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Severe factor (F) XIII deficiency is a rare, life-threatening inherited bleeding disorder that affects both sexes and occurs with a high frequency in consanguineous families [1,2]. Due to the risk of intracranial hemorrhage (ICH), most patients receive regular replacement therapy. The therapy of choice is presently, when available, a plasma-derived concentrate, rather than plasma or cryoprecipitate, as it contains a reliably high FXIII concentration in a small volume and minimizes the risk of blood-borne disease [3,4]. A recombinant FXIII subunit A concentrate has been proven to be well tolerated and effective in correcting FXIII deficiency at doses ranging from 20 to 75 IU kg−1; however, it would be ineffective for managing patients with isolated subunit B deficiency [5,6].

Due to the low incidence of severe FXIII deficiency, published evidence on the efficacy of FXIII replacement therapy includes mostly case reports, small series or retrospective surveys [1,7–10]. We conducted a prospective, non-controlled study, to assess the effectiveness and safety of a highly purified plasma-derived virus-inactivated FXIII concentrate (Fibrogammin® P; CSL Behring GmbH, Marburg, Germany) in severe congenital FXIII deficiency.

All patients with inherited severe FXIII deficiency (defined as having a FXIII level below the limit of detection, which was 0.01–0.06 IU mL−1 according to the sensitivities of the various methods used), who had been treated with plasma-derived FXIII, were eligible to participate in the study. Candidates were excluded if they presented with inhibitors against FXIII, recent thrombosis or myocardial infarction, progressive fatal disease and/or life expectancy less than 3 months.

At entry into the study, a thorough physical examination was performed and a medical history was taken, documenting FXIII dose, duration of treatment and regimen, hemorrhages attributable to FXIII deficiency, usage of concomitant therapeutic agents, number of days hospitalized or missed from school or work due to FXIII deficiency and adverse events in the previous 12 months.

During the study, patients were evaluated every 3–6 months, using the same methods as at baseline. Clinical response to FXIII for the treatment of major hemorrhages was rated by the investigators as poor, moderate, good or excellent. Biological efficacy was assessed as the rise in plasma FXIII activity per unit administered, per kg bodyweight, 30 min after the end of infusion. FXIII activity was measured using either a chromogenic test (Berichrom® Factor XIII assay; Dade Behring Inc., Deerfield, IL, USA) or a semi-quantitative clot lysis assay (Staclot FXIII Diagnostica Stago, Asnières, France). FXIII inhibitor was assessed using the same procedure as the FVIII inhibitor assay (i.e. a revised Bethesda method), and the FXIII activity test currently used. Adverse events (AEs) were defined as severe if they resulted in death, were life threatening, required patient hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability/incapacity or in a congenital anomaly/birth defect.

Nineteen patients belonging to 16 distinct families were enrolled at 15 French centres between March 1999 and July 2001. The median age at inclusion was 13.3 years, ranging from 18 days to 47 years (Table 1). During the 12 months preceding the study, the median FXIII consumption was 1 IU kg−1 per week (range, 0.2–38.6) among the six patients receiving on-demand therapy and 9.5 IU kg−1 per week (range, 2.5–16.5) among the 12 patients receiving prophylaxis. One patient received both treatment regimens (surgery).

Table 1.   Patients’ main data
PatientWeight (kg)Height (cm)Age (years)SexGeographic originDoseHemorrhages: site : numberClinical response
Range (U kg−1 per bw per week)Median (U kg−1 per bw per week)
  1. bw, bodyweight; CNS, central nervous system; NS, not specified; Δ, not applicable because no hemorrhages occurred. *Hemorrhage into CNS before study entry, during on-demand therapy only.

