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Orthopaedic Surgery Anticoagulants
FloSeal® – Haemostasis in the Coagulopathic Patient
M a r k B e c h t e r, B M
Senior Director, BioSurgery, Medical Affairs, Baxter Healthcare Corporation, Westlake Village, California
Abstract
Bleeding during any type of surgery is a serious risk that needs to be controlled. In recent years, as medical surgical technology and skills
have advanced, there have been increased complications in terms of bleeding. In parallel, there have been developments in the available
haemostasis agents, but many of the commonly available traditional agents work at the beginning of the biological process alongside
platelet activation, and their efficacy is affected if factors are missing. Thrombin works at the final stage of the coagulation cascade, which
is considered to be the most important component; however, it requires a 3D structure to support it for maximal effectiveness. FloSeal® is
an agent that contains thrombin, therefore it works at the end of the clotting cascade and in a large number of patient types. It also contains
a gelatin matrix to provide the structure needed to support clot formation.
Keywords
FloSeal®, haemostasis, clotting cascade, thrombin, blood, bleeding
Disclosure: Mark Bechter is Senior Director of BioSurgery Medical Affairs at Baxter Healthcare Corporation.
Received: 10 July 2009 Accepted: 18 July 2009
Correspondence: Mark Bechter, Senior Director, BioSurgery Medical Affairs at Baxter Healthcare Corporation, One Baxter Way, Westlake Village, CA 91362, US.
E: [email protected]
One of the most challenging aspects of orthopaedic surgery in any
situation in any kind of patient is the management of surgical
bleeding. Coping with bleeding takes time and resources and can
further complicate already complex procedures for surgical staff.
Blood loss can slow the patient’s recovery and obscure vision of the
operating field.1 Allogenic blood supplies can be used to replace lost
blood, but this procedure is now considered a procedure of last
resort.2 The real risks and increased post-operative morbidity and
mortality associated with transfusion of blood products3 have been
frequently documented. In addition, extensive bleeding can mean that
post-operative healing and recovery schedules are compromised.
that the patient has his/her own clotting factors in order that they
can work quickly or be effective at all.
In recent years, as medical surgical technology and skills have
advanced, there are increased complications in terms of bleeding.
For one, the age bracket for surgery is widening: 10 years ago a
person 75 years of age would have been less likely to receive a hip
replacement, whereas now it is more commonplace. Patients are
increasingly likely to be prescribed blood-thinning medications. With
increasing age, the overall effectiveness of a patient’s own clotting
mechanisms is subject to change.4 Once in hospital and largely
immobile, it is much more common to also be administered an
anticoagulant medication, such as heparin or warfarin. Overall, there
is an increasing propensity to use anticoagulant drugs in the basic
management of pre-operative patients, even those without obvious
co-morbidities. This means that, over and above the population who
are genetically unable to form blood clots, such as those with
haemophilia, there are many patients who are to some degree
coagulopathic. Consequently, there is an additional problem in terms
of haemostasis, as many traditional techniques and products require
At the final stage of the coagulation cascade is thrombin, which is
often considered to be the most important component of the
haemostatic process owing to both its activation and feedback
roles. Thrombin directly activates factors V and VIII and their
inhibitor protein C, factor XIII; most importantly, it also
enzymatically converts fibrinogen into fibrin monomers, which
polymerise to form the stable clot. For the vast majority of patients,
their ability to clot is enhanced by the addition of thrombin. The few
patients for whom this is not the case include those with either
afibrinogenaemia or disseminated intravascular coagulation (DIC), a
consumptive coagulopathy. In the former group, patients do not
have endogenous fibrinogen. The reported incidence of fibrinogen
deficiency is one in 1,000,000. In contrast, DIC – an extremely
serious condition caused by a variety of pathophysiological
processes including severe blood loss – effectively results in the
body using more coagulation factors than the liver can produce.
