Bolus Injection of Recombinant Factor VIIa (NovoSeven) can be More Effective than Continuous Infusion in Inhibitor Patients with Severe Hemophilia A

can be More Effective than Continuous Infusion in Inhibitor Patients with Severe Hemophilia A

C. Wermes, H. Pollmann, U. Nowak-Göttl, V. Rolf, M. von Depka Prondzinski and K.-W. Sykora

Background

Although in most inhibitor patients with hemophilia A, immune tolerance therapy (ITT) according to the Bonn protocol [1] is successful, a small number of patients does not reach a remission. These patients suffer from relapsing severe bleedings and are at high risk to develop hemophilic arthropathy. Bleedings have to be treated either by an activated prothrombin complex (FEIBA) [2, 3] or by recombinant activated factor VII (rFVIIa, NovoSeven), given as bolus injections (BI) [4–8] or continuous infusion (CI). Because of its short half-life, rFVIIa requires infusions every 2 hours in the immediate post-operative period [9, 10]. Then, time intervals can be increased but infusions often have to be continued for days. Treatment sche- dules are shown in Table 1 and 2. The administration of rFVIIa by continuous infu- sion is a wide-spread practice since several authors have shown that it is effective, less expensive [11–15], and more convenient than bolus injections.

Table 1. Treatment schedule for recombinant FVIIa – bolus injections.

NovoSeven - Bolus-Injection

Initial dose until bleeding stops: 4.5 kIU (90 µg)/kg bw, every 2h in case of failure: 6.0 kIU (120 µg)/kg bw , every 2h 24h after beginning of the treatment: 4.5 kIU (90 µg)/kg bw, every 3h 48h after beginning of the treatment: 4.5 kIU (90 µg)/kg bw, every 3–4h

Table 2. Treatment schedule for recombinant FVIIa – continuous infusion.

NovoSeven - Continuous Infusion (not licensed) Initial bolus: 4.5 kIU (90 µg)/kg bw Continuous infusion: 1.0–1.5 kIU (20–30µg)/kg bw 24 h stable at 25°C after reconstitution

I. Scharrer/W. Schramm (Ed.)

34

Hemophilia Symposium Hamburg 2003

” Springer-Verlag Berlin Heidelberg 2005

Case-Report History

The 12-year-old boy with severe hemophilia A (factor VIII <1%) developed a high- titer factor VIII inhibitor in early infancy. ITT with the Bonn protocol was without success. Recurrent bleedings were treated initially with FEIBA. Because of allergic reactions the “on demand treatment“ was continued with NovoSeven in case of bleedings. Recurrent joint bleedings had led to the development of hemophilic arthropathy of several joints at stage II° – III° according to Arnold and Hilgartner [16]. For the clinical status of the joints see Table 3.

Long-time ITT had led to irreversible damage of his peripheral veins. In the past, several central venous lines (two Broviak-catheters and 4 port-a-cath systems) had been implanted. The actual port-a-cath was occluded by a thrombus and treat- ment of bleedings became impossible because of lack of venous access. Once more, a port-a-cath implantation was indicated.

Treatment Course

In Figures 1 and 2, rFVIIa bolus doses are shown as daily doses per kilogram (kg) body weight (bw) per hour (h). For example, on day 9 (Fig. 2) he received 12 boli of rFVIIa with 6 kIU/kg each, which amounted to 3 kIU/kg/h. In this way, doses of bolus treatment and continuous infusion can be compared easily.

The patient was prepared for surgery by starting a CI. He received a bolus of 180 kIU rFVIIa (4.5 kIU/kg bw), followed by CI with 60 kIU per hour (1.5 kIU/kg/h) as shown in Figure 1. At the beginning of the operation the boy showed respiratory symptoms that were suspected to be an allergic reaction to NovoSeven. Operation and the treatment with NovoSeven were stopped.

Two days later the boy developed an hemarthros of his right knee. The circum- ference of the knee increased 3.5 to 4 centimeters. Again CI with NovoSeven (1.0 kIU/kg/hour) was started, giving first a test dose with steroid and antihistamine premedication (Fig. 2). The treatment with NovoSeven was well tolerated but was without clinical effect concerning the bleeding of his knee. The swelling persisted.

