the potential role of factor viia in transfusion medicine

PROFESSOR

DEPARTMENT OF PATHOLOGY

DUKE UNIVERSITY MEDICAL CENTER

LABORATORY MEDICINE SERVICE

DURHAM VA MEDICAL CENTER

DURHAM, NORTH CAROLINA, USA

S U M M A R Y

MAUREANE HOFFMAN, MD, PhD

• Blood products

• Hemostasis

• Plasma

• Platelets

Therapy with high doses of recombinant factor VIIa (rFVIIa) is effective in promoting

hemostasis in hemophiliacs. There is also some evidence to support the idea that

this agent can enhance hemostasis in patients with platelet function defects,

thrombocytopenia and liver failure, as well as in persons without a preexisting

bleeding disorder. Because of this hemostatic effect in a wide range of clinical

settings, it is possible that rFVIIa could serve as a substitute or supplement to the transfusion

of blood products.

The Potential Role of Factor VIIa in Transfusion Medicine

Transfusion Alternatives in Transfusion Medicine VOLUME 5 NUMBER 5 SUPPLEMENT DECEMBER 2003( Page 20 )

TATM 2003;5(5 Suppl):20-22 )(


The Potential Role of Factor VIIa in Transfusion Medicine MAUREANE HOFFMAN

Transfusion Alternatives in Transfusion Medicine VOLUME 5 NUMBER 5 SUPPLEMENT DECEMBER 2003( 1 )

At the start of my career in Blood Banking the unspokenassumption existed that blood was good for you. It was notuncommon to give a patient a transfusion just before he wenthome from the hospital so he would feel better. Of course, theAIDS “epidemic” taught us what we should have already known:receiving a blood transfusion is the most intimate possible contactwith a stranger and the potential for transmission of infectiousdisease is always present. We are also increasingly recognizingthe direct immunosuppressive effects of transfusion and also thattransfusion may be associated with a worse clinical outcome insome settings.1,2 These potential risks as well as the escalatingcost of blood products have provided an impetus for attemptingto reduce or eliminate the transfusion of blood productswhenever possible. Strategies for optimizing transfusion therapyand transfusion sparing techniques during surgery can reduceblood product use to a certain degree. In addition,antifibrinolytics can reduce the need for transfusion duringcardiac surgery. However, there are certain clinical settings whereno alternatives to the transfusion of blood products have existed.

A great deal of work has been done on the development ofred blood cell substitutes.3 A number of products are also indevelopment as platelet substitutes.4 However, none of thesealternatives to transfusion have yet made it on to the market.It would be desirable to have a non-blood-derived productthat could substitute for the transfusion of plasma productsand platelet concentrates to enhance hemostatic function.Could recombinant coagulation factor VIIa (rFVIIa) possiblyplay such a role?

Recombinant rFVIIa has been approved for the managementof bleeding in hemophiliacs with inhibitors.5 It has proven to bequite safe and effective in this setting. A growing number ofpublications document the off-label use of rFVIIa in managingbleeding in a variety of clinical settings, including plateletfunction disorders,6,7 thrombocytopenia,8 liver failure9 and livertransplantation,10 post-surgical11 and following trauma.12 It isdifficult to evaluate the overall clinical efficacy and safety of rFVIIain non-hemophiliac bleeding because the reports on its use havelargely been single cases or small, uncontrolled series. However,a recent blinded placebo-controlled clinical trial demonstratedthat the administration of a single dose of rFVIIa at the start ofthe operation reduced blood loss (and, hence, transfusionrequirements) in patients undergoing prostatectomy.13 While itis unlikely that rFVIIa would be given to all patients undergoingany given type of operation, this study demonstrates that apharmacological agent can reduce perioperative bleeding inpatients with no preexisting bleeding tendency.

The concept that a pharmacological agent could reducebleeding in otherwise normal surgical patients is not entirelynovel. There is good data to show that aprotinin is effective inreducing transfusion requirements in cardiac surgery patients.14

This agent is relatively cheap and has not been associated withsignificant thrombotic complications. However, it does appear

to be useful only in certain types of operative procedures. It isalso not effective in stopping ongoing hemorrhage, as rFVIIa hasbeen reported to be. Thus, it is possible that rFVIIa may be ableto fill a unique niche in managing hemorrhage in surgical patientsand thereby reducing the need for transfusion.

A related potentially important application of rFVIIa is in post-traumatic bleeding. One huge advantage of using rFVIIa forhemostasis in this setting is that it can be carried into the fieldto be administered to a patient before he can be brought to a sitewhere blood products are available. Of course, rFVIIa does notprovide volume or oxygen-carrying capacity as blood productsdo. However, if it could act as a hemostatic agent and slow therate of bleeding in trauma victims it could prolong survival andallow time for the transport of the patient to a treatment center.

