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Keywords:

  • hemophilia;
  • inhibitors;
  • megadose;
  • NovoSeven®;
  • rFVIIa

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Summary.  Recombinant activated factor VII (rFVIIa, NovoSeven®) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa ‘megadose’ (300 µg kg−1 bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 µg kg−1 every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 µg kg−1) was higher than with standard boluses (180–270 µg kg−1), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL−1; range: 19.8–54 U mL−1). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.

The first report of surgical synovectomy in a patient with severe hemophilia A and inhibitor successfully performed under the cover of recombinant activated factor VII (rFVIIa, NovoSeven®) and tranexamic acid was published in 1988 [1]. Since then, the use of rFVIIa for elective surgical procedures and for various bleeding episodes in inhibitor patients has been increasingly reported [2–5]. However, while rFVIIa is considered a safe and effective treatment for bleeding episodes in hemophilia patients with inhibitors, the optimal dose and best treatment regimen have yet to be established.

Due to its very short half-life (2.7 h in adults) [6], rFVIIa has been administered primarily in treatment regimens that involve frequent and recurrent bolus injections (standard bolus dose of 90 µg kg−1 every 2–3 h; total dose of 180–270 µg kg−1). For example, Key et al. [7] reported an overall success rate of 92% following the home treatment of hemarthroses with 90 µg kg−1 bolus doses at 3-hourly intervals. Effective home treatment, with hemostasis achieved in most patients after 2–3 standard bolus injections, has also been reported by other groups [8,9]. In accordance with previous reports, when early intervention was practicable in these studies higher efficacy and faster hemostasis were achieved [10,11].

The inconvenience of frequent bolus injections and the risk of bleeding complications in cases of missed or delayed dose administration (especially when prolonged treatment is necessary, for example, in surgical patients), have prompted the use of continuous infusion (CI) of rFVIIa in many hemophilia centers. CI is primarily used for surgical procedures in inhibitor patients, although it has also been adopted for the treatment of some bleeding episodes. CI has proven to be an effective and well tolerated means of rFVIIa delivery, permitting, in some patients, dose reduction compared with the standard dosing regimen [12–18]. However, since the kinetics of thrombin generation influence the structure of the fibrin clot and its susceptibility to lysis [21,22], in some patients recurrent boluses of rFVIIa may provide better hemostatic effects than CI.

In 1996, we reported on the use of CI of rFVIIa in surgical patients with hemophilia and inhibitors [12]. We subsequently extended our use of rFVIIa CI to include the treatment of hemarthroses and muscle bleeding episodes in inhibitor patients. At this time, our treatment regimen consisted of a standard 90 µg kg−1 bolus dose followed by CI at an initial rate of 15–16 µg kg−1 h−1, with the aim of achieving a trough blood FVII:C level of 10 IU mL−1. This protocol was used to treat patients over periods of 12 h, or for longer periods when required. Since 1998, we have used an augmented CI protocol, in which the initial IV bolus dose and the rate of CI were doubled, with the aim of attaining higher levels of blood trough FVII:C of 20–30 IU mL−1. We have successfully used this augmented protocol to treat hemarthroses and muscle bleeds over periods of 6 h or longer [19].

In recent years, the understanding of the mechanism of action of rFVIIa in coagulation has improved. Data show that rFVIIa creates a thrombin burst, which is a crucial step in clot formation, by either combining with tissue factor or by promoting prothrombinase complex activity directly upon activated platelet surfaces [20]. High thrombin concentration has been shown to support clot formation and to decrease its susceptibility to fibrinolysis [21]. Nevertheless, the precise relationship between rFVIIa dose, the amount of thrombin generated, and measurable blood factor VII:C levels, has yet to be established.

Based upon the good results obtained through the use of our augmented CI protocol [19] and the anticipated benefit of generating an even higher initial thrombin burst, our present study was designed to evaluate the safety and efficacy of treating bleeding episodes in inhibitor patients using a single ‘megadose’ (300 µg kg−1) of rFVIIa. The results of treatment with the megadose regimen are presented here and compared to the previous CI regimens used in these patients and to the results standard bolus dose administration reported in the literature [7–10].

