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.

MASAC Consensus Conference: impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders.

A consensus conference conducted by the Medical and Scientific Advisory Council of the National Hemophilia Foundation was held in New Orleans, LA, on November 11, 2010, to discuss the impediments to conducting clinical research in persons with haemophilia, von Willebrand's disease and rare bleeding disorders. The conference combined presentations providing academic, non-profit and industry perspectives with periods of open discussion. The objective of this conference was to identify the many challenges involved in facilitating U.S. Food and Drug Administration approval of innovative products for these patient populations.

Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations.

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders.

We performed quantitative PCR-based serial chimerism testing of whole blood (WB) and CD3+ cells and retrospectively correlated the results of chimerism tests and the risk of graft loss in children undergoing transplant for non-malignant disorders. Twenty-four children were included in this study. All patients initially engrafted; subsequently, 12% lost the graft, 21% achieved complete donor chimerism and 67% had mixed chimerism (MC). Patients underwent delayed taper of cyclosporine (CsA) if they had MC. Overall survival was 87+/-7% (s.d.) at 5-years post transplant, and it was not affected by chimerism status. Both WB and CD3+ chimerism showed significant fluctuations with a peak in autologous cell signal occurring at a median of 7 months for WB and 2 months for CD3+ cells. Initial post transplant chimerism percentage in either WB or CD3+ lineage was not related to graft loss. Increasing MC to >30% host cells was seen in 33% of patients, and it was related to increased risk of graft loss, as previously published. However, 63% of children with increasing MC did not lose their graft. Additional studies of post transplant chimerism are required to improve our ability to accurately identify children at risk of graft loss following transplant for non-malignant disorders.

Factor V deficiency: a concise review.

Factor V (FV; proaccelerin or labile factor) is the plasma cofactor for the prothrombinase complex that activates prothrombin to thrombin. FV deficiency can be caused by mutations in the FV gene or in genes encoding components of a putative cargo receptor that transports FV (and factor VIII) from the endoplasmic reticulum to the Golgi. Because FV is present in platelet alpha-granules as well as in plasma, low FV levels are also seen in disorders of platelet granules. Additionally, acquired FV deficiencies can occur in the setting of rheumatologic disorders, malignancies, and antibiotic use and, most frequently, with the use of topical bovine thrombin. FV levels have limited correlation with the risk of bleeding, but overall, FV-deficient patients appear to have a less severe phenotype than patients with haemophilia A or B. The most commonly reported symptoms are bleeding from mucosal surfaces and postoperative haemorrhage. However, haemarthroses and intramuscular and intracranial haemorrhages can also occur. Because no FV-specific concentrate is available, fresh frozen plasma remains the mainstay of treatment. Antifibrinolytics can also provide benefit, especially for mucosal bleeding. In refractory cases, or for patients with inhibitors, prothrombin complex concentrates, recombinant activated FVIIa, and platelet transfusions have been successfully used. Some patients with inhibitors may also require immunosuppression.

Risk of human immunodeficiency virus type 1 infection among sexual and nonsexual household contacts of persons with congenital clotting disorders.

The status of human immunodeficiency virus type 1 (HIV-1) infection at the time of transmission to sexual contacts remains poorly defined. Transmission to nonsexual household contacts has appeared to be rare. A total of 505 sexual and nonsexual contacts of HIV-1-infected hemophiliacs in 349 households was observed. At entry, 10% of 201 sexual partners were anti-HIV-1-positive. Follow-up of 151 uninfected partners during a total of 351 person-years of observation showed no sero-conversions, although there were 13 pregnancies during that period. Eighty-seven percent of the seronegative respondents to a detailed questionnaire reported unprotected sexual contact at least occasionally. Among 304 other household members, including 108 parents who helped administer clotting factor concentrates to their children, none was seropositive at entry. Follow-up of 263 showed no seroconversions during a total of 605 person-years of observation. Thus, anti-HIV-1-positive hemophiliacs transmitted to their partners earlier in their course but were not found to do so when prospectively observed. No relationship to level of viremia as indicated by CD4 count, HIV-1 p24 antigenemia, or acquired immunodeficiency syndrome was found. Anti-HIV-1-positive hemophiliacs had not transmitted to their nonsexual household contacts before study entry and did not do so subsequently, indicating that the risk from even close nonsexual contact is extremely low.

