Timing of Agent Resumption and Therapeutic Targets in the Pathophysiology of Traumatic Brain Injuries

Abstract

An estimated 69 million people worldwide suffer from traumatic brain injuries each year. Direct head trauma can cause traumatic brain hemorrhage, which can be life-threatening if not treated quickly. Current studies suggest the use of antithrombotic therapy for treatment, but the optimal duration of such therapy in neurosurgery remains controversial. This article critically reviews recommendations regarding the ideal timing of antiplatelet and anticoagulant therapy for diseases such as subarachnoid hemorrhage, subdural hematoma, skull fractures, brain contusions, and diffuse axonal injury. . Additionally, the role of these agents in the context of prosthetic valves and stents will be examined, and their effects on bleeding time and platelet aggregation will be evaluated. This review highlights possible directions for future research in this area and highlights the limitations inherent in the current literature. In the case of hemorrhage in TBI, the standard of care is to resume appropriate AAT at intervals to reduce the risk of ICH, but timing and treatment vary among clinicians. Various studies have shown that restarting AAT reduces the long-term risk of thrombotic events and ischemic stroke. However, this benefit should be weighed against the risk of her developing ICH if AAT is restarted too soon. Timing of resumption of AAT should be determined based on multidisciplinary risk stratification considering patient risk factors and comorbidities that may predispose to thromboembolic complications due to prolonged discontinuation of AAT cessation.

Full text

Abdurrahman F. Kharbat1§, Drashti Patel2§, Kiran Sankarappan3, Raja Al-Bahou2, Faisal Alamri4, Anjali Patel2, Rajvi Thakkar2, Ryan
D. Morgan5, Kishore Balasubramanian3, Brandon Lucke-Wold*6
1Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
2College of Medicine, University of Florida, Gainesville, FL, USA.
3College of Medicine, Texas A and M University, Houston, TX, USA.
4King Salman Hospital, Riyadh, Kingdom of Saudi Arabia.
5Division of Neurosurgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
6University of Florida, Department of Neurosurgery, Gainesville, Florida, USA.
§A.K. and D.P. contributted equally to this paper.
Correspondence to: Brandon Lucke-Wold, University of Florida, Department of Neurosurgery, Gainesville, Florida, USA.
Received date: March 28, 2024; Accepted date: April 05, 2024; Published date: April 15, 2024
Citation:
Copyright: ©2024 Kharbat AF, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Keywords:
Traumatic brain injury, Subarachnoid hemorrhage, Subdural
hematoma, Aspirin, Clopidogrel, Antiplatelet and anticoagulant
therapy.
Abbreviations:
TBI: Traumatic Brain Injury; SAH: Subarachnoid Hemorrhage;
SDH: Subdural Hematoma; DAI: Diffuse Axonal Injury; ICH:
Intracranial Hemorrhage; AAT: Antiplatelet and Anticoagulant
Therapy; CT: Computerized Tomography; CATE: Secondary
Cardiogenic Arterial Thromboembolism; DAPT: Dual Antiplatelet
Therapy; CFR: Cyclic Flow Reduction; NOAC: Novel Oral
Anticoagulants; DOAC: Direct Oral Anticoagulants
Introduction
Traumatic brain injury (TBI) refers to a devastating and
complex medical condition that can cause death or severe
disability [1]. TBI typically arises from direct physical trauma to
the head, and it is alarmingly prevalent, with an estimated 69
million individuals worldwide suffering from TBI annually.
Individuals in Asia and the Western Pacific experience the
greatest burden of disease, including more severe symptomsand
an increased mortality rate; however, Europe and North
America have the highest number of recorded TBI cases [2].
Traumatic brain bleeds can occur in TBI due to various
mechanisms, such as blunt force trauma, penetrating injuries,
or acceleration-deceleration forces, leading to damage to the
brain vasculature [3]. When traumatic brain hemorrhage
occurs in association with traumatic brain injury, treatment of
these injuries becomes even more complex. Two examples of
traumatic brain hemorrhage commonly seen in TBI patients
are subarachnoid hemorrhage (SAH) or subdural hematoma
(SDH) [4]. SAH is most commonly caused by TBI, and traumatic
SAH can lead to progressive neurological deterioration and
increased patient morbidity and mortality [5]. Similarly, SDH is
another possible consequence of TBI. 11% of mild to moderate
TBIs and 20% of severe TBIs present with SDH [6]. SDH further
compounds the challenges faced by patients with TBI, as
evidenced by the 60% of patients who either die or become
severely disabled following SDH [7]. This highlights the
important role played by the cerebrovascular system in
maintaining the health of nervous tissue. Damage to these
blood vessels can lead to life-threatening complications.
