The hemostatic profile of recombinant activated factor VII. Can low concentrations stop bleeding in off-label indications?

Altman, Raúl; Scazziota, Alejandra; Herrera, Maria de Lourdes; Gonzalez, Claudio

doi:10.1186/1477-9560-8-8

Cited by 6 publications

(4 citation statements)

References 32 publications

(41 reference statements)

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“…This is as would be predicted given the global reduction in clotting factors observed in this patient cohort. A similar result was observed by Altman et al [ 30 ] using a model of dilutional coagulopathy. This suggests that rFVIIa may be inappropriate to use in isolation to treat bleeding.…”

Section: Discussionsupporting

confidence: 90%

Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass

Percy

Hartmann

Jones

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Recently, lower thrombin generation has been associated with excess bleeding post-cardiopulmonary bypass (CPB). Therefore, treatment to correct thrombin generation is a potentially important aspect of management of bleeding in this group of patients. The objective of the present study was to investigate the effects of fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), prothrombin complex concentrate (PCC) and tissue factor pathway inhibitor (TFPI) inhibition on thrombin generation when added ex vivo to the plasma of patients who had undergone cardiac surgery requiring CPB. Patients undergoing elective cardiac surgery were recruited. Blood samples were collected before administration of heparin and 30 min after its reversal. Thrombin generation was measured in the presence and absence of different concentrations of FFP, rFVIIa, PCC and an anti-TFPI antibody. A total of 102 patients were recruited. Thrombin generation following CPB was lower compared with pre-CPB (median endogenous thrombin potential pre-CPB 339 nmol/l per min, post-CPB 155 nmol/l per min, P < 0.0001; median peak thrombin pre-CPB 35 nmol/l, post-CPB 11 nmol/l, P < 0.0001). Coagulation factors and anticoagulants decreased, apart from total TFPI, which increased (55–111 ng/ml, P < 0.0001), and VWF (144–170 IU/dl, P < 0.0001). Thrombin generation was corrected to pre-CPB levels by the equivalent of 15 ml/kg FFP, 45 μg/kg rFVIIa and 25 U/kg of PCC. Inhibition of TFPI resulted in an enhancement of thrombin generation significantly beyond pre-CPB levels. This study shows that FFP, rFVIIa, PCC and inhibition of TFPI correct thrombin generation in the plasma of patients who have undergone surgery requiring CPB. Inhibition of TFPI may be a further potential therapeutic strategy for managing bleeding in this group of patients.

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Section: Discussionsupporting

confidence: 90%

Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass

Percy

Hartmann

Jones

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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“…In addition to multiple case reports and nonrandomized single-institution and large database studies, 2 randomized trials using rFVIIa doses between 40 and 90 μg/kg have documented the efficacy of rFVIIa in controlling hemorrhage when used in either the intraoperative or postoperative setting [1, 6]. In 2005, we proposed that low-dose rFVIIa (20–40 μg/kg) may be adequate to achieve hemostasis in patients with intact hemostatic systems [15], and other reports have since supported this approach [4, 5, 18–20]. The rationale for early rFVIIa dosing appears further supported by the findings of a large Canadian review of rFVIIa use in cardiac procedures, in which the authors concluded the efficacy of rFVIIa may be improved if administered early in the setting of adequate coagulation factors [11].…”

Section: Commentmentioning

confidence: 99%

Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations

Andersen

Bhattacharya

Williams

et al. 2012

The Annals of Thoracic Surgery

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Background Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Methods Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Results Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Conclusions Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.

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“…In patients with intact mechanisms of thrombin generation, higher rFVIIa doses may augment thrombin production distant to the site of bleeding in a tissue factor-independent manner, resulting in thromboembolic complications without improved hemostatic effects (47). In vitro data suggests that a low dose of rFVIIa (equivalent to 20 μg/kg) has similar efficacy to higher doses (100 – 200 μg/kg) as measured by thrombin generation (48). Similarly, in moderate to severe thrombocytopenia, 50 μg/kg of rFVIIa was as effective as 100 μg/kg at decreasing the Ivy bleeding time (49).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human Factor VIIa for Alveolar Hemorrhage Following Allogeneic Stem Cell Transplantation

Elinoff

Bağcı

Moriyama

et al. 2014

Biology of Blood and Marrow Transplantation

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The mortality rate of alveolar hemorrhage following allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high dose steroids. We performed a retrospective cohort analysis to assess the benefits and risks of rFVIIa as a therapeutic adjunct for alveolar hemorrhage. From 2005 to 2012, 57 episodes of alveolar hemorrhage occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median (interquartile range) steroid dose was 1.9 mg/kg/d (0.8 – 3.5; methylprednisolone equivalents) and did not differ statistically between the two groups. The median rFVIIa dose was 41 μg/kg (39-62) and a median of 3 doses (2-17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [141-262]); 72% required mechanical ventilation and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of alveolar hemorrhage (p = 0.50), duration of mechanical ventilation (p = 0.89), duration of oxygen supplementation (p = 0.55), or hospital mortality (p = 0.27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa when used in combination with corticosteroids did not confer clear clinical advantages compared to corticosteroids alone. In patients with AH following hematopoietic stem cell transplant, clinical factors (i.e. worsening infection, multiple organ failure or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

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The hemostatic profile of recombinant activated factor VII. Can low concentrations stop bleeding in off-label indications?

Cited by 6 publications

References 32 publications

Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass

Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass

Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations

Recombinant Human Factor VIIa for Alveolar Hemorrhage Following Allogeneic Stem Cell Transplantation

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