Author Affiliations: Ophthalmic Oncology Service (Drs Francis, Nagiel, Marr, and Abramson) and Department of Pediatrics (Dr Dunkel), Memorial Sloan-Kettering Cancer Center, Service of Interventional Neuroradiology, Departments of Neurosurgery, Neurology, and Radiology (Dr Gobin) and Pediatric Hematology/Oncology (Dr Kucine), Weill Cornell Medical College of New York-Presbyterian Hospital, and Department of Ophthalmology, Mount Sinai School of Medicine (Dr Brodie), New York.
We have previously reported on our experience of ophthalmic artery chemosurgery (OAC) for the treatment of retinoblastoma,1 during which heparinization is intended to reduce the risk of thromboemboli forming at the catheter contact site. After femoral artery puncture but prior to catheterization, intravenous heparin is given to reach a target activated coagulation time (ACT) of 200 to 300 seconds (or 2-3 times the baseline), usually achieved with a single bolus of 70 IU/kg. Furthermore, the femoral arterial sheath is slowly flushed with a heparinized saline solution (500 IU of heparin in 500 mL of saline). Since the procedure usually lasts less than 1 hour, no further heparin is given. Herein, we report on 3 patients with heritable thrombophilic conditions: 1 that was known and prophylactically managed prior to catheterization and 2 that were identified following adverse events related to chemosurgery.
An 11-month-old girl with unilateral retinoblastoma, Reese-Ellsworth group 5B, International Classification D, received 5 cycles of OAC. Given a history of Factor V Leiden in the maternal grandmother, the patient underwent a coagulation workup and was found to have a heterozygous prothrombin mutation. At the beginning of the procedure, it was discovered the usual dose of heparin was insufficient, and 125 IU/kg of heparin were required to reach the target ACT. Chemosurgery was performed via the orbital branch of the middle meningeal artery in 2 cycles and was balloon assisted for 3 cycles. All OAC sessions showed good ophthalmic artery filling and choroidal blush, and her treatment course was uneventful. Following adjuvant laser, cryotherapy, and plaque brachytherapy, tumor control was achieved.
As previously reported,1 a 27-month-old boy with unilateral retinoblastoma, Reese-Ellsworth group 5A, International Classification D, received an initial OAC treatment using melphalan and topotecan hydrochloride with good intraoperative choroidal blush. Follow-up at 1 month revealed vitreous hemorrhage and tumor response. During the second OAC treatment, the ophthalmic artery filled, but the choroidal blush had vanished. Follow-up ultrasonography displayed massive choroidal material that was inhomogeneous and of low to medium reflectivity. Because of concerns of choroidal invasion, the eye was enucleated. Histopathological examination indicated subretinal hemorrhage and a completely calcified tumor. Hemoglobin electrophoresis was performed and revealed a diagnosis of sickle cell trait.
An 8-month-old girl with bilateral retinoblastoma, Reese-Ellsworth group VB, International Classification C in the right eye and Reese-Ellsworth group VA, International Classification D in the left eye, presented with total retinal detachment in the left eye. Electroretinogram responses were normal in the right eye and extinguished in the left eye. Initial OAC treatment demonstrated good arterial filling and choroidal blush. A second OAC treatment to the right eye was uneventful, but vasospasm of the left ophthalmic artery was initially noted and resolved with time. Recatheterization in the left eye was successful with good arterial filling and choroidal blush before and after catheterization. Following the second OAC treatment, the family noticed decreased vision and the patient was noted to have no light perception or pupillary responses in either eye. Her right fundus revealed a pale, edematous perifoveal and juxtapapillary retina with “boxcarring” and attenuation of the vessels (Figure 1A). Scattered retinal and subconjunctival hemorrhages were evident in the left eye (Figure 1B), along with purpura on both lower extremities (Figure 2). Neurological evaluation, computed tomography, and magnetic resonance imaging findings were all normal. The family reported a viral prodrome prior to the second OAC treatment. The patient was given sildenafil citrate, steroids, and antihypertensive drops, and over the next week, the retinal vascular tree returned to normal in the right eye (Figure 3A) and the hemorrhages resolved in the left eye (Figure 3B). Retinal and choroidal flow were confirmed with fluorescein angioscopy. Four months later, the child gained fixation and following vision in the left eye, and with resolution of the retinal detachment, the electroretinogram improved to recordable “fair” levels. In the right eye, electroretinogram responses decreased from “very good” to “good.” With local therapy, disease was controlled in both eyes at 6 months' follow-up. Given concerns for an occlusive event, a coagulation workup was performed and, in addition to elevated acute phase reactants, a plasminogen activator inhibitor-1 4G/5G polymorphism was found with elevated plasminogen activator inhibitor levels.