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.

Prenatal diagnosis of hemophilia involving grandpaternal mosaicism.

Our Factor VIII and RFLP analyses identified previously unreported grandpaternal hemophilia A mosaicism in a male who transmitted the disease allele to 2 of 4 daughters and 2 of 4 grandsons. An uncommon flanking polymorphic DXS52 allele cosegregated with this grandpaternal mutant allele. This and other reports of mosaic hemophilia A carriers indicate that parental mosaicism can explain unusual segregation of low Factor VIII activities and DNA polymorphisms in about 1% of hemophilia A pedigrees.

Genetic mutations in ten unrelated American patients with symptomatic type 1 protein C deficiency.

Symptomatic patients with Type 1 protein C deficiency and venous thrombosis were analysed for defects in this gene using polymerase chain reaction amplification and direct sequencing of all nine exons. Ten different heterozygous point mutations were detected in 19 patients from eleven American families. Seven represent novel mutations. Two of these were found in the TATA box or near the transcription initiation site and presumably lead to loss of transcription, and seven missense mutations were found including G103R, P168L, R169W, I201T, P279L, T298M, and C384Y. These may lead to abnormal folding or thermodynamic instability of the protein C molecule, potentially causing abnormal secretion or rapid clearance from the circulation. Two other protein C mutations, a nonsense mutation at codon Trp-145 and a deletion inducing a frameshift at codon 364 resulting in premature termination at codon 378, likely lead to unstable products. The previously published R169W mutation resulted in a Type 1 deficiency. The data show that diverse molecular defects result in similar phenotypes and emphasize that a wide variety of mutations are responsible for Type 1 protein C deficiency in the American setting of a diverse population.

Perioperative management of von Willebrand's disease in otolaryngologic surgery.

von Willebrand's disease (VWD) is the most common hereditary bleeding disorder. Unchecked or improperly managed, VWD-associated hemorrhage can lead to catastrophic surgical outcome. Based on the authors' recent experience with 21 procedures in 12 patients, a contemporary protocol for successful perioperative management of VWD in otolaryngologic surgery is presented. In patients with VWD type 1 or 2a, desmopressin, a synthetic vasopressin analog, is administered both pre- and postoperatively to release von Willebrand factor (VWF) from storage sites. In type 2b or 3, a factor VIII concentrate rich in VWF is administered. In addition, a 10- to 14-day course of intravenous and/or oral Amicar (Immunex Corp., Seattle, WA) may be prescribed postoperatively. Intraoperatively, the surgical laser is used to further decrease blood loss and augment hemostasis. This medical and surgical protocol minimizes the risk of hemorrhage and of transfusion-related complications through the judicious use of preoperative and postoperative coagulation replacement products. Using these guidelines in a variety of otolaryngologic cases, the authors have had no bleeding complications at their institution.

Management of hemophilia in otolaryngologic surgery. A contemporary protocol.

Hemophiliacs are well known to be among the high-risk groups for acquiring acquired immunodeficiency syndrome due to their frequent exposure to pooled blood products. We reviewed our recent experience involving hemophiliacs undergoing a variety of otolaryngologic surgical procedures. A protocol was developed to minimize the risks of hemorrhage through the judicious use of preoperative and post-operative coagulation replacement products. Modern hemostatic techniques, such as the use of the surgical laser, also had a role in lessening the incidence of bleeding problems. The relative risks of the various hemostatic products with regard to the transmission of communicable diseases such as acquired immunodeficiency syndrome and hepatitis were evaluated. Recent data suggest that heat treatment of factors VIII and IX concentrates eliminates the risk of acquired immunodeficiency syndrome transmission, and these heated concentrates should be used in preference to older products. Hepatitis remains a problem, but this risk may be reduced to some degree through immunization with hepatitis B vaccines that have recently been proved safe and effective.

