Whole blood coagulation in children with thrombocytopenia and the response to platelet replacement, recombinant factor VIIa, and a potent factor VIIa analogue

Abstract

SummaryThe present study evaluated dynamic coagulation profiles, platelet aggregation, and thrombin generation in whole blood (WB) from eight children with thrombocytopenia during chemotherapy, and the haemostatic potential of platelets (+60 · 10 9 /l), recombinant factor VIIa (rFVIIa -, and a potent rFVIIa analogue (NN1731) both at 1 and 4 lg/ ml. Dynamic WB coagulation profiles were recorded by thrombelastometry employing activation with tissue factor (TF -Innovin Ò ) at low concentrations. The baseline WB coagulation patterns were characterised by a prolonged clotting time (CT) and a pronounced reduction in clot propagation (MaxVel). WB platelet aggregation signal was five times lower in the study group compared with measurements in modelled thrombocytopenic WB from healthy volunteers. In vitro addition of fresh platelets reversed the coagulopathy. Addition of rFVIIa induced no significant changes in the thrombelastographic profile, whereas spiking with NN1731 shortened the CT significantly. The changes in WB thrombin generation reflected the changes in the MaxVel. In modeled thrombocytopenic WB from healthy individuals, both rFVIIa and NN1731 exhibited a pronounced haemostatic effect with NN1731 showing greater potency than rFVIIa. Compromised platelet function in the study group was assumingly responsible for the weakened haemostatic potential of rFVIIa as well as that of NN1731.

Combination of recombinant factor VIIa and fibrinogen corrects clot formation in primary immune thrombocytopenia at very low platelet counts

“…Recombinant FVIIa provided a dose‐dependent effect on clot initiation and a reduction in lag‐time of thrombin generation, which corresponds well to previous findings where rFVIIa particularly enhanced the initial thrombin generation and platelet activation in thrombocytopenia‐like conditions (Kjalke et al , ). In contrast to previous findings in malignancy‐related thrombocytopenia (Larsen et al , ), rFVIIa also improved the propagation phase and increased the thrombin generation. This disparity may partly be explained by the augmented platelet function in ITP compared to malignancy‐related thrombocytopenia demonstrated by our data in line with others (Misgav et al , ).…”

“…The ITP patients displayed markedly increased platelet aggregation compared to previously published data on patients with malignancy‐related thrombocytopenia with similar platelet counts (64·7 ± 52·0 aggregation units (AU) vs. 9·1 ± 4·9 AU, P = 0·004; Fig ; Larsen et al , ). However, the aggregation of the WB thrombocytopenia model was not significantly different from the ITP patients (38·9 ± 24·3 AU, P = 0·14; Fig ).…”

“…The incidence and severity of bleeding manifestations in ITP are largely associated with the platelet count (Lacey & Penner, 1977). The haemostatic efficacy of rFVIIa in thrombocytopenia also appears to be affected by the platelet count (Kristensen et al, 1996;Monroe et al, 1997) and function (Larsen et al, 2009). Nevertheless, systematic reports on the correlation between the haemostatic response to potential interventions and the platelet count are still lacking.…”

Factor VIIa analog has marked effects on platelet function and clot kinetics in blood from patients with hemophilia A

“…(or MCF) response to rFVIIa has been observed previously [10,17,22,24,25] and it may be due to a relatively lower contribution of platelets to these parameters. These data may suggest that the hemostatic effects of rFVIIa and NN1731 can be monitored by the PCF and CEM parameters, respectively.…”

“…For example, Sørensen's research group has monitored rFVIIa using a variety of TF dilutions ranging from 1 : 50 000 (0.0875 pmol/l) to 1 : 17 000 (approximately 0.350 pmol/l) [10,[21][22][23]. One possible concern with using too high concentrations of TF as the activator when assessing effects of rFVIIa is the risk of having the TF/FVIIa complex drive the generation of thrombin and thus making the reaction mixture extremely sensitive to FVIIa and not reflecting the mode of action of rFVIIa in a physiological environment.…”