3.1 Coagulopathy Following TBI
Coagulopathy induced by TBI is a recognized and common complication that can lead to adverse clinical outcomes. Post-traumatic coagulopathy, known as Trauma-Induced Coagulopathy (TIC), may manifest as either hypercoagulability or hypocoagulability. Since uncontrolled post-traumatic bleeding remains the leading cause of death among trauma patients [8], research and clinical focus primarily gravitate towards the hypocoagulable phenotype of TIC [9]. Traditionally, this has been attributed to consumption of coagulation factors, hemodilution due to fluid resuscitation, hypothermia, and acidosis [10]. Recent understanding posits that the primary mechanism involves activation of protein C, which following significant tissue injury and endothelial damage due to hypoperfusion, releases activated protein C that inhibits the activities of coagulation factors Va and VIIIa, leading to a hypocoagulable state. Activated protein C also suppresses plasminogen activator inhibitor-1 (PAI-1), leading to hyperfibrinolysis [7, 8, 10]. Given that TBI does not typically result in hemorrhagic shock, and that acute phases rarely see hypothermia due to restrictive fluid resuscitation aimed at preventing intracranial hypertension, it suggests that TBI-induced coagulopathy may have unique pathogenic pathways. Some scholars propose that disruption of the blood-brain barrier leads to the rapid release of brain-derived substances into the circulation, causing systemic coagulopathy. Others suggest that TBI-induced hyperfibrinolysis is independent of fibrin formation [11]. Recent studies have shown the incidence rate of the hypercoagulable phenotype of TIC to be between 22.2% and 85.1%, thereby increasing the incidence of post-traumatic thrombotic events by two to four-fold, and doubling the mortality rate. The main pathophysiological mechanism involves tissue injury during trauma, releasing a large amount of tissue factors, activating the extrinsic coagulation pathway, and leading to significant thrombin generation. Simultaneously, a decrease in anticoagulant activity promotes thrombus formation, while the release of a large volume of inflammatory mediators also activates and amplifies the coagulation system [9, 10]. Increasing attention is being paid to the hypercoagulable state in trauma patients due to its direct association with VTE. As an independent risk factor for VTE [12], approximately 54–63% of patients with TBI will experience VTE if not adequately prophylaxed with medication [13]. However, the transition from a hypocoagulable to a hypercoagulable state remains uncertain, with studies indicating that most patients transition within 24 hours [14–16], much earlier than previously recognized. Currently, there are no definitive markers to indicate which stage the patient is in. Clinically, platelets, prothrombin time, international normalized ratio, and thromboelastography are commonly used for monitoring, which may be somewhat instructive but still imprecise. Future research is needed to identify better indications for more accurately guiding clinical management.
3.2 TBI and Prophylactic Anticoagulation Therapy
Given the early risk of exacerbating intracranial hemorrhage in patients with TBI, the initiation of pharmacological prophylaxis is often delayed. And a delayed start increasing the risk of VTE [17]. Studies have shown that the incidence rates of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in TBI patients without any prophylactic measures are between 6%-20% and 3.7%-6%, respectively [18]. A retrospective study conducted over four years by Mabrouk et al. found an 11% incidence rate of PE in TBI patients [17]. PE is the third leading cause of death within the first 24 hours post-trauma among survivors [19]. The optimal timing for initiating prophylactic anticoagulation in TBI patients and whether anticoagulation increases the risk of hemorrhage remain uncertain. In TBI patients, 63% experience progression in lesion size post-injury [20]. An analysis of 123 TBI patients indicated a hemorrhage progression rate of 29.4% [21]. A study involving 1,215 patients showed that those treated with Low Molecular Weight Heparin (LMWH) had an 18% higher risk of hemorrhage progression (24% vs. 42%) compared to patients not treated with anticoagulants [22]. The majority of literature suggests that initiating pharmacological prophylaxis for anticoagulation 24–72 hours after hemostasis in TBI is considered safe [18, 23–26]. A prospective analysis indicated that TBI patients treated with Unfractionated Heparin (UFH) after 24 hours of injury stability on CT had a bleeding progression rate of 0.78%, compared to 2.8% in patients without pharmacological prophylaxis, with no statistically significant difference (P = 0.33) [18, 24]. However, another multicenter prospective study found that initiating anticoagulant therapy earlier post-TBI (median 4.5 days) was associated with worsened clinical outcomes, whereas the median initiation time in the group with no adverse clinical outcomes was 11 days [27]. In practice, anticoagulant therapy can be considered 7–14 days post-TBI, depending on individual circumstances. The Brain Trauma Foundation recommends the use of low-dose UFH or LMWH in conjunction with mechanical therapy for VTE prevention in TBI patients [28]. Evidence also suggests that UFH and LMWH can reduce cerebral edema and improve neurological recovery by inhibiting the recruitment of leukocytes [29, 30]. For the prevention of VTE events, most experts and studies prefer LMWH over UFH, as LMWH has a similar risk of bleeding but a lower incidence of DVT and is associated with reduced mortality [31–34].