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

This was an open-label, single center (National Israeli Hemophilia Center) study carried out between October 1999 and November 2001.

Patients

Eligible patients were recruited by the National Hemophilia Center. Patients with hemophilia A or B, an inhibitor titer greater than 5 BU, and who presented with an acute hemarthroses, intramuscular or soft tissue bleeding episode were enrolled in the study. Exclusion criteria were: age above 40 years, presence of other hemostatic disease, personal or family history of thrombosis or thrombophilia, clinically significant abnormal blood biochemistry, previous treatment with rFVIIa or any other hemostatic agent during the 24 h prior to the first study dose, and previous evidence for hypersensitivity to rFVIIa. All patients (or their guardians) gave informed consent before entering the study. The concomitant use of hemostatic or antifibrinolytic agents other than rFVIIa was not permitted in patients treated with the megadose protocol.

Patients with acute bleeding episodes were considered suitable for inclusion in the study if they could self-inject rFVIIa or if they were able to travel to the hemophilia center for treatment within a given time frame. Acute bleeding episodes were defined as bleeds treated within 4 h of the initiation of symptoms. Of the hemarthroses treated, target joint bleeds were defined as bleeding into a joint that had undergone at least five spontaneous bleeds within the last year.

Treatment

Recombinant FVIIa was reconstituted according to the manufacturer's instructions. The evolution of our rFVIIa treatment regimens is illustrated in Table 1. The CIa protocol consisted of rFVIIa delivered as a 90 µg kg−1 bolus dose followed by CI at an initial rate of 15–16 µg kg−1 h−1, while the CIb protocol involved administration of a 180 µg kg−1 bolus dose of rFVIIa followed by CI at an initial rate of 30 µg kg−1 h−1. The megadose was administered as a single bolus injection of rFVIIa (300 µg kg−1). However, additional bolus doses (200–300 µg kg−1) given within 3–4 h of the previous megadose were permitted, if required.

Table 1.  The evolution of our different rFVIIa treatment regimens
 CIaCIbMegadose
Bolus (μg kg−1)90180300
Initial rate (h−1)15–1630
Time-frame (h−1)12 (or more)6 (or more)0 (or more)

Citrated blood samples for routine analysis of FVII:C levels were obtained 10–20 min after rFVIIa administration. All patients were either examined or contacted 24 h after rFVIIa administration for documentation of adverse events or rebleeding.

Study end-points

The primary efficacy endpoint was the response to treatment, which was defined as definite pain relief and incidence of rebleeding. Patients were asked to document the time elapsing before the onset of pain relief following rFVIIa administration. Rebleeding was defined as bleeding into the same site within 24 h of treatment onset. Secondary study end points included the determination of FVII:C blood levels and total rFVIIa consumption per bleeding episode. Safety endpoints were evaluated by the number and type of adverse events recorded. Adverse events were defined as any undesirable effects emerging within 24 h of rFVIIa administration and were graded as serious or non-serious according to severity, and in terms of their probable relation to the study drug.

Statistical analysis

Statistical analysis of data was performed using Statistical Program for Social Sciences (SPSS) version 8.0 software. The Chi2 test was used for comparison of proportions, while analysis of variance (anova) was used for all other data. A P-value of <0.05 was considered to be significant.

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Patients

Three patients treated at the National Israeli Hemophilia Center received treatment under three treatment regimens (CIa, CIb, and megadose). Patients were HIV negative and aged 19, 16 and 22 years with inhibitor levels of 6 BU, 120 BU and 8 BU, respectively.

