INTRODUCTION:

One of the main causes of morbidity and mortality in pediatric patients is traumatic brain injury (TBI). According to World Health Organization statistics, up to 950 000 kids under the age of 18 per year pass away from injuries, with TBI accounting for about half of those deaths^1,2. However overall mortality in children is lower compared to adults (2.5% vs. 10.4%) and certain elements may indicate less favorable results³. One of its poor outcome factors is the development of coagulopathy within the early hours of injury⁴. The incidence of TBI related coagulopathy is as high as 97.2%⁵ with the mortality among patients harboring traumatic coagulopathy reached 86%⁶.

Traumatic coagulopathy has numerous criteria and definitions, activated partial thromboplastin time of more than 36 seconds, for instance, and platelet count less than 100,000 per mm³ and INR greater than 1.2⁷. While cerebral edema, subarachnoid hemorrhage, hypotension upon admission, GCS score of <or=8, ISS >or=16, as independent risk factors for coagulopathy in isolated head trauma⁸. Later on, increasing age and intraparenchymal lesions was added as another independent factors. The severity of head injury may reflect the degree of coagulopathy, vice versa^9–11.

While early operation is mandatory to relieve the increased intracranial pressure (ICP) in some operable cases, the dilemmatic appears when the patient develops coagulopathy. Let alone the operation, in term of intracranial pressure monitoring, textbook has suggested normalization of coagulation parameters prior to inserting ICP monitors¹², which in consequence may delay the increased ICP controlling. Trauma-Induced coagulopathy has two different form with the different approach in management^13–15. The latest 2019 Guideline for the management of pediatric severe TBI patient was focused on ICP management without any subsequent discussion on the general effect of severe TBI, especially recommendations concerning correction of coagulopathy^16,17. Consequently, this current study's goal was to investigate the management of TIC in pediatric isolated severe TBI patients with the latest pertinent literatures.

CASE REPORTS:

A 5 years old boy brought to emergency department with decrease of consciousness after hit by a motorcycle. He was referred from the district hospital without proper stabilization within 3 hours after the injury. He had seizure 10 times before arrived on our hospital. From the initial physical examination, patient’s blood pressure was 80/50mmHg, heart rate was 154x/minutes and peripheral oxygen saturation of 80%. After stabilization and intubation, his Glasgow coma scale (GCS) was E1VintubatedM3. The pupil was unequal with diameter 3mm/5mm. There was open degloving at the frontal area with depressed fracture exposed (Figure 1).

From the blood examination, hemoglobin level was 8.1 g/dl, base deficit -9.9mEq/L with PTT and aPTT no coagulation suggesting coagulopathy. Emergency non-contrast head CT Scan was performed and showed anterior skull base fracture with discontinuity in left squamous suture suggesting a diastases fracture with an air hypodensity lesion in left frontal area suggesting a pneumocephalus. There was also a hyperdense lesion with crescent shape in frontal and interhemispheric region suggesting subdural hematoma. A 3x5x5cm hyperdense lesion with 35cc volume, surrounded by perifocal edema was seen in left fronto-basal region suggesting a burst lobe intracerebral hematoma (Figure 2). We decided to perform emergency craniotomy to evacuate the blood clot and reconstructed the frontal bone and planned to do local flap for controlling the bleeding. Prior to operation, dilemmatic occurred due to low hemoglobin level and abnormal coagulation function. We delayed the operation for almost 6 hours to do whole blood and fresh frozen plasma transfusion. The operation was successfully done with additional installation of intraventricular ICP monitoring on right Kocher’s point to evaluate the patient’s intracranial pressure during the hospitalization. Two days after surgery the patient underwent tracheostomy and in day twenty, he was discharged with Glasgow Outcome Scale (GOS) of 2. Upon 2 years follow up, the patient still wasn’t able to perform normal daily activity.

Figure 1: Open degloving wound with frontal bone expose.

Figure 2: Computed tomography and 3D reconstruction showing intraparenchymal haemorrhage, subdural haemorrhage, pneumocephalus and impressed fracture.

