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This report is being filed to provide additional information in h.6 and h.10.Investigation: seven patients with tdt diagnoses of beta thalassemia major (5), hemoglobin e-beta thalassemia (1), and four gene deletion alpha thalassemia (1) were enrolled (table 1).The average age was 30 years (range 20¿45 years).All patients were on single-agent chelation therapy while on st therapy, and this continued when they started rce (five jadenu, one exjade, and one ferriprox).A second oral chelation agent was added due to worsening iron overload for three patients when it became available.Rce was performed at a median of every 3 weeks (range every 2¿8 weeks).On simple transfusion (st) therapy, the average hemoglobin for five patients was not at the recommended hemoglobin target of greater than 95 g/l.On rce, average post-transfusion hemoglobin was greater than 95 g/l in six patients, but only one patient had an average pre-rce hemoglobin of greater than 95 g/l.Hepatic iron overload was suspected in all patients prior to rce initiation due to baseline hyperferritinemia (table 2).One patient had confirmed iron overload by hepatic t2* mri prior to rce.Five patients had confirmed hepatic iron overload by mri while on rce for a median of 17 months (range 6¿50, see figure 1).Hepatic t2* scores improved temporally after dual chelation therapy was started in one of three patients.After rce discontinuation, four patients had improved hepatic t2* values by mri.One patient developed biopsy-proven cirrhosis which was not evident on imaging prior to initiation of rce.Four patients had worsening splenomegaly after starting rce; two of which required splenic artery embolization for management (table 2).Three patients developed paraspinal masses.None had symptoms or imaging evidence of spinal cord compression.One patient developed adrenal insufficiency and diabetes related to iron overload while on rce.No other endocrinopathy was noted.Three patients (patients 3, 4, and 7) developed cardiac dysfunction which developed during rce with resultant morbidity.One patient (patient 3) developed biventricular dilatation and heart failure with a drop in ejection fraction (ef) from 58% to 52% while on rce despite normal cardiac iron.The patient had syncope during rce which was deemed secondary to cardiac dysfunction.After cessation of rce and ongoing chelation therapy, their ef improved back to 58%.A second patient (patient 4) developed dilated cardiomyopathy with no evidence of iron overload on mri after initiation of rce.A third patient (patient 7) had baseline documented cardiac iron overload (t2* 14 ms) prior to rce start.Cardiac t2* score improved after optimized chelation at 10 months on rce but they developed symptomatic heart failure (nadir ef 46%).Due to recurrent hypotension and presyncope during rce, the patient was switched back to st.Three patients had transfusion- or apheresis-related complications.Patients 3, 4, and 7 had syncope during rce.In patient 3, syncope was cardiac in nature (see above).Patient 4 had an air embolus leading to syncope during an rce event.Patient 7 had presyncope and hypotension during rce exacerbated by reduced ef and developed anti-kpa antibody despite red cell genotyping and prophylactic matching for extended rh, kell, duffy, jka, and jkb.Patient 5 developed a transient auto-e antibody and inconclusive antibody that did not result in any complications.No bleeding, thrombotic, or hemolytic events were observed in any patients.Although rce was hypothesized to reduce iron overload in patients with tdt, we did not observe an improvement in iron status in patients with tdt after starting rce.This review of seven patients highlights possible complications related to rce in patients with tdt and reinforces the need for adequate transfusion therapy to help minimize complications related to extramedullary hematopoiesis.Iron status improved in several patients only after adding a second iron chelator or an increased dose of single-agent chelation.Definitive conclusions cannot be made due to the retrospective design of this study and the small sample size.However, this study can serve as hypothesis-generating data for future research.While we found no evidence to routinely support the use of rce in patients with tdt for routine transfusion, rce may be of value in patients with alpha thalassemia with four gene deletion and who have refractory hemolysis and thrombosis.This study highlights the importance of access to optimal chelation therapy and monitoring for complications related to iron overload in patients with tdt.The authors attributed myocardial iron deposition