Phillips or Flathead:  Thrombin or Fibrin Sealant – Using the right tool for the job and understanding the difference between risk and uncertainty

I have had considerable opportunity  to work with marketing departments during my career.   One observation is that while those that actually do the work try hard to understand the product/science while the upper echelon focuses on lunch and travel.   One particularly egregious example is fibrin sealant and thrombin.  While thrombin is a component of fibrin sealant, thrombin and fibrin sealant are not competing products.  Thrombin is a hemostatic agent while fibrin sealant is sealant and, as a derivative product such as fibrin foam, can fill a space and serve as a matrix.  Thrombin can be used with other matrix agents such as gelatin or collagen.   The point is that thrombin and fibrin sealant should not be  considering  as competing for market share; there is competition with other therapeutics such as cyanoacrylates, gelatins,  and collagen fleeces (1).   The reader is directed to the title - Phillips or Flathead?   While you can get a flathead to move a Phillips screw, it is difficult, may ruin the screw and you will have to get someone with more talent to drill the screw out, and finally engender considerable derision from the individual with more talent.   I know of no way to get a Phillips to move a flathead screw.  In current discussion, I would posit that while you can use thrombin in place of fibrin sealant and vise-versa. there some applications, such as treatment of pseudoaneurysms (2) and perhaps esophageal varices (3) where thrombin is the reasonable choice and other applications as autologous grafts with burns (4) and liver resection (5) where fibrin sealant is more effective.   I could find relatively few studies which compared thrombin and fibrin sealant.   While thrombin does use endogenous fibrinogen at a wound site to form a clot for hemostatic purposes, the fibrinogen concentration of blood is not of sufficient concentration to provide sealant strength (6).   The adhesive strength of a fibrin product has been shown to be dependent on fibrinogen concentration (7,8) although factor XIII also has an effect (9).  Notwithstanding this comment, thrombin and plasma were used as fibrin sealant for suturing canine (10) and human nerve fibers (11).  It is noted that Sedson and Medawar (11) commented on the need for the development of a dried plasma or fibrinogen but also suggested the need for serum components.   These studies, although limited, provide support for the use of fibrin sealant in nerve grafting as currently used (12).  It is no small interest that the Medawar cited above (10,11) is the Sir Peter Brian Medawar who subsquently was awarded (together with Sir Frank MacFarlane Burnet) the Nobel Prize for Medicine in 1960 for their work on acquired immune tolerance(13).

The use of human thrombin as a therapeutic first gained extensive use during WWII both as a free-standing hemostatic agent (14) and as a component of fibrin(ogen)-based products such as fibrin sealant (15), fibrin foam (16) and fibrin film (17).  The continued use of human thrombin as a hemostatic agent ceased after WWII because of viral transmission (18) and the loss of the coordinated blood coagultion system developed during WWII (19,20).  Bovine topical thrombin was developed by Smith and coworkers at the University of Iowa and after WWII was developed into a commercial product by Parke-Davis (21).  One of the inventors told me that the University of Iowa group envisioned topical thrombin in barber shops (22). There was a steady development of thrombin as a hemostatic agent in the following 50 years as reviewed by Lundblad and others (23).

There have also been some recent review articles focusing mainly on the defense of the use of the bovine product (24-25).  The issue here was the development of antibodies to the use of topical bovine thrombin; this was shown mostly likely to be directed against factor V impurity in the product and subsequent process development seems to have removed this as an issue (26).   Nevertheless, interest continues in the development of a therapeutic human thrombin (27-29) including a recombinant human thrombin (30,31).  A fibrin sealant composed of recombinant proteins has been developed (32).  While, a bit off message at this point, I still find the potential of oral thrombin (33) to be an intriguing possibility.