Along with SAH and SDH, other complications of TBI may also
result in traumatic brain bleeds, including skull fractures,
cerebral contusions, and Diffuse Axonal Injury (DAI). Notably,
skull fractures resulting from TBI serve as a significant predictor
of Intracranial Hemorrhage (ICH) [8]. One study by Lukas
ABSTRACT
An estimated 69 million people worldwide suffer from traumatic brain injuries each year. Direct head trauma
can cause traumatic brain hemorrhage, which can be life-threatening if not treated quickly. Current studies
suggest the use of antithrombotic therapy for treatment, but the optimal duration of such therapy in
neurosurgery remains controversial. This article critically reviews recommendations regarding the ideal timing
of antiplatelet and anticoagulant therapy for diseases such as subarachnoid hemorrhage, subdural hematoma,
skull fractures, brain contusions, and diffuse axonal injury. . Additionally, the role of these agents in the context
of prosthetic valves and stents will be examined, and their effects on bleeding time and platelet aggregation will
be evaluated. This review highlights possible directions for future research in this area and highlights the
limitations inherent in the current literature. In the case of hemorrhage in TBI, the standard of care is to resume
appropriate AAT at intervals to reduce the risk of ICH, but timing and treatment vary among clinicians. Various
studies have shown that restarting AAT reduces the long-term risk of thrombotic events and ischemic stroke.
However, this benefit should be weighed against the risk of her developing ICH if AAT is restarted too soon.
Timing of resumption of AAT should be determined based on multidisciplinary risk stratification considering
patient risk factors and comorbidities that may predispose to thromboembolic complications due to prolonged
discontinuation of AAT cessation.
Review Article
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Kharbat AF, Patel D, Sankarappan K, et al. Timing of Agent Resumption and Therapeutic Targets in the Pathophysiology of Traumatic Brain Injuries,
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Timing of Agent Resumption and Therapeutic Targets in the Pathophysiology of Traumatic Brain Injuries
IJMRS

Leitner, et al. assessed over 1700 patients with TBI and found
a statistically significant correlation between skull fractures
and ICH, as well as ICH-related outcomes [8]. Survival rates
for patients with ICH remain distressingly low, with less than
50% of patients surviving to the one-year mark [9]. Those who
do survive face the sequelae of complications resulting from
traumatic brain bleeds, substantially compromising their quality
of life. Cerebral contusion, another complication associated with
TBI, is also linked to ICH. These contusions inflict permanent
damage to cerebral tissue, stemming from the absorption of
kinetic energy during direct head trauma. This trauma results
in hemorrhagic lesions that can expand and worsen over
time. Potential complications of contusions include seizures,
hydrocephalus, severe disability, coma, and death [10]. DAI
is also a TBI-related complication with many adverse effects,
the most prominent of which is dysautonomia [11]. Overall,
damage resulting from TBI varies greatly and has the potential
If a patient sustains a traumatic brain injury while taking AAT,
these drugs can affect the blood's ability to clot, increasing the
risk of brain hemorrhage. Furthermore, excessive use of AAT
may also falsely induce hypotension, which may reduce
cerebral blood flow [12, 18]. Therefore, medical professionals
should continue or use these medications during the acute
phase of TBI treatment, striking a delicate balance between
preventing further intracerebral hemorrhage and minimizing
the risk of blood clot-related complications. The benefits and
risks of discontinuation must be carefully weighed [19].
This paper aims to review the literature to better ascertain the
to culminate into life-threatening traumatic brain bleeds.
Traumatic cerebral hemorrhage can cause various sequelae
that require emergency treatment to improve patient
prognosis. Elevated blood pressure is associated with poor
prognosis in traumatic cerebral hemorrhage, with an additional
risk of contributing to hematoma expansion [12]. Although the
use of antithrombotic therapy (AAT) is often indicated for the
treatment of traumatic cerebral hemorrhage, there are a
number of patient factors that need to be considered before
initiating AAT, as shown in Figure 1. For example, given the
high prevalence of traumatic brain injury in the elderly, many
patients may have other comorbidities such as atrial fibrillation
and deep vein thrombosis, and may be at risk for stroke or
blood clots. AAT is required to reduce the risk of associated
events [13-17]. The usefulness of AAT in other such diseases
may complicate its use in the treatment of traumatic cerebral
hemorrhage.
appropriate duration of AAT in the context of traumatic brain
bleeds. Our aim is to provide a comprehensive review of the
current literature regarding the ideal duration of AAT
administration after traumatic SAH and in acute or chronic
SDH. Additionally, we examine the optimal duration of
antiplatelet therapy and its impact on patient care in skull
fractures, brain contusions, and DAI. We will also look at the
impact of AAT on prosthetic valves and stents, and the impact
of AAT on bleeding time and platelet aggregation. Our
discussion will extend to the potential future implications for
research concerning the utility of AAT in the context of
traumatic brain bleeds, emphasizing the existing limitations
within the current
Figure 1: The use of AAT in Patients with TBI.
