Intracranial haemorrhage in von Willebrand disease: a report on six cases.

The incidence of intracranial haemorrhage (ICH) in von Willebrand disease (VWD) is not well documented. We describe our single centre experience regarding ICH in children with VWD and identify how such children presented and were managed. Thirty-three head trauma events leading to medical attention occurred in 24 of 153 children with VWD followed in our institution. In only 15 of these were computed tomography (CT) imaging studies performed; seven in children with type 1 VWD, one in a child with type 2N VWD and seven in children with type 3 VWD. In six of these 15 episodes an ICH was identified: two children with type 1 VWD, one child with type 2N VWD and three children with type 3 VWD. In two of the 6 cases an ICH was only confirmed following a second CT scan. Neurological symptoms, including vomiting (noted in all six), headache, irritability, lethargy and/or alteration in the level of consciousness were present in all children with confirmed ICH. In contrast vomiting, irritability and alterations in level of consciousness were never present in those children without confirmed ICH. All three children with type 3 VWD who experienced an ICH were commenced on long-term prophylaxis. ICH, although rare, does occur in children with VWD and particularly in children with type 3 VWD. A much larger cohort of patients with VWD experiencing an ICH is needed to make recommendations regarding treatment of such events, including the role of prophylaxis in patients with more severe forms of VWD.

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN).

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.

DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype.

In most individuals with moderate/mild haemophilia A, FVIII:C levels increase following DDAVP administration to a haemostatic range, thus avoiding the need for FVIII concentrates. We sought to determine the relationship between responsiveness to DDAVP in boys (<18 years old) with mild/moderate haemophilia and patient age, haemophilic severity and haemophilic genotype. Our cohort consisted of 13 boys with moderate and 61 boys with mild haemophilia who, between them, had 38 different mutations; 21 had unique mutations not shared by any other clinic patient, whereas 53 shared one of 17 mutations with some other clinic patient (included 26 boys with ≥ 1 haemophilic brother). Patient age and endogenous FVIII:C levels were strong predictors of response to DDAVP. Younger patients responded less well to DDAVP and 10 of the 11 patients, when retested at an older age, showed an improved response to DDAVP. Only 1 patient with moderate haemophilia responded to DDAVP, whereas 80% of patients with mild haemophilia responded (including all patients with an endogenous FVIII:C of >0.15 U mL(-1)). Almost all patients with the same mutation had the same response to DDAVP or only a minor discordance in response. Patient's age, disease severity and genotype all are predictors of response to DDAVP.

Expanded phenotype-genotype correlations in a pediatric population with type 1 von Willebrand disease.

BACKGROUND: Recent phenotype-genotype studies have provided valuable insights into the pathophysiology of type 1 von Willebrand disease (VWD); however, no study has examined an exclusively pediatric cohort. OBJECTIVES: To describe phenotype-genotype correlations in a selected pediatric cohort with a historical diagnosis of type 1 VWD, using first-degree family members as controls. METHODS: Comprehensive phenotypic assessment included standard assays of von Willebrand factor (VWF) level and function, bleeding score, desmopressin response, VWF propeptide (VWFpp) level, and platelet-derived VWF mRNA level. RESULTS: Fourteen VWF mutations were identified in 17 of 23 index cases (ICs) (aged 5-17 years), including four that were previously unreported (L60P, nt1658 insT, Q1388X, and C2237F). VWFpp levels were lower in ICs than in unaffected controls (median 49 vs. 86 U dL(-1) , P < 0.0001). A VWFpp/VWF antigen ratio of > 1.6 was observed in eight of nine ICs with a suboptimal response to desmopressin, including four of four with the R1205H (Vicenza) mutation (median 7.9), and three of four IC with the R1315C mutation (median 1.9). The R1315C mutation was also associated with a reduced absolute VWFpp level (median 32 U dL(-1) ), a previously unreported finding. The amount of platelet-derived VWF mRNA was significantly reduced in individuals with nonsense mutations. CONCLUSIONS: Increased VWF clearance and intracellular retention are important mechanisms underlying type 1 VWD in pediatric patients, concordant with the observations of larger, predominantly adult, cohort studies. Additionally, in some patients, nonsense-mediated decay of mutant mRNA transcripts may be contributory. Several mechanisms underlie the variable phenotype associated with the R1315C mutation. The potential utility of VWFpp as an independent marker of VWF biosynthesis and release warrants further research.

