Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT03741023 |
| Other study ID # |
181982 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 12, 2019 |
| Est. completion date |
December 31, 2026 |
Study information
| Verified date |
March 2024 |
| Source |
Vanderbilt University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of the proposed study is to test these hypotheses through the following aims:
1. To determine if early plasmin activation following severe injury correlates with SIRS,
TIC and complications throughout convalescence in both trauma and surgical patients.
2. To determine if early plasmin activation following severe injury correlates with
plasminogen consumption and poor plasmin activity later in convalescence.
Description:
Significance: Severe injury is a leading cause of death and disability worldwide, affecting
approximately 2.8 million individuals and accounting for over 200,000 deaths annually across
the United States1,2,3. Large cohort studies have demonstrated that approximately 64% of
trauma-related deaths are due to complications including thrombosis, bleeding, infection, and
organ dysfunction, and each complication corresponds with an 8% increase in risk of
mortality4. While advances in critical care medicine have significantly improved the initial
survival from traumatic injuries, the proportion of morbidity and mortality from
complications experienced during traumatic convalescence has correspondingly skyrocketed.
Early in convalescence, these patients are at risk of developing life-threatening
complications instigated by trauma induced coagulopathy (TIC) and systemic inflammatory
response syndrome (SIRS). Specifically, approximately 40% of patients with severe injuries
develop TIC and approximately 70% develop SIRS5,6. While these conditions individually
increase the risk of secondary sequelae, in concurrence, they dramatically increase the risk
of bleeding, thrombosis, infection, and multi-organ dysfunction syndrome (MODS)7,8,9. Later
in convalescence, patients experiencing severe injury are at risk of suffering complications
from pathologic tissue homeostasis and repair. For example, depending on the injury, 25-65%
of severely injured patients' rehabilitation and quality of life are limited by poor bone
health, including the development of osteoporosis, impaired bone healing, and/or the
development of heterotopic ossification10,11,12. Together, early and late complications of
convalescence reportedly account for over $671 billion in healthcare expenditure and
disability losses yearly1. Thus, there is an unmet need for improved therapeutic and
diagnostic measures for these patients to prevent or treat complications of early and late
convalescence.
The Acute Phase Response (APR): Following injury, the APR resolves the four principle
problems provoked by disruption of tissue: bleeding, pathogen invasion, tissue hypoxia, and
tissue dysfunction. After an isolated injury, e.g., femur fracture, the APR follows a
predictable and quantifiable time-course with minimal risk of complications (Figure 1A). The
survival phase contains the injury and prevents infection through hemostasis (fibrin
deposition) and acute inflammation. The later repair phase effectively removes damaged
tissue, regenerates new tissue, and restores function. Severe trauma derails the
survival-APR, provoking complications in both in early and late convalescence (Figure 1B). In
order to prevent exsanguination, severe trauma must provoke an adequate survival-APR in
proportion to the severity of the injury. However, unrestrained and prolonged activation of
coagulation and survival-inflammation lead to the development of TIC and SIRS and
significantly increasing the risk of bleeding, thrombosis, and MODS6,5,8. Additionally, if a
patient persists within the survival-APR for an extended period of time, the prolonged
activation of cellular inflammation promotes disorders of tissue homeostasis, e.g.,
osteoporosis, and delays the transition to the repair-APR, stalling or preventing healing
tissue and crippling recovery in these patients13,14. Therefore, APR complications are
mechanistically linked, that is, dysfunction of the survival-APR contributes to dysfunction
of the repair-APR. Although there are many reports suggesting potential molecular
determinants of a dysfunctional APR, the primary molecular targets driving this phenomenon
are unknown.
Severe Trauma-Provoked Changes in Plasmin Activity: Plasmin is converted from its zymogen,
plasminogen, by its activators: tissue plasminogen activator (tPA) and urokinase plasminogen
activator (uPA). While plasmin is a multifunctional protease, its canonical role is the
degradation of fibrin (fibrinolysis). While fibrinolysis occurs during the repair-APR
following an isolated injury, a severe injury provokes early hyperactivation of plasmin
(Figure 2)15,16. Fibrinolysis was first observed by anatomist Giovanni Morgagni and surgeon
John Hunter in the late 1700s during autopsies of individuals that suffered traumatic
injuries17,18. Both Morgagni and Hunter noted that blood from these individuals strangely did
not clot. It was later determined that blood clots formed following traumatic injury or
invasive surgery spontaneously dissolved, leading to the discovery of plasmin.
The immediate and most-recognized clinical consequence of this inappropriate
hyperfibrinolysis is bleeding, as the degradation of fibrin opposes effective hemostasis19.
The clinical significance of injury- induced hyperfibrinolysis was propelled by improvements
in critical care medicine that permitted not only survival of previously fatal traumatic
injuries, but also invasive, elective surgical procedures through the use of antifibrinolytic
therapeutics. Specifically, recent clinical studies in >40,000 trauma patients have
demonstrated that prevention of plasmin activation by antifibrinolytics (e.g., aminocaproic
acid (Amicar), tranexamic acid (TXA)) significantly reduced blood loss and increased survival
when administered early after injury20,21. Thus, it has been established that inappropriate,
early plasmin activation (hyperfibrinolysis) is a significant cause of bleeding and mortality
following severe injury19,16.
Pathologic Fibrinolysis - Hemorrhage is the Tip of the Iceberg: Both hyperfibrinolysis and
hypofibrinolysis occur following trauma and have been associated with complications
throughout convalescence22,23, indicating that plasmin's biologic role following injury is
more complex than previously understood. Indeed, since the initial investigations of
plasmin's role in bleeding, our knowledge of the biological role of plasmin has greatly
expanded beyond its role in hemostasis. Currently, it is recognized that plasmin is activated
during virtually all tissue repair, where it degrades intra- and extravascular fibrin24,25.
In addition to fibrinolysis, plasmin also acts through non-canonical pathways to promote
tissue repair including programming and migration of macrophages and progenitor cells, growth
factor activation, and promotion of angiogenesis26,27,28,29. Additionally, plasmin stimulates
an acute inflammatory response, promoting tissue regeneration30,31,32. Thus, plasmin is
essential for tissue maintenance and repair. Specifically, our lab has extended this premise
by determining that plasmin is essential for proper bone homeostasis, as well as bone and
muscle repair33,34,35. Thus, following trauma, the biological role of plasmin is not limited
to intravascular activity and bleeding. Instead, it plays well defined, albeit less
understood, roles in pro- and anti-inflammatory responses, tissue homeostasis, and repair of
virtually all tissues. While these studies would suggest that plasmin plays beneficial role
in recovery following trauma, judicious prevention of early plasmin activation is clearly
beneficial in preventing life threatening hemorrhage.
The purpose of the proposed study is to test these hypotheses through the following aims:
1. To determine if early plasmin activation following severe injury correlates with SIRS,
TIC and complications throughout convalescence in both trauma and surgical patients.
2. To determine if early plasmin activation following severe injury correlates with
plasminogen consumption and poor plasmin activity later in convalescence.
