Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05738642 |
| Other study ID # |
2022-0955 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2023 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
January 2023 |
| Source |
Second Affiliated Hospital, School of Medicine, Zhejiang University |
| Contact |
yongan xu, doctor |
| Phone |
13757164833 |
| Email |
xuyongan2000[@]163.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Uncontrolled hemorrhage within 24 hours after severe trauma is the main cause of death in
trauma patients. Hemorrhagic shock may be accompanied by traumatic coagulopathy in the early
stages of severe trauma. Among them, the main pathogenesis of traumatic coagulation disorder
is tissue injury, hypoperfusion, inflammatory response and acute neurohumoral system
activation leading to the activation of endogenous protein C, increased consumption of
coagulation factor, loss of coagulation factor caused by massive bleeding, low temperature
and other factors aggravate the disorder of coagulation function and cause hyperfibrinolysis.
Studies have shown that the fatality rate of patients with severe traumatic coagulopathy is
4-8 times higher than that of patients without coagulopathy. Active and effective
injury-controlled resuscitation and surgical treatment, target-oriented supplementation of
coagulation substrate and correction of coagulation function are the main measures for
high-quality treatment of patients with severe trauma. Therefore, early improvement of
coagulation function is the key to improve the comprehensive treatment level of patients with
severe trauma.
At present, four-factor prothrombin complex (4F-PCC) is a compound preparation containing
coagulation factors Ⅱ, VII, IX and X separated from fresh plasma of healthy people. It is
used in clinical treatment of patients with coagulation factor deficiency or bleeding
complicated by taking anticoagulant drugs to achieve rapid hemostasis effect. However,
large-scale, long-term observation of the efficacy and safety of the early application of
cluster infusion of 4F-PCC in traumatic massive hemorrhage, correction of cocoagulation
dysfunction, and improvement of clinical prognosis has not been proven.
This study intends to conduct a clinical intervention study on early bunching and sufficient
use of 4F-PCC in patients with severe traumatic massive hemorrhage, and evaluate its efficacy
in early use of severe traumatic massive hemorrhage through a randomized controlled and
open-label clinical study of multi-center, bunching use of PCC in patients with severe
traumatic massive hemorrhage.
Description:
Trauma causes at least 5.8 million deaths globally every year, accounting for 1/10 of the
global annual death toll [1, 2]. Uncontrolled bleeding within 24h after trauma is the main
cause of death in trauma patients [3, 4], and about 1/3 patients are accompanied by traumatic
coagulopathy upon admission [5, 6]. Studies and analyses have shown that fatal traumatic
hemorrhage is the most common preventable death factor [7]. The implementation of early
deterministic and effective hemostatic measures for patients with severe traumatic massive
hemorrhage can significantly reduce clinical massive hemorrhage and timely correct
hemorrhagic shock, and it is necessary to correct traumatic coagulopathy and other traumatic
complications [8, 9]. The occurrence of traumatic coagulopathy is caused by multiple factors,
including severe tissue trauma and hypoperfusion drive, traumatic blood loss, massive
intravenous infusion of hypocoagulable blood products such as crystal solution or red blood
cells resulting in blood dilution, acidosis, depletion of coagulation factors, and even
hypothermia and excessive inflammation can lead to the exacerbation of coagulopathy. Patients
with systemic hypocoagulation and hyperfibrinolysis. In addition, traumatic coagulopathy, as
one of the "death triad" of severe trauma, is associated with the increased need for
hospitalization blood transfusion, prolonged mechanical ventilation, multiple organ failure
and other increased risk of trauma complications. In addition, the fatality rate of trauma
patients with severe traumatic coagulodysfunction is 4-8 times higher than that of patients
without severe traumatic coagulodysfunction [5, 10, 11]. Therefore, for patients with severe
traumatic hemorrhage complicated with coagulopathy, positive values should be adopted to
rapidly improve the coagulopathy of patients and improve clinical prognosis.
The treatment of severe traumatic hemorrhage, hemorrhagic shock and traumatic coagulopathy
includes timely correction of massive hemorrhage, timely use of proportional transfusion of
blood products to ensure effective fluid volume resuscitation and temperature maintenance,
and achieve target-oriented correction of coagulopathy while taking into account thrombosis
prevention and other comprehensive therapeutic strategies [12]. Among them, proportional
infusion of RBC and Fresh Frozen Plasma (FFP) in clinical mass transfusion protocol (MTP) is
still the most commonly used therapeutic measure [13, 14]. However, with the increasing
imbalance between supply and demand of blood products, some treatment units often face the
dilemma of lack of blood products. Therefore, more and more European and American countries
begin to apply Coagulation Factor Concentrates (Coagulation Factor Concentrates, CFCs)
included Prothrombin Complex Concentrates (PCC) and Fibrinogen Concentrates (FC) for early
resuscitation and target-directed coagulation management. Compared with FFP alone, the
advantages of CFCs to correct coagulation dysfunction include: by providing standardized and
high concentration of coagulation factors, reducing virus transmission and
transfusion-related adverse reactions (such as acute respiratory distress syndrome, sepsis
and multiple organ failure), immediate use without matching, and easy operation [15, 16]; The
bunching of PCCS can effectively reduce the need for blood transfusion, achieve faster
correction of coagulation function and reduce in-hospital mortality [12, 17-19]. A
prospective, single-center, randomized controlled trial found that early use of fibrinogen
concentrate (FC) may reduce blood transfusion volume and the incidence of multiple organ
failure [17]. However, at present, for patients with severe trauma and massive hemorrhage,
the use of MTP and blood products can only be effectively implemented on the basis of the
completion of coagulation function test, accurate thrombus elastogram (TEG) and dynamic
evaluation of the body's coagulation function [12, 17]. However, the acquisition of TEG test
results is often slow, which cannot timely and effectively guide clinicians to carry out
target-oriented use of blood products and clinical mass transfusion in early stage. In
addition, when hemorrhagic shock cannot be effectively corrected in patients with severe
traumatic massive hemorrhage in the early stage, timely treatment of coagulopathy is delayed.