Dental disease in type 3 Von Willebrand disease: a neglected problem.

Type 3 Von Willebrand disease (VWD) is a rare, severe, autosomal recessive bleeding disorder. In our institution, we follow 17 children with type 3 VWD. We have observed a high prevalence of dental disease in these patients prompting us to undertake a retrospective review of our cohort of patients with type 3 VWD to catalogue the extent of their dental disease. Sixteen of these patients have been assessed by our dentistry department. Five children have undergone minor dental procedures (e.g. restorations, stainless steel crowns) and seven major procedures (e.g. dental extractions, pulpotomies and root canal treatments). These patients have collectively used 85,400 (ristocetin cofactor) IU of Humate-P on dental procedures alone. In addition to the considerable costs of factor are the cost of operating room time, dentists' costs, and the cost of other topical haemostatic agents (e.g. Tisseel) used during their dental procedures. As such there is considerable morbidity and cost from dental disease in these patients that is much higher than what is seen in patients with haemophilia or in the normal paediatric population. We speculate that the combination of these patients having a significant mucosal bleeding disorder together with various socioeconomic factors contribute to the significant degree of dental disease seen in this group of patients. We would suggest that better preventive dental care needs to be provided to these patients to avoid the considerable morbidity and very high burden of dental disease in type 3 VWD.

The use of prophylaxis in 2663 children and adults with haemophilia: results of the 2006 Canadian national haemophilia prophylaxis survey.

Prophylaxis is standard of care for boys with severe haemophilia A. Indications for prophylaxis in adulthood, non-severe haemophilia A, haemophilia B and haemophilia with inhibitors are less well defined. This survey, conducted in 2006, aimed to describe prophylaxis use in patients of all ages and severities with haemophilia A or haemophilia B in Canada. Data on 2663 individuals (2161 haemophilia A; 502 haemophilia B), including 78 inhibitor-positive patients, were returned by 22/25 Canadian haemophilia treatment centres. This represented 98% of the Canadian haemophilia population. Frequency of prophylaxis use, defined as infusion of factor VIII/IX concentrate at least once weekly for >/=45 weeks of the year, was highest in individuals with severe haemophilia A (69%). It was lower in individuals with severe haemophilia B (32%), moderate haemophilia A (18%) or B (5%) and mild haemophilia A (1%) or B (1%). Among individuals with severe haemophilia A, the frequency of prophylaxis use was 84% in children (18 years). Thirteen per cent of inhibitor-positive individuals were receiving prophylaxis with bypassing agents. Comparison with data obtained from a 2002 Canadian survey showed a greater use of prophylaxis in children

Intracranial bleeding in haemophilia beyond the neonatal period--the role of CT imaging in suspected intracranial bleeding.

We conducted a review of a single institutional experience of patients with haemophilia presenting with suspected intracranial haemorrhage (ICH) who underwent computed tomographic (CT) neuro-imaging. We found that over a 9-year period (1996-2004) 43 patients with haemophilia presented 73 times with suspected ICH: 10 presented multiple times (range: 2-9 times). The median age at presentation was 3.5 years (range: 0.5-17). Preceding trauma occurred in most (62/73; 85%) episodes. ICH was confirmed in 11 of the 73 (16%) episodes in eight patients. Patients with severe haemophilia accounted for a disproportionate number of episodes of suspected (60/73; 82%) and of confirmed ICH (10/11; 91%). All ICH occurred in patients not on prophylaxis; five occurred in three inhibitor-positive patients. Altered consciousness at presentation was present in 10/11 (91%) cases of confirmed ICH but only in 5/62 (8%) (ICH-negative) episodes. The positive and negative predictive values of altered consciousness to predict/rule out an ICH was 67% and 98%, respectively. The following were associated with an increased risk of presenting with suspected ICH and of having a confirmed ICH: (i) having severe haemophilia; (ii) not being on prophylaxis; (iii) having an inhibitor; and (iv) presenting with an altered level of consciousness. Patients without any of these features may not need to undergo CT imaging when presenting with suspected ICH. Ideally a prospective study to evaluate this hypothesis should be conducted.

