Ann Marie Stain

Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

Summary.  When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti‐CD20 monoclonal antibody, which has shown promise in the treatment of B‐cell‐mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m−2 of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half‐life). Patients are concurrently placed on recombinant FVIII (100 U kg−1 day−1). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non‐responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.

Sonography for assessment of haemophilic arthropathy in children: a systematic protocol

Summary.  Radiological imaging of joints in children with haemophilia is important to detect abnormalities, grade their severity and monitor the effects of treatment. Scoring systems for staging haemophilic arthropathy have been developed based on plain film or magnetic resonance imaging (MRI) findings. Radiographs alone may be inadequate for evaluating joint disease in children with haemophilia on prophylaxis while MRI may be difficult to access and require the child to be sedated. Sonography can be a useful complementary modality in the evaluation of haemophilic arthropathy that is readily available and does not require the child to be sedated. In this paper, we briefly review the current imaging scales available for the assessment of haemophilic arthropathy and present a systematic protocol for sonographic assessment of the knee and ankle in haemophilic children along with examples of findings in joint effusion/hemarthrosis, synovial hypertrophy and cartilage loss. Also, we correlate the ultrasound findings with the corresponding MRI images demonstrating the anatomic planes used for imaging acquisition. Sonography is a promising technique for the assessment of soft tissue changes which are the earliest findings in haemophilic arthropathy. Further investigation is required for evaluation of osteochondral changes given limitations of sonography in this regard and in minimizing operator dependency, especially if applied in multicentric clinical trials.

A prospective, longitudinal study of central venous catheter-related deep venous thrombosis in boys with hemophilia.

Summary.  Background: Central venous catheters (CVCs) are often inserted into boys with hemophilia to secure venous access for factor prophylaxis and immune tolerance induction therapy. Complications associated with CVCs include catheter‐related infections, local hemorrhage, and mechanical failure. Less frequently reported is CVC‐related deep venous thrombosis (DVT). We conducted a prospective study to determine the frequency and outcome of this complication. Methods: All boys (n = 16) with congenital hemophilia A or B with a CVC in place who were registered in the pediatric comprehensive care program at the Hospital for Sick Children, Toronto, were included in the study. They were prospectively assessed by imaging studies and clinical examinations for CVC‐related DVT at two time‐points, 2 years apart. Each boy was evaluated for inherited hypercoagulability. Results: Eleven (69%) of the 16 boys had radiological evidence of DVT at the first evaluation and 13/16 (81%) at the second evaluation. In two boys there was improvement in the venogram findings at the second evaluation. None of the CVC‐related DVTs completely resolved. Median age at the time of initial insertion of a CVC was 1.0 years (range 0.02–6.7 years). Median duration of CVC placement was 6.4 years (range 3.3–15.5 years). Only 4/13 boys with DVTs had clinical evidence of upper venous system obstruction. Only one boy, who did not develop a DVT, had a low protein C level. Conclusions: CVC‐related DVTs occur in the majority of boys with hemophilia who have CVCs inserted for a prolonged period of time. Annual screening with imaging is recommended for boys with CVCs in place for ≥ 3 years. Consideration should be given to removing CVCs as soon as peripheral venous access is feasible.

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

Summary.  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.

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

Summary.  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.