It is my purpose to get into a discussion of bovine versus human or plasma-derived versus recombinant.   It is my sense that this has devolved into a marketing issue, not a scientific issue.   We use plasma-derived therapeutics such as IVIG and albumin without major consequence. We scrupulously remove any animal protein from our media and yet have no problem with bovine thrombin.   I recently performed my approximately bimonthly blood donation to the ARC. This is not arduous and usually occurs in the Student UNC at UNC which gives me a brief exposure to the undergraduates.  As usual, there was the usual series of questions about possible pathogen exposure.   It is my sense that "we" need to take a deep breath and focus on risk-analysis rather than marketing by fear (or diagnosis by TV advertisement).  I commend all to an excellent article by Menitove and coworkers (34) on risk analysis in transfusion medicine.


References


1.  Spotnitz, W.D. and Burks, S., Hemostats, sealants, and adhesives III: A new update as well as cost and regulatory considerations for components of the surgical toobox, Transfusion 52, 2243-2255, 2012.
2.  Kang, S.S., Labropoulos, N., Mansour, M.A., and Baker, W.H., Percutaneous ultrasound guided thrombin injection: a new method for treating postcatheterization femoral pseudoaneurysms, J.Vasc.Surg. 27, 1032-1038, 1998.
3.  McAvoy, N.C., Plevris, J.N., and Hayes, P.C., Human thrombin for the treatment of gastic ectopic varices, World J.Gastroenterol. 18, 5912-5917, 2012.
4.  Drake, D.B. and Wong, L.G., Hemostatic effect of Vivostat patient-derived fibrin sealant on split-thickness skin graft donor sites, Ann.Plastic Surg. 50, 367-372, 2003.
5.  Schwartz, M., Madariaga, J., Hirose, R., et al., Comarison of a new fibrin sealant with standard topical hemostatic agents,  Arch.Surg. 139, 1148-1154, 2004.
6.  Lundblad, R.L., Biotechnology of the Plasma Proteins, p. 404, CRC Press/Taylor & Francis, Boca Raton, Florida, USA, 2012.
7.  Sierra, D.H., Feldman, D.S.,Saltz, R., and Huang, S., A method to determine shear adhesive  strength of fibrin sealants, J.Appl.Biomater. 3, 147-151, 1992.
8.  Kjaergard, H.K. and Weis-Fogh, U.S., Important factors influencing the strength of autologous fibrin glue: the fibrin concentration and reaction time - comparison of strength with commercial fibrin glue, Eur.Surg.Res. 26, 273-276, 1994.
9.  Hickerson, W.L., Nur, I., and Meidler, R., A comparison of the mechanical, kinetic, and biochemical properties of fibrin clots formed with two different fibrin sealants, Blood Coag.Fibrin. 22, 19-23, 2011.
10.  Young, J.Z. and Medawar, P.B., Fibrin suture of peripheral nerves. Measurement of the rate of regeneration, Lancet 239, 350-352, 1942.
11.  Seddon, H.J. and Medawar, P.B., Fibrin suture of human nerves, Lancet  240, 87-88, 1942.
12.   Whitlock, E.L., Kasukurthi, R., Yan, Y., et al., Fibrin glue mitigates the learning curve of microneurosurgical repair, Microsurgery 30, 218-222, 2010.
13.  Cosimi, A.B., Nobel prizes in medicine in the field of transplantation, Transplantation 82, 1558-1562, 2006.
14.  Edsall, J.T., Ferry, R.M., and Armstrong, S.H. Chemical, clinical, and immunological studies on the products of human plasma fractionation, XV, The proteins concerned in the blood coagulation mechanism, J.Clin.Invest. 23, 557-565, 1944.