Bleeding episodes

A total of 244 bleeding episodes in these three patients were treated with rFVIIa. Of these, 58, 72 and 114 episodes were treated using the CIa, CIb, and megadose protocols, respectively. Of the bleeds treated with the megadose protocol, 82/114 occurred in target joints. In all cases, hemostasis was achieved following rFVIIa administration. Approximately 70% of bleeding episodes treated with either of the CI regimens responded within the protocol time-frame (CIa ≤ 12 h; CIb = 6 h) as compared to 95/114 (83.3%) of hemarthroses treated with a single megadose of rFVIIa (P = 0.625) (Table 2). In 19/114 episodes treated using the megadose protocol, a second injection was required to achieve 100% hemostasis. The second bolus dose consisted of 300 µg kg−1 in 17/19 episodes. Two target joint hemarthroses in the same patient were treated by a second bolus dose of 200 µg kg−1 (total dose for 19/114 cases: 500–600 µg kg−1). A third bolus dose was never required.

Table 2.  Results of bleeding episodes treated by different protocols
 CIaCIbMegadose
Number of bleeding episodes5872114
Median therapy duration (h) (range, h)12 (8–100)6 (4–18)0 (0–6)
Response rate (%)707283
Minimal time to pain relief (h−1)310.5
Full response within 6 h0/5827/36114/114
Median rFVIIa dose (μg kg−1) (range, μg kg−1)270 (210–1080)360 (300–720)300 (300–600)
FVII:C blood levels (U mL−1) (range U mL−1)12.65 (9.7–19.8)22.7 (18–25.3)27.4 (19.8–54)

Of these episodes that did not fully respond to initial bolus, 18/19 (94.7%) occurred at the same target joint in a single patient. Hence, 18/82 (22.2%) of hemarthroses in target joints treated with the megadose protocol required a second bolus dose of rFVIIa.

Primary end-points

Patients treated with the megadose protocol reported faster pain relief following rFVIIa administration (30–90 min; median 40 min) compared with those treated with CIa (3–8 h; median 4 h) or CIb (1–3 h; median: 100 min) (Table 2, Fig. 1). Duration of therapy was significantly (P < 0.001) longer for patients receiving either of the CI regimens (median 12 h, range 8–100 h for CIa; and median 6 h, range 4–18 h for CIb) (see Table 2), compared with therapy duration under the megadose protocol (median 0 h; range 0–6 h). In bleeding episodes that were treated by the megadose protocol, hemostasis was either achieved within the time taken for a single bolus injection or after the second bolus injection given 3–4 h after initiation. As a result, patients found the megadose protocol to be more effective and convenient than either of the CI protocols used.

image

Figure 1. Minimal time to patient response (pain relief): CIa = rFVIIa 90 µg kg−1 bolus followed by infusion rate of 15 µg kg−1 h−1; CIb = rFVIIa 180 µg kg−1 bolus followed by infusion rate of 30 µg kg−1 h−1; megadose = rFVIIa 300 µg kg−1; standard boluses = rFVIIa 90 µg kg−1 every 3 h.

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Rebleeding occurring within 24 h was reported in 6/58 (10.5%), 8/72 (11.1%) and 11/114 (9.6%) of bleeding episodes treated with the CIa, CIb or megadose protocols, respectively. These differences were not considered statistically significant (P = 0.95).

Blood FVII:C levels obtained 10–20 min following administration of the megadose injection were higher (median: 27.4, range 19.8–54 U mL−1) than FVII:C levels previously recorded under either CI regimen (see Table 2). Median rFVIIa consumption per bleeding episode was significantly lower (P < 0.001) under the megadose protocol compared with CIb (300 µg kg−1, range 300–600 µg kg−1 vs. 360 µg kg−1, range 300–720 µg kg−1, respectively) (see Table 2 and Fig. 2).

image

Figure 2. Median rFVIIa consumption per patient per bleeding episode. The consumption (mg) of rFVIIa was calculated for a patient of average weight (50 kg): CIa = rFVIIa 90 µg kg−1 bolus followed by infusion rate of 15 µg kg−1 h−1; CIb = rFVIIa 180 µg kg−1 bolus followed by infusion rate of 30 µg kg−1 h−1; megadose = rFVIIa 300 µg kg−1; standard boluses = rFVIIa 90 µg kg−1 every 3 h.

