Prothrombin Complex Concentrates, Thrombosis, Factor VIII Inhibitors, and Factor VIIa

Having just sent another book off to the publisher, I am now catching up on other literature before starting the next project.  A recent study by Ekezue and coworkers (1) got my attention as it related to some studies in my laboratory in Chapel Hill now some 40 years ago (2,3).  Ekezue and workers (1) have studied the incidence of same-day thrombotic events occurring after the administration of coagulation protein concentrates and observed increased same-day thrombosis in situations where a clotting protein such as factor VIIa was administered to an individual without a clotting factor deficiency; increased incidence was also reported for factor IX complex (presumably prothrombin complex concentrate).
Going back some 40+ years , while there had been earlier reports of thrombotic complications after the use of prothrombin complex concentrate (PCC)(4,5), the report by Blatt and coworkers (2) was the first which provided direct laboratory evidence for the presence of activated coagulation factors in PCCs. This work in my laboratory at the University of North Carolina at Chapel Hill used an assay technique which I learned in my graduate studies at the University of Washington.  This assay, the non-activated partial thromboplastin time, had been developed by Earl Davie and Oscar Ratnoff at Western Reserve University for the study of coagulation factor activation(6).  Further work in my Chapel Hill laboratory provided data suggesting the manufacturing processes for PCCs could result in the activation of coagulation factors, most notably factor VII, which would then result in the activation of factor X. Other mechanism which would involve factor XII and factor XI could result in the formation of factor IXa.  
There were continuing observations on the thrombogenicity of PCCs and a concomitant effort on the part of manufacturers to change the manufacturing processes to avoid the formation of activated coagulation factors.  The changes in manufacturing were not published and the new products contained less material which was "thrombogenic" in our assay system (7).  However the "new" PCCs were not as a effective as the "old" PCCs in the treatment of factor VIII inhibitor patients (8). These observations resulted in the development of "activated" PCCs (aPCC) for use in factor VIII inhibitor patients (9,10).   It should be noted that there are studies which did not observed a therapeutic difference in the use of an aPCC (Autoplex®) and a PCC (Proplex®) in factor VIII inhibitor patients (11).   While activated coagulation factors were considered the most likely candidates for thrombogenic activity, it possible that increased levels of prothrombin could be prethrombotic (12). Samama (13) has recently discussed the issue of increased prothrombin concentration as a risk factor in the use of PCCs.  Prothrombin has a substantially longer half-life than factor and very high levels of prothrombin were reported in hemophilia B patients following the use of PCCs.  I have been unable to find such reports and suspect they were made during discussions at meetings.
In subsequent years, there was considerable conjecture about the identity of the active components in aPCCs (14-16).  Hultin (15) presented data suggest that factor IXa was the most prominent activated coagulation factor in non-activated and activated PCCs.  Hultin further suggested that factor IXa in PCCs may be responsible for thrombogenicity of these therapeutic materials.  Hultin did not measure factor VIIa in her studies but did cite the work of Seligsohn and workers (16) who had demonstrated the presence of substantial amounts of factor VIIa in PCCs and activated PCCS with greater amounts of factor VIIa in the activated PCCs.  These investigators observed the presence of factor VIIa in the circulation following administration of PCCs and activated PCCs.  Only traces of factor IXa were detected and no factor Xa could be detected.  It would be expected that factor Xa would be rapidly inactivated by antithrombin while the rate of inactivation of either factor VIIa or factor XIa by antithrombin is much slower than that of factor Xa. Vinazzer (17) compared Autoplex® and FEIBA® and found higher concentrations of factor VIIa and factor IXa in Autoplex® than in Feiba.®   While this early work was useful, quantitative information on the composition of Autoplex® was provided by Lundblad and coworkers in 1998 (18).  Factor VIIa and Factor IXa were present at the highest concentrations with lesser quantities of thrombin, factor Xa and factor XIa;  while the mean concentration of factor IXa was higher than that of the other activated coagulation factors, there was also greater variability in measurement of this analyte.   The above data suggested that factor VIIa or/and factor IXa would be the active component in aPCCs.  However, conventional wisdom suggested that factor XIa would not bypass a factor VIII inhibitor and most subsequent work focused on factor VIIa.
However, I want to make a few comments about factor IXa before moving on.  Hultin (15) had suggested that factor IXa was responsible for the thrombogenicity of PCCs.   More recently, Lowe(19) has reviewed the possible role of factor  IX(IXa) in thrombosis.  A role for factor IXa in thrombosis is also suggested by early work by Wessler and coworkers (20) on serum factors important in thrombosis.  While not cited herein, there is a considerable body of work suggesting that factor IX/IXa is important in thrombosis.  While it was not suggested by the various studies, it is possible that factor IXa could have been active in the treatment of factor VIII inhibitor patients. 
The late Walt Kisiel has reviewed the development of factor VIIa as therapeutic for the treatment of inhibitors in hemophilia A patients(21).  The early studies were performed with plasma-derived factor VIIa, recombinant factor VIIa (Novoseven®) became available for the treatment of inhibitors in hemophilia A patients(22).   While pleasing from an aesthetic perspective, it is not clear that Novoseven® is more effective than an aPCC(FEIBA®) (23,24).   It should be noted that there is only one plasma-derived aPCC (FEIBA®) available on the market; Autoplex® is no longer available.
The hemophilia A inhibitor market is not large with perhaps 10-20% of hemophilia A patients developing inhibitors.  If one assumes a global population of 500,000 hemophilia A patients, then there would be perhaps 100,000 inhibitor patients with an episodic requirement for inhibitor patients.   I want to emphasize that these numbers are speculative and are intended to show a rationale for expanding the market for factor VIIa beyond use for inhibitor patients.  Specifically, factor VIIa has been proposed for use as a hemostatic agent for internal bleeding and there is some success in this use (25,26) but as noted by Ekezue and coworkers (1), not without problems.   I have heard some discussion of the use of factor VIIa for the routine prophylaxis of hemophilia A patient.  However, the factor VIII market is becoming incredibly congested with new products and I suspect market entry will be challenge.  More recent studies have shown that either aPCC or recombinant VIIa were able to reverse dabigatran toxicity (27).   When considering the clinical use of factor VIIa, it is important to note also that the canonical function of factor VIIa requires tissue factor for effective expression of activity; that said, there is a report (28) which suggests that recombinant VIIa does require tissue factor for hemostatic function in hemophilia A blood.  To add further complication, there is another report (29) that recombinant factor VIIa requires the contact system for fibrin deposition in hemophilic blood.  It would appear that while one would consider the mechanism of action of recombinant VIIa to be straightforward, it would appear to be more complex that activation of factor X bypassing the need for "tenase."  It also leaves open the question, at least in my mind, as to whether factor IXa is effective in correcting hemostasis in hemophilia A inhibitor patients.  I should emphasize that I am not a physician and thus do not have the clinical knowledge to make such judgments.  However, I can recall conversations with physicians responsible for the treatment of hemophilia A patients who would related instances where FEIBA® worked and Autoplex® did not  and vice versa. 
I would like to think that my laboratory in Chapel Hill provided data which helped develop a safer PPC  for hemophilia B and an effective aPCC for the treatment of inhibitors in hemophilia B.  The concept of the presence of activated coagulation factor in therapeutic concentrates was by no means a well-accepted concept in the intial phases  of work.  In turn, our work would not have been possible without the earlier work from the laboratories of Earl Davie and Oscar Ratnoff at Western Reserve University (now Case-Western Reserve University) in Cleveland, Ohio.  The VIIa market in turn should be appreciative of the work of Sam Rapaport and his colleagues.

