Overview
ZymoGenetics is developing recombinant
thrombin (rThrombin) for use as a topical hemostat
to control surgical bleeding. One thrombin product available in the U.S. is derived from bovine blood and
has been used for more than thirty years
to control blood loss in a variety of
surgical settings. However, bovine-derived
thrombin has been associated with the
development of antibodies that may crossreact
with human blood proteins and in some
cases, these antibodies appear to be related
to serious bleeding complications (1,2).
Recombinant coagulation proteins have
been readily accepted by the medical community
as safe alternatives to plasma-derived
proteins as demonstrated by the rapid
acceptance of recombinant forms of coagulation
Factor VIII and Factor IX (3, 4).
(Above photo: 3-D representation of recombinant Thrombin protein structure)
Hemostasis and Thrombin
Excessive blood loss is a common complication
of surgery, physical trauma and burn injuries.
The human body has a tightly regulated
process for controlling bleeding, known
as hemostasis, that limits blood loss
through damaged blood vessels. Hemostasis
is controlled through a complex cascade
of enzyme activation, in which one enzyme
activates another and so on until blood
coagulates and bleeding ceases.
The rate of clot formation is dependent
on the concentration of thrombin at the
site of injury as well as the concentration
of fibrinogen, another plasma protein.
Thrombin converts fibrinogen to fibrin
through an enzymatic reaction. The fibrin
molecules are incorporated into the blood
clot and act to both strengthen the clot
and prevent its rapid degradation by fibrinolytic
enzymes. In addition, thrombin has other
direct effects on coagulation through
activation of platelets, activation of
other coagulation enzymes and cellular
signaling. For these reasons, purified
thrombin is used extensively to stop diffuse
bleeding during major surgical procedures.
Plasma-derived Thrombin
Plasma-derived thrombin has been used
as a hemostatic agent for more than 30
years and is applied topically to surgical
incisions, sutures and burns to help stop
bleeding at these sites. Today only Thrombin-JMI,
derived from bovine blood, and marketed
by King Pharmaceuticals, is available
in the U.S. as a stand-alone product. Human
plasma-derived thrombin is marketed as
a component of fibrin sealants (Tisseel®
and Hemaseel®).
The potential for development of antibodies
to bovine thrombin or other protein impurities
in the bovine product is a reported safety
concern related to use of the product
(1,2). Although bovine thrombin can function
in the context of the human clotting cascade,
it is still recognized as foreign by the
human immune system and can trigger the
production of antibodies. Other proteins
present in the bovine product may trigger
an antibody response; in some cases, antibodies
produced against bovine proteins cross-react
with homologous human proteins and lead
to significant bleeding disorders (2,5,6,7).
Recombinant Thrombin (rThrombin)
Development
Thrombin is a proven effective agent for
controlling bleeding in surgical and medical
settings.
Bovine-derived thrombin is used in more than 1 million surgeries each year in the U.S. Thrombin is also used as a component in a number of surgical sealants.
The use of recombinant DNA technology to
develop replacement versions of therapeutic
proteins that were previously derived from
human blood is well documented. Examples
of this include the coagulation factors
Factor VIII and Factor IX. In both cases,
the recombinant form of the protein rapidly
replaced the blood-derived version on the
marketplace. Given the large market for
thrombin-containing products, ZymoGenetics
believes that rThrombin has significant
revenue potential.
In the fall of 2006, ZymoGenetics completed a Phase 3 clinical trial
with rThrombin for use as a topical hemostat
to control bleeding in surgical settings. The Phase 3 pivotal study showed that rThrombin had comparable efficacy and superior immunogenicity compared to the marketed bovine thrombin product. ZymoGenetics' Biologics License Application for rThrombin has been accepted for review by the FDA. The Company is evaluating the use of rThrombin
for other potential indications, including
its use as a component in surgical sealants
where bovine-derived and human plasma-derived
thrombin are currently used. ZymoGenetics is collaborating with Bayer HealthCare to develop and commercialize rThrombin.
References:
-
Sarfati
MR, Dilorenzo DJ, Kraiss LW, Galt
SW. Severe coagulopathy following
intraoperative use of topical thrombin.
Ann Vasc Surg 2004;18(3):349-351.
-
Streiff,
M., Ness, P. Acquired FV Inhibitors:
a Needless Iatrogenic Complication
of Bovine Thrombin Exposure. Transfusion,
January 2002, 42:18-26.
-
Lundblad
RL, Bradshaw RA, Gabriel D, Ortel
TL, Lawson J, Mann KG. A review
of the therapeutic uses of thrombin.
Thromb Haemost 2004;91(5):851-860.
-
Bishop
P, Lawson J. Recombinant biologics
for treatment of bleeding disorders.
Nat Rev Drug Discov 2004;3(8):684-694.
-
Ortel,
T., Mercer, M., et al. Immunologic
Impact and Clinical Outcomes After
Surgical Exposure to Bovine Thrombin.
Annals of Surgery 2001, 233:88-96.
-
Dorion, R.P., Hamati,
H., et al. Risk and Clinical Significance
of Developing
Antibodies Induced by Topical Preparations.
Arch Pathol Lab Med, October 1998,
122:887-894.
-
Nelson PA, Powers JN, Estridge TD, et al. Serological analysis of patients treated with a new surgical hemostat containing bovine proteins and autologous plasma. J Biomed Mater Res 2001;58(6):710-9.
For
more information:
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