Cardiopulmonary complications are a major cause of morbidity and mortality in sickle cell disease (SCD) as shown by worse prognosis in patients who have experienced acute chest syndrome or who have an elevated tricuspid regurgitant jet velocity (TRV) on echocardiogram at clinical baseline. Here we describe an unexpected and novel cardio-pulmonary complication in HbSS, right-to-left shunting through extra-cardiac arterial-venous malformations (AVMs), which may contribute to pathophysiology. Extracardiac AVMs are rare in the general population, with an estimated incidence of 1/5000. Of 2111 shunt evaluation echocardiograms performed at our institution over 12 months only 81 (3.8%) of individual studies were positive.
We evaluated 36 HbSS patients who presented with subjective dyspnea or hypoxia with clinical exam and with echocardiogram utilizing agitated saline to assess for vascular right-to-left shunts. We compared this group with the remaining 81 HbSS patients in our database. 19 of 36 symptomatic patients were found to have an extracardiac right-to-left shunt. We then compared these 19 patients with the 17 symptomatic HbSS patients who did not have a shunt. 10 HbSC and 5 S-beta-thalassemia patients were also studied and did not have a right-to-left shunt; only HbSS are included in comparative analyses.
Patients with symptoms did not differ in age (32.7±10.3 years vs 31.7±11.7 years) from patients who did not present with hypoxia or subjective dyspnea (n=81). Symptomatic patients were more likely to have macroalbuminuria (>300 mg/g albumin-to-creatinine, 9/36 vs 8/63 evaluable, p=0.05), more likely to have a TRV ≥3 meters/second (9/36 vs 11/74 evaluable, p=0.09), and were more hypoxic at rest (96 ±5% vs 98±2% oxygen saturation, p=0.07). We found delayed left-sided bubble visualization in 19/36 symptomatic HbSS subjects (53%) consistent with extra-cardiac AVMs.
HbSS subjects with (n=19, Group I) or without (n=17, Group II) a positive bubble study were clinically and demographically similar (age, gender, WBC, total Hgb, HgbF%, LDH, eGFR, proportion with macroalbuminuria, baseline oxygen saturation, and elevated TRV). However, group I patients had a higher reticulocyte count (15.4±5.5% vs 9.8±6.7% p<0.005). Of Group I patients, 42.1% had history of acute chest while 70.6% of Group II had such history (p=0.09). Group I patients were less likely to be on hydroxyurea (52.78% vs 47.22% p<0.05).
Extra-cardiac AVMs are observed in 16% of all subjects with HbSS, compared with 3.8% of general medical patients at a tertiary center undergoing shunt evaluation and .02% in the general population. In HbSS, symptomatic subjects are more likely to have evidence for vasculopathy (macroalbuminuria, elevated TRV) and hypoxia; one-half of these symptomatic patients have extracardiac AVMs. We speculate that this finding is unlikely to be clinically silent, and a bubble-echocardiogram may be an important additional clinical evaluation for symptomatic dyspnea or hypoxia. The impact of this novel clinical finding on morbidity and mortality in this disease remains under investigation.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.