as potential of a complication of cardiac dysfunctions.Hence, there is no failure mode or associated risk that can be evaluated.According to therapeutic apheresis: a physician's handbook, adverse events occur during therapeutic procedures with a frequency of 4.8%.Some of the most common reactions include fever, urticaria, hypocalcemic symptoms, pruritus, dyspnea, tachycardia, and mild hypotension.Vasovagal incidents occur around 0.5% of procedures.The reactions generally manifest as pallor and diaphoresis.In a full blown attack, the reaction progresses from pallor and sweating to pulse slowing and blood pressure decreasing.More severe vasovagal reactions may include nausea, vomiting, and/or convulsions.According to therapeutic apheresis: a physician's handbook, air embolism is a very rare complication of apheresis when large amounts (>3-8 ml/kg) of air enter the venous system; it is characterized by dyspnea, tachypnea, cyanosis, tachycardia, and hypotension.These states result when air enters the right ventricle and pulmonary artery, with obstruction of right ventricular output and pulmonary artery vasoconstriction.In the rare event this complication occurs because of a malfunction or error in setup, the donor is turned to the trendelenburg position on his or her left side, thereby trapping the air in the apex of the right ventricle.Eventually the air dissolves.According to the aabb circular of information for the use of human blood components (revised 2017), delayed hemolytic reactions occur in previously red-cell-alloimmunized patients in whom antigens on transfused red cells provoke amamnestic production of antibody.The amamnestic response reaches a significant circulating level while the transfused cells are still present in the circulation; the usual time frame is 2 to 14 days after transfusion.Signs may include unexplained fever, development of a positive dat result, and unexplained decrease in hemoglobin/hematocrit.Hemolytic transfusion reactions in patients with sickle cell anemia may be particularly severe, with destruction of autologous as well as transfused red cells, resulting in a lower hemoglobin level after transfusion.This is suggestive of hyperhemolysis syndrome.Immediate treatment may include steroid use, ivig, and avoiding transfusions if possible.Since this was a retrospective analysis of red cell exchange (rce) using spectra optia in seven transfusion-dependent thalassemia (tdt) patients with severe iron overload despite oral chelation between 2008 and 2019, the lot numbers were not requested; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Root cause: a root cause assessment was performed for the reported cardiac dysfunctions.According to the authors, ¿in patients with tdt, cardiac dysfunction is a potential complication that can arise from myocardial iron deposition and can lead to morbidity or death.Two patients with cardiac dysfunction had recurrent syncopal events during rce.We observed decreased ef in two patients and dilated cardiomyopathy in one patient.We hypothesize these cardiac complications are secondary to iron overload and chronic under-transfusion leading to anemia-related cardiomyopathy.Observations of presyncopal, syncopal, and hypotensive events during rce suggest that tdt patients with cardiac dysfunction are at higher risk of transfusion complications related to shifts in intravascular volume.¿ a root cause assessment was performed for the air embolism.Based on the available information a definitive root cause could not be determined but it is likely due to one or a combination of the possible causes listed below: * device malfunction * error in setup a root cause assessment was performed for the reported syncope.According to the authors, ¿in patient 3, syncope was cardiac in nature.Patient 4 had an air embolus leading to syncope during an rce event.Patient 7 had presyncope and hypotension during rce exacerbated by reduced ef¿.A root cause assessment was performed for the reported hypotension.According to the authors, ¿patient 7 had presyncope and hypotension during rce exacerbated by reduced ejection fraction (ef)¿.A root cause assessment was performed for the reported transfusion reactions.According to the authors, patient 7 developed anti-kpa antibody despite red cell genotyping and prophylactic matching for extended rh, kell, duffy, jka, and jkb.Patient 5 developed a transient auto-e antibody and inconclusive antibody that did not result in any complications.¿ wall e, bolster l.Complications of red cell exchange for anemia management in patients with transfusiondependent thalassemia.Transfusion.2023.
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