DISCUSSION:

Coagulopathy induced by trauma is defined as the derangement of the coagulation system caused by trauma which is manifest in two phenotypes: thrombotic and bleeding phenotypes as the result of hypercoagulation and hypocoagulation. Some authors also differ two types of coagulopathy into acute (ATC) and resuscitation (RTC)^18,19. In terms of clinical and hematological parameters, TIC can be differed from every study and this variation will lead to clinical heterogenity. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, the international normalized ratio (INR), the platelet count, the disseminated intravascular coagulation (DIC) score, Other suggested values are the alpha-2 plasmin inhibitor value and the modified coagulopathy value^20,21. In our center, we calculate platelet count, aPTT, partial thromboplastin time (PTT), and sometimes INR in which we are able to evaluate bleeding disorder, intrinsic-common pathway of coagulation, and probable use of heparin therapy. Based on certain studies above, it is mentioned that the parameters also can predict the outcome of traumatic brain injury patients.

The definition of coagulopathy provided by Gent et. al. included various combinations of INR, platelet count, prothrombin time (PT), aPTT, fibrinogen, disseminated intravascular coagulation score, modified coagulopathy score, and alpha-2 plasmin inhibitor value. However, this definition was not consistent. In general, the utilized cut off value and duration of blood drawing appear to be substantially correlated with occurrence of coagulopathy following TBI. PT analyses carried out by several universities should have less interassay variance, the current investigation used the INR rather than a prolonged PT as a marker for coagulopathy^22–24. Therefore, it is important to recheck the coagulation test values especially PT and aPTT to avoid misinterpretation of the result. TBI patients continue to be at risk for coagulopathy days after the even ²². Coagulation factors must be interpreted accurately before any invasive procedure and should be confirmed by the clinical pathology division closely since the variation of coagulation factors change rapidly in hours post traumatic accident^5,25,26.

In case of major trauma in which ATC has been known to be associated with massive tissue injury and haemorrhagic shock, the incidence of coagulopathy among TBI patients is high. It occurred between 10 to 97.2% with the mortality ranged from 17 to 86%, compared to those without coagulopathy, and more than 30-fold raises the likelihood of a poor outcome. From Asia region, one study from level 1 trauma center in India showed an incidence of traumatic brain injury induced coagulopathy was in cases of serious head injuries, 63.75%, and 55% of individuals with significant head injuries^27–29. From this result, the severity of head injury is correlated to the presence of coagulopathy which in our case showed the same appearance of coagulopathy in isolated sever traumatic brain injury. Despite the high incidence of coagulopathy among moderate and severe traumatic brain injury, the prevalence of coagulopathy and trombocytopenia increased up to 2.5 times fold within 3^rd days of care as a result of secondary brain insult^30–33.

Coagulopathy which previously did not really taken as an important parameter in the management of trauma care has recently put into consideration³⁴.The haemostatis disorder may lead to multiple organ dysfunction and failure which in turn worsen the outcome^35,36. Intracranially, coagulopathy may also play an important role in blossoming ICH from a brain contusion³⁷ . This phenomenon may require aggressive operation. TBI patients mostly is privileged by the most causal factors of coagulopathy like substantial blood loss, exaggerated fluid resuscitation, and throughout the acute period, there is a lower risk of developing hypothermia. Some theories have been postulated to explain the pathophysiology of the occurrance of coagulopathy in TBI. There are two main conditions that are important to be discussed: the breakage of the blood-brain barrier which generates brain injury systematically and hypercoagulability and hyperfibrinolytic circumstances inducing persistent intracranial bleeding ³⁸.

During the course of primary and secondary brain injury, the blood brain barrier, which is crucial for sustaining both passive and transporter-mediated flow of fluid and macromolecules between the blood and the interstitial spaces, is disrupted^39,40. It permits vascular leakage and disperses chemicals produced from the brain into the bloodstream, which causes systemic coagulation⁴¹. The spreading of the molecules need sufficient cerebral blood circulation, but it is considered to be limited by the presence of the high intracranial pressure in TBI. This would explain the attempt of lowering intracranial pressure and decompressive craniectomy may follow a similar pattern of ischemic reperfusion injury by restoring cerebral blood flow and inadvertent widespread release of brain-derived substances⁴².

