DISCUSSION
Fibrinolysis is a physiologic mechanism by which clots are degraded to
maintain the patency of microvasculature. Pathologic over- or
under-activation of fibrinolysis has significant clinical implications
regarding optimal treatment interventions and patient outcomes in trauma
patients22-28 . This study is the first to categorize
these fibrinolysis phenotypes in cardiac surgery patients. The data
suggest that indiscriminate AF administration may have deleterious
effects unless clinically indicated, but the sample size is too small to
make definitive recommendations.
Hyper-, physiologic, and hypo-fibrinolytic phenotypes are well
established among trauma patients. In theory, AF should have its most
favorable effect in those with hyperfibrinolysis. In contrast,
hypercoagulability associated with fibrinolytic shutdown is reported to
occur in 46% to over 64% of trauma patients22-32. On
this basis alone, it is reasonable to propose that all patients likely
do not benefit from TXA11. Despite the high
prevalence, it remains controversial if fibrinolytic shutdown is a
physiological or maladaptive response to traumatic
injury33, 34. Our study demonstrates a distribution of
fibrinolytic phenotypes in cardiac surgery patients that is distinctly
different than the established distributions among trauma patients. In
particular, our data shows that cardiac surgery patients exhibited a
rate of fibrinolytic shutdown of 32% compared to the reported range for
trauma patients of 46-64%.
There are multiple proposed mechanisms by which fibrinolytic shutdown
occurs, including: i) tissue plasminogen activator (t-PA) inhibition,
ii) inadequate t-PA release in response to injury, iii) fibrinolytic
resistance via cell free DNA, and iv) elevated plasmin to antiplasmin
ratio26, 30,32, 35, 36. In vivo studies in
animal models have demonstrated that tPA release is predominantly driven
by shock rather than by tissue injury and that altered clot formation
has no correlation with altered clot degradation22,36,
37. Subsequent studies have yet to identify a correlation between
injury severity score or injury mechanism and fibrinolytic phenotype36, 38. Nevertheless, changes in the fibrinolytic
system after tissue injury have significant treatment implications
regarding the treatment decision to administer or withhold AF therapy.
Although distinct fibrinolytic phenotypes are well-established in trauma
patients, equivalent phenotypes are yet to be fully characterized in
other surgical fields. Many studies have investigated the efficacy of
empiric AF treatment across surgical groups; however, there is limited
discussion of the prevalence or influence of distinct fibrinolytic
phenotypes on treatment responsiveness and outcomes. In particular,
there may be an increased potential for preventable harm if AF is
administered to a patient who is already hypofibrinolytic (i.e.
fibrinolysis shutdown=hypercoagulable), or if withheld from a patient
who is hyperfibrinolytic (i.e. hypocoagulable).
In the United States, patients undergoing cardiac surgery demonstrate
particularly high blood transfusion rates. In 2010, 34% of cardiac
surgery patients received a perioperative transfusion despite the
implementation of blood conservation guidelines in
200739-41. Thus, AF is often used in this population
to minimize perioperative blood loss 42. It is well
established that AF therapy reduces bleeding and allogeneic transfusion
requirements29. Myles et al studied the effectiveness
of TXA versus placebo in a randomized control study of 4631
coronary-artery surgical patients and demonstrated that death or
thrombotic complication occurred in 18.1% of placebo patients versus
16.7% of TXA patients43. Transfusion requirements
were reduced from 7,994 total units in placebo to 4,331 in the TXA
group, with seizures reported in 0.1% of placebo versus 0.7% of TXA
patients43. A recent metanalysis by Alaifan et al
reported that TXA reduced bleeding in cardiac surgery, but surprisingly
did not significantly impact overall mortality49. A
randomized control trial by Leff at el comparing TXA and ACA in 114
cardiac surgery patients demonstrated that ACA was associated with less
transfusions than TXA; though, both TXA and ACA significantly reduced
perioperative bleeding and transfusions with no increase in adverse
events45. The efficacy of AF in reducing perioperative
bleeding and transfusion requirements has been reported by several
others46-48.