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body of research on this topic.
AAT Duration in Traumatic SAH and Acute or Chronic
SDH
Researchers have long endeavored to elucidate and support
the specific decision-making processes involved in deciding
whether a patient should continue AAT after traumatic SAH
[20]. This is an increasingly common topic, with many research
papers finding an association between administration of the
oral anticoagulant warfarin and increased risk of ICH,
prompting further research on this topic [ 21 ].
Additionally, antiplatelet drugs such as aspirin are being
studied for their role in preventing inflammation and
aneurysm rupture, as shown in Figure 2.
The Role of Aspirin in Patients with SAH
The optimal timeframe for initiating oral anticoagulation
therapy depends on numerous personalized patient factors.
Taking this into account, Yan-Huang Li, et al. proposed a
straightforward three-step model for determining the ideal
timing of AAT administration [20].
•
A patient's risk of developing further thromboembolism or
ICH is evaluated by considering a variety of factors,
including history of atrial fibrillation, mechanical valve
defects, and previous experience of deep vein thrombosis
or pulmonary embolism. The decision to weigh the pros
and cons of continuous anticoagulation therapy depends
on the patient's specific brain disease [20].
•
The correct AAT is chosen, and the optimal timing for
therapy is determined based on the conclusions drawn
from step one. It is essential to recognize that the decision
to initiate AAT should be a multidisciplinary effort, with
the involvement of neurologists, neurosurgeons, and
interventional cardiologists, promoting a team-based
approach to patient care [20].
•
Clinicians take additional measures to manage any chronic
comorbidities that the patient may be experiencing, such
as hypertension, heart failure, or diabetes [20].
The first step of this model focuses on evaluating risk scores
for thromboembolism and ICH, which can prove to be a
complicated process. For instance, one study by Vivien H Lee, et
al. established a simple scoring system known as the HAIR score
(Hunt and Hess score, age, intraventricular hemorrhage, re-
bleed) [22]. This scoring system, ranging from 0 to 8, offers insight
into the various risks associated with SAH and was formulated
based on data from 400 patients suffering from traumatic SAH
and acute and chronic SDH. The study found that a higher HAIR
score was associated with increased hospital mortality among
their patients [22]. Another study examined the aneurysmal
rupture risk scores in patients with SAH in a large prospective
study involving a cohort of 319 patients. Surprisingly, this team
of researchers concluded that the aneurysmal risk scores did
not correlate with a patient’s increased risk for mortality or
intracranial bleeding [23]. This discrepancy between studies
calls for more research in the development of models that
accurately predict a patient’s risk assessment in order to draw
better conclusions regarding the duration of AAT.
The Optimal Timing for AAT in SAH and SDH
A retrospective study by Yana Puckett aimed to determine the
best timing for resuming AAT in 256 patients with TBI between
2009 and 2012. The study reported that resuming AAT between
7 and 9.5 days after TBI may lead to fewer adverse events when
compared to previous recommendations of 3-10 days. The study
analyzed patient metrics, such as coagulation studies, type of TBI,
treatment, and AAT resumption timing, and it evaluated patient
outcomes during a six-month follow-up. Rates of complications
were also assessed, including mortality, myocardial infarction,
stroke, re-bleeding, venous thromboembolism, and pneumonia.
Adverse events were least observed (10%) in the group restarting
AAT between 7-14 days, while the group not resuming AAT had
the highest rate of adverse events (68.8%). One limitation of
this study was low statistical power due to follow-up limitations
and a patient cohort with shorter hospital observation periods
and more benign brain injuries [17]. Further research should
focus on patients with more severe TBIs with longer durations
of hospitalization.
Another review article by Jochen A. Sembill concluded that
Figure 2: The role of aspirin in patients with SAH.
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physicians typically initiated AAT as early as one week for
patients without significant risk factors like atrial fibrillation
or a history of thromboembolism [24]. For patients with other
relevant medical histories, the timing of re-initiation was
adjusted based on individual risk factors. On the other hand,
a survey of multiple neurosurgeons by Yan Xu et al. revealed a
lack of consensus regarding the timing of re-initiating therapy,
with 40% of physicians preferring to recommence treatment
between 14 days and 3 months after the initial injury [25]. In
conclusion, the literature offers varying recommendations, with
some favoring re-initiation of therapy within one week, others
suggesting a 1-2 week delay, and still others advocating for even
longer intervals exceeding one month [17,24-29].