Trauma causes tissue damage, blood loss, and tissue injury, which results in hypoxemia. The endothelium releases thrombomodulin during tissue hypoperfusion, which then combines with thrombin to activate protein C and block factors V and VIII. These activities inhibit the extrinsic coagulation pathway. Additionally, tissue plasminogen activator is produced, which triggers fibrinolysis. After a patient experiences brain damage, the brain's abundance of the tissue factor "thromboplastin" is discharged into the bloodstream. It causes a state of consumptive coagulopathy, which may lead to numerous organ failure and raise the risk of mortality, by activating the extrinsic pathway of coagulation. Additionally, platelet number and function are compromised on both a qualitative and quantitative level, making patients more prone to bleeding. A strong predictor of the course of catastrophic cerebral hemorrhage, platelet counts depletion and dysfunction have been linked to fatality rates. Patients' platelet counts are rarely reduced to a critical level (<100 x 10 /L) when they arrive to emergency rooms, and they decline more slowly than fibrinogen levels do⁴³. According to a study by Martin et al., the administration of blood products during the resuscitation of the isolated TBI patient did not affect the results of viscoelastic and platelet function testing. However, there may be considerable platelet dysfunction after trauma even with a normal platelet count and standard coagulation tests^44–46.

Coagulation:

Studies on TBI-induced coagulopathy revealed that the fibrinolytic agent D-dimer and fibrinogen degradation products are found during the first few minutes of injury, while prothrombin and partial thromboplastin times are recently observed, roughly six hours after the initial TBI^47,48. The timing is correct in relation to a rapid change from a hyper to a hypocoagulated reaction. According to research by Zhang et al, brain-derived cellular microvesicles are a causative component. The study showed an increase of the microvesicles in the circulation of a mouse model leading to a systemic hypercoagulable condition. The microvesicles express tissue factors and phosphatidylserine found in the cerebral tissue^41,49,50. The lactadherin inhibits coagulopathy by facilitating the phagocytosis of those procoagulant substances via anionic phospholipids⁴². The microvesicles and the phospholipids propose thrombin formation by combining the coagulation factor V and VIII to construct the complexes of prothrombinase and tenase. Antithrombin and the TM-protein C pathway are two examples of endogenous anticoagulants that control the activation of coagulation in healthy individuals. In contrast, severe trauma results in an immediate impairment of endogenous anticoagulant activity and the dysregulation of coagulation activation. Numerous investigations have shown that severe trauma causes an early drop in antithrombin activity, and thrombin generation assays have demonstrated a negative association between antithrombin activity and produced thrombin, despite a decrease in the prothrombin concentration⁵¹. This finding suggests that dysregulation of thrombin production results from reduced antithrombin activity ^51,52.

Coagulation activation and hyperfibrino (geno) lysis are both seen in cases of severe trauma. Compared to the levels of other regularly studied coagulation markers, the plasma fibrinogen level drops more frequently and earlier (prothrombin time, activated partial thromboplastin time, and platelet count). The other coagulation components are more easily diluted by infusion or transfusion than fibrinogen, which led to low fibrinogen levels and severe bleeding^43,53. Another coagulation factor activity, factor V, is also decrease more based on the severity of trauma^54,55. These basic patomechanisms are in line with the consideration of early operative management performed in our center. When coagulation activation and other conditions such as hyperfibrinolysis and coagulopathy in traumatic brain injury begin, the operative management should be considered to be done earlier regardless of normal value of the coagulation tests due to its variability in early phase of traumatic brain injury patients with coagulopathy.

Fibrinolysis:

Fibrinogen splitting the thrombin to produce fibrin in fibrinolysis processs⁵⁶. Tissue plasminogen activator and plasminogen find noncompetitive, high-affinity sites in the fibrin αC-domain. tPA initialize plasminogen to the serine protease plasmin dissolving fibrin polymers⁵⁷. The fibrinolytic activity reacts slowly because tPA's role in normal hemostasis is limited to fibrin polymers trapped in a platelet clot⁵⁴. Otherwise, in TBI-induced coagulopathy, the fibrinolysis process reacts more quickly^58,59. There is a hypothesis demonstrated that the process is facilitated and accelerated by the fibrin produced on the surface of the circulating microvesicles. Meanwhile, in one study, decreased level of tPA persistently minimalizes intracerebral hematoma but not able to prevent coagulopathy systemically. One study found that there is an imbalance between the fibrinolysis and the inhibitor agents. In mice with low level of plasminogen activator inhibitor-1 (PAI-1), intracerebral hematoma post TBI easily evolved yet its level was elevated together with increased level of plasminogen, plasmin activity, and D-dimers⁶⁰.