Definitions for haemophilia prophylaxis and its outcomes: the Canadian consensus study.

The creation of acceptable standard definitions for terms used in the care and assessment of haemophilia patients has become increasingly important, as a growing number of international clinical studies have been initiated. The Delphi approach has been used in health research to reach consensus in large groups and can be used to develop definitions by using several iterations of surveys eliciting opinions from specialists in the field. Three consecutive surveys were designed based on the Delphi approach and distributed to specialist physicians, nurses and physiotherapists in order to develop definitions for seven haemophilia terms: 'primary prophylaxis', 'secondary prophylaxis', 'target joint', 'joint bleed', 'significant soft-tissue bleed', 'superficial soft-tissue bleed' and 'mucosal bleed'. Suggestions were solicited, compiled into a subsequent survey and fed back to the group to rank-order the importance of each suggested component of the definition. Final definitions were created using the top-ranked suggestions and sent back to the experts for approval. Five of the seven terms were highly endorsed with greater than 90% agreement. Some differences in agreement were found when analysed by profession. Haemophilia terms were successfully defined using the Delphi approach. Further refinement from members of the international haemophilia community will ensure that comprehensive standard definitions can be used in multicentre studies in the future.

Central venous catheter-related thrombosis presenting as superior vena cava syndrome in a haemophilic patient with inhibitors.

We report the case of a 10.5-year-old boy with severe haemophilia A (SHA) and inhibitors who presented with superior vena cava (SVC) obstruction while on immune tolerance induction (ITI) with daily recombinant factor VIII (rFVIII) and factor eight bypassing activity (FEIBA) (75 U kg(-1)) twice a week. The boy had a right-sided implanted central venous catheter. Imaging revealed a large occlusive thrombus in the SVC with all upper venous system drainage occurring through the azygos and collateral veins. Despite initial success with local thrombolytic therapy using recombinant tissue plasminogen activator, the thrombus persisted. Mechanical thrombolysis and angioplasty resulted in the successful removal of the thrombus and resolution of the SVC syndrome. Unfractionated heparin was used to prevent thrombus reformation/propagation. A work-up did not reveal any underlying genetic prothrombotic risk factors. The occurrence of such a profoundly symptomatic thromboembolism (TE) in a boy with SHA with inhibitors is unusual. A combination of risk factors, including the ongoing infusion of high doses of FVIII in the context of a disappearance of inhibitors together with the infusion of clotting factors known to be potentially thrombogenic, may place haemophilic patients on ITI (immune tolerance induction) at risk for this rare, life-threatening complication. The appropriate management of TEs in such a setting is unknown.

Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A.

BACKGROUND: Inhibitors are rare in boys with mild hemophilia A (MHA; factor (F)VIII:C > 5%) but may arise following intense FVIII exposure, e.g. continuous infusion (CI). OBJECTIVES: To determine the impact of intense FVIII exposure in inhibitor formation in MHA at our institution and to compare this with previous reports. PATIENTS AND METHODS: We reviewed FVIII exposure and inhibitor development in boys (ages 0-18 years) with MHA followed at our institution from 1996 to 2001 and conducted a Medline search (1966-2002) on the experience of inhibitor development following intensive/CI exposure to FVIII. RESULTS: We identified 54 boys with MHA. Twenty-nine (54%) had been exposed to FVIII. Seven had received FVIII by CI. Four developed inhibitors; three high titer (at ages 10 years, 16 years and 17 years) and one low titer (at 1 month old). All four had received a CI of recombinant (r) FVIII of at least 6 days within 6 weeks of developing inhibitors. Baseline FVIII levels fell to < 1% in all cases and the three with high-titer inhibitors developed severe bleeding. Immune tolerance therapy (ITT) was attempted in two boys and was successful in one. Our literature search identified 35 cases (only four children) with MHA developing inhibitors following intense FVIII exposure often in the context of surgery. CONCLUSIONS: The incidence of inhibitors in our MHA population was 7.4%. If expressed according to exposure the incidence was significantly higher: 14% (4/29) for any exposure to FVIII and 57% (4/7) for exposure by CI. A prospective study to address whether CI is associated with an increased incidence of inhibitor development in MHA is warranted.

