Improved clot formation by combined administration of activated factor VII (NovoSeven) and fibrinogen (Haemocomplettan P).
BACKGROUND
Recombinant activated factor VII (rFVIIa) is increasingly used for treating refractory bleeding after cardiac surgery. However, hemostasis also depends on coagulation factors, including fibrinogen, which stabilizes platelet plugs at sites of vascular injury. We compared the hemostatic effects of rFVIIa, fibrinogen, or their combination.


METHODS
Blood samples were obtained from 12 volunteers and from 7 patients after cardiopulmonary bypass (CPB). The in vitro effects of rFVIIa (1.5 microg/mL), fibrinogen (100 mg/dL), and the combination were evaluated under simulated coagulopathy in volunteer plasma using heparin (0.1 U/mL) or tissue plasminogen activator (0.1 microg/mL). Hemostatic interventions were compared using thromboelastometry, which measures clotting time (CT, s), angle of thrombus formation, and maximal clot firmness (MCF, mm). The Thrombinoscope was used to quantitate thrombin generation after addition of fibrinogen and/or rFVIIa.


RESULTS
In heparinized volunteer plasma, rFVIIa shortened CT (1st and 3rd quartiles) from 663 (522-736) to 435 (397-531) s, but it did not affect MCF. Fibrinogen increased MCF from 26.0 (24.4-26.7) to 30.5 (26.3-31.5) mm without affecting CT. The combination of rFVIIa and fibrinogen in heparinized samples was most effective in improving CT to 359 (324-522) s and MCF to 29 (27.8-31.0) mm. In tissue plasminogen activator-treated volunteer plasma, fibrinolysis increased by more than 45% by the addition of rFVIIa. After CPB, both CT and MCF were most improved with coadministration of rFVIIa and fibrinogen. Thrombinoscope evaluation demonstrated that rFVIIa decreased the lag time and increased peak thrombin generation, whereas fibrinogen had no effect.


CONCLUSIONS
The onset of fibrin formation and thrombin generation were shortened after rFVIIa addition, but fibrin clot strength was only increased after fibrinogen supplementation. In vitro clot formation was most improved by using both rFVIIa and fibrinogen in whole blood after CPB.
Tanaka
Kenichi A
KA
Department of Anesthesiology, Division of Cardiothoracic Anesthesia, Emory University School of Medicine, 1364 Clifton Rd., NE, Atlanta, GA 30322, USA.
Taketomi
Taro
T
Szlam
Fania
F
Calatzis
Andreas
A
Levy
Jerrold H
JH
D001780:Blood Coagulation Tests; D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass; D003029:Coagulants / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D015942:Factor VIIa / Q000494:pharmacology* / Q000627:therapeutic use; D005340:Fibrinogen / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D019106:Postoperative Hemorrhage / Q000097:blood / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D003029:Coagulants; D011994:Recombinant Proteins; D005340:Fibrinogen; C103587:recombinant FVIIa; D015942:Factor VIIa