Fifty per cent of cases are observed in obstetric scenarios, but this
66
The Clotting Cascade
Many of the commonly available, traditional haemostasis agents, such
as collagen and cellulose, work at the beginning of the biological
process alongside platelet activation (see Figure 1). They have little or
no haemostatic effect in patients with factor deficiencies or who are
taking heparin or other anticoagulants. To be maximally effective in as
many patients as possible, a haemostasis agent needs to also work
towards the end of, or outside, the cascade.
© TOUCH BRIEFINGS 2009
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FloSeal ® – Haemostasis in the Coagulopathic Patient
Figure 1: The Clotting Cascade and Haemostatic Agents
FloSeal Hemostatic Matrix MOA
Resting platelets
Contact activation
Collagen
Gelatin
Collagen from damaged
vascular endothelium
FloSeal Matrix
Hemostatic Sealant
Cellulose
Intrinsic pathway
VIII
vWFGP1b
Fibronectin
Pre-kallikrein
Kallikrein
Extrinsic pathway
HMW kininogen
VIIa
XIIa
XII
Platelet
activation
Tissue damage
Tissue thromboplastin
(tissue factor
Ca++)
VII
XIa
XI
Ca++
IX
IXa
PF3
Ca++
VII
Platelet granule
release factors
X
Xa
Va
PF3
Ca++
V
Thrombin
Prothrombin
XIIIa
Fibrinogen
FloSeal Matrix
Hemostatic Sealant
Fibrin
monomer
Ca++
XIII
Fibrin
polymer
Fibrin clot
Figure adapted with permission from Oz MC, Rondinone JF, Shargill NS, et al., FloSeal Matrix: new generation topical hemostatic sealant, J Card Surg, 2003;18(6):486–93.16
Most haemostats require a functional coagulation cascade and clotting factors to stop bleeding. FloSeal works at both the beginning17 and the end of the coagulation cascade, reducing the
impact of clotting-factor deficiencies and platelet dysfunction.16,17
The efficacy of FloSeal requires a normal fibrinogen level to provide fibrin for clot formation. Thus, it is ineffective in those who have afibrinogenemia, a rare coagulation disorder.16
remains a significant although rare medical challenge that could be
encountered in orthopaedic practice.
Second, and more importantly, the sponges lack the ability to conform
to irregularly shaped lesions, unlike a more flowable mixture.
The haemostatic matrix FloSeal® (Hemostatic Matrix, Baxter, Deerfield,
Illinois) is a mix of proprietary gelatin matrix (cross-linked gelatin
granules of bovine origin) and human thrombin. Therefore, it works at
both ends of the coagulation cascade, and is not compromised by most
deficiencies of the clotting cascade. It can work even if the patient has
been fully heparinised, such as in cases of cardiopulmonary bypass. In
the presence of blood or other fluids, the gelatin granules swell by
10–20%, forming a physical barrier and a structure to support the clot.
Blood percolates between the granules and comes into contact with a
high concentration of thrombin; the thrombin synergistically promotes
clot formation. The resulting clot will naturally be broken down by the
body and resorbed in six to eight weeks as part of the normal course of
wound healing. Untoward effects are not common provided that any
excess product not incorporated into the clot has been washed away.
Many Indications
The most similar alternative to FloSeal is thrombin, delivered in
conjunction with gelatin sponges or matrices. While superficially a
similar agent, these products differ in a few important respects:
primarily, the sponge will swell to many times its original size, which
can obscure vision of the operative field and put pressure on nearby
structures. The maximal swell of FloSeal can be observed within 10
minutes and predictably does not exceed 20% of its initial volume.