Lastly, in terms of how long AAT should be administered, one
study by Hormuzdiyar H Dasenbrock, et al. found that long-term
AAT was associated with several significant benefits, including
shorter hospital stays, reduced risk of venous thrombotic
events, and a decreased likelihood of cardiac complications
[30]. Similarly, another study concluded that the long-term
administration of this therapy (>2 weeks) substantially
lowered the overall incidence of delayed cerebral ischemia,
particularly when it was concurrently applied with endovascular
treatment [31]. Moreover, it was associated with improved
patient outcomes and reduced mortality rates. Conversely,
a retrospective review study conducted by Ben King, et al.
examined the guidelines for resuming anticoagulant therapy
and demonstrated the potential risks of hemorrhage and
thrombosis [32]. Consequently, these divergent findings suggest
that there is an identifiable optimal timing for resuming therapy
that falls within the current window for re-initiation.
AAT indications for other complications of TBI
Skull fractures, anterior cranial and temporal bone contusions,
and administration of AAT after DAI are topics of ongoing
research and clinical discussion. However, the lack of strong
research such as randomized controlled trials has limited the
availability of evidence-based clinical recommendations in this
area [19]. Decisions regarding the management of AAT
administration are complex and multifactorial, taking into
account the patient's general health status, injury severity and
location, and risk of thromboembolic and hemorrhagic events.
Therefore, the approach to managing these patient cohorts is
highly dependent on the empirical assessment and clinical
experience of the physicians. This reliance on clinical judgment
may contribute to the lack of an established protocol for
determining the optimal time frame for resumption of AAT in
patients after TBI [14, 17, 19].
AAT Indications for Minor TBI and Skull Fractures
The current literature presents a range of recommendations
concerning the duration of AAT following TBI. For instance,
in cases of minor skull fractures or minor TBI with negative
Computerized Tomography (CT) images, there is typically no
recommended reversal of AAT. Instead, it is advised to monitor
the patient in the intensive care unit and perform repeat scans
to rule out any potential bleeding [13,19]. If the subsequent
scans do not reveal any bleeding, the resumption of AAT may
be considered within a matter of days to weeks, contingent
upon other clinical and radiological assessments. However, the
optimal duration of AAT for patients with skull fractures remains
a topic of ongoing research. This highlights the need for further
clinical trials and consensus guidelines to provide clearer
recommendations to healthcare practitioners managing these
complex cases [16].
AAT Indications for Severe TBI, Cerebral Contusions, and
DAI
In cases involving severe TBIs characterized by extensive
contusions or DAI, the potential benefits of AAT must be
carefully weighed against the associated bleeding risks. This
decision often requires multidisciplinary collaboration among
neurologists, neurosurgeons, and hematologists to optimize
patient outcomes while minimizing complications. However,
rapid AAT reversal is recommended in patients with ICH, with
platelet transfusion being the suggested approach for reversing
aspirin or clopidogrel therapy [13, 19]. In cases of warfarin-
induced coagulopathies, effective treatment can typically be
achieved with fresh frozen plasma and intravenous vitamin
K. However, the use of recombinant activated factor VII in
warfarin-associated traumatic ICH remains uncertain, mainly
due to limited clinical benefits, cost considerations, and safety
concerns in trauma cases [13].
Albrecht, et al. conducted a retrospective investigation into
the risk of adverse outcomes in TBI patients hospitalized for
one year. They compared those who resumed warfarin therapy
to those who did not, revealing a reduced risk of thrombotic
events (RR, 0.77; 95% CI, 0.67–0.88) and hemorrhagic or
ischemic strokes (RR, 0.83; 95% CI, 0.72–0.96) associated with
warfarin resumption. However, warfarin resumption was also
linked to an increased risk of hemorrhagic events (RR, 1.51;
95% CI, 1.29–1.78). These findings suggest an overall net
benefit in resuming anticoagulation for most patients [33].
Another study, which included 3355 participants, reviewed the
outcomes related to neurological deterioration or progression
of hemorrhagic TBI on repeat head CT scans in patients who
received anticoagulation within 60 days post-injury. The median
administration time for anticoagulation after injury was found
to be 9 days, and there were no indications of neurological
decline attributable to the administration of anticoagulation;
however, 6 patients exhibited an advancement of hemorrhagic
TBI in follow-up head CT scans. Furthermore, multiple logistic
regression analysis revealed that patients aged 65 and older
were significantly linked to the advancement of hemorrhagic
TBI following therapeutic anticoagulation (odds ratio, 15.2; 95%
confidence interval, 1.1-212.7; P=0.04) [34].