1.  Ekezue, B.F., Sridhar, G., Ovanesov, M.V., et al., Clotting factor product administration and same-day occurence of thrombotic events, as recorded in a large healthcare database during 2008-2013, J.Thromb.Haemost. 13, 2168-2179, 2015.

2.  Blatt, P.M., Lundblad, R.L., Kingdon, H.S., McLean, G., and Roberts, H.R., Thrombogenic materials in prothrombin complex concentrates, Ann.Int.Med. 81, 766-770, 1977.

3.  White, G.C. 2nd, Roberts, H.R., Kingdon, H.S., and Lundblad, R.L., Prothrombin complex concentrates: potentially thrombogenic materials and clues to the mechanism of thrombosis in vivo., Blood 49, 159-170, 1977.

4.  Kasper, C.K., Postoperative thrombosis in hemophilia B, New Engl.J.Med. 289, 160, 1973.

5.  Steinberg, M.H. and Drelling, B.J., Vascular lesion in hemophilia B, New Engl.J.Med. 289, 592, 1973.

6.  Ratnoff, O.D., Davie, E.W., and Mallett, D.L., Studies on the action of Hageman factor: evidence that activated Hageman factor in turn activates plasma thromboplastin antecedent, J.Clin.Invest. 40, 803-819, 1961.

