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Insights From a Pyruvate Kinase Deficiency Registry: Broad Spectrum of Severity, Broad Role for Monitoring

December 30, 2021

No guidelines exist for the diagnosis, management, and monitoring of patients with red cell pyruvate kinase (PK) deficiency – the most common glycolytic defect causing congenital non-spherocytic hemolytic anemia. Clinical features vary widely and the frequency of complications (e.g., jaundice, gallstones, iron overload, severe anemia, thrombosis, and osteopenia) has not been determined.

To characterize the clinical manifestations, complications, and treatment for patients with PK deficiency, Rachael F. Grace, MD, of the Dana-Farber/Boston Children's Cancer and Blood Disorder Center in Massachusetts, and co-authors conducted the retrospective and prospective longitudinal cohort PK Natural History Study (NHS). According to an update from the registry published in Blood, PK deficiency manifests a broad spectrum of anemia severity, but there are few early clinical predictors of clinical severity.

"Together with the absence of predictors for disease severity, the potential for serious complications highlight[s] the importance of close monitoring and follow-up of these patients by a hematologist – even in those patients with mild anemia," the researchers noted.

The NHS included 254 patients (median age = 19.0 years; range = 0.1-69.9 years) with biochemically or molecularly diagnosed PK deficiency; people were enrolled between June 2014 and April 2017 from 31 centers in five countries, including 55 patients from the Amish community (22% of total cohort). Thirty-five percent of the total population was related to another participant in the study.

Medical history and laboratory and radiologic data were retrospectively collected at enrollment. The researchers found that perinatal complications occurred in about one-quarter of participants (n=65/233; 28%): preterm birth (56%), prenatal anemia requiring in utero transfusions (47%), and preterm labor (42%) were the most common.

"Most newborns present with significant jaundice," the authors noted. However, 10 percent did not have perinatal jaundice. Although "the diagnosis of PK deficiency should be suspected in patients with perinatal jaundice and hemolysis," the absence of this feature does not exclude the possibility of PK deficiency.

Splenectomy was a common treatment approach for PK deficiency; among the entire cohort, 150 participants (59%) underwent splenectomy. This procedure was observed at a higher rate in the Amish community, compared with the rest of the cohort (p<0.0001) and in adult patients (75% vs. 42% of pediatric patients; p<0.0001). The most common reasons for splenectomy – according to medical record review – were to improve baseline anemia (88%), decrease transfusion burden (85%), improve patient quality of life (83%), and reduce jaundice (57%). In most patients (90%), the transfusion burden was reduced following splenectomy, with a median change in hemoglobin of 1.6 g/dL (range = –5.5-4.9 g/dL; n=72).

Predictors of response to splenectomy included higher pre-splenectomy hemoglobin (p=0.007), lower indirect bilirubin (p=0.005), and the presence of missense PKLR mutations (p=0.0017).

A total of 250 patients had a known transfusion history: 210 (84%) received a blood transfusion in their lifetimes, including 98 percent (n=198/202) of patients older than 5 years. "Most patients with PK deficiency … received regular transfusions in early childhood," the authors noted, adding that the management of PK deficiency in pediatric patients is "highly variable." Most patients (61%) delayed splenectomy beyond age 5 but received regular transfusions or transfusions for acute triggers; six children younger than 5 years (12%) underwent splenectomy and six had never received transfusion (12%). "This likely reflects both variability in clinical severity and differences in management strategies by hematologists, as the hemoglobin nadirs overlap between transfusion groups," they explained.

“Together with
the absence of
predictors for
disease severity,
the potential
for serious
highlight[s] the
importance of
close monitoring
and follow-up …”

—Rachael F. Grace, MD

Among those older than 5 years at the time of enrollment, 79 patients were receiving regular transfusions until the time of splenectomy. Sixty-two (78%) could discontinue transfusions after the procedure, which suggests that splenectomy is effective for most patients in this group. However, the authors noted, "in young patients who continue to rely on regular transfusions, the risk of transfusions must be balanced with the risks of splenectomy," which comes at a higher risk of bacterial infections.

Seven percent of patients (n=17/252) had a history of thrombosis, and splenectomized patients had a significantly higher incidence of thrombosis, compared with those with intact spleens (11% vs. 0%; p=0.0001).

"Although this important potential complication must be considered, the rates of post-splenectomy thrombosis and post-splenectomy pulmonary hypertension are not so elevated that splenectomy should be avoided in this patient population," the authors commented.

Gallstones were a frequent complication of PK deficiency across all age groups, occurring in 45 percent of patients (n=112/248) at a median age of 14.3 years (range = 2.2-60.4 years). Most (62%) occurred in patients younger than 18 years.

Forty percent of patients (n=101/254) underwent a cholecystectomy; among 85 patients who had information on timing of procedures, cholecystectomy was performed with splenectomy in 21 percent (n=18) and after splenectomy in 66 percent (n=56). Of the 121 patients who underwent splenectomy without prior or simultaneous cholecystectomy, 58 (48%) required this procedure at a later date. "Just prior to splenectomy, all patients with PK deficiency should be screened by ultrasound for gallstones," the researchers advised. "If gallstones are present, concurrent cholecystectomy should be considered, as observation of asymptomatic pigmented gallstones may lead to unnecessary complications."

There was no significant difference in hemoglobin for patients who did or did not require cholecystectomy (median = 8.8 g/dL vs. 8.9 g/dL; p=0.78). Those who underwent cholecystectomy:

  • had significantly higher total bilirubin levels (median = 4.2 mg/dL vs. 3.4 mg/dL; p=0.0024)
  • had higher absolute reticulocyte counts (median = 0.5×106 cells/uL vs. 0.2×106 cells/uL; p=0.0011)
  • were older at diagnosis (median = 0.7 years vs. 0.3 years; p=0.04)

"A genotype-phenotype relationship was identified in this international cohort, in which patients with two missense mutations in the PKLR gene had a lower likelihood of splenectomy [p<0.0001], fewer lifetime transfusions [p=0.0015], and a lower rate of iron overload [p=0.0013]," compared with patients with non-missense mutations, the authors reported.

The study is limited by its retrospective design, limited patient population, and partial reliance on patient records.

Some of the authors are scientific advisors to Agios Pharmaceuticals.


Grace RF, Bianchi P, van Beers EJ, et al. The clinical spectrum of pyruvate kinase deficiency: data from the pyruvate kinase deficiency natural history study. Blood. 2018 March 16. [Epub ahead of print]


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