Major Haemorrhage and Recombinant Factor VIIa Concentrate

Major Haemorrhage and Recombinant Factor VIIa Concentrate

A 40-year-old female intravenous drug user presented with a diffusely swollen right lower leg. She had injected heroin into her right thigh one week previously. The swelling started 3 days later. Initial observations revealed T 39.6, HR 135, NIBP 100/87, RR 32, Sats 96% on air. On examination, she was pale and sweaty. She had a swollen right lower leg with mottling of her foot and poor pedal pulses. Following initial fluid resuscitation, chest X-ray, cultures and broad-spectrum antibiotics (Flucloxacillin, Metronidazole and Gentamicin), she underwent CT angiogram of her lower limbs which showed oedematous and expanded muscle compartments of the thigh and calf but patent arterial flow to the feet. There was also right common femoral vein thrombosis with some vessel patency. Initial labs revealed neutrophilia (9.2), thrombocytopaenia (16) and deranged coagulation (PT 16, APPT 33, Fib 2.6). CK was 57000. She underwent right leg fasciotomies and was brought to ICU ventilated and on Noradrenaline to maintain MAP >65. She commenced Immunoglobulin IV 1gram/kg per day for 2 days for suspected Streptococcus Group A sepsis. That night she had massive transfusion requirements due to ongoing haemoserous ooze from her fasciotomy sites, losing up to 1 litre of haemoserous fluid per hour. Overnight she received 10 units RCC, 8 x FFP, 6 x Platelets and 2 x Cryoprecipitate, as well as Vitamin K (guided by Hb on ABG, formal lab results and thromboelastography). She was discussed with the Haematology Consultant and it was decided that, if rapid blood loss continued despite full correction of her clotting factors, fibrinogen and platelets then Factor VII could be given. However, over the next 2 hours, losses were much reduced following product replacement, and since she already had clot in her femoral vein, Factor VII Concentrate was not given.

What is the role of Recombinant Factor VIIa in major haemorrhage?

Craig Walker

Recombinant activated factor VII (rFVIIa) is currently licensed in Europe for use in patients with haemophilia A or B to bypass inhibitors to factors VIII and IX, as well as for treatment of congenital factor VII deficiency and Glanzmann’s thrombasthenia (1). However, use of rFVIIa for other reasons is widespread. A retrospective analysis of 21 academic centres in the United States found that 645 of 701 patients (92%) who received rFVIIa did so for off-label indications (2). Of the 315 notes reviewed, rFVIIa had been used to prevent bleeding in 119 (37.8%) patients and to treat bleeding in the remaining 196 (62.2%).

rFVIIa was initially thought to act by increasing activity of the extrinsic tissue factor (TF)-dependent coagulation pathway (forming the TF/FVIIa complex). However, the levels of rFVIIa required to cause haemostasis are far higher than would be required to fully saturate TF so another effect pathway is thought to be mainly responsible:  When given in high doses, rFVIIa bypasses TF, binds to the surface of activated platelets localised at the site of injury and promotes Factor X activation (and Factor IX activation in non-haemophilic conditions) and thrombin generation above normal levels; this increases local platelet activation and accumulation (3)(4).

Whilst there is a pathophysiological mechanism by which rFVIIa might be of benefit in patients with haemorrhage, much of the available evidence for off-label indications is based on case studies/series, small trials and observational data.  In a retrospective observational analysis of 32 patients who had received rFVIIa in the context of massive haemorrhage that could not be controlled by conventional transfusions, a significant reduction was seen in red blood cell (RBC) transfusions (mean 20.1 units before rFVIIa and 8.7 afterwards: p<0.001, CI 6.4-16.5) and fresh frozen plasma (FFP) transfusions (19.3 to 9.3: CI 4.2-15.6, p=0.001) requirements in the 48 hours after administration.

Similarly, 2 parallel, randomised controlled trials in patients with severe blunt (143) or penetrating (134) trauma found that both RBC transfusions were significantly reduced in the blunt trauma group (estimated reduction 2.6 units compared to control; p=0.02) with a non-significant reduction in requirements in the penetrating trauma group (5).

A 2008 meta-analysis of 22 RCTs of 3184 non-haemophilic patients who received rFVIIa found that RBC transfusions were significantly lower in the treatment groups but that there was no significant difference in mortality. 15% of these patients died and 7.8% had thromboembolic events (6). In a 2011 systematic review of patients given rFVIIa for intracranial haemorrhage, cardiac surgery, trauma, liver transplantation or prostatectomy, there was again no significant difference in overall survival.  When given for intracranial haemorrhage or cardiac surgery, there was a significantly increased risk in thromboembolism (7).


Lessons Learned

Recombinant Factor VIIa has multiple physiological actions to suggest that it would reduce bleeding. It is being increasingly given for off-label uses and, over this wide range of applications, it would appear that it can significantly lower blood product requirements. However, this reduction has not translated into any mortality benefit and it may increase the risk of thromboembolism in some cases. Its use should not therefore be routinely recommended unless future high-quality, large-scale trials demonstrate statistically significant morbidity or mortality benefits.  


References

  1. Kessler CM. New products for managing inhibitors to coagulation factors: a focus on factor VIIa concentrate. Current Opinion in Haematology 2000: 7; 408.
  2. MacLaren R, Weber LA, Brake H, et al. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion 2005: 45; 1434.
  3. Lisman T, Adelmeijer J, Cauwenberghs S, Van Pampus EC, Heemskerk JW, De Froot PG. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost. 2005; 3(4); 742.
  4. Monroe DM, Hoffman M, Allen GA, Roberts HR. The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia. Semin Thromb Hemost 2000; 26: 373.
  5. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel, randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005: 59; 8-15.
  6. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized controlled trials. Ann Surg.2—8: 248(1); 61.
  7. Yank V, et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications. Ann Intern Med 2001: 154(8); 529-540.
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