Tykocki and Guzek, et al. also reported a relatively low risk
of hemorrhagic complications in the early resumption of
antithrombotic therapywithin 3-17.5 days after TBI. Furthermore,
their findings indicate that the risk of such complications may be
even lower when non-vitamin K antagonist oral anticoagulants
are used, compared to vitamin K antagonists [35].
Antiplatelet Therapies
The Effects of AATs on Prosthetic Valves and Stents
AAT therapy is also indicated for use in traumatic brain bleeds
for patients with prosthetic valves and stents. For instance,
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one study by Makkar, et al. found that clopidogrel and aspirin
therapy significantly reduced thrombus formation in ex vivo
porcine models with deployed nitinol stents in external
arteriovenous shunts. The study investigated the acute actions
of these regimens and found that a combination of clopidogrel
and aspirin demonstrated significant effects for reducing acute
thrombus formation over the deployed stents, even at low
doses. Aspirin showed synergistic effects when combined with
clopidogrel, enhancing its anti-thrombotic effects, but models
treated with aspirin alone had almost complete obliteration of
the stent by the thrombus. Similarly, pigs treated with clopidogrel
alone had an insignificant level of diminished thrombosis unless
given in relatively high doses when compared to the combined
treatment regimen [36].
In another study involving a rabbit model, the combined
regimen was assessed in ex vivo heart valves and compared with
the acute effects of warfarin. The study found that clopidogrel
and aspirin therapy resulted in a greater reduction of thrombus
over the heart valves than warfarin or control groups [37].
Similarly, in a different experiment involving baboons, Harker, et
al. examined the efficacy of clopidogrel and aspirin in preventing
platelet depositions on externally placed arteriovenous shunts
with stainless steel stents. The study examined the cumulative
effect of clopidogrel in inhibiting platelet depositions over six
days on the hypercoagulable stent; it studied low doses of the
clopidogrel and examined the additive effects of aspirin when
combined with clopidogrel. The study also investigated heparin
in an ex vivo placed stent, both alone and in combination with
clopidogrel. The study demonstrated that heparin did not
significantly reduce platelet depositions over the placed stent
unless it was combinedwithclopidogrel. Thestudy also foundthat
the combination of these regimens did not significantly increase
the bleeding time when compared to clopidogrel alone [38].
McKellar, et al. also contrasted the effects of clopidogrel and
aspirin with dalteparin in preventing thrombus formation over
various periods of time. The study involved a post-mortem
analysis of thrombus size over implanted aortic valves. The
researchers studied swine for 30 days divided into three
treatment groups: 1. combined treatment with clopidogrel
and aspirin, 2. single treatment with clopidogrel, aspirin, or
dalteparin, or 3. non-treated group. Swine receiving Dual
Antiplatelet Therapy (DAPT) had a drastic reduction in thrombus
size in comparison to the control group. Additionally, swine
treated with single therapies had a larger thrombus size when
compared to the DAPTs, but their effects were deemed to be
insignificant. The swine receiving dalteparin had the largest
thrombus size compared to the other treatment groups,
followed by aspirin and clopidogrel. Dalteparin-treated swine
had a thrombus size nearly three times larger than DAPTs.
DAPTs were also compared to the control group over 150 days.
Mean thrombus size in the aspirin and clopidogrel combined
group was significantly smaller than the control group, with a
four times greater size reduction. Interestingly, there were no
reported deaths due to thromboembolic events in the short-
term, long-term, or non-treated group [39]. Hence, it can be
concluded that a combination of aspirin and clopidogrel is the
most effective treatment for thrombi in prosthetic valves and
stents.
The Effects of AATs on Intravascular Thrombosis
The debate regarding AAT also extends to the topic of
intravascular thrombosis. For instance, one double-blinded
randomized control trial studied two groups of cats receiving
either aspirin or clopidogrel to investigate the incidence of
Secondary Cardiogenic Arterial Thromboembolism (CATE).
The researchers found that clopidogrel-treated cats had a
significantly decreased likelihood of recurrent CATE and an
increased median time for the event to occur. Additionally, the
clopidogrel group was less likely to die due to cardiac causes
[40].
The aforementioned study by Harker, et al. also found that
although heparin and clopidogrel significantly reduced platelet
aggregation on the placed stent, they did not decrease the
platelet deposition on a vascular graft when compared to
clopidogrel alone. Contrastingly, clopidogrel combined with
aspirin diminished graft platelet depositions dramatically [38].
Another study measured the acute Cyclic Flow Reduction (CFR)
in the coronary arteries of pigs with induced unstable angina
and its relation to clopidogrel and aspirin when used alone or
combined. These researchers found that clopidogrel and aspirin
together, even at low doses, exhibited rapid and effective action
in decreasing the CFR whilst inhibition of platelet aggregation
was delayed. In fact, aspirin or clopidogrel alone with the same
doses did not show any effects at all [41].