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Safety

We experienced two incidents of unexplained fever in a single patient following the administration of a second megadose injection within 3 h of the first dose. Fever (38.2, 38.4 °C) was noted 2–2.5 h after the second injection and was accompanied by nausea. No chills were documented. Bacterial cultures were negative and the fever subsided spontaneously within a few hours. Following this reaction, the dosage of subsequent recurrent injections was reduced to 200 µg kg−1. However, the second bolus dose was again increased to 300 µg kg−1 after two additional bleeding episodes in the same patient, due to insufficient response (rebleeding). Fever never recurred. No thrombosis or any other adverse events were observed following administration of rFVIIa irrespective of protocol used.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References

Recombinant FVIIa represents an important mode of treatment for hemophilia patients with inhibitors [2–5]. Key et al. reported home treatment of hemarthroses with rFVIIa to be effective and well tolerated [7], and similar outcomes have been observed with other groups [8–10], including our own.

While Key et al. reported a 92% success rate when treating bleeding episodes with standard bolus doses (i.e. 90 µg kg−1 every 3 h), our data shows a success rate of 83% and 70–72% in patients administered rFVIIa by megadose or CI protocols, respectively (Table 2). The differences between the rates of success reported by Key et al. vs. our own data could be attributed to an earlier initiation of treatment in the Key study [10,11]. An important point of consideration when comparing our data with previous reports is the definition of ‘response to treatment’ used. Whereas Key and others defined ‘success’ or ‘good response’ as whether hemostasis was achieved, we defined ‘success’ as hemostasis obtained within our regimen's predefined time frame. Most of our patients treated with the megadose protocol achieved hemostasis following a single bolus injection of 300 µg kg−1 and, in the remaining patients, hemostasis was achieved after one additional dose. In contrast, in the previously mentioned home-treatment patients, a single injection was seldom sufficient [7–10].

In our study, therapy duration was much shorter for patients administered the megadose regimen compared with CI regimens because most bleeding episodes responded to the high initial bolus dose. As a result, the same patients reported faster and more effective pain relief following megadose administration compared with our own CI regimens or recurrent injections (2–4 injections at 3-hourly intervals) required by the standard protocol [7–10], as shown in Fig. 1. Most patients treated by standard bolus protocols report relief of pain within 3–6 h from the initiation of treatment, as compared to a median of 40 min response time reported by patients administered the megadose protocol. Whereas full response (good hemostasis as clinically assessed by patients and treating physician) after 6 h of treatment was considered satisfactory when we used the augmented CI regimen (CIb), time to full response was considered unsatisfactory when the standard CI (CIa) protocol was used (Table 2). Hence, this regimen is no longer recommended in our center for the treatment of bleeding episodes.

Faster initial pain relief prior to full hemostasis was reported by all three patients on administration of the megadose regimen as compared to previous treatment regimens (CIa or CIb) in the same patients (Table 2 and Fig. 1). The use of opiates and strong analgetics was documented, demonstrating that these drugs were consumed by patients in < 10% of bleeding episodes during the various regimens. Non-steroidal anti-inflammatory drugs were prohibited. Since a higher initial bolus dose correlated with faster response in terms of relief of pain (Fig. 3), we conclude that response is dose dependent, and that the greater efficacy observed with increasing doses stems from a higher thrombin burst resulting in more stable fibrin clots. In vitro analyses of the fibrin clots formed in the presence of a high thrombin concentration have shown that such clots have a different type of architecture and are far more resistant to degradation by fibrinolytic enzymes compared with normal clots [21,22]. One of the mechanisms for this resistance to fibrinolysis is via the activation of thrombin-activatable-fibrinolysis inhibitor (TAFI), which occurs only in the presence of high thombin concentrations [23].

image

Figure 3. Minimal time to patients' response as a function of initial bolus dose.