15.  Hawn, C.V., Bering, E.A., Bailey, O.T., and Armstrong, S.H., Chemical, clinical,and immunological studies on the products of human plasma fractionation. XIX. A note on the use of fibrinogen and thrombin in the surface treatment of burns, J.Clin.Invest, 23, 580-585, 1944. 
16.  Bering, E.A., Chemical, clinical, and immunologica studies on the products of human plasma fractionation. XX. The development of fibrin foam as a hemostatic agent and for use in conjunction with human thrombin, J.Clin.Invest. 23, 586-590, 1944.
17.  Ferry, J.D. and Morrison, P.R., Preparation and properties of serum and plasma proteins: human fibrin in the form of an elastic film, J.Am.Chem.Soc. 69, 400-409, 1947.
18.  Lesses, M.F. and Hamolsky, M.W., Epidemic of homologous serum hepatitis apprarently caused by human thrombin,  J.Am.Med.Assoc. 147, 727-730, 1951.
19.  Kendrick, D.B., Blood Program in World War II, Office of the Surgeon General, Department of the Army, USA, Washington, DC., 1989.
20  Hess, J.R. and Thomas, M.J.G. Blood use in war and disaster: lessons from the past century, Transfusion 43, 1622-1633, 2003.
21.    Seegers, W.H., Warner, E.D., Brinkhous, K.M., and Smith, H.P., The use of purified thrombin as an hemostatic agent, Science  89, 86, 1939.
22.  Brinkhous, K.M., personal communication, 1972.
23.   Lundblad, R.L., Bradshaw, R.A., Gabriel, D., et al., A review of the therapeutic uses of thrombin, Thromb.Haemost. 91, 851-860, 2004.
24. Ofosu, F.A., Crean, S., and Reynolds, M.W., A safety review of topical bovine thrombin-induced generation of antibodies to bovine proteins, Clin.Ther. 31, 679-691, 2009.
24.  Crean, S., Michels, S.L.,  Moschella, K., and Reynolds, M.W., Bovine thrombin safety reporting: an example of study design and publication bias, J.Surg.Res. 58, 77-86, 2010.
25. Clark, J.A., Humphries, J.E., Crean, S., and Reynolds, M.W., Topical bovine thrombin: a 21-year review of topical bovine thrombin spontaneous case safety reports submitted to the FDA’s Adverse Event Reporting System, Pharmacoepidemiol.Drug.Saf. 19, 107-114, 2010.
26.  Patterson, C.A., Pixton, G.C., Proskin, H.M.,  et al., Immune responses associated with perioperative exposure and reexposure to topical bovine thrombin do not impair hemostasis, Clin.Appl.Thromb.Hemost. 27, 620-620, 2011.
27.  Kessler, C.M. and Ortel, T.L., Recent developments in topical thombins. Thromb.Haemost. 102, 15-24, 2009.
28. Rodgers, G.M., Immune-mediated coagulopathy associated with topical bovine thrombin: review of the pediatric literature, J.Pediatr.Hematol.Oncol.i 33, 86-88, 2011.
29.  Menkis, A.H., Martin, J., Cheng, D.C., et al., Drugs, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) 2011, Innovations 7, 229-241, 2012.  
30.  Bowman, L.L., Anderson, C.D., and Chapman, W.C., Topical recombinant human thrombi in surgical hemostasis, Semin.Thromb.Hemost. 36, 477-484, 2010.
32.  Singla, N.K., Foster, K.N., Alexander, W.A., and Pribble, J.P., Safety and immunogenicity of recombinant human thrombin: a pooled anlaysis of results from 10 clinical trials, Pharmacotherapy 32, 998-1005, 2012.
32. Carlson, M.A., Calcaterra, J., Johanning, J.M.,  et al., A totally recombinant human fibrin sealant, J.Surg.Res. 187, 334-342, 2014.
33.  Edmunds, V., Oral thrombin in the treatment of haematemesis, Brit.Med.J. Vol. 1 (No 4824), pp. 1371-1372, 1953.
34.   Menitove, J.L., Bennett, J.L., Tomasuo, P., and Katz, L.M., How safe is safe enough, who decides and how?  From a zero-risk paradigm to risk-based decision making, Transfusion 54, 753-757, 2014.


© Roger L. Lundblad,  April, 2014.