In utero arterial embolism from renal vein thrombosis with successful postnatal thrombolytic therapy.

Thromboembolic events in the pediatric age group occur most commonly in neonates, and newborns of diabetic mothers are particularly at risk. We report a newborn with right renal vein and inferior vena cava thrombosis who apparently embolized across the foramen ovale antenatally with resultant right brachial artery occlusion. The baby was delivered by cesarean section from an insulin-dependent diabetic mother. At the time of birth, there was severe right arm ischemia with absent brachial and radial pulses. There was clinical evidence of distal embolization with a "trash" lesion of the distal right middle finger as well as a midforearm area of full-thickness skin loss. Ultrasound demonstrated a right renal vein thrombosis and a 95% occlusion of the inferior vena cava. Regional urokinase therapy was instituted through a lower extremity vein with a 5,000 U/kg bolus and then 5,000 U/kg/h continuous infusion. Twelve hours of infusion of urokinase led to clinical resolution of the right arm ischemia, with return of pulses. Follow-up ultrasound showed the right renal vein thrombosis and inferior vena cava clot to be completely resolved. The right middle finger and forearm lesions subsequently have healed primarily. We report this as a case of in utero arterial embolization with successful postnatal therapy using regional urokinase infusion.

Relapsing post-hepatitis aplastic anemia. Immunosuppressive therapy.

A 20-month-old Hispanic male developed severe aplastic anemia after an episode of non-A, non-B hepatitis. Prompt and complete recovery of all hematopoietic cell lines occurred after treatment with antithymocyte globulin (ATG) and high-dose corticosteroids. Severe aplasia recurred two months later coincident with a mild upper respiratory infection. A second course of immunosuppressive therapy was followed by complete, sustained improvement. The authors' experience provides clinical evidence indicating that immunologic mechanisms are important in the treatment of severe post-hepatitis aplastic anemia. Children in whom aplastic anemia recurs after immunosuppressive treatment may respond to a second course of therapy.

Variability in serial CD4 counts and relation to progression of HIV-I infection to AIDS in haemophilic patients. Transfusion Safety Study Group.

OBJECTIVE--To examine the CD4 count and its near term changes relative to progression to AIDS within 30 months and to subsequent CD4 counts. DESIGN--Longitudinal clinical and laboratory study. SETTING--Haemophilia treatment centres in six large American cities. PATIENTS--555 people with congenital clotting disorders who were infected with HIV, initially without AIDS, and seen at follow up for 6-30 months in 1986-9. MAIN OUTCOME MEASURES--Absolute CD4 counts and incidence of AIDS. RESULTS--Outset CD4 count and age were independently related to progression to AIDS (p less than 0.0001 and p less than 0.005 respectively). Patients with CD4 counts of 0.30-0.49 x 10(9) cells/l had an age adjusted risk of AIDS within 30 months of only 9% that of patients with counts less than 0.20 x 10(9)/l. Children under 10 years old had only 16% of the CD4 adjusted risk of AIDS of people aged greater than or equal to 45 years. Analysis of 149 patients' CD4 counts at the beginning and end of two successive six month intervals showed an average decrease of 11% in each six months regardless of the outset count (greater than or equal to 0.20 x 10(9)/l). For individual patients the decrease in the second six month period was unaffected by the decrease in the first six month period. CONCLUSIONS--Antiviral treatment of asymptomatic people, particularly children, with CD4 counts greater than or equal to 0.3 x 10(9)/l is questionable if predicted on near term progression to AIDS. Because of individual CD4 count variability and the low rate of progression to AIDS near term declines in individual CD4 counts are a poor index for identifying people who will rapidly progress to AIDS.

PMNs in normal spinal fluid examined by the cytocentrifuge technique.

The presence in unconcentrated CSF specimens of even a single polymorphonuclear (PMN) cell has been regarded as diagnostic of central nervous system (CNS) disease. In 18 of 50 consecutive cytocentrifuged specimens obtained from patients without evidence of CNS disease, however, we found 1 to 6 PMN cells. The observation of occasional PMN cells in concentrated CSF specimens does not appear to be diagnostic of a CNS abnormality.

