Patent foramen ovale in adults with sickle cell disease and stroke
Authors: Sheila Razdan, John J. Strouse, Anusha Reddy, Danielle F. Resar, Rani K. Hasan, Jon R. Resar, Rakhi P. Naik, Victor C. Urrutia, Sophie Lanzkron, Linda M.S. Resar
Journal: American Journal of Hematology (2016)

To the Editor: Stroke is a leading cause of death in adults with sickle cell disease (SCD), although little is known about the underlying pathophysiology or associated risk factors 1-3. By 45 years of age, 24% of patients with hemoglobin (Hb) SS and 10% with HbSC will have had a stroke 1. Patients with HbSS have a higher incidence (0.61 per 100 patient years) and overall prevalence (4%) of stroke as compared to all other genotypes, whereas the combination of alpha thalassemia and SCD is associated with a reduced risk of stroke 1. Patent foramen ovale (PFO) or other intracardiac shunts are associated with ischemic stroke in children with SCD and young adults without SCD 3-5. PFO is common with a prevalence of ∼24% in the general population 4. Importantly, PFOs can be managed medically or closed using a minimally invasive procedure, which could potentially prevent embolic strokes in individuals with SCD at risk for stroke. We therefore investigated the frequency of PFOs in adults with SCD and stroke. We retrospectively identified a cohort (n = 65) of all adults (≥18 years old) with SCD and stroke followed in our Adult Sickle Cell Program (550 total patients) between 2012 and 2014 (Supporting Information Fig. 1). The majority of patients (54/65) had an echocardiogram with Doppler imaging at or near the time of stroke; one (1/54) patient had an obvious PFO. There were no echocardiograms with evidence of valvular vegetations or other cases of anatomical abnormalities associated with stroke. From these 54 adults, 14 patients (ages 18–74 years) also underwent evaluation for an intracardiac shunt (transthoracic or transesophageal echocardiography with color Doppler imaging and contrast studies with agitated saline; Supporting Information Fig. 1; Table 1). As noted above, one additional patient had an obvious PFO on echocardiography and therefore did not undergo contrast studies with agitated saline. The mean age at time of first stroke was 21.2 years (range 1.5–60 years). HbSS genotype was present in 11/15 patients, HbSC in 3/15 patients, and HbSβ+ thalassemia in 1/15 patients. The mean age at time of first stroke was lower in patients with HbSS (17.4 years) as compared to those with HbSC (33.3 years) and 1 patient with HbSβ+ (27 years). Magnetic resonance imaging and magnetic resonance angiograms (MRI/MRA) showed 10 ischemic strokes, 3 hemorrhagic strokes, and 2 consistent with fat emboli. The cohort with HbSS and stroke included 8/11 patients with ischemic strokes and 3/11 patients with hemorrhagic strokes. HbSC patients with stroke (n = 3) included 2 with ischemic strokes and 1 with fat embolism on imaging studies. The patient with HbSβ+ had findings consistent with fat embolism on MRI/MRA. Evaluation for intracardiac shunting revealed a prevalence of 33% (5/15) for PFOs (Supporting Information Fig. 1); 4 of these patients had HbSS and 1 had HbSC. PFOs were identified in 4/10 ischemic strokes and 1/3 hemorrhagic strokes. The mean age at the time of first stroke in patients with PFO was 14.6 years, while the mean age in patients without PFO was 24.6 years. Deep vein thrombosis (DVT) was identified in three patients with PFOs during the hospitalization for stroke; one patient with PFO developed DVT several years later. No patients without PFOs were found to have DVT at the time of stroke, although 2 of those 10 patients had a history of DVT. Three of seven patients with recurrent ischemic strokes also had PFOs. One of five patients with moyamoya syndrome or aneurysms at the time of stroke had a PFO. Most patients in this cohort (10/15) had their first stroke as adults (≥18 years); of these, 3/10 had PFOs (30% prevalence). In five patients whose first stroke occurred at or before age 10, two had PFOs (40% prevalence). One patient with HbSC had recurrent strokes as an adult and fat emboli on imaging studies; her echocardiogram was consistent with an intrapulmonic arteriovenous shunt. A cardiac catheterization was performed and showed no intracardiac shunt. A second patient in our cohort (with HbSS and first stroke at age 19 years) also had the appearance of late bubbles on echocardiogram suggesting an intrapulmonic shunt. In summary, our pilot study revealed a prevalence of 33% (5/15) for PFOs in adults with SCD and stroke, which is similar to PFOs in the general population (24%). The prevalence was similar in patients who had their first stroke during childhood (40%) or as adults (30%). HbSS was the most common genotype and there was also a high prevalence of DVT in patients with PFO and stroke (4/5 patients). Recent studies indicate that DVTs are frequent complications in adults with SCD 6 and ischemic stroke could be a manifestation of this hypercoagulable state. In fact, 6/15 patients in our stroke cohort had a history of DVT. Hypercoagulability associated with SCD could place individuals with SCD at higher risk for PFO-related stroke compared to the general population, although larger cohorts are needed to test this hypothesis. It is also plausible that patients with SCD suffer more significant sequelae from PFO-related strokes due to underlying vasculopathy and hypercoagulopathy caused by SCD. Unexpectedly, we also found evidence for intrapulmonic shunts in 2/10 (20%) patients who had their first stroke as adults, suggesting that this could contribute to stroke in a subset of patients. Because our pilot study was limited by the small patient population who underwent evaluation for intracardiac shunting, prospective, longitudinal studies with intracardiac shunt evaluation are needed to determine the true prevalence of PFO, intracardiac shunting, and intrapulmonic shunts in this population. However, because PFOs and intracardiac shunts can be managed medically or closed with a minimally invasive procedure [4], this pilot study highlights the need for further research to ascertain the significance of these lesions in SCD. Strokes are highly morbid complications in SCD; thus, interventions to identify individuals at highest risk and prevent strokes will have a profound impact on this patient population. Authors thank American Society of Hematology (ASH Trainee Award to SR). SR, JJS, AR, DR, VU, RN, SL, LR reviewed data and recorded results, SR, DR, AR, LR wrote the letter, RKH, JRR interpreted the echocardiograms. Sheila Razdan,1,2 John J. Strouse,1,2,3 Anusha Reddy,1,2 Danielle F. Resar,1,2 Rani K. Hasan,4 Jon R. Resar,4 Rakhi P. Naik,1,2 Victor C. Urrutia,5 Sophie Lanzkron,1,2 and Linda M.S. Resar1,2,3,6,7* 1Hematology Division, 2Department of Medicine, 3Department of Pediatrics, 4Department of Cardiology, 5Department of Neurology, 6Department of Oncology, 7Institute for Cellular Engineering, the Johns Hopkins University School of Medicine, Baltimore, Maryland. Additional Supporting Information may be found in the online version of this article. Supporting Information Figure 1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.