 118.5108.04.5MOther1.6–2.82.50Δ
 283.0178.023.5MCaucasian2.5–2.62.5Joints: 3Good: 2; NS: 1
 366.0178.013.4MCaucasian2.5–3.02.7Other: 1NS
 43.250.50.0MOther2.6–4.63.60*Δ
 540.5152.513.3MCaucasian3.3–3.73.50Δ
 617.0103.04.7MCaucasian3.2–7.35.20NS
 740134.58.2FCaucasian6.4–7.36.6Soft tissue: 6NS
 8110.0188.028.3MCaucasian6.0–8.67.60Δ
 990.0170.032.1MCaucasian9.2–10.29.6Soft tissue: 1NS
1058.6160.537.7MCaucasian7.1–14.87.70Δ
1118.8116.55.7MCaucasian10.0–17.410.90Δ
129.672.00.9MCaucasian11.8–19.315.60Δ
1358.0170.032.0FCaucasianNANAMuscle: 2Good: 1; Moderate: 1
1413.982.02.0MOriental4.0–9.46.00Δ
1558.0155.010.7FOriental3.1–6.34.2CNS: 1Excellent
1636.5139.011.3FCaucasian12.4–15.614.2Urogenital system: 11; Other: 2Good: 8
1778.0184.039.6MCaucasianNANAGastrointestinal tract: 1Excellent
1865.0166.014.5MCaucasianNANAJoints: 1; Soft tissue: 2 Muscle: 2Excellent
1955.0160.046.9FCaucasianNANAMuscle: 2NS

After study entry, 16 out of 19 patients received prophylaxis, with infusions of 1.55–14.8 IU kg−1 per week every 4–6 weeks, with the aim of maintaining a minimum level of circulating FXIII above the threshold of detection, according to previously reported pharmacokinetic studies [11]. The biological response to FXIII, determined in 10 patients whose ages ranged from 0.9 to 24 years at the time of assessment, was 2.25% ± 0.34% IU kg−1 (mean ± SD) in patients over 6 years of age, whereas it was 1.63 ± 0.34 in children up to this age.

Over the study period, 10 patients out of 19 experienced a total of 35 hemorrhages. In the 15 cases requiring treatment with the FXIII concentrate, its efficacy was considered as moderate (1), good (11) or excellent (3). Five out of six patients experienced bleeding when they were having on-demand therapy, and three of these five patients (one of whom developed ICH) were subsequently switched to prophylaxis during the study, and did not experience any further hemorrhage. In contrast, once under prophylaxis, the majority of patients (10/16, 62.5%) had no hemorrhage. Two out of 16 patients exhibited only easy bruising, and one had heavy menses requiring additional FXIII therapy on demand (i.e. both treatment regimens). Prophylaxis with FXIII was thus associated with a significant reduction in the risk of hemorrhage and in the number of days of hospitalization as compared with on-demand therapy. Furthermore, the only ICH observed occurred in a 10-year-old boy receiving on-demand therapy. Among the six patients in the lowest tertile of prophylactic doses (i.e. < 5 IU kg−1 per week), three experienced at least one hemorrhage as compared with three of the other 10 patients, suggesting that the prophylactic dose should be > 5 IU kg−1 per week. The ideal prophylactic schedule remains to be determined using reliable FXIII activity assays. There were no severe AEs or thrombotic events.

This is the first prospective cohort study reporting a systematic longitudinal follow-up among patients with severe FXIII deficiency, receiving FXIII replacement therapy with a highly purified virus-inactivated plasma-derived FXIII concentrate. The effectiveness of plasma-derived FXIII concentrate in managing hemorrhage was rated good or excellent in 95% of cases. These results are in accordance with those of previous studies in the USA [8,9]. FXIII concentrate was well tolerated and safe, with no cases of thrombosis observed.

As the incidence of ICH is higher in FXIII deficiency than in most other congenital bleeding disorders, and most bleeding-related deaths are caused by ICH [1,12,13], the United Kingdom Haemophilia Centre Doctors’ Organisation has recommended in its guidelines that all patients with severe FXIII deficiency (< 0.01 IU mL−1) receive prophylactic replacement therapy with FXIII concentrate from the time of diagnosis [13]. The present study provides support for these recommendations. As compared with on-demand therapy, prophylactic replacement therapy resulted in lowering the number of bleeds and in preventing the occurrence or recurrence of ICH, especially in patients who received more than 5 IU kg−1 per week of FXIII concentrate, suggesting that doses > 20 IU kg−1 per month should be used for optimal management.

Disclosure of Conflict of Interests

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  2. Disclosure of Conflict of Interests
  3. References

The authors state that they have no conflict of interest.

References

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  2. Disclosure of Conflict of Interests
  3. References
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