The ideal haemostasis agent is one that is applicable to many
different types of patient in various circumstances. FloSeal has been
successfully used in many different types of surgery, including
vascular surgery,6,7 nephrectomy,8,9 pituitary,10 cardiac,11 endoscopic
sinus surgery12,13 and spinal surgery.14 It has been shown to be superior
to competitor products, such as Gelfoam®, particularly in controlling
more severe bleeding when mixed with thrombin.7,11
EUROPEAN MUSCULOSKELETAL REVIEW
FloSeal provides clotting support to patients with various degrees of
coagulopathy, and has utility in different sorts of blood flow. Most
importantly, it is the only haemostasis product that is indicated for
pulsatile blood flow.5 As FloSeal has both physical and bioactive
components, it has a double effect that allows it to cope with even
major arterial bleeds. Venous bleeding may not appear to be as
significant as spurting arterial bleeds, but because veins lack the
ability to contract in a similar way to arteries they can stay patent
following transection; the resultant continual slow blood loss is
equally serious and needs to be controlled. Blood oozing through a
bony surface poses a different problem. Although many haemostasis
products are designed to cope with one type of bleeding, few can
handle all of the different scenarios that may present.
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Orthopaedic Surgery Anticoagulants
The pivotal trial of FloSeal compared the product with the nearest
similar agent: thrombin-soaked Gelfoam sponges. The randomised
prospective study involved 309 patients undergoing cardiac, vascular
or spinal surgery at 10 institutions, and the primary end-point was
haemostasis success at 10 minutes for the first bleeding site treated.
Supplementary end-points were time to haemostasis for the first
bleeding site treated, haemostasis success and time to haemostasis
for all treated bleeding sites. Furthermore, the safety of FloSeal was
assessed by recording adverse events at 12–36 hours and again at six
to eight weeks post-operatively.15,16
As FloSeal has both physical and
bioactive components, it has a double
effect that allows it to cope with even
spurting arterial bleeds.
Haemostasis success rates across all surgical specialities were
statistically significantly higher for FloSeal than for the control (96
versus 77% overall). FloSeal achieved haemostasis with a median time
of two minutes, compared with six minutes in the control group.
Specifically, patients in the cardiac group were fully heparinised in order
to undergo cardiopulmonary bypass. In these patients, haemostasis
success was significantly higher in the FloSeal group than in the
controls (89 versus 36%). Some cardiac patients from each group had
their heparin-induced coagulopathies reversed using protamine
sulphate. For control patients, this reversal increased the success of
haemostasis to 75% – an equivalent rate to FloSeal in heparinised
patients – while with protamine treatment those in the FloSeal group
achieved an even higher level of haemostasis, at 96%. No serious
adverse events were related to the use of either haemostatic agent.15,16
The fast and sustained effectiveness of FloSeal for all types of bleeding
events in all kinds of surgery (with the sole exception of ophthalmic
surgery), irrespective of heparin use, suggests that this product can
function as a high-quality first line of defence for any patient group.
Convenience
Critical to the overall effectiveness of a haemostatic product is the
ease of use. FloSeal comes as a complete kit. The two components
are reconstituted by ‘swooshing’ them together and FloSeal can then
be applied. With other product combinations, separate thrombin
needs to be added to a sponge or delivery agent in the right quantity
1.
2.
3.
4.
5.
6.
7.
68
Szpalski M, Gunzburg R, Sztern B, An overview of
blood-sparing techniques used in spine surgery during the
perioperative period, Eur Spine J, 2004;13(Suppl. 1):S18–27.
Feagan BG, Wong CJ, Johnston WC, et al., Transfusion
practices for elective orthopedic surgery, CMAJ,
2002;166(3):310–14.
Taylor JM, Gropper MA, Critical care challenges in
orthopedic surgery patients, Crit Care Med, 2006;34
(9 Suppl.):S191–9.
Mari D, Coppola R, Provenzano R, Hemostasis factors and
aging, Exp Gerontol, 2008;43:66–73.
Goodnough LT, Shander A, Brecher ME, Transfusion
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Baxter, Floseal Hemostatic Matrix Instructions For Use.
Accessed March 2005. Available at: www.baxter.com/
products/biopharmaceuticals/downloads/FloSeal_PI.pdf
Reuthebuch O, Lachat ML, Vogt P, et al., FloSeal: a new
at the right times. Moreover, FloSeal can be prepared in as little as two
minutes.5 In a pivotal study, three questions regarding ease of use
were asked of surgeons who recruited patients: how well the material
(FloSeal) conformed to the tissue surface, ease of delivery to the
bleeding site and ease of application of product to the bleeding site.