Hemoglobin H (Hb H) disease in Canada: molecular diagnosis and review of 116 cases.

Over the past decade, we have characterized at the DNA level a total of 116 hemoglobin H (Hb H) disease patients living in Canada. The majority of patients were of southeast Asian descent (Chinese, Filipino, Laotian, Vietnamese), with a small number being of Mediterranean, Middle Eastern or East Indian background. A total of 15 distinct genotypes were detected, all but one being compound heterozygotes for a two-gene cis deletion and a single-gene deletion (-alpha/-) or a non-deletion mutation of the alpha2-globin gene (alpha(T) alpha/-). Seven different two-gene cis deletions were encountered, along with nine single-gene deletions and point mutations. The wide range of mutations associated with Hb H disease in Canada is a reflection of the population heterogeneity. The diagnosis of Hb H disease at the molecular level is important with respect to genetic counseling and the identification of families at risk for having pregnancies affected with Hb Bart's hydrops fetalis syndrome and/or Hb H disease. Six of the Hb H disease patients in our cohort had spouses who carried single-gene deletions, making these couples at risk for having children with Hb H disease. More important, seven patients had partners who carried two-gene cis deletions. These couples are at reproductive risk for both Hb Bart's hydrops fetalis syndrome and Hb H disease.

Identification of two new alpha-thalassemia mutations in exon 2 of the alpha1-globin gene.

The most common causes of alpha-thalassemia are deletions that remove one or both of the functional alpha-globin genes. In addition, more than 30 different point mutations and small deletions/insertions have been reported for the alpha-globin genes. Here, we describe two new mutations occurring in exon 2 of the alpha1-globin gene. One mutation is an insertion of 21 bp that gives rise to a predicted alpha-globin chain containing a duplication of amino acid residues 93-99. The second mutation is a 33 bp deletion resulting in a predicted alpha-globin chain that is missing amino acid residues 64-74. Neither mutation results in a detectable hemoglobin variant, indicating that the variant alpha-globin chains are highly unstable. Carriers of these mutations have mild microcytosis and the phenotype of alpha+-thalassemia trait.

von Willebrand disease in a pediatric-based population--comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay.

Definitive diagnosis of type 1 von Willebrand Disease (VWD) remains a problem. Provisional consensus guidelines for the diagnosis of definite and possible type 1 VWD were prepared by the Scientific Subcommittee on von Willebrand factor (VWF) of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) during the 1996 annual meeting for the specific purpose of further evaluation in retrospective and prospective studies by a Working Party on Diagnostic Criteria (1996 Annual Report of the SSC/ISTH Subcommittee on VWF). In the first phase of this study, we compared 2 definitions of type 1 VWD. each with 3 criteria: significant bleeding history, laboratory investigations, and family history. Using the ISTH consensus guidelines for type 1 VWD definition, significantly fewer patients were diagnosed with definite type 1 disease as compared to our "in house" Hospital for Sick Children (HSC) criteria (4 vs. 31). While we recognize that the provisional ISTH consensus guidelines were not intended for clinical use, we believe that the results of our studies are of interest and will assist in any future refinements to the ISTH guidelines. In the second phase of this study, we investigated the utility of 2 new tests, a laboratory screening test and a functional test, for VWD in our well characterized, pediatric-based population. The Platelet Function Analyzer (PFA-100) provides an in vitro measure of primary hemostasis under conditions of high shear, using disposable cartridges containing collagen and either epinephrine or ADP. All tested subjects with types 2 or 3 VWD had prolonged PFA-100 closure times (CTs) with both cartridge types (n = 17) and prolonged bleeding times (n = 14). In subjects with definite type 1 VWD, 20/24 (83%) had prolonged CTs with the collagen/ADP cartridge (19/24 (79%) with collagen/epinephrine), compared with 7/26 (27%) with prolonged bleeding times. In subjects with definite types 1, 2, or 3 VWD, collagen/ADP CTs were abnormal in 37/41 subjects, giving an overall sensitivity of 90%. With this high sensitivity, the PFA-100 is a better screening test for VWD than the bleeding time. We also tested a VWF collagen-binding assay (VWF:CBA) as a functional test for VWF, in comparison with the more routinely-used ristocetin cofactor assay (VWF:RC0). The VWF:CBA is based on an ELISA technique, which has the potential to be more reproducible than the VWF:RC0. We found that the VWF:CBA detected 43/49 (88%) subjects with definite types 1, 2, or 3 VWD, performing as well as the VWF:RC0, that detected 42/48 (88%). We also showed that, used in conjunction with VWF antigen levels, the VWF:CBA may be useful in classification of VWD subtypes.