34 C. Wermes et al.

Table 3. Clinical status of the patient’s joints using the Neutral-0-Method

Hemophilic arthropathy

Right knee E/F 0 - 5 - 140°

Left knee E/F 0 - 10 - 140°

Right ankle E/F 0 - 5 - 40°, reduced movement Left ankle E/F 0 - 5 - 30°, reduced movement Right elbow E/F 0 – 20 - 130°

Left elbow E/F 0 – 0 - 135°

Pronation/Supination normal

(E=extension, F=flexion).

The port-a-cath implantation took place two days later (day 5) under CI with NovoSeven (1.0 kIU/kg/hour) as shown in figure 2. Because of severe post-operati- ve bleedings, with life-threatening swelling of the neck and the throat and a decrea- se in hemoglobin level (>2.0g/dl), the NovoSeven dose was increased up to 1.5 kIU/kg/hour without success.

After changing the treatment regime to bolus injections (240 kIU every 4 hours

= 6 kIU/kg) instead of CI, the bleeding in the operative site stopped. Also, the bleed- ing in the right knee could be treated successfully although the daily dose had not been changed in comparison to CI.

Three days later (day 8) the boy suffered from a bleeding in the other knee under the treatment with rFVIIa. The circumference of the knee increased 2.0 cm. For the therapy of this bleeding, a higher dose of NovoSeven (240 kIU (6 kIU/kg) every 2

0 2 4 6 8 10 12

1 2 3 4 5

BI rFVIIa (kIU/kg/h) CI rFVIIa (kIU/kg/h) Right knee, increase circumference (cm) Left knee, increase circumference (cm) Hemoglobin (g/dl)

OP OP

= bleeding/surgery OP = surgery

Fig. 1. Treatment course with rFVIIa (continuous infusion) before the first surgery (interrup- ted) and during a joint bleeding.

0 2 4 6 8 10 12

1 3 5 7 9 11 13 15 17 19 21

BI rFVIIa (kIU/kg/h) CI rFVIIa (kIU/kg/h) Right knee, increase circumference (cm) Left knee, increase circumference (cm) Hemoglobin (g/dl)

6

8

6 4

12

OP OP

doses/d

= bleeding/surgery

= day with BI

Fig. 2. The whole treatment course with rFVIIa during a port-a-cath implantation and for two

joint bleedings. Comparison of two different treatment schedules: continuous infusion versus

bolus injections.

hours) was needed (Fig. 2). Therefore the frequency of the injections was increased using constant single doses. Also the higher daily dose was well tolerated without any side-effects and could be reduced after 5 days (day 13). At this time both knees had reached the original circumferences and no more signs of acute bleedings were seen. For the port-a-cath implantation the patient was treated for a total of 12 days with rFVIIa without side-effects. The initial suspicion of an allergic reaction to NovoSeven was not confirmed.

Discussion

In this patient, a joint-bleeding of his right knee could not be treated effectively by CI. In addition, after port-a-cath implantation the boy suffered from life-threat- ening postoperative bleedings during a regular treatment with CI. Only when the treatment regime was changed and bolus injections were given, the bleedings could be treated successfully. So, in this patient, bolus injections of rFVIIa were better in controlling his bleedings than CI, although CI has been described to be effective and safe by several authors [9-15].

Recombinant FVIIa is approved as a “bypassing” agent to promote hemostasis in hemophilia with inhibitors. High doses of FVIIa (peaks) can optimize the throm- bin formation via tissue factor. In addition, several studies suggest that high-dose FVIIa acts independently of its usual cofactor, tissue factor, to enhance platelet sur- face thrombin generation [17-19]. A platelet-dependent mechanism of action pro- bably explains why factor VIIa does not cause systemic activation of coagulation, since the activated platelets on which FVIIa acts localize it to sites of injury.

In conclusion, the management of bolus injections of rFVIIa in the postoperati- ve period seems to be more effective than CI in some patients and should be tried when continuous infusion failed. The daily dose does not necessarily have to be increased.

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