To cite this article: Konkle BA, Ebbesen LS, Erhardtsen E, Bianco RP, Lissitchkov T, Rusen L, Serban MA. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5: 1904-13. Summary. Background: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. Objectives: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on-demand therapy. Methods: Thirty-eight male patients entered a 3-month preprophylaxis period to confirm high baseline bleeding frequency (mean ‡ 4 bleeds per month). Twenty-two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 lg kg )1 for 3 months, followed by a 3-month postprophylaxis period. Results: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 lg kg , respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. Conclusion: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on-demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.

Allogeneic blood transfusions are claimed to be an independent risk factor for postoperative infections in open colorectal surgery due to immunomodulation. Leukocyte-depletion of erythrocyte suspensions has been shown in some open randomized studies to reduce the rate of postoperative infection to levels observed in nontransfused patients. Using a double-blinded, randomized design, we studied the postoperative infection rate in patients undergoing open colorectal surgery transfused with either leukocyte-depleted erythrocyte suspensions (LD-SAGM) or non-leukocyte-depleted erythrocyte suspensions (SAGM). Unselected patients (n 279) were allocated to receive LD-SAGM (n 139) or SAGM (n 140) if transfusion was indicated. Forty-five percent were transfused, yielding 48 patients in the LD-SAGM group and 64 in the SAGM group. Thirteen patients were excluded because they received one type of transfusion in spite of randomization to the other type. No significant differences in the rates of postoperative infections (P=0.5250) or postoperative complications (P=0.1779) were seen between the two transfused groups. Infection rates were 45% and 38% in the transfused groups and 21% and 23% in the nontransfused groups. No significant difference between the transfused groups was seen on any single infectious event, mortality rate, or duration of hospitalization. Leukocyte-depletion of erythrocyte suspensions transfused to patients undergoing open colorectal surgery does not reduce postoperative infection rates.

Summary. Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 lg kg )1 ) for 3 months, followed by 3 monthsÕ postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.

Predicting the clinical effect of bypassing agents such as recombinant activated factor VII in haemophilia patients with inhibitors is hampered by the limited availability of reliable laboratory monitoring tools. This multicentre, open-label trial aimed to explore the dose-response relationship between recombinant activated factor VII concentration and thromboelastography parameters in blood samples from patients with haemophilia A or B with inhibitors in a nonbleeding state. Citrated whole blood samples from 16 patients (>or=16 years) with haemophilia A or B were spiked ex vivo with recombinant activated factor VII (1.2, 1.6, 2.0, 2.6, 3.0, 3.5 microg/ml), corresponding approximately to doses of 90-270 microg/kg. Samples were analysed by Thromboelastograph or Rotation Thromboelastography (three United States and three European centres, respectively) within 30 min (final lipidated recombinant tissue factor 1: 17 000; final CaCl2 15 mM). Thromboelastograph/Rotation Thromboelastography parameters showed large intersubject variation in the baseline profiles. There was a clear effect when recombinant activated factor VII was added; however, a clear concentration-response relationship was only detected for one patient. This is likely due to the fact that the curves were not sufficiently abnormal that led to reduced assay sensitivity. Our preliminary results suggest that thromboelastography may potentially be a clinically useful tool for monitoring changing concentrations of recombinant activated factor VII in haemophilia patients, but only when the baseline curve is significantly abnormal. Thus, test conditions may need to be optimized before Thromboelastograph/Rotation Thromboelastography can be utilized for all inhibitor patients.

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