In conclusion, timely and sufficient supplement of prothrombin complex PCC and other blood
products may have certain application value for timely and effective correction of
coagulation dysfunction.
Prothrombin complex (PCC) is a kind of plasma protein concentrate containing coagulation
factor which is isolated and prepared from healthy human mixed plasma. Currently, there are
two types of clinically available PCCS: 3-factor prothrombin complex (3F-PCC) and 4-factor
prothrombin complex (4F-PCC) [20]. 4F-PCC is a compound preparation containing coagulation
factor Ⅱ, VII, IX and X, which has been used in clinical treatment of patients with
coagulation factor deficiency or bleeding complicated by taking anticoagulant drugs to
achieve rapid hemostatic effect. Studies have shown that compared with 3F-PCC, 4F-PCC can
better reduce mortality and treatment costs in the management of traumatic coagulopathy [21].
However, the efficacy and safety of 4F-PCC in early dosing and bunching of traumatic massive
bleeding have not been demonstrated by prospective multicenter randomized controlled trials.
In addition to the application of PCC in patients with traumatic hemorrhage complicated by
anticoagulant drugs, the European Guidelines for Massive Hemorrhage 2019 Edition lacks clear
guidelines for the treatment of patients with severe traumatic hemorrhage complicated with
coagulopathy. Nevertheless, there is widespread clinical concern that PCCS increase the risk
of thromboembolic complications; In trauma patients, retrospective studies have shown that
the incidence of different thrombus varies from 2% to 15% [17, 19, 22]. A previous
retrospective study in the hospital where the author worked showed that 17.5% of severe
trauma patients used 4F-PCC empirically, and the incidence of thrombosis and other adverse
events in these patients was about 3%. Since the late 1990s, in order to improve safety,
activators have been removed and anticoagulant factors added to most PCC processes to balance
the risk of thrombotic complications [23]. In vitro studies of severe trauma have also found
that appropriate doses of 4F-PCC can safely improve coagulation function and reduce blood
loss [24], and the thrombotic potential of 4F-PCC is lower than that of aPCC or rFVIIa [25].
Pharmacovigilance data suggest that the risk of thromboembolic complications in PCC may be
low, but the primary source of these data is vitamin K antagonist reversal [26]. Therefore,
for the application of PCC in the management of traumatic coagulopathy, there is still a lack
of scientific clinical practice guidance basis, and systematic prospective research is needed
at the same time.
We noted that two large randomized controlled trials were registered in ClinicalTrials.gov by
European and American teams. One was the combination of PCC+FC administration in patients
with traumatic bleeding, and the other was the use of PCC alone, but both trials did not take
reduction of transfusion of blood products as the main evaluation index [20, 27, 28]. It is
worth mentioning that a recently published meta-analysis of retrospective studies found that
the use of PCCS was associated with reduced mortality in trauma patients [29]. Therefore, we
can assume that early use of 4F-PCC in severe trauma with hemorrhagic shock can correct
bleeding and coagulodysfunction as soon as possible, thereby preventing circulatory,
respiratory and renal multiple organ failure and improving prognosis. In addition, the lack
of blood products and the difficulty in the implementation of massive blood transfusion plan
also put forward a higher demand for the early and efficient use of clotting substrates in
the treatment of patients with massive traumatic hemorrhage. This has also become an
important research content in this study, such as the early empirical use of 4-PCC to improve
the clinical prognosis of patients with severe traumatic massive hemorrhage, reduce the need
for blood products, quickly correct coagulation dysfunction, and reduce the risk of
thrombosis events. Therefore, this study intends to conduct early empirical bunching of 4-PCC
in patients with severe traumatic massive hemorrhage, and evaluate its effectiveness and
safety in the early stage of severe traumatic massive hemorrhage through a multicenter,
randomized controlled, open-label study. To further improve the treatment of traumatic
massive hemorrhage to provide a certain reference basis; It also provides the theoretical
basis and clinical practice for correcting coagulation dysfunction in the early stage of
severe trauma treatment.