In each instance a higher proportion of responses was favourable for
FloSeal compared with the control agent (p<0.001 in all cases).
Conclusions and Summary
The modern surgeon has to cope with a wide variety of patients in
myriad situations, some of which will be difficult and unpredictable.
While the coagulation status of the patients will ideally be known, it
cannot be assumed, and more and more patients are presenting with
some degree of anticoagulation. A first-line haemostasis agent is one
that can be used in many situations and in the majority of patients. As
there are certain genetic and exogenous coagulopathies that inhibit
clotting factor formation early in the coagulation pathway, the more
effective haemostasis agent will be one that acts lower down the
cascade. This means its ability to create clots will not be affected by
lack of particular factors.
Many of the older haemostasis agents require patients to have a
functional clotting cascade and all clotting factors present in order to
work. However, these only provide a scaffold and so help initiate
clotting through contact activation and/or promotion of platelet
aggregation. There are bioactive agents available, namely thrombin,
which interact with fibrinogen in the blood to help formation of a fibrin
clot, but without a physical structure to bind to these are of limited
use with stronger blood flows. FloSeal matrix combines both
approaches with gelatin granules that restrict the flow of blood,
combined with thrombin to create the clot structure. This means it is
both effective and adaptable, and studies have shown that it can be
successfully used in almost all types of surgery with all types of
bleeding, in nearly every type of patient. ■
Mark Bechter is Senior Director of Medical Affairs at
Baxter Healthcare, based in Westlake Village, California.
Following an initial career in anaesthesia and
emergency medicine, he moved into the healthcare
industry, where he now works as a pharmaceutical
physician. With experience in a wide variety of medical
specialities, Dr Bechter now heads the Global
BioSurgery Medical Affairs Team for Baxter, taking
responsibility for a portfolio of topical haemostat,
sealant and anti adhesive products that are routinely used in surgeries throughout the
globe. He graduated from the University of Southampton Medical School.
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2000;29:204–6.
8. Weaver FA, Hood DB, Zatina M, et al., Gelatin-thrombinbased hemostatic sealant for intraoperative bleeding in
vascular surgery, Ann Vasc Surg, 2002;16:286–93.
9. Richter F, Schnorr D, Deger S, et al., Improvement of
hemostasis in open and laparoscopically performed
partial nephrectomy using a gelatin matrix-thrombin
tissue sealant (FloSeal), Urology, 2003;61:73–7.
10. Bak JB, Singh A, Shekarriz B, Use of gelatin matrix
thrombin tissue sealant as an effective hemostatic agent
during laparoscopic partial nephrectomy, J Urol, 2004;
171:780–82.
11. Ellegala DB, Maartens NF, Laws ER Jr, Use of FloSeal
hemostatic sealant in transsphenoidal pituitary surgery:
technical note, Neurosurgery, 2002;51:513–15, discussion 5–6.
12. Oz MC, Cosgrove DM III, Badduke BR, et al., Controlled
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Chandra RK, Conley DB, Haines GK III, et al., Long-term
effects of FloSeal packing after endoscopic sinus surgery,
Am J Rhinol, 2005;19:240–43.
Chandra RK, Conley DB, Kern RC, The effect of FloSeal on
mucosal healing after endoscopic sinus surgery: a
comparison with thrombin-soaked gelatin foam, Am J
Rhinol, 2003;17:51–5.
Baxter International Inc., FloSeal Hemostatic Matrix
instructions for use, 2005. Available at: www.baxter.com/
products/biopharmaceuticals/biosurgery/sub/floseal.html
Oz MC, Rondinone JF, Shargill NS, FloSeal Matrix: new
generation topical hemostatic agent, J Card Surg,
2003;18:486–93.
Data on file, Baxter Healthcare Corporation.
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