Potential Thrombogenic Complications

Recombinant activated Factor VII (FVIIa; NovoSeven, Novo Nordisk, Copenhagen) was approved by the Food and Drug Administration in the US in March, 1999, for the alternate hemostatic management of hemophilia patients who develop antibodies to FVIII. Although medically useful, there have been reports of adverse thrombogenic complications associated with its use (1,2,3). In an article published in the Journal of the American Medical Association (JAMA) in December, 2005, the US FDA cautioned that administration of NovoSeven for heretofore unlicensed indications to healthy, non-hemophilic individuals could result in such complications as stroke and MI, possibly leading to death. The vast majority of these clotting complications were detected in older individuals administered NovoSeven to reverse bleeding not related to hemophilia. Clotting complications rarely have occurred in the much younger individuals with hemophilia related antibodies, who have received NovoSeven to treat or prevent active bleeding.

Because anecdotal reports have provided the impression that life and limb threatening and overwhelming bleeding complications in desperate situations could be treated successfully and rapidly with NovoSeven administration, the use of this genetically engineered coagulant protein has been promoted by many medical experts for expanded usage in the management of medical, surgical and trauma associated bleeding in hospitalized patients. There is no questions that NovoSeven administration has been associated with numerous "miraculous saves" however, there also is a dearth of well-controlled clinical trials which could provide insight into what criteria should be applied to maximize its safe use in the context of its known potential thrombogenicity. More recently the Israeli and US armies have used NovoSeven for the control of bleeding occurring with battlefield and combat trauma. The US Army has developed and posted guidelines for the use of recombinant FVIIa in military hospitals. While this use of NovoSeven is off-label and non-standardized, the Army is to be commended for exploring its usage in the management of bleeding in battlefield conditions where the conventional methods were not always effective.

A recent article Dangerous Remedy. Military doctors in Iraq say that Factor VII saves wounded soldiers, but other doctors and medical research suggest that it can cause fatal clots (Baltimore Sun, November 19, 2006) authored by Robert Little, a Sun reporter, has provided a comprehensive review of the adverse thrombogenic complications associated with the use of NovoSeven. This article reported that the US army has injected more than 1000 trauma inflicted soldiers with NovoSeven . The thrombogenic effect of recombinant FVIIa has been attributed to its upregulated ability to trigger the formation of blood clots at sites of bleeding by complexing with a substance called tissue factor, which is present at sites of injury. The Baltimore Sun article is based on the extensive battlefield observations and research conducted by the reporter. Moreover, the reporter has also interviewed several experts in the field of hemostasis and thrombosis and sought their opinion about how to assess the risk to benefit ratio of the clinical situation before administering NovoSeven. Army trauma surgeons and advisors on combat medical care have stated that recombinant FVIIa is one of the most useful new tools the Army has to control bleeding in combat situations. While these statements may be true, the potential complications with the use of this drug should not be ignored. In fact, at military hospitals in Germany and in the US, physicians have reported an increased prevalence of unexplained strokes, MIs and PEs in soldiers evacuated from combat.

The Baltimore Sun's article represents a comprehensive news item of great public and clinical impact, which has initiated a major debate and rightful concerns on the off-label use of NovoSeven. Our soldiers are already in great danger and the availability of a life-saving drug such as NovoSeven is welcome. It is, however, equally important to recognize and investigate the reported adverse reactions with its use to avoid additional risk to these army personnel.

The posted guidelines in battlefield hospitals encourage the liberal use of recombinant FVIIa in bleeding patients, and the drug is injected routinely upon suspicion of bleeding, even before it occurs. There is no risk stratification. Upon review of the available information on the use of recombinant FVIIa in Army hospitals the following items of concern were identified.

