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H. Al-Samkari et al.
ease.9,36,44 Approximately 15% of patients with PKD will be regularly transfused despite splenectomy.36 Although response to splenectomy is difficult to predict, those patients who continue to require transfusions despite splenectomy tend to have two drastic (e.g. non-missense) PKLR mutations and a higher pre-splenectomy rate of hemolysis.36
The decision to proceed with splenectomy is more com- mon in US centers, whereas in European centers, more patients with PKD remain on transfusions and iron chela- tion with intact spleens. This practice variation likely reflects provider and patient preferences and values assigned to the potential risks and benefits of splenecto- my. International expert guidelines recommend splenec- tomy in patients with PKD who receive regular transfu- sions or do not tolerate their anemia. Cholecystectomy may be recommended at the time of splenectomy given the persistent risk of bilirubin gallstones, but patients should be counseled about the risk of intrahepatic cholestasis and other complications.40 Full splenectomy is recommended given the reported poor hemoglobin response to partial splenectomy.45 Pre- and post-splenecto- my vaccinations are critical for preventing sepsis, and antibiotic prophylaxis should be considered according to country-specific guidelines but is often considered life- long. Post-splenectomy thromboprophylaxis can be con- sidered in the immediate postoperative period in patients with additional thrombotic risk factors. If thrombopro- phylaxis is given, low-dose aspirin can be considered in adults with additional risk factors (including advanced age, a history of thrombosis, or cigarette smoking) until the platelet count is <500×109/L and in children until the platelet count is <1,000×109/L.
Patients with a mildly low hemoglobin without symp- toms of anemia, even with concurrent infections, can clearly avoid splenectomy. However, the management of many patients, like the one in this case, is not straightfor- ward. He has received a considerable number of transfu- sions, possibly each time he has had a viral infection, and he likely has a high hemolytic rate and low hemoglobin at baseline. He would benefit from a post-splenectomy rise in hemoglobin, which could help him to avoid transfu- sions with illnesses going forward. Inquiring about age- specific signs and symptoms of fatigue will help to deter- mine whether a chronically low hemoglobin is associated with daily symptoms, an additional reason to support moving forward with full splenectomy and cholecystecto- my in this patient. Further complicating this discussion is the potential for future targeted treatments for PKD, including mitapivat (AG-348), an oral small molecule allosteric activator of PK currently in phase III clinical trials in adults. If the patient has at least one missense PKLR mutation, consideration could be given to delaying splenectomy while awaiting potential regulatory approval of this treatment. Off-target mild aromatase inhibition may, however, delay the future availability of this treat- ment until adulthood.46
Curative treatment with stem cell transplantation has been pursued in a small number of patients with only 16 transplanted patients reported worldwide. These patients had a high rate of grade IV graft-versus-host disease and only a 74% cumulative survival at 2 years; however, they had variable ages at transplant, were given different types of transplants, and were treated with a variety of condi- tioning regimens.16 Transplant could be considered for the
patient in this case, particularly with an HLA-matched unaffected sibling. In the rare case that transplantation is under serious consideration, splenectomy and its associat- ed infectious and thrombotic risks should be avoided. Given that patients with two drastic PKLR mutations and a higher hemolytic rate are less likely to benefit from splenectomy or mitapivat, consideration should be given to a stem cell transplant and the availability of matched donors prior to splenectomy. However, given the available data regarding the risks of transplant versus supportive care and the treatments in development, including gene thera- py, an approach of ongoing supportive care with splenec- tomy and/or regular red cell transfusions is recommended rather than stem cell transplantation in the majority of patients, including the patient in this case.
Transfusion in pyruvate kinase deficiency
CASE: AB (age 38) and BB (age 35) are brothers with PKD diagnosed by enzyme assay and confirmed by genetic testing. Both had splenectomies in childhood, and subsequently had baseline hemoglobin levels of 8-9 g/dL with 20-35% reticulo- cytes. In early childhood both brothers had similar burdens of fatigue and activity limitation attributable to PKD. In adulthood, the brothers have had divergent paths owing to decisions regard- ing regular transfusion.
AB is relatively sedentary and is transfused once or twice a year, only for worsening symptoms of anemia. He is unemployed. He is concerned about iron overload and refuses regular transfu- sion with iron chelation due to side effects of chelation therapy in the past. He, therefore, resists red blood cell transfusions until he is clinically more symptomatic.
BB, in contrast, is an active, working, married man with four children. In order to maintain this active lifestyle, he is regularly transfused to keep his hemoglobin concentration above 10-11 g/dL. To prevent iron overload with regular transfusions, he takes an oral iron chelation drug.
Patients with PKD frequently live with chronic fatigue, poor exercise tolerance, and suboptimal work productivi- ty.47 These symptoms may improve if the hemoglobin concentration is raised consistently with regular transfu- sions.
The decision to transfuse a patient with PKD is based on the patient’s tolerance of anemia and demands of their lifestyle rather than an arbitrary hemoglobin threshold. In the above cases, two brothers with the same baseline hemoglobin and symptom level, the decision to regularly transfuse one but not the other was based on the impact of their disease on their quality of life. For the regularly- transfused sibling, red cell transfusions allow him to work, support his family, and live an active lifestyle; by contrast, his brother prioritizes avoiding the side effects of iron chelation and opts for on-demand transfusions only.
The asymptomatic patient with severe anemia
CASE: An 8-year-old child with transfusion-dependent con- genital anemia of unclear etiology is diagnosed with PKD follow- ing enzyme assay and confirmatory genetic testing, which demonstrated the presence of two deleterious non-missense muta- tions, c.721G>T (p.Glu241X) and c.284-2A>C (abnormal splicing), predicted to result in a complete absence of the PK-R isoform. During the course of his diagnostic workup, his 2,3- diphosphoglycerate levels were measured at over three times the upper limit of the reference range. He underwent splenectomy with resolution of transfusion dependency and a post-splenecto- my baseline hemoglobin of 7.0 g/dL. Despite continued severe
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haematologica | 2020; 105(9)