Serum iron concentration and transferrin saturation in the diagnosis of iron deficiency in children: normal developmental changes.

A group of 359 healthy children and 49 adults were studied for the purpose of estimating the normal limits for serum iron concentration and transferrin saturation. The 144 children and seven adults who has any other laboratory evidence of iron deficiency (abnormal values of serum ferritin, free erythrocyte protoporphyrin, hemoglobin concentration, or mean corpuscular volume) were excluded. In evaluating the 215 children and 42 adults who met the criteria to be considered normal we found that serum iron concentration and transferrin saturation were significantly lower in children between the ages of 0.5 and 12 years than in adults. We conclude that in children between the ages of 0.5 and 12 years, a transferrin saturation of less than 16% constitutes good evidence of iron deficiency only in conjuction with anemia and low mean corpuscular volume.

Utilization of care in haemophilia: a resource-based method for cost analysis from the Haemophilia Utilization Group Study (HUGS).

The Haemophilia Utilization Group Study (HUGS) was created 10 years ago to examine the annual utilization and cost of haemophilia-related healthcare services. Retrospective chart reviews for 336 patients with haemophilia A receiving treatment in one of five comprehensive haemophilia treatment centres (HTCs) during 1995 were completed through interview of the provider. This method provided adequate collection of data from patient charts without the abstractor having direct access to patient health information. Utilization data were used to impute the costs of different components of care (e.g. physician visits, factor VIII concentrate, emergency room, hospitalization). The total annual cost of care was 139,102 dollars (SD $304,033). Factor VIII concentrate costs comprised the largest proportion of these costs; mean factor VIII concentrate use was 128,517 units per patient per year. Unbilled physician utilization accounted for 7.8% of the mean total physician costs per annum, while mean allied healthcare costs accounted for 33.5% of the total annual allied healthcare costs per patient. In the ordinary least-squares regression model, higher costs were associated with severe factor VIII deficiency, arthropathy, more comorbid conditions, an inhibitor to factor VIII concentrate, infusing through a port and prophylaxis. Although factor VIII concentrate is the most costly component, the treatment of haemophilia uses many healthcare resources. HUGS has demonstrated that patient clinical characteristics and physician practices predominantly drive the costs of haemophilia care. Specifically, patients with more severe arthropathy had greater healthcare costs. As future funding decisions are made, it is important to provide for all components of care.

Anemia in patients with juvenile rheumatoid arthritis.

Patients with juvenile rheumatoid arthritis may have an anemia attributable to the chronic disease, to iron deficiency, or to a combination of the two. The contribution of iron deficiency is often difficult to determine by routine laboratory studies. We studied 51 patients with pauciarticular and polyarticular juvenile rheumatoid arthritis with red blood cell counts, indices, free erythrocyte protoporphyrin, and serum ferritin. Fifteen of the 18 who were anemic were restudied after a 3 to 6-month period of iron therapy. Thirteen of the 15 responded by these criteria: a rise in hemoglobin of 1.0 gm/dl or more and an increase in mean corpuscular volume of 3 fl or more; in 11 of these 13, hemoglobin values returned to the normal range for age. These findings indicate that iron deficiency can be a major component of the anemia that is commonly found in patients with active juvenile rheumatoid arthritis.

Magnetic resonance imaging of transfusional hemosiderosis complicating thalassemia major.

Tissue deposits of hemosiderin, a paramagnetic iron-protein complex, resulted in marked abnormalities of magnetic resonance (MR) spin-echo signal intensity within the viscera of three children with transfusional hemosiderosis and thalassemia major. In all patients the liver and bone marrow demonstrated abnormally low spin-echo intensities and the kidneys and muscles had abnormally high intensities. These observations correlate with in vitro MR observations of ferric (Fe+3) solutions, in which concentrations of ferric salts greater than 20 mmol yielded a low MR intensity signal and ferric concentrations less than 15 mmol yielded higher intensities than did water alone. MR imaging is sensitive to the tissue deposition of hemosiderin, and MR intensity appears to provide a rough measure of the amount of iron deposited.