Even once a trauma victim has arrived at a well-equippedhospital, he may experience bleeding that is very difficult tocontrol. Following trauma (or complicated surgery) a patientmay bleed for any of several reasons. Of course, bleeding maybe due to an anatomic defect. This type of bleeding is generallycorrectable surgically. However, the patient may develop diffusemicrovascular oozing which is not surgically correctable. This isdue to development of a coagulopathy related to dilution orconsumption of coagulation factors and platelets as well as hypothermia, metabolic acidosis, hyperkalemia andhypocalcemia. While it may seem that microvascular oozingwould not lead to significant blood loss, in fact coagulopathicpatients can lose enough blood in this way to require massivetransfusion.

Biochemical changes occur over time in red blood cell unitsduring storage. These include decreased levels of 2,3-DPG, adecrease in pH, and an increase in supernatant potassium (K+)with a concurrent decrease in intracellular K+. Transfusion oflarge amounts of blood products may be essential to replaceoxygen carrying capacity and procoagulants, but can alsoexacerbate the acidosis and hyperkalemia that may already bepresent in coagulopathic patients. In addition, infusions of thecitrate anticoagulant in blood components can worsenhypocalcemia, and the infusion of cold products can worsenhypothermia. Thus, it can be very difficult to manage thetransfusion therapy and metabolic derangements in such patients.

There are now a large number of case reports suggesting thatrFVIIa can reduce the microvascular bleeding that occurs in thesetting of trauma or surgery complicated by a coagulopathy. Nocontrolled clinical trials of rFVIIa in trauma patients have beencompleted. Such trials may be very difficult to conduct given theheterogeneous nature of trauma patients and the difficulties inobtaining informed consent. However, this is an important areafor study since there are no other pharmacological agents thatcan be used to manage coagulopathic bleeding and even themassive transfusion of blood products may not be effective insuch cases. In the foreseeable future, it may be possible to developan algorithm for managing trauma patients in which therapy

with rFVIIa could supplement transfusion therapy in patientswho continue to exhibit microvascular bleeding followingtransfusion of some predetermined volume of blood products.

Any strategy for managing hemorrhage in trauma patientsmust include careful attention to correcting acidosis andhypothermia. Platelet adhesive function is impaired by evenmild hypothermia15 and increasing hypothermia results inprogressive inhibition of the coagulation reactions. Acidosishas an even more profound effect on the coagulation reactions.Reduction in pH to around 7.0 virtually abolishes activity ofmost of the coagulation enzymes.16 Thus, it is unlikely thateven optimal transfusion and pharmacological therapy canmanage coagulopathic bleeding in the face of significantacidosis and hypothermia.

A final potential application for rFVIIa is as a supplement totransfusion of platelet concentrates in patients with quantitativeand qualitative platelet defects. Platelet concentrates areprecious resources that are expensive and difficult to prepare,have a short shelf life and are often used in large quantities.Many patients become refractory to platelet transfusion eitherthrough development of antibodies to platelet-borne antigensor due to non-immune platelet destruction. rFVIIa does notincrease the platelet count, but appears to enhance hemostasisin patients whose platelet counts are low, or whose plateletsare functionally defective.

rFVIIa promotes the adhesion of even functionally defectiveplatelets17 at a site of injury, by enhancing local thrombin

generation.18 rFVIIa also appears to enhance the amount ofthrombin generated on each platelet in a hemostatic plug, therebypromoting more effective fibrin clot formation at any givenplatelet count.19,20 A large registry documents the effectiveness ofrFVIIa in enhancing hemostasis in patients with inherited plateletfunction defects, especially Glanzmann thrombasthenia.6,7 Thesepatients can be notoriously difficult to manage, since they oftenbecome alloimmunized after transfusion of platelet products thatbear the GPIIb/IIIa antigen that their platelets lack. Such patientsare then refractory to further platelet transfusion therapy andhave a severe bleeding tendency. Clearly, rFVIIa can serve as theonly known alternative to platelet transfusion in these cases.

rFVIIa also appears to enhance platelet localization andthrombin generation in patients with thrombocytopenia.8,21,22 Theuse of rFVIIa could reduce the requirement for plateletconcentrates in these patients, or potentially be an effectivesubstitute for transfusion of platelets in those patients who arerefractory.

While there are many potential applications of rFVIIa as asupplement or substitute for transfusion of blood products, therehave been very few well-designed trials to examine this potential.Furthermore, current dosing recommendations are based on thetherapy of hemophiliacs. There is no validated dosing regimenfor the management of postsurgical bleeding, thrombocytopeniaor other off-label indications. It seems likely that new informationwill greatly expand the clinical utility of rFVIIa in the near future.

The Potential Role of Factor VIIa in Transfusion Medicine MAUREANE HOFFMAN

1. Engoren MC, Habib RH, Zacharias A, Schwann TA, RiordanCJ, Durham SJ. Effect of blood transfusion on long-term survivalafter cardiac operation. Ann Thorac Surg 2002;74:1180-6.