7.  White, G.C., II, Lundblad, R.L., and Kingdon, H.S., Prothrombin complex concentrates: preparation, properties, and clinical uses, Curr.Top.Hematol. 2, 203-244, 1979.

8. Penner, J.A. and Abildgaard, C.F., Ineffectiveness of certain commercial prothrombin complex concentrates in treatment of patients with inhibitors of factor VIII and IX, New Engl.J.Med. 300, 565-566, 1979.

9. Penner, J.A., Management of patients with factor VIII inhibitors, Sem.Thromb.Hemostasis 1, 386-399, 1975.

10.  Penner, J.A., Management of haemophilia in patients with high-titre inhbiitors: focus on the evolution of activated prothrombin complex concentrates AUTOPLEX T, Haemophilia Suppl. 3., 1-9, 1999.

11.  Lusher, J.M., Blatt, P.M., Penner, J.A., et al., Autoplex versus Proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII, Blood 62, 1135-1138, 1983.

12. Penner, J.A., Prothrombin complex concentrates and coagulation, Ann.Int.Med. 85, 531-532, 1976.

13.  Samama, C.M., Prothrombin complex concentrates: a brief review, Eur.J.Anaesthesiol. 25, 784-789, 2008.

14.  Prowse, C.V., Activated prothrombin complex concentrates: approaches to their preparation, Thrombosis Res. 25, 213-218, 1982.

15.  Hultin, M.B., Activated clotting factors in factor IX concentrates, Blood 54, 1028-1038, 1979.

16.   Seligsohn, U., Kasper, C.K., Østerud, B., and Rapaport, S.I., Activated factor VII: Presence in factor IX concentrates and persistance in the circulation after infusion, Blood 53, 828-837, 1979.

17. Vinnazer, H., Comparison between two concentrates with factor VIII inhibitor bypassing activity, Thromb.Res. 26, 21-29, 1982.

18.  Lundblad, R.L., Bergstrom, J., De Vreker, R., et al., Measurement of active coagulation factors in Autoplex®-T with colorimetric active site-specific assay technology, Thromb.Haemost. 80,811-815, 1998.

19.  Lowe, G.D.O., Factor IX and thrombosis, Brit.J.Haematol. 115, 507-513, 2001.

20.  Wessler, S., Reimer, S.M., and Freiman,  D.G., Thrombosis inducing factors in serum, Thromb.Diath.Haemorrh. Suppl. 4, 201-210, 1960.

21.  Kisiel, W., Recollections on the discovery of factor VIIa as a novel therpeutic agent for hemophiliacs with inhibitors, J.Thromb.Haemost. 7, 1053-1056, 2009.

22.  Macik, B.G., Hohneker, J., Roberts, H.R., and Griffin, A.M., Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a  hemophilic patient with a high titer inhibitor, Am.J.Hematol. 32, 232-234, 1989.

23.  Kempton, C.L. and Meeks, S.L., Toward optimal therapy for inhibitors in hemophilia, Blood 124, 3365-3372, 2014.

24.  Matino, D., Makris, M., Dwan,K.,D'Amico, R., and Iorio, A., Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors, Cochrane Database Syst.Rev. Dec 16, 12:CD004449, 2015.

25.  Karimi, A., Daigle, S.S., Smith, W.B., Janelle, G.M., and Klodell, C.T., Efficacy and safety of recombinant factor VII as rescue for severe perioperative bleeding in Heartmate II recipients, J.Card.Surg. 30, 500-505, 2015.

26. Anselmi, A., Guinet, P.,Rugglieri, V.G., et al., Safety of recombinant factor VIIa in patients with extracorporeal membrane membrane oxygenation, Eur.Cardiothorac.Surg. 49, 78-84, 2016.

27.  Lindahl,T.L., Wallstedt, m., Gusafsson, K.M., Persson,E., and Hillarp, A., More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate, Thromb.Res. 135, 544-547, 2015.

28.  Augustsson, C. and Persson, E., In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia, Blood 124, 3172-3174, 2014.

29.  Li, R., Panckeri, K.A., Fogarty, P.F.,and Diamond, S.L., Recombinant factor VIIa enhances platelet deposition from flowing haemophilic blood but requires the contact pathway to promote fibrin deposition, Haemophilia 21, 266-274, 2015.