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In our study, target joint bleeds consisted of 71.9% of hemarthroses. The response rate in this subgroup following a single bolus injection was slightly lower (78%) as compared to the total group and to other studies [7–10]. The comparison of the relatively small number of patients treated by us with previously reported large series is responsible for the large proportion of target joint bleeds, thus affecting the outcome in our data. Rebleeding occurred in approximately 10% of our patients, irrespective of rFVIIa treatment regimen used, and this data is in agreement with the previously reported data of Key et al. However, in contrast to Key et al. rebleeds in our patients occurred exclusively in target joints. These data suggest that target joint bleeds may require special consideration in terms of the dosing treatment interval used and implies the need for further consolidation or prophylaxis.

We did not identify any other parameters that allowed prediction of response to therapy in any of the rFVIIa regimens used. FVII:C blood levels were higher in patients treated with the megadose protocol, but since they are not a ‘real-time’ parameter they could not be used to predict treatment success in any of the protocols.

Despite the relatively high rFVIIa dose used in the megadose regimen, we found rFVIIa consumption per bleeding episode to be lower with this protocol compared with the median dose consumed during our own CI regimens used previously in the same patients (Table 2). The median value of standard bolus injections required to achieve hemostasis in home-treated patients [7–10] has been reported as 180–270 µg kg−1 per bleeding episode. If we take into account the standard manufactured vial content (4.8 mg) and the median weight of our adolescent patients (about 50 kg), we can assume that, had the same bleeding episodes been treated by standard bolus injections, the total median rFVIIa consumption would have been 9.6–14.4 mg per patient per bleeding episode compared with 14.4–15.6 mg required with the megadose protocol (Fig. 2). Thus, the cost of our proposed megadose regimen is similar to that of standard treatment. It should be noted that when younger children with inhibitors are treated for bleeding episodes, price differentials, in terms of the actual doses required for each of the above regimens, may be much lower. In addition, the benefit of convenience may compensate for the slightly higher rate of rFVIIa consumption required for some bleeding episodes compared with that consumed under standard treatment or when using our own CI regimens.

As recent clinical data suggest, the use of rFVIIa appears to be safe [24,25] The prevalence of thrombotic events with the use of rFVIIa is extremely low, especially in view of the many high-risk clinical situations in which the drug is administered. There have been at least three cases describing laboratory evidence of disseminated intravascular coagulation (DIC) with the use of rFVIIa [26]. It is unclear, however, whether laboratory markers of activated coagulation are predictive of subsequent thrombotic events. Baudo and colleagues have recently reported a lack of clinical complications during treatment with rFVIIa despite laboratory evidence of DIC [25]. Roberts' review of the safety of rFVIIa in 1998 cited two cases of angina in elderly people following rFVIIa administration. Recombinant FVIIa should probably be used with caution in elderly patients with known heart disease and other chronic diseases [27,28]. In our small group of young hemophilia inhibitor patients, no thrombosis was observed and we can conclude that neither the high doses of rFVIIa administered, nor the high blood FVII:C levels obtained during treatment, increased the risk for thromboembolic complications in our patients. The only adverse event that was noted with use of the megadose protocol was fever, which subsided uneventfully. The febrile reaction may stem from the release of inflammatory mediators when a repeat megadose is administered. Excessive rFVIIa binding to blood macrophage-borne tissue factor may play some role in the inflammatory process – however, this has never been proven and the exact cause of our patient's fever following administration of a second megadose bolus remains to be clarified.

Currently, the precise relationship between FVIIa dose, the level of thrombin burst generated, and the measurable blood FVII:C level is unclear. Thus, so far, the potential benefits to hemostasis of maintaining FVII:C levels above trough levels by CI administration compared with the generation of recurrent high thrombin bursts cannot be established. However, our results support the idea that the use of a single rFVIIa megadose in young hemophilia patients, as opposed to standard, recurrent bolus doses, may offer the opportunity to ‘normalize’ the lives of our patients with inhibitors and enable them to be treated in the same manner as bleeding patients with no inhibitors.

We conclude that the use of the rFVIIa megadose protocol is safe and effective in young patients. It may also provide a faster rate of response without significantly augmenting FVIIa requirements. Further studies are needed to better define the role of this regimen for the treatment of bleeding episodes or minor surgical procedures in young patients.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. References
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