2. Langley SM, Alexiou C, Bailey DH, Weeden DF. Theinfluence of perioperative blood transfusion on survival afteresophageal resection for carcinoma. Ann Thorac Surg2002;73:1704-9.

3. Klein HG. Blood substitutes: how close to a solution?Oncology (Huntingt) 2002;16:147-51.

4. Blajchman MA. Novel platelet products, substitutes andalternatives. Transfus Clin Biol 2001;8:267-71.

5. Hedner U. Recombinant factor VIIa (Novoseven) as ahemostatic agent. Semin Hematol 2001;38:43-7.

6. Poon MC, d'Oiron R. Recombinant activated factor VII(NovoSeven) treatment of platelet-related bleeding disorders.International Registry on Recombinant Factor VIIa andCongenital Platelet Disorders Group. Blood CoagulFibrinolysis 2000;11 Suppl 1:S55-68.

7. Poon MC, d'Oiron R, Hann I, et al. Use of recombinant factorVIIa (NovoSeven) in patients with Glanzmann thrombasthenia.Semin Hematol 2001;38:21-5.

8. Gerotziafas GT, Zervas C, Gavrielidis G, et al. Effectivehemostasis with rFVIIa treatment in two patients with severethrombocytopenia and life-threatening hemorrhage. Am JHematol 2002;69:219-22.

9. Berthier AM, Guillygomarc'h A, Messner M, PommereuilM, Bader G, De Mello G. Use of recombinant factor VIIa totreat persistent bleeding following dental extractions in twocirrhotic patients. Vox Sang 2002;82:119-21.

10. Hendriks HG, Meijer K, de Wolf JT, et al. Reducedtransfusion requirements by recombinant factor VIIa inorthotopic liver transplantation: a pilot study. Transplantation2001;71:402-5.

11. Hendriks HG, van der Maaten JM, de Wolf J, WaterbolkTW, Slooff MJ, van der Meer J. An effective treatment of severeintractable bleeding after valve repair by one single dose ofactivated recombinant factor VII. Anesth Analg 2001;93:287-9.

12. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment oftraumatic bleeding with recombinant factor VIIa. Lancet1999;354:1879.

13. Friederich PW, Henny CP, Messelink EJ, et al. Effect ofrecombinant activated factor VII on perioperative blood loss inpatients undergoing retropubic prostatectomy: a double-blindplacebo-controlled randomised trial. Lancet 2003;361:201-5.

14. Kovesi T, Royston D. Pharmacological approaches toreducing allogeneic blood exposure. Vox Sang 2003;84:2-10.

15. Wolberg A, Meng Z, Monroe D, Hoffman M. A systematicevaluation of the effect of temperature on enzyme rate andplatelet function in normo- and hypothermic coagulation.J Trauma 2003; in press.

16. Meng Z, Wolberg A, Monroe DM 3rd, Hoffman M. The effectof temperature and pH on the activity of FVIIa: Implicationsfor the efficacy of high-dose FVIIa in hypothermic and acidoticpatients. J Trauma 2003;55:886-91.

17. Lisman T, Moschatsis S, Adelmeijer J, Nieuwenhuis HK,De Groot PG. Recombinant factor VIIa enhances depositionof platelets with congenital or acquired alpha IIb beta 3deficiency to endothelial cell matrix and collagen underconditions of flow via tissue factor-independent thrombingeneration. Blood 2002;101:1864-70.

18. Galan AM, Tonda R, Altisent C, Maragall S, Ordinas A,Escolar G. Recombinant factor VIIa (Novoseven) restoresdeficient coagulation: experience from an ex vivo model.Semin Hematol 2001;38(4 Suppl 12):10-4.

19. Monroe DM, Hoffman M, Allen GA, Roberts HR. Thefactor VII-platelet interplay: effectiveness of recombinantfactor VIIa in the treatment of bleeding in severethrombocytopathia. Semin Thromb Hemost 2000;26:373-7.

20. Hoffman M, Monroe DM 3rd, Roberts HR. Activated factor VIIactivates factors IX and X on the surface of activated platelets:thoughts on the mechanism of action of high-dose activatedfactor VII. Blood Coagul Fibrinolysis 1998;9 Suppl 1:S61-5.

21. Waddington DP, McAuley FT, Hanley JP, Summerfield GP.The use of recombinant factor viia in a jehovah's witness withauto-immune thrombocytopenia and post-splenectomyhaemorrhage. Br J Haematol 2002;119:286-8.

22. Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR,Hedner U. High-dose factor VIIa increases initial thrombingeneration and mediates faster platelet activation inthrombocytopenia-like conditions in a cell-based modelsystem. Br J Haematol 2001;114:114-20.

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the potential role of factor viia in transfusion medicine

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