more occasions were included. Cases were defined as patients with documented joint infection. Characteristics of the cases were compared with those of haemophilia patients without infection. Among the 8026 eligible patients with 36 015 person-years of follow-up, 30 (0.37%) had a documented joint infection (incidence rate 83 per 100 000 person-years). In a logistic regression model, only increasing age (OR = 6.1 for age > or =30), race/ethnicity other than white (OR = 3.9), presence of inhibitor (OR = 3.9), invasive procedure in the past year (OR = 2.7) and presence of one or more target joints (OR = 3.2) remained statistically significant. Central venous access devices use and hepatitis C virus and HIV infection were not associated with septic arthritis risk after adjusting for potential confounders. Study limitations include possible underestimation of septic arthritis rate in this population and its retrospective design. We conclude that septic arthritis is an uncommon complication of haemophilia occurring primarily in joints most affected by bleeding and reparative surgical interventions.

Practice patterns in haemophilia A therapy -- global progress towards optimal care.

This paper reports the findings of a global survey of practice patterns for the management of patients with haemophilia A. A total of 147 haemophilia treatment centres worldwide responded to the questionnaire, supplying data for 16 115 patients with haemophilia A. From these responses, 38% (range: 25-48%) of patients were under 18 years old. Almost half (47%) of patients were reported to have mild or moderate haemophilia A, 48% had severe haemophilia A (no inhibitor) and 5% were inhibitor patients. Less than half of patients with severe haemophilia A received prophylactic therapy (37%, excluding inhibitor patients) and 54% received on-demand treatment; the remaining 9% were inhibitor patients. Primary prophylaxis rates for severe haemophilia ranged from 73% in Sweden to 17% in the USA. Most respondents (80%) ranked infrequent bleeds as one of the top five reasons for not administering prophylactic treatment, followed by venous access (60%) and cost (45%). Of patients with severe haemophilia (non-inhibitor), 32% on primary prophylaxis and 27% on secondary prophylaxis had indwelling catheters. Risk of infection and the patient's inability to maintain the line were the key concerns cited by nurses relating to venous access. The mean ratio of nurses to patients with haemophilia A was 1:69 and nurses felt that they were either fully (26%) or mostly (45%) autonomous in assessment and treatment decisions. Results from this current survey suggest that worldwide research should be continued so as to improve outcomes through the identification of optimal treatment protocols for the management of haemophilia A.

Severe hemophilia A due to a 1.3 kb factor VIII gene deletion including exon 24: homologous recombination between 41 bp within an Alu repeat sequence in introns 23 and 24.

Partial or complete factor (F)VIII gene deletions are found in about 5% of families with severe hemophilia A. Relatively few deletions have been well characterized and, of these, recombination occurred between either common repeat elements or non-homologous sequences. In evaluating a family with severe hemophilia A, an exon 24 deletion was suspected when no fragment was obtained on attempted PCR amplifications. A combination of the 5' primer of exon 23 and the 3' primer of exon 25 fragments was used with prolonged extension times to amplify a normal 2.9 kb fragment that included exons 23 through 25; the patient's amplified product was 1.6 kb indicating a 1.3 kb deletion. A mixture of normal and patient DNA showed both sized fragments as did that from an obligate carrier. Carrier detection was applied to two women at risk; one was and one was not a carrier. Sequencing the proband's 1.6 kb fragment revealed that a 1328 bp deletion occurred between homologous sequences of 287 and 285 bp in introns 23 and 24, respectively; these share 85% identity. Blast nucleotide search revealed that these represent Alu elements. Comparison with an alignment of each of the two homologous sequences further localized recombination to a 41-bp segment. However, a simple recombination event would not account for the proband's sequence. The most likely explanation is that the homologous recombination was accompanied by incomplete mismatch repair.

Consensus recommendations for use of central venous access devices in haemophilia.

Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.

Barriers to compliance with prophylaxis therapy in haemophilia.