  1. The doses of recombinant FVIIa used have been rather high and may be excessive. The drug is available in 1.2, 2.4, and 4.8 mg lyophilized FVIIa vials, which are reconstituted with sterile water to obtain a 1 mg/ml solution. The recommended dosage of the rFVIIa is 120 ?g/kg IV bolus. Additional redosing is recommended at 20 minutes if hemorrhage continues (4). Depending upon the weight of the recipient, 3 - 4 vials may be combined representing a total amount of 7.2 - 9.6 mg of FVIIa to be injected as a bolus. A 1 mg/ml solution of recombinant FVIIa represents a potent procoagulant which upon contact with blood in the trauma patient activates coagulation beyond the intended hemostatic effect.
  2. It should be understood that trauma patients have massive blunt injuries resulting in tissue damage, massive fractures leading to the presence of bone fragments and marrow sap in circulation which are rich in tissue factor. Unlike hemophiliacs, in trauma cases the circulating tissue factor and other procoagulant materials combine with VIIa and may trigger disseminated thrombogenesis. The obvious complications which are PE, MI, and stroke.
  3. Along with the administration of recombinant FVIIa the battlefield trauma victims are simultaneously administered either other hemostatic agents such as packed red cells, whole blood, fresh frozen plasma, cryoprecipitate, fibrin sealants, and/or antifibrinolytic agents. All of these are capable of augmenting the procoagulant effect of recombinant FVIIa by virtue of the presence of pre-formed tissue factor from red cells and platelet fragments or by interfering with the body�??s mechanisms to modulate clotting. Thus, the liberal use of any or all of these ancillary products may trigger excessive clot formation and lead to hypercoagulable complications. The interactions of NovoSeven with each of these products, alone and combined, must be fully understood in trauma settings before optimal dosing and hemostatic regimens can be established for individuals with blunt or penetrating trauma.
  4. The therapeutic and procoagulant effects of NovoSeven in Army hospitals are apparently monitored by determining the prothrombin time (PT) and derived International Normalized Ratio (INR) values. Such a method as INR is meaningless in these settings as the INR is only applicable to those patients who are under treatment with oral anticoagulants. Moreover, recombinant FVIIa and activated prothrombin complex concentrates produce falsely low INR values by interfering with the PT test. At the same time some of these trauma victims sustain disseminated intravascular coagulation (DIC) which itself can cause an increase in the INR necessitating additional measures to correct it. This may be a dangerous approach and may result in fatal outcomes. To date there are no reliable or reproducible laboratory assays which uniformly correlate the procoagulant effects of NovoSeven with clinical outcome or which can predict safety or efficacy.
  5. The current guideline also calls for a repeat administration of recombinant FVIIa 20 minutes after the initial dosage, if in the evaluation of an Army doctor the bleeding has not stopped. Such a practice will also add to the thrombogenic complications associated with the use of this drug.

The above represents the concerns of the undersigned and is provided to underscore the important considerations which should be taken into account at all levels to optimize the safe use of NovoSeven in battlefield conditions. It is the intention of this editorial to bring out these concerns to the attention of those involved in the control of bleeding in medical, surgical, and trauma patients as addressing these concerns will be helpful in identifying adverse events and their potential management. The authors are thankful to the Baltimore Sun in publishing this timely and serious report which requires immediate action on the part of all concerned parties. We are also thankful to the US Army Medical Corps who have objectively identified some of these issues and will be responsible in a stepwise resolution of some of the concerns in eventually providing our soldiers safer approaches to utilize newer drugs in combat medicine. There is no question that the judicious use of recombinant FVIIa on the battlefield and careful analysis of the benefits and risks associated with its use will provide the proof of principle for the use of this procoagulant in civilian trauma and surgical bleeding scenarios. Such observations should also serve to stimulate the conduct of well designed clinical trials to ascertain safety and efficacy data and to establish optimal treatment regimens


  1. Hoots W.K., Challenges in the therapeutic use of a "so-called" universal hemostatic agent: recombinant factor viia. Hematology (ASH online 1). 426-431, 2005.
  2. Stein D.M., Dutton R.P., O Connor J., Alexander M., Scalea T.M. Determinant of futility of administration of recombinant factor viia in trauma. Trauma. 59(3): 609-615, 2005.
  3. MacLaren R. Weber L.A., Brake H., Gardner M.A. and Tanzi M. A multicenter assessment of recombinant factor viia off-label usage:clinical experiences and associated outcomes. Transfusion. 45:1434-1438, 2005.
  4. Midla G. CPT., Recombinant factor viia and its clinical applications. Army Medical Department Journal. PB 8-04-7/8/9 Jul/Aug/Sep.

Jawed Fareed, Ph.D. - Loyola University Medical Center, Maywood, IL
Rodger L. Bick, M.D., Ph.D.,F.A.C.P. - University of Texas, Southwestern Medical Center
Sylvia Haas, M.D.- Technical University of Munich, Department of Surgery, Munich, Germany
Craig Kessler, M.D. - Professor of Medicine, Lombardi Cancer Center, Georgetown, MD
Harry L. Messmore, M.D. - Professor Emeritus, Pathology & Medicine, Loyola University Medical Center
Gundu Rao, Ph.D. - University of Minnesota, Professor of Pathology & Biomedical Eng., Minneapolis, MN
Arthur Sasahara, M.D. - Professor Emeritus, Harvard Medical School, Boston, MA
Rakesh Wahi, M.D. - Grant Memorial Hospital, Petersburg, WV