DDAVP challenge tests in boys with mild/moderate haemophilia A*

Summary. Desmopressin (DDAVP) increases plasma factor VIII coagulant activity (FVIII:C) levels in patients with mild/moderate haemophilia A. In some subjects, FVIII can be increased to haemostatic levels, thereby avoiding use of factor VIII concentrates. We reviewed our hospitals experience with 62 boys with FVIII:C levels 0·01–0·3 IU/ml who had a DDAVP challenge test (i.v. 0·3 µg/kg) following diagnosis. A therapeutic response was defined as a 1 h post‐FVIII:C increase at least twofold over baseline and > 0·3 IU/ml. Of the total group, 29 (47%) boys responded to DDAVP, all of them with mild haemophilia (baseline FVIII:C ≥ 0·05 IU/ml), yielding a response rate of 57% in this subgroup. Boys who responded to DDAVP had higher baseline FVIII:C levels (mean ± SEM, 0·17 ± 0·01 vs 0·10 ± 0·01 IU/ml, P < 0·01) and were older (5·2 ± 0·8 vs 3 ± 0·4 years, P = 0·02) than those who failed to do so. The association between DDAVP response and age, however, remains unclear: seven boys who failed the initial challenge test responded to re‐challenge after a mean of 6·3 years (median 4·9, range 0·5–12·5), increasing the response rate in boys with mild haemophilia to 71%. Age and FVIII:C association with DDAVP response are both important in boys with mild/moderate haemophilia A. Absence of response to DDAVP should therefore be confirmed by later re‐challenge.

Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability

Summary.  Understanding the pharmacokinetics (PK) of factor VIII (FVIII) is important in the management of patients with haemophilia A. We studied the PK of FVIII in order to determine aetiological factors contributing to PK variability of FVIII in children.

Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010.

The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL−1). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty‐four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high‐risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg−1 day−1 X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99–1.23) with each increase of 100 dose‐intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14–27.17) and 5.08 (95% CI: 1.11–23.31) respectively. ID according to FVIII concentrate used was: Advate ® 18/50 (36%), Kogenate FS® or Helixate FS® 15/36 (42%), Wilate® 0/11 and Xyntha® 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11–122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08–18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure.

Therapeutic consequences for misdiagnosis of type 2N von Willebrand disease.

Patients presenting with a low FVIII:C and with normal VWF levels are usually presumed to have hemophilia (males) or be carriers for hemophilia (females). Some of these patients may instead have VWD:2N. Such patients if misdiagnosed are likely to suffer from insufficiently treated bleeds. We report 2 males and 1 female who presented with a low FVIII:C (1–21%) and minimally reduced/normal VWF and were assumed to have, or be a carrier for, hemophilia A. Eventually all were found to have VWD:2N. Prior to the correct diagnosis the males had been treated with rFVIII with poor responses and ultimately adverse clinical consequences. Pediatr Blood Cancer 2011; 57: 1081–1083.

Consequences of delayed therapy for sports-related bleeds in patients with mild-to-moderate haemophilia and type 3 von Willebrand's disease not on prophylaxis.

two of the reported mutations involve cysteine residues and as cysteines are critical for VWF folding and multimerization, this change would have profound biological and hence clinical significance in this type of disease. We have also demonstrated the highly conserved nature of Cys410 across a number of species. Our patient has major bleeding symptoms, and aside from the suggested defective synthesis of large multimers, it is highly likely that as seen from the recombinant expression studies together with the DDAVP data, there may be an almost total absence of functional VWF. In a recent novel study by Zhou et al., [9], using electron microscopy (EM) of the VWF at molecule level, the authors report a detailed account of disulphide linkages and the structure of homologous domains of VWF with further sequence analysis and tests of domain boundaries by truncation. In combination with EM findings, these studies provide a comprehensive view of the architecture of individual domains and how they are organized within the VWF. These findings have furthered the role of D1 and D2 domains and have clarified their role on how mature VWF is stored and finally released from the Weibel-Palade bodies. Identification of mutations causing type 2A(IIC) VWD, together with such comprehensive studies of VWF molecule domains would help in better understanding of VWF and VWD. In summary, we have identified a homozygous p.Cys410Ser mutation in a family with type 2A(IIC) VWD. Expression of this mutation simulated the defective secretion of abnormal VWF as seen in the homozygous patients, but not the heterozygous parents or the brother, indicating the recessive nature of this mutation causing this sub-type compared with the other dominant type 2 VWD. Although the phenotypic testing of these families would aid the diagnosis of these very rare sub-types genetic testing would confirm and identify the pathogenic mechanism of these haemostatic abnormalities. An assured diagnosis would also help in providing a better genetic counselling in countries, such as Iran, where these diseases are more common due to widespread practice of consanguineous marriage.