Prophylaxis, or the practice of routine replacement infusions of clotting factor concentrate in persons with severe haemophilia, is a demanding medical regimen. Prophylactic infusions require direct venepuncture or sterile entry into a central venous access device on a regular basis. A telephone survey was conducted to elicit information regarding the barriers to compliance with prophylaxis. The Mountain States Regional Haemophilia and Thrombosis Center has recommended prophylaxis to 52 male patients with haemophilia A or B. The haemophilia nurse attempted to contact all of these patients or their parents, and contact was made with 38 (73.1%) of them. Respondents were asked about the following issues: their decision to initiate prophylaxis; their self-rated compliance; the challenges, barriers, and facilitators of prophylaxis; and their perceived value of the therapy. Four patients (10.5%) elected not to begin prophylaxis. Of the 34 persons who began prophylaxis, 20 respondents (58.8%) rated their compliance as excellent. Nearly one-third of the families with excellent compliance (giving 75-100% of prescribed infusions) stated that the time-consuming nature of prophylaxis was the most significant challenge of the regimen. In addition, 58.3% of the families that gave less than the prescribed number of infusions reported that the time commitment was the primary reason for missing infusions. Knowledge of the benefits of prophylaxis was the primary facilitator of compliance for 44.1% of families. Ninety-seven percent of respondents rated prophylaxis as very valuable. These data show that despite the known benefits of prophylaxis, it is a demanding medical regimen, and compliance is imperfect. In addition, this study underscores the importance of providing continuing support and education for patients and families who are implementing prophylaxis.

MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage.

We hypothesized that magnetic resonance imaging (MRI) scans taken prior to radiosynoviorthesis may be predictive of response to the procedure in persons with haemophilia. Specifically, response would be inversely related to the severity of synovial hyperplasia. Radiosynoviorthesis was administered to 21 joints with recurrent haemorrhage (target joints). A detailed self-report of haemorrhage history, joint evaluation with scoring according to the World Federation of Haemophilia orthopaedic joint and pain scales, plain radiographs, and MRI studies of the joints were performed pre- and post-radiosynoviorthesis. To augment comparison of the MRI findings to those assessed using the Arnold-Hilgartner and Pettersson scales, a provisional MRI scale for evaluation of haemophilic arthropathy was designed. We found the MRI findings prior to the procedure were not predictive of clinical response; independent of the severity of synovial hyperplasia, most joints bled less and showed improvement by the WFH orthopaedic score. There was generally no change in the severity of synovial hyperplasia after the procedure. We conclude that MRI evaluation is not routinely indicated prior to radiosynoviorthesis.

Use and morbidity of venous access devices in patients with hemophilia.

To obtain information on venous access devices (VADs) used for the treatment of patients with hemophilia and infections associated with the use of VADs, a questionnaire was sent to 153 hemophilia treatment centers in the United States and Puerto Rico. Information regarding the treatment of 10,421 patients and 568 VADs was obtained. Infections were reported with 159 (45%) of 353 internal devices and 126 (71%) of 178 external devices. These results indicate that VADs used for the treatment of hemophilia are associated with significantly higher infection rates than are those used in oncology or mixed patient populations.

Results of secondary prophylaxis in children with severe hemophilia.

In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0-12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8-127) in the year prior to prophylaxis, of which a mean of 24 (range 5-46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII-deficient boys and for the one factor IX-deficient boy. Two of three factor VIII-deficient boys responded to an increase to 30 U/kg prior to the 3-day interval. The dose frequency was increased to three times a week for the factor IX-deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII-deficient boys plus seven other factor VIII-deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of > 1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one-half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted.

Magnetic resonance imaging visualization of hemorrhage into a suprapatellar pouch in a child with hemophilia.

PURPOSE: Magnetic resonance imaging (MRI) was used for evaluation of refractory joint swelling in a 7-year-old boy with hemophilia. PATIENT AND METHODS: This patient with no evidence of an inhibitory had refractory left knee swelling despite receiving appropriate factor VIII concentrate infusions. RESULTS: A plain radiograph showed soft tissue swelling and a calcification in the left suprapatellar region. On MRI a discrete suprapatellar pouch could be detected and was subsequently surgically resected. CONCLUSION: We believe that MRI should be considered when evaluating children with hemophilia who have refractory joint swelling and no evidence of an inhibitor.

Utility of magnetic resonance imaging for management of hemophilic arthropathy in children.

