Keywords
glioblastoma - free tissue flaps - thrombophilia
Glioblastoma multiforme (GBM) is the most aggressive tumor of the central nervous system.[1] It frequently induces a hypercoagulable state and carries the highest risk of thromboembolic events of any malignancy, affecting up to 60% of patients.[2]
[3] Treatment consists of surgical resection via open craniotomy in conjunction with postoperative chemotherapy and radiation.
Intermittently, patients will present with postoperative wound breakdown in conjunction with osteoradionecrosis of the bone flap, hardware exposure, and chronic infection.[4]
Deconditioning, malnutrition and advanced age are frequent confounding variables. The ability of local flaps to provide stable wound coverage is often compromised by the presence of broad radiation fields.[5] Additionally, regional flaps lack reliability when extending their reach to cover wounds of the cranial vertex.
In many cases, free tissue transfer is the only reasonable method of providing well vascularized coverage with nonradiated soft tissue, despite the relative contraindication of an underlying hypercoagulable state.[6]
Currently, there is little or no information available regarding anticoagulation management during free flap reconstruction in the GBM patient. This case is presented to share our experience and the anticoagulation protocol utilized in the successful treatment of a complex, radiated scalp wound with a free muscle flap following GBM resection.
Case Presentation
The patient is a 67-year-old female who underwent an open craniotomy for resection of a GBM (World Health Organization [WHO], grade IV). Her postoperative treatment included six cycles of bevacizumab and temozolomide and 6,000 cGy of external beam radiation therapy. In 2012, the patient developed a deep vein thrombosis in all four extremities requiring a 3-month course of anticoagulation utilizing enoxaparin injections. During the 6-month postoperative visit, she was found to have a small region of exposed bone and was referred to a wound care center for local care. On the 11-month postoperative visit, the wound was found to be enlarged with exposed hardware and seropurulent drainage. She was returned to the operating room where the hardware was removed and the nonvascularized portion of the bone flap was resected. Soft tissue coverage was provided a scalp rotation flap and a small region of exposed bone was covered with Integra collagen glycosaminoglycan wound matrix. Operative cultures demonstrated coagulase-negative Staphylococcus, Actinomyces neuii, and Peptoniphilus harei for which she received a 6-week course of intravenous (IV) antibiotics (cefepime/vancomycin). Despite initial successful wound healing, she represented during the postoperative week 7 with multiple draining sinuses and exposed dura suggesting the presence of underlying chronic osteomyelitis ([Fig. 1]). Preoperative ultrasound failed to demonstrate any active deep venous thrombosis (DVT) and the prothrombine time (PT) and partial thromboplastin time (PTT) were 13.5 and 31.4 seconds.
Fig. 1 Radiated scalp wound with recurrent infection and multiple draining sinuses 7 weeks after local flap closure.
She was returned to the operating room where extensive bony debridement was performed.
A subcutaneous flap was elevated in the right preauricular region and extended to the cranial wound. The superficial temporal artery was identified and skeletonized for later microvascular anastomosis. The associated superficial temporal vein was found to be of small caliber. In response, a Doppler was used to identify a signal approximately 1 cm above the zygomatic arch and 2-cm anterior to the tragus. A vertical incision was created in the superficial layer of the deep temporal fascia exposing a large middle temporal vein (MTV) traversing the temporal fat pad ([Fig. 2]).
Fig. 2 Exposure of superficial temporal artery and middle temporal vein following extensive debridement.
Attention was now focused on the right thigh were a distal vastus lateralis muscle flap was harvested providing a lengthy pedicle (∼11 cm) that would permit a microvascular anastomosis without the need of vein grafts ([Fig. 3]). Following ligation of the vascular pedicle, the later circumflex femoral artery was copiously irrigated with heparinized saline until a clear venous effluent was present. The flap was delivered to the head and neck and inset covering the exposed dura. The muscle was sutured to the perimeter of the bony defect utilizing a series of cranial drill holes in an effort to prevent compression of the underlying brain. The superficial surface of the pedicle was marked with a surgical pen in an effort to avoid twisting of the pedicle during delivery through the subcutaneous tunnel. An end-to-end microvascular arterial anastomosis was performed with interrupted 10–0 nylon. A single venous anastomosis was achieved with a 3-mm vein coupler (Synovis, Birmingham, Alabama, etc.). In response to the patient's history of multiple DVTs and the hypercoagulable nature of her primary tumor, the decision was made to employ perioperative anticoagulation. A 3,000-unit bolus of heparin was provided 15 minutes prior to removal of the vascular clamps. A heparin drip was then initiated at 300 unit/hour and transitioned to 200 unit/hour prior to leaving the operating room ([Figs. 4], [5]). The exposed muscle segments were covered with meshed, split-thickness skin graft. The heparin drip was maintained for 7 days and the PTT was not routinely monitored. On postoperative day 7, oral anticoagulation was initiated (apixaban 5 mg orally twice a day). The first dose was provided 2 hours prior to discontinuation of the heparin drip and therapy was maintained for 3 months then transitioned to apixaban 2.5 mg orally twice a day for 3 additional months. This intraoperative anticoagulation protocol is the current protocol that the senior author uses when facing pedicle thrombosis in microsurgical cases. The use of apixaban at higher doses initially and then decreasing the dosage was a direct recommendation from the consultant hematologist at our institution.
