At 90 Micrograms Per Kilogram, Recombinant Factor VIIa Partially Corrects Abnormal Hemostatic Function in Blood from Factor IX Deficient Patients.

Reports of the potential clinical utility of recombinant Factor VIIa (rFVIIa, NovoSeven®, NovoNordisk) in a variety of bleeding disorders have raised the possibility that this agent may have broad spectrum hemostatic properties. We have previously demonstrated that rFVIIa produces dose dependent correction of hemostatic status in patients with Factor VIII deficiency and/or Factor VIII inhibitor. In this study we measured the dose dependent effects of rFVIIa on Platelet Contractile Force (PCF), Clot Elastic Modulus (CEM) and Thrombin Generation Time (TGT) (Hemodyne® Analyzer, Hemodyne, Inc.) in patients with factor IX deficiency. Results were compared to those seen with recombinant factor IX (BeneFIX® [GI, Wyeth]) and factor nine concentrate (Mononine® [Aventis-Behring]). Blood from three patients with factor IX deficiency was collected via aseptic venipuncture into evacuated tubes containing 3.2% sodium citrate. The samples were spiked with increasing amounts of each hemostatic agent so as to yield levels ranging from 25 to 200% of the recommended dose. At baseline, each of the factor IX deficient patients had prolonged TGT, decreased PCF and decreased CEM. Despite the fact that each patient had less than 1% of normal factor IX activity, there was significant variability between the patients in their baseline values. TGT for the three patients varied from 587 to 1200 seconds. Baseline PCF ranged from 0.9 to 1.4 Kdynes, while CEM varied from 1.6 to 5.4 Kdynes/cm2. Normal TGT, PCF and CEM values for asymptomatic controls (mean ± SD, n=25) were 392±100 seconds, 7.8±1.3 Kdynes and 18.8±5.6 Kdynes/cm2 respectively. At the 100% of recommended dose, each of the factor IX agents produced shortening of the TGT, and increases in PCF and CEM. The degree of normalization of these parameters did not appear to depend on the baseline values. The patient with the worst baseline parameters completely normalized his values at 100% doses of BeneFIX® and Mononine®. The patient with the best baseline values also normalized his parameters with BeneFIX® but not with Mononine®. The patient with intermediate baseline abnormalities improved all parameters with both factor IX products but appeared to respond better to BeneFIX® at the 100% dose level. The response to NovoSeven®, at 100% of the dose recommended for treatment of factor VIII inhibitor patients, was detectable but clearly inferior to the response to the factor IX agents. These results indicate significant variability in hemostatic status between factor IX deficient patients both at baseline and in response to factor replacement. While rFVIIa has activity in these patients, the dose previously shown to correct TGT in factor VIII deficient patients may not be appropriate for factor IX deficient patients.