We hypothesized that magnetic resonance imaging (MRI) would improve clinical and plain-radiograph assessments of children with hemophilic arthropathy. Thirteen children, aged 7 to 16 years, with severe factor VIII deficiency and one or more target joints were identified. A target joint was defined as a joint into which hemorrhage had occurred at least twice a month for at least the previous 6 months. After review of history, examination, and plain radiography, a recommendation regarding synovectomy or prophylaxis with factor VIII concentrate was made for each target joint. The MRI of each target joint was then reviewed. Fourteen target joints (three elbows, three knees, eight ankles) were evaluated. On the basis of clinical and plain-radiograph data, synovectomy was recommended for five and prophylaxis for seven joints. Discontinuation of prophylaxis was recommended for two ankles in one child. The MRI examination confirmed that four of five potential synovectomy candidates had markedly hypertrophied synovium and could benefit from surgery; one of five was excluded from synovectomy because synovial hypertrophy was minimal. Two of seven children recommended for prophylaxis were given substantially altered plans after MRI. In all, approximately 40% of joint assessments were modified as a result of the MRI findings. We conclude that MRI should be included in the evaluation of some children with hemophilic arthropathy.

Intracellular mechanisms governing the acute phase of beta-endorphin secretion from the corticotrope in vitro.

It is not certain which protein kinase (A, C or both) is involved in the acute phase of beta-endorphin (beta-EP) release stimulated in the corticotrope by vasopressin (VP) and corticotropin-releasing factor (CRF). We have employed an isolated ovine anterior pituitary cell superfusion system to determine the dynamic effects of forskolin, a protein kinase A (PKA) stimulator, and phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator. Both secretagogues stimulated beta-EP release within 5 min and therefore both PKA and PKC are potential mediators of the acute phase of hormonal stimulation of the corticotrope. Pretreatment with PMA specifically desensitized the pituitary cell columns to subsequent PMA exposure while not significantly altering sensitivity to forskolin or 50 mM KCl.

Desensitization of superfused isolated ovine anterior pituitary cells to human corticotropin-releasing factor.

Abstract We have employed an in vitro system to study the time-course of beta-endorphin (beta-EP) immunoreactivity release from anterior pituitary cells stimulated with corticotropin-releasing factor (CRF) and whether exposure to CRF desensitizes the cells to subsequent stimulation. Ovine anterior pituitaries were enzymatically disrupted into single cells, mixed with Siegel P2 and superfused in mini-columns with carbogen-gassed medium at 37 degrees C. Superfusate fractions were collected at 5-min intervals and beta-EP immunoreactivity in the eluate was measured by radioimmunoassay. Peaks of beta-EP release that rose significantly above baseline noise were detected using the PULSAR algorithm. Unstimulated cell columns did not display any spontaneous peaks of beta-EP discharge detectable by PULSAR whereas peaks were identified in the output of columns exposed to 1 nM CRF for 100 min. beta-EP release increased after 10 min of stimulation and maximum stimulated output was achieved after 20 min of continuous CRF exposure. Between 20 and 60 min of CRF stimulation the rate of beta-EP release declined progressively but stabilized in the last 40 min of the exposure at a level significantly above controls for baseline secretion. Peak duration did not depend on the inclusion of calcium in the superfusion medium while peak amplitude and area were significantly reduced when cells were denied extracellular calcium. Following a 100-min exposure to 1 nM CRF, pituitary cell columns were given a 30-min rest period then restimulated with either 1 nM CRF or 50 mM KCI for 20 min. The columns given prior exposure to CRF did not mount a response (detectable by PULSAR) to a subsequent dose of 1 nM CRF whereas PULSAR detected a clear response in all members of a control group that had not received prior CRF challenge. Both CRF exposed and control columns responded to 50 mM KCI although the response was significantly attenuated in the cells that had received prior CRF treatment. These results indicate that unstimulated superfused isolated ovine anterior pituitary cells do not possess an inherent rhythmicity of beta-EP release that can be detected by the PULSAR algorithm while treatment of the cells with CRF results in detectable discharge. The rapid response of beta-EP discharge to CRF treatment suggests the presence of intracellular beta-EP stores available for rapid mobilization. Continuous exposure to 1 nM CRF can tonically amplify corticotrope output for the duration of its presence in the environment of the corticotrope, but the maximum rate of release cannot be maintained. An inrush of extracellular calcium is not essential for the corticotrope to mount a detectable response to continuous CRF exposure but the release of a maximum amount of beta-EP relies on calcium entry. Long-term treatment with CRF prevents the corticotrope releasing a detectable peak of beta-EP on subsequent CRF stimulation and therefore CRF exposure leaves a lasting impression on the physiological machinery of the corticotrope. The attenuation of responsiveness to 50 mM KCI after long-term CRF treatment indicates that depletion of beta-EP stores may play a part in corticotrope desensitization although a reduction in CRF receptor number and an alteration in the intracellular mechanisms controlling beta-EP release may also be a factor.