Our data demonstrated significant outcome differences in those who
received AF versus those who did not. We show that cardiac surgery
patients who received AF had significantly higher rate of all cause
morbidity (n = 19, 51%) versus those who did not (n = 10, 25%, P =
0.017). Patients who received AF also had more days with a chest tube (P
= 0.037) and an average of 559mL more output from the chest tube
compared to patients who did not receive TXA (P = 0.075). Unfortunately,
the sample size was not large enough to determine if these outcome
differences were related to the fibrinolytic phenotype.
There was no obvious effect of age, gender, race, or ethnicity on the
distribution of fibrinolysis phenotypes. There was a near equal
distribution of physiologic, hyper-, and hypo-fibrinolytic phenotypes
between patients who received AF (46% vs 30% vs 24%) and did not
receive AF (45% vs 33% vs 22%, P = 0.962). This suggests that a
patient’s fibrinolytic phenotype was not a contributing factor in the
decision to administer or withhold AF.
The use of AF in other surgical populations has generally been
efficacious; though, there is significant heterogeneity across
specialties. For instance, patients with hepatic dysfunction are at a
markedly increased risk of excessive bleeding or coagulopathy during
liver surgery or transplantation due to altered hepatic production of
essential clotting factors49. Previously, AF were
administered empirically in these patients; however, empiric therapy has
since been questioned due an observed increase in rates of coagulopathy,
venous thromboembolism, and mortality49-51. In current
practice, the use of AF during hepatic operations is variable due to the
considerable physiologic changes that occur pre- and post-liver
transplantation. Accordingly, most liver transplant centers use TEG or
viscoelastic monitoring with rotational thromboelastometry to guide AF
administration if a patient exhibits
hyperfibrinolysis52-54. Similarly, it has been
established that only some trauma patients benefit from empiric AF
therapy. Thus, the use of AF in trauma is generally informed and guided
by TEG or comparable monitoring techniques.
The practical significance of fibrinolytic phenotype and therapeutic
response has only recently been recognized. Even among the fields of
liver and trauma surgery, where fibrinolytic variability has been
consistently reported, there is still limited discussion of the
relationship between AF and clinical outcomes across distinct
fibrinolytic phenotypes.
Ultimately, further investigation is needed to assess the role of
fibrinolytic phenotypes in modulating AF responsiveness and clinical
outcomes, especially because AF therapy has a demonstrated utility in
cardiac surgery. Ultimately, TEG -guided AF therapy might assure
administration only when clinically indicated..
Our study is limited by its small sample size and retrospective
methodology, which precluded subgroup analysis of AF outcomes across
fibrinolytic phenotypes. Our small study size also hindered statistical
significance of some outcome variables; though, we still observed
clinically significant differences among patients who received AF,
including an average of 325mL more EBL (P = 0.127) and 2 units more of
RBCs transfused (P = 0.152) compared to patients who did not receive AF.
Considering that fibrinolytic phenotypes and most demographic factors
were relatively equal between patients who did and did not receive AF,
these observed differences following AF may suggest a contributory role
of fibrinolytic phenotype on patient outcomes. Therefore, a better
understanding of fibrinolytic phenotypes may be especially significant
in guiding the decision to administer or withhold AF in surgical
patients.
In summary, this study is the first to describe three distinct
fibrinolytic phenotypes in cardiac surgery patients. This distribution
is different than the established distribution of fibrinolytic
phenotypes in trauma patients. In most surgical specialties,
intra-operative AF safely and effectively reduces bleeding
complications, but there is on strong evidence from trauma patients that
fibrinolytic phenotypes in modulating treatment responses to AF. In
context with these current findings, we hope to open the dialog on
whether it is safe to administer AFs to cardiac surgery patients who are
normo- or hypofibrinolytic. Further studies are clearly indicated in
cardiac surgery patients to investigate the clinical utility of pre- and
post-operative TEG data to discern fibrinolytic phenotypes and guide AF
use.