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A few publications have appeared on treatment of factor (F)VII-deficient patients with rFVIIa [1,2] and the general clinical experience has been quite satisfying, including adequate hemostasis and the absence of serious adverse events. Monitoring of ELISA-detectable antibodies against FVIIa in FVII-deficient patients undergoing treatment with rFVIIa has identified two seropositive cases [3,4]. An infant who had accidentally been exposed to extraordinarily high doses of rFVIIa 20–40 times higher than the suggested dose presented with highly titered antibodies to FVIIa that might have been inhibitory since there was no normalization of the prothrombin time after rFVIIa infusion [3]. In another child, antibody development was detected, but rFVIIa treatment was rated effective [4].

Available literature and the outcome of a postal interview circulated to centres who had enrolled patients to the International Registry on F VII deficiency have not revealed data pointing to the existence of known inhibitors to FVII [2]. Therefore, the likelihood that inhibitory antibodies should occur in severe FVII deficiency is probably very low. In support of this assumption, total gene deletions have not been seen in FVII deficiency. Moreover, most patients in need of substitution treatment are homozygous or doubly heterozygous, often with a status of near-normal or moderately lowered amount of FVII antigenic material in plasma [cross-reacting-material positive (CRM+)]. Further, no detailed report on the detection and course of FVII inhibitors in FVII deficiency has been published so far.

The patient reported here is a 39-year-old caucasian female who suffered from severe FVII deficiency caused by homozygosity for a nucleotide substitution that causes an amino acid 100 GLN[RIGHTWARDS ARROW]ARG shift. As has been reported by others, this mutation gives a CRM+ phenotype; in our case a level of FVII:Ag at 0.17 U mL−1 was found, whereas the FVII:C is < 0.01 IU mL−1.

In the past, the patient had received treatment with various plasma-derived prothrombin complex concentrates as well as a FVII concentrate in at least one instance. Since 1995 all treatment has consisted of rFVIIa, and the cumulative exposure to rFVIIa during 1995–2001 was 161 mg of rFVIIa.

As a result of various musculoskeletal bleedings in the past, chronic arthropathy developed that required arthroplasty of a knee-joint and a hip-joint replacement, both of which were performed without complaints. Due to chronic synovitis, an elbow synovectomy was scheduled for late 2001, but the efficacy of single doses of rFVIIa seemed diminished. At this time a routine preoperative in vivo response to a dose of 1.2 mg of rFVIIa (20 µg kg−1 bw) was found to be significantly decreased at 0.32 IU mL−1 of FVII:C 10 min after injection compared with previously recorded FVII:C levels at 7.0–8.3 IU mL−1 following the same dose of rFVIIa. Subsequent laboratory work revealed an inhibitor against rFVIIa as well as against plasma-derived FVII:C. Despite this finding, an acute bleeding episode was managed successfully with only one injection of 1.2 mg of rFVIIa. A Bethesda assay for FVII:C inhibitors was developed in which the inhibitor was reacted with FVII of a commercial plasma standard (Verify; Dade Behring, Marburg, Germany) or recombinant activated FVII concentrate (NovoSeven; Novo Nordisk, Gentofte, Denmark) at 37 °C. A time-course study revealed completion of the inhibitory activity after 2 h of incubation.

Employing the traditional Bethesda plot and the inhibitory plasma dilution factor, the inhibitor activity in the patient's plasma was calculated and expressed in Bethesda Units (BU) per mL of plasma.

The time-course of inhibitor activity is displayed in Fig. 1. The initial titration studies revealed a high responder inhibitor at 16 BU mL−1 against plasma factor VII:C, and an inhibitor activity against rFVIIa at 88 BU mL−1. With time and no further treatment with rFVIIa or other FVII-containing material, the inhibitor titer decreased. Re-exposure to rFVIIa 1.2 mg for a bleeding episode resulted in anamnesis with a marked increase in inhibitor levels (Fig. 1).

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Figure 1.  Initial detection and course of factor (F)VII:C inhibitors in a patient with severe FVII deficiency, as recorded by a FVII:C inhibitor assay following the Bethesda method principles for plasma FVII. Arrow indicates infusion of a single dose of rFVIIa at 1.2 mg.

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In summary, this communication reports on the detection of FVII:C inhibitor activity occurring in a patient with severe FVII deficiency who had previously received plasma FVII-containing concentrates as well as recombinant activated FVII for treatment of various bleeding episodes. During 5 years preceeding the discovery of inhibitors the patient had exclusively received rFVIIa. The inhibitors were detected at a visit routinely planned for screening and assessment of the in-vivo response prior to planned orthopedic surgery. On follow-up, inhibitor activity gradually diminished with no further exposure to rFVIIa, but anamnesis occurred after renewed exposure to rFVIIa for a bleeding problem. Our case illustrates that patients with severe FVII deficiency may develop inhibitors to FVII/FVIIa. In vitro, the inhibitor titer appeared to be higher against rFVIIa compared with plasma FVII. This is not entirely unexpected, since the function/mass relationship between activity and antigen is considerably increased for activated FVII and hence, the same amount of immunoglobulin might block more coagulation units of FVII:C from the activated molecule compared with unactivated FVII. In our case, the inhibitor level was more than five times greater against rFVIIa compared with plasma FVII. No evidence has been established on the incidence and natural history of inhibitors in FVII-deficient patients, but inhibitors might be suspected if patients display an abnormally low in vivo recovery and/or an inadequate hemostatic effect of treatment with a FVII concentrate. Interestingly, the hemostatic effect of rFVIIa was reported by the patient as only slightly decreased. We did not attempt to administer doses of rFVIIa in excess of the ∼ 20 µg kg−1 bw dose utilized in all of her previous bleeding episodes.

In consequence of the reported finding, the International Registry for Factor VII has initiated a prospective study on treatment of FVII deficiency, including inhibitor recordings. Information can be obtained from G. Mariani, e-mail: gmariani@cc.univaq.it

Note

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A plasma sample collected at the time of first detection of the inhibitors was studied in the Laboratory of Novo Nordisk A/S, and investigation disclosed the presence of patient's immunoglobulin binding to rFVIIa as determined by a radioimmuno assay.

References

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  2. Note
  3. References
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    Mariani G, Testa MG, Di Paolantonio T, Molskov Bech R, Hedner U. Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies. Vox Sang 1999; 77: 1316.
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    Ingerslev J, Knudsen L, Hvid I, Tange MR, Fredberg U, Sneppen O. Use of recombinant factor VIIa in surgery in factor VII deficient patients. Haemophilia 1997; 3: 215218.
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    Nicolaisen EM, Hansen LL, Poulsen F, Glazer S, Hedner U. Immunological aspects of recombinant factor VIIa (rFVIIa) in clinical use. Thromb Haemost 1996; 76: 2004.
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    Nicolaisen EM. Antigenicity of activated recombinant factor VII followed through nine years of clinical experience. Blood Coagul Fibrinolysis 1999; (Suppl. 1): S11923.
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    Mariani G, Herrmann FH, Dolce A, Batorova A, Etro D, Peyvandi F, Wulff K, Schved JF, Auerswald G, Bernardi F. Clinical phenotypes and FVII genotype in Congenital Factor VII Deficiency. Thromb Haemost 2005; (In press).