The antithrombotic effects of clopidogrel, ticlopidine, and
prasugrel were singly compared in rat models after induction
of carotid arterial thrombosis in a different study. The study
measured vessel occlusion time after induction of thrombosis
and treatment in comparison to the non-treated group.
Prasugrel displayed more potent and faster actions, compared
to clopidogrel and ticlopidine, in keeping patent vessels and
reducing thrombus formation [42]. Moreover, these drugs
were examined for their ability to prevent arteriovenous shunt
thrombosis in rats; their results were strikingly similar to the
previously mentioned study [42,43]. In another experiment
involving rat models, aspirin, clopidogrel, enoxaparin, and
heparin were compared with each other as single therapies
or in combination with aspirin for the inhibition of CFR post-
induction of carotid artery thrombosis. This study concluded
that clopidogrel combined with aspirin was more effective than
enoxaparin and aspirin or heparin and aspirin in the reduction
of thrombus formation [44]. Combined therapy with aspirin and
clopidogrel is more effective in treating intravascular thrombosis
than other combination or stand-alone treatment regimens.
The Effects of AATs on Platelet Aggregation
Clopidogrel substantially inhibits ADP-induced platelet
aggregation in a dose-dependent manner; however, it has no
effect on collagen-induced aggregation. Contrastingly, aspirin
prevents collagen-dependent aggregation in a dose-dependent
pattern with a minimal effect on ADP-induced aggregation. A
combination of both regimens resulted in a delayed effect on
ADP-dependent aggregation without a significant effect on
collagen-induced aggregation [41]. On the other hand, prasugrel
displayed stronger and faster inhibition of platelet aggregation
in both mechanisms, and its inhibitory effects increased when
combined with aspirin, even at low doses [45,46].
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The Effects of AATs on Bleeding Time
The aforementioned study by H. J. Daykin, et al. compared
bleeding time in association with the administration of AAT alone
or in combination with aspirin. The tail bleeding times associated
with heparin and enoxaparin were significantly increased at
higher doses when compared to aspirin or clopidogrel alone.
Combining anticoagulants with aspirin further increased
bleeding time in contrast to the combination of clopidogrel
and aspirin [44]. Similarly, rivaroxaban had a minor increase
in bleeding time compared to clopidogrel with aspirin, but no
statistically significant differences were found [47]. Clopidogrel
and prasugrel also had no significant difference in the bleeding
time [46]. Further research should focus on assessing bleeding
time with combination therapies with larger sample sizes.
Ticagrelor, Prasugrel, and Clopidogrel
Another experimental study involved ex vivo and in vivo rat
and dog models to compare ticagrelor therapy to clopidogrel
and compounds 072 and 105, chemical compounds identical
to prasugrel and its active metabolite, respectively. J.J.J. van
Giezen, et al. found that ticagrelor has distinguishing chemical
properties when compared to both prasugrel and clopidogrel.
For instance, ticagrelor is an active compound that does not
need to be converted by the liver to exert its effects, unlike
thienopyridines. Additionally, the high affinity of ticagrelor
saturates active sites and leaves it able to more rapidly reach
equilibrium when compared to clopidogrel and prasugrel [48].
Ticagrelor is also capable of reversibly binding to the active site,
Table 1: Drugs commonly used to manage coagulopathy in traumatic brain bleeds.
Drug Interactions in Patients with Multiple Comorbidities
In patients with multiple comorbidities, polypharmacy is a
prevalent issue that further complicates the use of AAT. This
polypharmacy environment significantly heightens the potential
for drug interactions, making it an area requiring comprehensive
study. Certain medications, such as NSAIDs and specific
antibiotics, can interact with anticoagulants to exacerbate the
risk of bleeding. These drug interactions are not merely additive
but can often produce synergistic effects, amplifying the risks
associated with each medication [56].
Duration of Therapy
As noted earlier, optimal duration for which AAT should be
unlike prasugrel and clopidogrel. Additionally, in vivo and ex
vivo studies revealed no significant difference in bleeding time
and thrombus formation between ticagrelor and prasugrel [49]
Future Implications for Research on the Use of AATs
in Traumatic Brain Bleeds
Duality of Efficacy and Side Effects
The core concern when administering AAT in cases of traumatic
brain bleeds revolves around the balance between potential
therapeutic benefits and associated risks. These medications
are invaluable for mitigating the danger of thrombotic events
such as ischemic strokes. However, their mechanism of action
also significantly elevates the risk of further hemorrhagic
complications such as increased intracranial pressure, brain
herniation, neurological deficits, epilepsy, and cerebral edema
[50]. While it is widely accepted that platelets regulate primary
hemostasis, the impact of antiplatelet medications on subdural
hematomas or subarachnoid hemorrhages remains an area of
active investigation [51]. However, antiplatelet use has been
associated with an increased risk of acute ICH post-head trauma,
albeit with a low risk for delayed ICH [52-54]. Thus, immediate
head CT imaging is recommended for all such patients [55]. In
clinical scenarios where anticoagulation is crucial for the patient,
such as in atrial fibrillation or specific cardiac conditions, the
decision to recommence treatment should be more meticulously
calculated. Overall, the drugs that are currently in use in the
context of traumatic brain bleeds are outlined in Table 1.
