First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study.

INTRODUCTION/BACKGROUND: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. AIM: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. PATIENTS/METHODS: Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h. RESULTS: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. CONCLUSION: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.

BACKGROUND: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. OBJECTIVES: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. PATIENTS/METHODS: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. RESULTS: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. CONCLUSIONS: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.

Atypical haemolytic uremic syndrome complicated by microangiopathic antiphospholipid-associated syndrome.

A 4-year-old boy with an atypical course of haemolytic uremic syndrome (HUS), who developed microangiopathic antiphospholipid-associated syndrome (MAPS) with signs of multiple organ failure during the course of his disease, is reported. Early and aggressive treatment with intravenous gammaglobulin, pulse methylprednisolone and plasmapheresis resulted in an excellent clinical recovery. Our patient showed a concomitant presence of multiple factors that could precipitate atypical HUS, including positive antiphospholipid antibodies, decreased level of factor H and positive anti-ADAMTS-13 antibodies. We suggest that, along with infections, autoimmune conditions or defined genetic abnormalities of complement regulatory genes, MAPS should be considered among the pathogenic mechanisms in patients with atypical HUS.

The co effect of prophylaxis and radiosynovectomy on bleeding episodes in haemophilic synovitis.

Prophylactic substitution treatment and radiosynoviorthosis have a leading role in preventing irreversible haemophilic arthropathy. The aim of the study was to evaluate the effects of prophylaxis treatment and radiosynovectomy on the length of intervals between subsequent haemorrhages in haemophilic patients. Thirty-three joints were treated with radiosynovectomy in 28 patients with bleeding disorders. (90)Y colloid was used in knees and (186)Re colloid for elbows, shoulders and ankles. Twenty patients were on prophylaxis. Joint X-rays were evaluated on the Pettersson scale between 0 (normal) and 13 (severe joint destruction). During an observation period (range 6-44 months) bleeding episodes were recorded and data statistically analysed. Before radiosynovectomy, increasing intensity of the prophylaxis 10% lengthens intervals between two haemorrhages by 1% (P < 0.05). In patients with a Pettersson score higher than nine, intervals between bleedings are shorter by 73% (P < 0.05), in comparison with patients with lower Pettersson scores of 0-5. After radiosynovectomy, the length of the first non-bleeding interval increased by 120% (to 60 days) in comparison with the intervals before the procedure (P < 0.001). But, in the following year and half, every subsequent non-bleeding interval was 8% shorter (P < 0.1). In that period, prophylaxis shortened the non-bleeding interval by 1.7% (P < 0.05) per 10% increase of its intensity. Radiosynovectomy is more efficient in patients with less affected joints and is less efficient in younger patients. Prophylaxis reduced time between the bleedings episodes after isotope application. Before radiosynovectomy, prophylaxis reduces the number of haemorrhages. Our findings support data previously published by Rodriguez-Merchan et al. [J Thromb Haemost, 5 (2007) P-W-126].

Haematuria in patients with haemophilia and its influence on renal function and proteinuria.

To investigate renal function in a group of patients with a history of haemophilia and haematuria. We reviewed 32 medical records of the patients with haemophilia and gross haematuria identified through a computerized haemophilia registry, from January 1993 to December 2004. In all patients but three (two refused to participate and one died) clinical and laboratory tests were performed by the nephrologist. One patient had chronic renal failure because of diabetic nephropathy. In two patients reduced renal function was detected by creatinine clearance measurements, and one of them had Duchenne muscular dystrophy. In four patients minimal proteinuria was diagnosed by the biuret method. Mild reduction in renal function of unknown cause was found in only one of the 29 patients tested.

Screen of 55 Slovenian haemophilia A patients: identification of 2 novel mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Mutation in brief no. 241. Online.

Using polymerase chain reaction, single-stranded conformational polymorphism (SSCP), TaqI restriction analysis and direct sequencing, exons 1, 7, 8, 9, 12, 13, 14, 18, 22, 23, 24, and 26 of the factor VIII gene were screened for point mutations in 55 Slovenian haemophilia A patients. In eighteen patients eleven different mutations were found; one (in six patients) in exon 26, one (in two patients) in exon 24, two in exon 23, one in intron 23, one in exon 18, one in exon 12, one in exon 8, two (1 + 1 in two patients) in exon 7 and one in exon 1. Of the mutations detected one has recently been reported by us (Q602X), and two are novel; S-1R in exon 1 and IVS23+1G-->A in intron 23.