Fig. 3 Elevation of vastus lateralis free muscle flap.
Fig. 4 End-to-end microvascular anastomosis of superficial temporal artery and middle temporal vein to the descending branches of the lateral femoral circumflex artery and vein. A 3,000-unit bolus of heparin was provided prior to reperfusion and a heparin drip was initiated at 300 unit/hour.
Fig. 5 Well-perfused vastus lateralis free muscle flap with supportive heparin drip at 200 unit/hour.
Lastly, a second course of culture-specific IV antibiotics were provided for treatment of osteomyelitis. The postoperative course was uncomplicated. The flap remained well perfused, no hematomas, DVTs, or significant wound healing complications were encountered; however, two units of packed red blood cell (PRBC) were transfused during the hospital course ([Fig. 6]). Follow-up at 18 months failed to demonstrate any evidence of recurrent osteomyelitis. Unfortunately, the patient succumbed to recurrent disease 22 months after reconstruction.
Fig. 6 Postoperative day 12 with viable flap and good skin graft take. Anticoagulation transitioned to apixaban 5-mg orally twice a day.
Discussion
GBMs grow rapidly and are often quite large before symptoms arise. Despite optimal treatment, the cancer often recurs and prognosis is poor with a mean survival time between 12 to 15 months.[7] The potential complications of infection, hardware exposure, and impaired wound healing following radiotherapy in patients with GBM are well known.[4]
[8]
[9] Additionally, GBM patients are at a significantly increased risk for developing DVT and other thromboembolic events.[6]
[10]
[11] Postoperative immobility often confounded by hemiparesis and hemiplegia is felt to play a causal role in DVT formation.[12]
A hallmark feature of GBM on magnetic resonance imaging (MRI) is the presence of two contrasting regions composed of a central necrotic zone encompassed by a leading edge of mobile, rapidly proliferating tumor cells.[13] This thin-layer of cells, migrating away from the necrotic core, are commonly referred to as “pseudo palisades,” and are a well-known feature of GBM.[14] This pattern is felt to arise from a prothrombotic environment within the tumor that ultimately promotes the development of a systemic hypercoagulable state. Rong et al characterized the formation of pseudo palisades as a multistep process beginning with tumor cell induced endothelial dysfunction.[15] Genetic alterations within tumor cells (EGFR [epidermal growth factor receptor] amplification/PTEN [phosphatase and tensin homolog] loss) produce upregulation of angiopoietin-2 (Ang-2) and tumor necrosis factor (TNF)-α culminating in endothelial damage and apoptosis. Tissue factor (TF), the principle cellular initiator of thrombosis is also overexpressed on tumor cells further promoting a hypercoagulable environment. Thrombosis of the intratumoral vasculature produces regional hypoxia and activation of PAR-1 facilitating a wave of tumor cell migration away from the occluded vessels and the formation of pseudo palisades. In response to this severely ischemic environment, the pseudo palisading tumor cells secrete proangiogenic factors including VEGF and interleukin (IL)-8 stimulating microvascular hyperplasia at the periphery of the tumor. In turn, the new vasculature promotes further tumor growth and expansion. The enlarging tumors subsequently produce dysregulation of plasma clotting factors with marked elevation of procoagulants including plasminogen activator inhibitor 1 (PAI-1) and TF. Concomitantly, decreased expression of anticoagulant and fibrinolytic substances including tissue plasminogen activator (tPA) are common.
Recent studies have observed that tumor cell expression of the transmembrane glycoprotein podoplanin (PDPN) correlates with susceptibility to VTE and overall mortality.[11]
Patients with tumors exhibiting high levels of PDPN are at significantly increased risk for developing VTE (25%) as compared with those without expression (5%). PDPN is known to produce platelet aggregation; however, the exact mechanism creating hypercoagulability is complex and incompletely understood. Lipid bilayer particles, carrying cargos of proteins, metabolites, and nucleic acids, are naturally released from cells and are referred to as extracellular membrane vesicles (EVs). Vesicles filled with PDPN released from GBM tumor cells circulate freely in the blood stream and likely contribute to the development of DVT and pulmonary emboli (PE). Soluble PDPN (sPDPN) can be detected in the blood stream with enzyme-linked immunosorbent assay (ELISA) testing. Elevated sPDPN correlates with active disease and metastasis; however, the level of sPDPN that is associated with the development of a hypercoagulable state has not yet been determined.
In the context of this case, the importance of addressing GBM's thrombogenic nature was essential for viable flap transfer and uncomplicated wound healing. Although heparin and apixaban were successfully employed, in future, consideration will also be given to the use antiplatelet medications as platelet aggregation appears to play a prominent role in this disease state.[16]
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Conclusion
GBM is associated with the highest rates of DVT and thromboembolic events of any malignancy. The mechanism of action is multifactorial and incompletely understood. Despite the presence of an underlying hypercoagulable state utilizing a combination of perioperative heparin and postoperative apixaban, a free tissue transfer was successfully utilized for coverage of a complex cranial wound following GBM resection and extensive radiation.