administered in the context of traumatic brain bleeds remains
controversial. Majeed et al. concluded that the optimal timing
for restarting anticoagulation should be between 10 and 30
weeks after the intracranial bleeding (55% had ICH), based on
the high risk of recurrent hemorrhage in the first 10 weeks
that decreased over time, and a rise in ischemic complications
beyond 30 weeks [57]. Meanwhile, Park et al. proposed that
OAC be reinitiated after 2 weeks to avoid the overriding effect
of intracranial hemorrhage recurrence on the prevention of
systemic thromboembolism and ischemic stroke [58]. Current
practice is largely empirical and there is a need for prospective,
randomized trials that compare short-term vs long-term therapy
to determine which provides an ideal risk-to-benefit ratio.
Drug
Mechanism
Side Effects
Drug interactions
Reversal agents
Warfarin
Vitamin K Antagonist
Bleeding, Bruising
NSAIDs, Antibiotics
Vitamin K, FFP
Dabigatran (Pradaxa)
Direct thrombin inhibitor
GI Upset, Bleeding
Antiplatelets
Idarucizumab
Rivaroxaban (Xarelto)
Factor Xa inhibitor
Bleeding, Liver dysfunction
NSAIDs, Antiplatelets
Andexanet alfa
Apixaban (Eliquis)
Factor Xa inhibitor
Bleeding, Nausea
NSAIDs, Antiplatelets
Andexanet alfa
Heparin
Antithrombin activator
Bleeding, HIT
Antiplatelets
Protamine Sulfate
Enoxaparin (Lovenox)
Low molecular weight
heparin
Bleeding, Bruising
NSAIDs, Antiplatelets
Protamine Sulfate
Clopidogrel (Plavix)
ADP receptor inhibitor
Bleeding, GI Upset
PPIs, Other antiplatelets
None
Lisinopril
ACE Inhibitor
Cough, Elevated blood K+
NSAIDs, Diuretics
None
Amlodipine
Ca2+ Channel blocker
Edema, Headache
Grapefruit juice
None
Metoprolol
Beta-Blocker
Fatigue, Bradycardia
Antiarrhythmics
Glucagon
Levetiracetam
SV2A modulation
Irritability, Dizziness
Other CNS depressants
None
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Citation: Kharbat AF, Patel D, Sankarappan K, et al. Timing of Agent Resumption and Therapeutic Targets in the Pathophysiology of Traumatic Brain Injuries

Alternative Therapies
Whilecurrent AAT has provenefficacious in various settings, their
limitations, and associated risks in the context of traumatic brain
hemorrhage illustrate the need for innovative pharmacological
strategies. The development of drugs with targeted mechanisms
of action that provide anticoagulant benefits without increasing
the risk of hemorrhage is of paramount importance. Promising
therapeutics include Novel Oral Anticoagulants (NOACs), next-
generation antiplatelet agents, antihypertensive medications,
antiepileptics, and statins.
NOACs such as dabigatran etexilate mesylate, rivaroxaban, and
apixaban represent a significant leap forward. A 2022 meta-
analysis revealed that Direct Oral Anticoagulants (DOACs) cut
the risk of ICH by nearly half compared to Vitamin K antagonists,
with dabigatran 110 mg identified as the safest DOAC in terms
of ICH risk [59-61]. Another study from 2020 found that despite
DOACs being reversed at nearly half the rate of warfarin, patients
with traumatic ICH on warfarin had higher 6-month mortality
rates, suggesting a potential survival advantage for DOACs in this
population [62]. As such, NOACs are increasingly becoming first-
line options for stroke prevention in atrial fibrillation patients at
high risk for ICH [63].
Next-generation antiplatelet agents, such as cangrelor and
ticagrelor, hold significant promise in the management of
patients who have experienced traumatic brain bleeds [64].
Unlike traditional antiplatelet drugs like clopidogrel, these newer
agents offer more targeted and controllable platelet inhibition.
