Effect of haemodilution, acidosis, and hypothermia on the activity of recombinant factor VIIa (NovoSeven®)

Background. A range of plasma volume expanders is used clinically, often in settings where haemostasis may already be impaired. The haemostatic agent, recombinant activated factor VII (rFVIIa, NovoSevenw), may be used to improve haemostasis but potential interactions with different volume expanders are poorly understood. Methods. Clot formation was measured by thromboelastography (TEG) using blood from healthy volunteers. In vitro effects of rFVIIa with haemodilution, acidosis, and hypothermia were examined. Conditions were induced by dilution with NaCl (0.9%), lactated Ringer’s solution, albumin 5%, or hydroxyethyl starch (HES) solutions [MW (molecular weight) 130–670 kDa]; by adjusting pH to 6.8 with 1 M HEPES (N-2-hydroxyethylpiperazine-N0-2-ethanesulphonic acid) buffer; or by reducing temperature to 328C. We also studied the effect of low vs high MW HES (MW 200 vs 600 kDa) and rFVIIa on in vivo bleeding time (BT) in rabbits. Results. Haemodilution progressively altered TEG parameters. rFVIIa improved TEG par-ameters in the presence of acidosis, hypothermia or 20 % haemodilution (P,0.05). At 40 % hae-modilution, the rFVIIa effect was diminished particularly with high MW HES. In vivo, rFVIIa shortened the BT (P,0.05) with low but not high MW HES. Conclusions. Efficacy of rFVIIa was affected by the degree of haemodilution and type of volume expander, but not by acidosis or hypothermia

Influence of cardiopulmonary bypass on the interaction of recombinant factor VIIa with activated platelets

Recombinant factor VIIa (rFVIIa) interacts preferentially with coated platelets characterized by a high exposure of phosphatidyl serine (PS), FV, FVIII, FIX, and FX binding, and fibrinogen. Cardiopulmonary bypass (CPB) is known to impair platelet function. In this study, the influence of CPB on formation of coated platelets and the interaction of rFVIIa with the platelets were studied. Blood was either exposed to a closed CPB circuit or obtained from patients undergoing CPB-assisted cardiac surgery, and platelets were analyzed by flow cytometry with and without dual agonist stimulation with thrombin and a GPVI collagen receptor agonist known to induce coated platelet formation. Platelets circulated within a closed CPB circuit did not spontaneously form coated platelets. Dual agonists stimulation caused formation of coated platelets at a reduced level compared to pre-CPB level (51 ± 21% vs. 80 ± 17% before CPB, p < .001). The rFVIIa interaction with the coated platelets was not impaired after CPB. Platelets isolated from patients undergoing CPB-assisted cardiac surgery also formed coated platelets only after dual agonist stimulation but to the same level as before surgery (76 ± 8% vs. 83 ± 14% before surgery, p = .17, n = 10). rFVIIa interaction with the coated platelets was not impaired after surgery. No spontaneous rFVIIa-binding platelets were found. The data indicate that CPB exposure in vivo does not compromise the platelet-dependent effects of rFVIIa either by spontaneous formation of coated platelets, thereby limiting the risk of systemic coagulation, or by impairing rFVIIa interaction with the agonist-induced coated platelets, thereby retaining the hemostatic potential of rFVIIa after CPB

Design of an ongoing phase I/II open-label, dose-escalation trial using the oral chelator deferasirox to treat iron overload in HFE-Related hereditary hemochromatosis (HH)

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