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

Abstract

SummaryHaemostatic treatment modalities alternative to platelet transfusion are desirable to control serious acute bleeds in primary immune thrombocytopenia (ITP). This study challenged the hypothesis that recombinant activated factor VII (rFVIIa) combined with fibrinogen concentrate may correct whole blood (WB) clot formation in ITP. Blood from ITP patients (n = 12) was drawn into tubes containing 3Á2% citrate and corn trypsin inhibitor 18Á3 lg/ml. WB [mean platelet count 22 9 10 9 /l (range 0-42)]was spiked in vitro with buffer, donor platelets (+40 9 10 9 /l), rFVIIa (1 or 4 lg/ml), fibrinogen (1 or 3 mg/ml), or combinations of rFVIIa and fibrinogen. Coagulation profiles were recorded by tissue factor (0Á03 pmol/l) activated thromboelastometry. Coagulation in ITP was characterized by a prolonged clotting time (CT, 1490 s (mean)) and a low maximum velocity (MaxVel, 3Á4 mm 9 100/s) and maximum clot firmness (MCF, 38Á2 mm). Fibrinogen showed no haemostatic effect, whereas rFVIIa reduced the CT and increased the MaxVel. The combination of fibrinogen and rFVIIa revealed a significant synergistic effect, improving all parameters (CT 794 s, MaxVel 7Á9 mm 9 100/s, MCF 50Á7 mm) even at very low platelet counts. These data suggest that rFVIIa combined with fibrinogen corrects the coagulopathy of ITP even at very low platelet counts, and may represent an alternative to platelet transfusion.

Complementary effect of fibrinogen and rFVIIa on clottingex vivoin Bernard-Soulier syndrome and combined use during three deliveries

“…The stabilization phase (MCF) was only influenced by fibrinogen. Similar additive effect has been previously shown ex vivo in post-cardiopulmonary bypass coagulopathy and in autoimmune thrombocytopenia [11,18].…”

“…Although its efficacy is not considered proven, the UKHCDO recommends the use of rFVIIa for postpartum bleeding in BSS [21]. Reports have also suggested a beneficial effect of fibrinogen supplementation in severe coagulopathies, even in the absence of hypofibrinogenemia [18,22] and, lately, also in immune thrombocytopenia [11]. To our knowledge no prior reports describe the use of fibrinogen supplementation alone or its administration together with rFVIIa in BSS.…”

“…An additive effect of rFVIIa and fibrinogen on clot formation has recently been reported in immune thrombocytopenia [11]. Also, hemostasis has been reported following rFVIIa administration in refractory thrombocytopenic conditions [12,13].…”

Alternatives to allogeneic platelet transfusion

“…RCTs in ITP, haematological malignancy undergoing chemotherapy, MDS and liver disease Antifibrinolytics (Estcourt et al, 2016) In clinical use largely outside the setting of thrombocytopenia. Fibrinogen concentrate Larsen et al (2013) In clinical use largely outside the setting of thrombocytopenia. Several large ongoing RCTs at present.…”

“…In vitro work combining the administration of fibrinogen concentrate and rFVIIa demonstrated normalisation of whole blood clot formation in an in vitro model of ITP and suggested the two agents may have a synergistic effect (Larsen et al, 2013) and trials administering fibrinogen concentrate to thrombocytopenic pigs demonstrated an improvement in maximum clot firmness (Velik-Salchner et al, 2007). In vitro work combining the administration of fibrinogen concentrate and rFVIIa demonstrated normalisation of whole blood clot formation in an in vitro model of ITP and suggested the two agents may have a synergistic effect (Larsen et al, 2013) and trials administering fibrinogen concentrate to thrombocytopenic pigs demonstrated an improvement in maximum clot firmness (Velik-Salchner et al, 2007).…”