For example, cangrelor is an intravenous P2Y12 inhibitor with
rapid onset and offset of action, providing clinicians with the
ability to quickly titrate its effects [65]. Ticagrelor, on the other
hand, is an oral agent that also acts on the P2Y12 receptor but
offers the benefit of reversibility [66]. These features balance
the need for antithrombotic efficacy with a minimized risk of
further hemorrhagic complications. This adaptability offers
clinicians greater flexibility in tailoring therapy to individual
patient needs, which can be particularly beneficial in scenarios
requiring surgical intervention or when there is a high risk of
recurrent hemorrhage.
The utilization of antihypertensive agents like ACE inhibitors,
calcium channel blockers, and beta-blockers, although
somewhat controversial, offers another strategy to mitigate the
risk of recurrent bleeds by maintaining optimal blood pressure
levels. Antiepileptic medications, such as levetiracetam, may be
utilized prophylactically to prevent seizures, which can elevate
intracranial pressure and potentially exacerbate bleeding [67].
While not directly aimed at reducing the risk of bleeding, some
clinicians consider the use of statins for their neuroprotective
effects, although further research is needed to validate their
efficacy in this context [68]. Lifestyle modifications also serve
as adjunctive strategies and should be monitored rigorously.
These include smoking cessation, alcohol limitation, and dietary
changes aimed at vascular health.
Strengthening Data Regarding the Duration of AAT Use
To refine our understanding of optimal anticoagulation duration
in the context of traumatic brain bleed, a comprehensive,
multifaceted approach is essential. This would serve to elevate
the quality of evidence, allowing clinicians to deliver evidence-
based care that maximizes therapeutic benefits while minimizing
adverse outcomes. Strategies for achieving this involve the
design of rigorous randomized clinical trials, longitudinal cohort
studies, meta-analyses, standardization of outcome metrics,
and patient risk stratification.
Randomized clinical trials remain the gold standard in clinical
research, providing robust evidence on the efficacy and safety
of interventions. However, longitudinal cohort studies offer
complementary insights into longer-term outcomes and
potential late complications associated with varying treatment
durations. Such studies could provide critical information on
the longitudinal safety and efficacy of anticoagulant regimens in
brain hemorrhage patients. Additionally, meta-analyses, which
synthesize data from multiple independent studies, offer more
reliable estimates of treatment effects which is valuable when
individual studies yield small or conflicting results. Outcome
standardization is another pivotal aspect. Clear definitions of
what constitutes a successful outcome such as clot resolution,
absence of rebleeding, or reduced morbidity would facilitate
comparability across studies.
A notable deficiency in the current state of research is the lack
of patient-stratified studies, which would consider individual
risk factors like age, comorbidities, and the specific nature of the
brain hemorrhage. For instance, anticoagulant therapy poses
a unique risk/benefit profile for elderly, stroke-prone patients
compared to younger cohorts [59]. Patient stratification could
pave the way for more individualized treatment plans, allowing
for the optimized use of anticoagulants and antiplatelets while
minimizing adverse outcomes.
Conclusion
As treatments for traumatic cerebral hemorrhage continue to
evolve, the need for comprehensive comparative studies
increases. Advances in personalized medicine are creating new
opportunities for personalized treatment plans that take into
account variables such as drug interactions, genetic
predisposition, and comorbidities. This multifaceted approach
should include not only evaluation of the optimal duration of
AAT, but also evaluation of new pharmacological alternatives
such as NOACs and next-generation antiplatelet agents.
In the case of hemorrhage in TBI, the standard of care is to
resume appropriate AAT at intervals to reduce the risk of ICH,
but timing and treatment vary among clinicians. Various
studies have shown that restarting AAT reduces the long-term
risk of thrombotic events and ischemic stroke. However, this
risk must be weighed against the risk of developing ICH if AAT
is restarted too soon. The timing of resuming AAT should be
determined based on multidisciplinary risk stratification
considering patient risk factors and comorbidities that may
lead to thromboembolic complications with long-term
discontinuation of AAT cessation.
Traumatic brain injury encompasses a spectrum of injuries
that can have significant and far-reaching consequences in
the short and long term. Achieving an accurate diagnosis and
implementing appropriate management strategies, including
decisions related to AAT, should be based on the most up-to-
date research and customized to meet the specific needs of
each patient whilst taking into consideration co-morbidities and
Page 16 of 19
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Citation: Kharbat AF, Patel D, Sankarappan K, et al. Timing of Agent Resumption and Therapeutic Targets in the Pathophysiology of Traumatic Brain Injuries

clinically complicating factors. The continually evolving body of
literature on this subject highlights the critical importance of
ongoing research efforts aimed at generating robust evidence
to guide the management and treatment of TBIs, especially in
the context of continued AAT.
Conflicts of Interest
The author have no conflicts of interest to report.
Funding
No.
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