Renal-cell carcinoma in children: a different disorder from its adult counterpart?

BACKGROUND: Renal-cell carcinoma (RCC) is a rare tumor in children. To address whether RCC in children differs from its adult counterpart, we report a series of 16 children with RCC (5 boys, 11 girls, mean age 9.6 years, range 3-19 years) presenting between 1979 and 1996 at three pediatric centers. PROCEDURE: Pathology showed papillary RCC in five patients (31%). Nonpapillary tumors were present in 11 (69%), of which nine were clear-cell type (56%), one was chromophobe-cell type (6%), and one was granular-cell type (6%). Cytogenetic studies were performed on four. RESULTS: In two tumors, normal karyotypes (45,XX or 45,XY) were found. In another, there were translocations: t(X;1), t(X;2) and t(6;14). In the fourth, analysis revealed 46,XX/46,X,t(X;17)(p11.2;q25),t(1;12). Several features in this series differ from those reported in adults. In adults, RCC is more frequent in males, is usually nonpapillary, and is characterized cytogenetically by deletions or rearrangements in the short arm of chromosome 3. In contrast, in our series there was no male predominance and a higher proportion of papillary tumors. In addition, two of four cytogenetically analyzed tumors had translocations involving the X chromosome. Translocations involving the Xp11.2 locus have been infrequently reported in both adults and children with papillary RCC. CONCLUSIONS: The higher frequency of papillary histology and the presence of translocations involving Xp.11.2 in two cases raise the possibility of a unique subtype of RCC in children.

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg(-1) kg(-1) d(-1) for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 x 10(9) l(-1). Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 x 10(9) l(-1) within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.

Sequential use of intravenous and oral acyclovir in the therapy of varicella in immunocompromised children.

BACKGROUND: Immunocompromised children are at risk for disseminated varicella infections. Standard management involves hospitalization and intravenous acyclovir for 7 to 10 days. This approach is expensive, is inconvenient and may not be necessary. We undertook a pilot study to assess the safety and efficacy of an alternative approach that utilized a combination of intravenous (i.v.) followed by oral (p.o) acyclovir in a cohort of immunocompromised children. METHODS: The cohort consisted of 26 immunocompromised children between the ages of 1.5 and 12.7 years (mean, 6.3). Therapy was commenced with i.v. acyclovir (1500 mg/m2/day in 3 divided doses). Concurrent management included holding or reducing immunosuppressive therapy (by 50%) and administering varicella-zoster immunoglobulin in 69% (11 of 16) of cases where exposure to chickenpox was recognized. Patients were eligible to switch to p.o therapy after receiving a minimum of 48 h of i.v. acyclovir therapy provided they were afebrile; had no new lesions for 24 h; had no internal organ involvement and were able to tolerate oral medications. Patients were observed in hospital for a further 24 h and then discharged provided they remained well. Oral acyclovir was continued for a total of 7 to 10 days (i.v. plus p.o). RESULTS: Of the 26 patients 25 were successfully switched from i.v. to p.o after 4.1 +/- 1.2 days (mean +/- SD) (range, 2.3 to 6) Children had fever for a mean of 2.0 +/- 1.6 days (range, 0 to 5) and developed new lesions for 2.9 +/- 0.7 days (range, 2 to 4). All 25 patients switched to p.o therapy had resolution of their disease and no patient required resumption of i.v. therapy. CONCLUSIONS: The sequential use of i.v. followed by p.o acyclovir is feasible in the treatment of varicella in immunocompromised children and results in a reduction in duration of intravenous therapy and hospitalization.