Figure 1. Abnormal retinal findings following the second ophthalmic artery chemosurgery treatment with carboplatin and topotecan hydrochloride in case 3. A, Fundus photograph demonstrating retinal edema, pallor, and “boxcarring” in the right eye. B, Fundus photograph showing existing retinal detachment with retinal hemorrhages in the left eye.
Figure 2. Left lower extremity of case 3 demonstrating purpura.
Figure 3. At 6 months' follow-up of case 3, the tumors have regressed and retinal abnormalities improved. A, Fundus photograph showing the vascular tree has normalized along with the retinal edema and pallor in the right eye. B, Fundus photograph demonstrating that the retinal detachment and hemorrhages have resolved in the left eye and the retinal pigment epithelium changes have become evident.
It is estimated that 15% of the population carries a heritable thrombophilic condition or antiphospholipid syndrome (Table). Thrombosis formation is more common in patients with malignancy, and thromboemboli are the second most common cause of death in adult cancer patients.2 When combined with endovascular intervention consisting of small vessel catheterization, certain chemotherapy, or even heritable thrombophilia, this risk may increase further.
In light of this, we routinely screen for patient or family history of thrombotic disorders and maintain a target ACT with adjusted heparin dosing. With this method, we diagnosed a patient with a heterozygous prothrombin mutation prior to catheterization and successfully prophylactically treated her with a higher heparin dose. However, in 2 other patients, a diagnosis of sickle cell trait and a plasminogen activator inhibitor-1 4G/5G polymorphism were not established until after an adverse event with OAC. It is unclear whether the blood condition was the sole cause or a contributor to the adverse event. These patients gave no pertinent family history and had no prior symptoms. All 3 heritable conditions have been associated with varying degrees of vas cular obstruction; they not only share systemic manifestations such as stroke and pulmonary embolism but also ocular pathology including occlusion of the retinal vasculature.3
Activated coagulation time is a functional measure of both the intrinsic and final common pathway of the coagulation cascade and is used to guide heparin dosing during endovascular procedures. One study established ACT as an adequate preprocedure screening test for bleeding complications in patients with no known bleeding disorder,5 but thrombophilia was not addressed. Some groups have debated on the utility of universal screening for heritable thrombophilia, particularly in at-risk populations.6 However, data are insufficient to determine whether this is justified and many argue for selective screening instead. Knöfler et al7 show that 14% of children with malignancy developed thrombosis after a central venous catheter insertion, and 64% of these had inherited prothrombotic risk factors. We suggest a patient or family history be established and if pertinent, then a selective screening performed before deciding on OAC as a treatment option, for instance, testing for sickle cell trait in African American patients (8%-10% are at risk). In the context of a known heritable condition, the heparin dose can be adjusted, as was done in our patient. In highly suspicious cases (or those with a previous adverse event), treatment modalities other than OAC may need to be considered. As OAC is adopted more widely, it is important for clinicians to be aware of these prothrombotic states, the adverse events associated with them, and how to prophylactically manage them.
Correspondence: Dr Abramson, Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 70 E 66th St, New York, NY 10065 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by The Fund for Ophthalmic Knowledge and the New York Community Trust.
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