3.3 Management of VTE in TBI Patients
Pharmacological anticoagulation is a recognized effective approach for the treatment of VTE [17, 35–37]. However, inappropriate use can lead to ineffective anticoagulation or increased risk of bleeding, potentially causing fatal outcomes [35]. Traditionally, acute VTE treatment begins with parenteral UFH, transitioning to oral Vitamin K Antagonists (VKAs) with an overlap of 10–14 days [37, 38]. The limitations of VKAs and the emergence of Novel Oral Anticoagulants (NOACs) have posed challenges to the existing treatment paradigm, with Rivaroxaban now approved for the treatment and prevention of VTE [38, 39]. Parenteral anticoagulants such as UFH, Low Molecular Weight Heparin (LMWH), or Fondaparinux deliver immediate anticoagulant effects. At the onset of treatment, LMWH and Fondaparinux are preferred over UFH due to a lower risk of major bleeding and Heparin-Induced Thrombocytopenia (HIT). UFH is recommended for patients anticipated to undergo direct reperfusion, those with severe renal impairment, or significant obesity due to its short half-life, ease of monitoring anticoagulant effects, and rapid neutralization by protamine sulfate [39, 40]. LMWH and UFH primarily act through the antithrombin system; thus, monitoring antithrombin activity before and during use is advised. Anticoagulation therapy is recommended for at least three months or until the risk of recurrent VTE from triggering factors is mitigated [37, 41]. The optimal treatment strategy for PE patients continues to evolve. Techniques such as catheter-directed thrombolysis or pharmacological thrombolysis have been shown to reduce mortality rates compared to anticoagulation alone, albeit at the expense of increased bleeding risks. Compared to systemic thrombolysis, catheter-directed thrombolysis presents a higher safety profile [42–44]. IVCF may be utilized for patients with a high risk of bleeding or contraindications to anticoagulation. However, the initiation of anticoagulation therapy should not be unnecessarily delayed, and there is no evidence to support using IVCF as an adjunct to anticoagulant therapy [39, 40]. Studies indicate that IVCF placement significantly reduces the risk of recurrent PE, increases the risk of DVT, but does not significantly affect overall mortality regardless of filter use [40, 45–47]. Complications associated with IVCF include thrombosis, IVC penetration, perforation, filter fracture, or migration [47, 48]. A single-center study reported a total complication rate of 10-20.6% for filters, with thrombotic complications constituting a significant percentage of these adverse events. [49]. Weinberg et al. reported that 19% of patients experienced filter-related complications within the first 32 days post-IVCF placement; 10.5% developed DVT, 4.2% developed PE, and 3.8% developed IVCF thrombosis. A study involving 62 institutions on IVCF placement indicated thrombosis in 78 cases (1.3%) [50]. A meta-analysis concluded that IVCF placement plays a role in reducing the short-term risk of subsequent PE but increases the long-term risk of VTE; thus, IVCF should be retrieved as soon as it is no longer needed [47, 51].
3.4 PAI-1 and Thrombosis Formation
Plasminogen Activator Inhibitor-1 (PAI-1) is the principal inhibitor of fibrinolysis in the bloodstream, acting as the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) [52]. The dynamic balance between t-PA and PAI-1 plays a crucial role in maintaining the homeostasis of the plasma fibrinolytic system. The 4G/4G genotype of PAI-1, a functional gain, is associated with elevated levels of PAI-1. An increase in PAI-1 levels can lead to reduced fibrinolytic activity, thereby enhancing the risk of thrombus formation [53, 54]. Studies by Folsom et al. demonstrated that this homozygous mutation occurs at a rate of 7.2% in patients with VTE compared to 3.4% in a healthy control group [53, 55], linking PAI-1 gene mutations with an increased susceptibility to VTE.
3.5 Characteristics and Management Insights from This Case
1. Multifocal Venous Thromboembolism: The patient exhibited hemodynamic instability on the fifth day of hospitalization, with Pulmonary Embolism (PE) and Deep Vein Thrombosis (DVT) confirmed through echocardiography, ultrasound of the lower limb deep veins, and pulmonary artery CT angiography. An IVCF was placed to prevent further thrombus detachment, which was followed by the formation of IVCF thrombosis and multiple thromboses in the external iliac, femoral, great saphenous, and popliteal veins. The multifocal venous thromboembolism in this patient was related to coagulopathy associated with TBI and lack of early prophylactic anticoagulation, with a significant contributory factor likely being enhanced PAI-1 activity, leading to decreased fibrinolytic activity and increased thrombus formation. 2. UFH Anticoagulation Therapy Guided by APTT: We opted for UFH anticoagulation due to its rapid onset, ease of monitoring, and reversibility with protamine sulfate. Concerns about expanding intracranial hematoma led to initial APTT targets around 45 seconds. As thrombosis progressed, the APTT target was increased to 50–60 seconds, accompanied by enhanced physical therapy. Conservative medical management of acute TBI complicated by VTE remains the preference for most teams. Treatment aims to achieve target APTT values early, with adjustments based on clinical changes to ensure safe and effective anticoagulation under APTT guidance. 3. Cutaneous Manifestations of IVC Thrombosis: Following IVCF placement, the patient developed IVCF thrombosis, presenting with lower limb swelling accompanied by petechiae and ecchymoses and a decline in platelet count. As the condition improved, the lower limb skin returned to normal, providing valuable clinical insights from this uncommon clinical presentation.