A combination of fibrinolysis and fibrino(geno)lysis known as hyperfibrino (geno) lysis is frequently seen in cases of severe trauma^43,61. Tissue-plasminogen activator (t-PA) is released acutely and coagulation is activated, which results in this hyperfibrinolysis. t-PA is one of the essential enzymes in fibrino(geno)lysis. Plasma breakdown of fibrin and fibrinogen is started by t-PA, which causes plasminogen to be converted into plasmin ⁶². The Weibel-Palade body in the cells of the systemic vascular endothelium is the primary source of plasma t-PA^62,63. Acute release of t-PA is the term for when t-PA is released from the Weibel-Palade bodies into the systemic circulation as a result of severe shock (tissue hypoperfusion)^63,64. Additionally, in hyperfibrino (geno) lysis t-PA is released rapidly and in high numbers.

Operative Management:

The cause of coagulopathy and its triggering mechanism remains unclear. Patients with coagulopathy brought on by TBI, severe bleeding (hemorrhagic shock) and resuscitation with fluids (hemodilution and hypothermia) are main causes of coagulopathy. However, in patients with isolated TBI, heavy blood loss is uncommon, and the volume of fluid resuscitation is frequently constrained, indicating that these factors might not be crucial in TBI-associated coagulopathy⁶⁵.

In our institution, surgical procedure should be considered and performed immediately in patients with TBI and coagulopathy while evaluating the risk and benefit. A major consideration is to avoid the presence of acidosis and hypothermia, which commonly appeared more dominant than TBI, aggravate coagulopathy known as vicious cycle⁶⁶. It is also recommended to recheck the coagulation factors such as PT and APTT which may vary in results due to the fluctuation affected by hypovolemic and hypoxic state. This may be caused by certain mechanisms in hours post traumatic accident. Study by Gent et al demonstrated that the patients who sustained TBI was susceptible to coagulopathy development until 72hours post initial trauma²². In order to prevent the progression of coagulopathy, the surgical intervention should not be delayed until the coagulation factors are restored.

Another study showed that preoperative laboratory assessment of the coagulation factors such as PT and aPTT in preoperative neurosurgical management was not provide reliable identification regarding to surgical bleeding complication⁶⁷. Therefore, it is recommended to perform surgical intervention without prolonged time in TBI with coagulopathy.

CONCLUSION:

In summary, localized injury at the brain manifesting in systemic coagulopathy requires special care. The first step is to recognize the manifestation of the coagulopathy by evaluating the multi-organ system (head-to-toe). Never underestimate continuous bleeding from open skin wound which might be a sign of coagulopathy. Second, strict and stagged laboratory criteria may help clinician to diagnose coagulopathy, but this value should not delay operative management in attempt to control ‘coagulopathy’ by controlling the source of bleeding. Third, careful resuscitation using colloid and blood product with additional tranexamic acid is the corner stone of medical management during the first hour of the injury. Finally, experience combined with the study of basic science coagulopathy in TBI will eventually improve the clinical outcome of patient and alleviate effective management in the future.

CONFLICT OF INTEREST:

The study's resources, methodology, or conclusions were all used without any conflicts of interest, according to the authors.

ETHICAL APPROVAL:

The study was approved by the Ethics Committee of the Affiliated Hospital of Dr. Soetomo Hospital/Universitas Airlangga in accordance with the World Medical Association Declaration of Helsinki after patient consent was obtained, processed, and documented in accordance with regional ethical committee regulations. The approved ethical reference is 1103/111/2XI/2021. Informed consent was signed by his parents with the approval of Ethics Committee. Written informed consent was obtained from the parents of patient for publication of this case report and any accompanying images.

DATA AVAILABILITY STATEMENT:

This article includes all of the data that were created or analyzed during this investigation. The appropriate author can be contacted for more information.

AUTHOR CONTRIBUTIONS:

M.R.A. drafted the paper and conducted the primary data collection and follow-up visits. M.A.P. designed and, in the end, authorized the published version. W.S. contributed to the draft's creation and substantial revision. The final submitted version has been read by and approved by all authors. All authors have pledged to take responsibility for their own work and guarantee that any queries about the veracity or integrity of any element of the work will be answered.

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Received on 31.05.2023 Modified on 19.07.2023

Research J. Pharm. and Tech 2023; 16(12):5569-5575.

DOI: 10.52711/0974-360X.2023.00900