What's new in emergencies, trauma, and shock? Heparin in severe traumatic brain injury: Beyond venous thromboembolism prevention?

In this issue of JETS, the authors of the article entitled “Early Initiation of Prophylactic Heparin in Severe Traumatic Brain Injury is Associated with Accelerated Improvement on Brain Imaging” showed that the early administration of heparin within 72 h from event onset in patients with severe traumatic brain injury (STBI) seems to improve patients’ outcomes, beyond their direct effect of venous thromboembolism (VTE) prevention suggesting that neurological improvement could be ascribed to the pleyotropic anti-inflammatory properties of heparin. Although this article represents only a generating hypothesis study with several methodological problems, such as retrospective nature, selection bias, absence of inflammatory and coagulopathy biomarker assays, and limited sample size; the hypothesis raised by the study is enchanting.

The initiation and orchestration of inflammation in STBI is complex and multifactorial.(1) Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. This posttraumatic response involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes; and the infiltration of blood leukocytes, and a humoral component regards the secretion immune mediators such as proinflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor, IL-6), anti-inflammatory cytokines (IL-4, IL-10, and beta transforming growth factor (TGF-beta), and chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain.[1234] The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well-accepted that neuroinflammation is responsible for beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair.[5] In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores.[678] However, except for corticosteroids, no anti-inflammatory agents have been tested in STBI, and the negative results with these may have been flawed by their multiple side effects.[9] Furthermore, the balance between VTE prevention and bleeding occurrence, hematoma enlargement or rebleeding represents the key point for the choice of pharmacological prevention in patients with STBI or intracranial hemorrhage (ICH), both spontaneous and traumatic, especially in the first 72 h from event onset. STBI has long been associated with abnormal coagulation parameters, but the exact mechanisms underlying this phenomenon are poorly understood.[10] Coagulopathy after STBI includes hypercoagulable and hypocoagulable states that can lead to secondary injury by either the induction of thrombosis or the progression of hemorrhagic brain lesions. The rationale for pharmacological prophylaxis is based on high burden of VTE in patients suffering for intracranial bleedings, both for incidence and related-mortality. The intracranial bleeding is considered an absolute or at least a relative contraindication to antithrombotic treatment which makes physicians reluctant to use. Otherwise the occurrence of a VTE episode during the acute phase of STBI or ICH represents a much more worrying problem for the use of parenteral and/or oral anticoagulant therapy. Vena caval filters could be an option but, unfortunately, are weighted from potential serious side-effects. Literature evidence on VTE pharmacological prophylaxis in the acute phase of STBI or ICH is poor and often of low methodological quality, due to the problems in randomizing this kind of patients which often have a wide spectrum of clinical and radiological presentation.[11] Meta-analyses based on few studies with the abovementioned limitations, demonstrate that the use of unfractioned (UFH) or low molecular weights heparins (LMWHs) in the acute phase of spontaneous intracranial bleeding significantly reduce the risk of pulmonary embolism (PE) and overall mortality and nonsignificantly reduce the risk of deep vein thrombosis (DVT) without a significant increasing of hematoma enlargement or rebleeding, whereas the early administration of pharmacological prophylaxis in traumatic intracranial hemorrhage within 72 h from bleeding onset significantly reduce the risk of PE, DVT, and overall mortality without increasing the hematoma progression.[1213] The most recent available guidelines recommend to start the pharmacological prophylaxis of VTE in immobilized patients with STBI or ICH by using UFH or LMWHs after 48-72 h from bleeding onset and anyway when clinical and neuroradiological examination is stable.[1415]

Therefore, prevent or reduce the inflammatory response after STBI could be a crucial attack point for improving outcomes of patients with intracranial bleedings. Animal experimental studies have been demonstrated the potential anti-inflammatory role of heparin. Heparin in fact seems to have the property to bind different chemokines and influence the inflammation by controlling the leukocytes migration and activation.[161718]

Clinical trials with anti-inflammatory agents that target multiple or central and downstream pathways, should be warranted in adult and pediatric STBI. From this point of view, the article by Kim L et al. suggests LMWH as a possible and feasible alternative therapeutic strategy.[19]