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1.
Blood ; 136(11): 1241-1249, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32702739

ABSTRACT

Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/therapy , Adolescent , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Anemia, Hemolytic, Congenital Nonspherocytic/epidemiology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Blood Transfusion , Chelation Therapy , Child , Child, Preschool , Cholelithiasis/etiology , Cholelithiasis/surgery , Clinical Trials as Topic , Disease Management , Female , Fetal Diseases/genetics , Genetic Therapy , Genotype , Hematopoietic Stem Cell Transplantation , Humans , Infant , Infant, Newborn , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron Overload/etiology , Jaundice, Neonatal/etiology , Jaundice, Neonatal/therapy , Male , Mutation , Pregnancy , Prevalence , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/diagnosis , Pyruvate Metabolism, Inborn Errors/epidemiology , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy , Splenomegaly/etiology , Splenomegaly/surgery
2.
Pediatrics ; 141(Suppl 5): S385-S389, 2018 04.
Article in English | MEDLINE | ID: mdl-29610156

ABSTRACT

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic hemolytic anemia, and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and splenomegaly. Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal cholestasis and a young adult with a severe form of PKD and having been transfusion dependent during childhood. After transplant, both patients have normal liver function test results and have considerably decreased their need for blood transfusion despite ongoing, mild hemolysis. We suggest that PKD can lead to severe liver dysfunction and that LT and splenectomy can be life-saving procedures in such cases.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/complications , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Liver Failure/etiology , Liver Failure/surgery , Liver Transplantation , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/complications , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy , Anemia, Neonatal/etiology , Blood Transfusion , Cholestasis/etiology , Humans , Infant , Male , Young Adult
3.
J Pediatr Hematol Oncol ; 40(7): e458-e460, 2018 10.
Article in English | MEDLINE | ID: mdl-29309376

ABSTRACT

Pyruvate kinase (PK) deficiency is the most common defect of the glycolytic pathway leading to congenital hemolytic anemia. We present the case of an 18-year-old boy with chronic nonspherocytic hemolytic anemia, who had remarkable sensitivity to heat. Moreover, the patient showed clinical impairment in the last year. For this reason, we excluded the immunologic or infectious nature (malaria, babesia), which may play a role in the worsening of anemia. Red blood cell enzyme assay showed the presence of a significant increase in other enzyme activities, except for PK, suggesting a PK deficiency in the patient. The molecular analysis of the PK-LR gene revealed the presence of a novel homozygote missense mutation (c.581G>C, p.Arg194Pro). The mutant enzyme displayed heat instability. In addition, we analyzed bilirubin uridine diphosphate (UDP)-glucuronosyltransferase 1A1 gene that revealed a heterozygous state ([TA]6/[TA]7). After a clear diagnosis of PK deficiency, the patient underwent splenectomy.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Hot Temperature , Mutation, Missense , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/genetics , Adolescent , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Glucuronosyltransferase/genetics , Heterozygote , Humans , Male , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/diagnosis , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy
7.
Pediatr Int ; 58(7): 634-6, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27460399

ABSTRACT

Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion-dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase-liver and RBC (PK-LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Erythrocytes/cytology , Fetal Blood/cytology , Hematopoietic Stem Cell Transplantation/methods , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/surgery , Anemia, Hemolytic, Congenital Nonspherocytic/blood , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Female , Humans , Infant , Pyruvate Kinase/blood , Pyruvate Metabolism, Inborn Errors/blood , Pyruvate Metabolism, Inborn Errors/diagnosis
8.
Am J Hematol ; 90(9): 825-30, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26087744

ABSTRACT

Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell pyruvate kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Erythrocyte Transfusion , Exchange Transfusion, Whole Blood , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/therapy , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Anemia, Hemolytic, Congenital Nonspherocytic/pathology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Child , Disease Management , Humans , Infant, Newborn , Phototherapy , Pyruvate Metabolism, Inborn Errors/enzymology , Pyruvate Metabolism, Inborn Errors/pathology , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy
9.
Br J Haematol ; 113(4): 932-7, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11442486

ABSTRACT

We describe two families with the 'cryohydrocytosis' form of stomatocytosis. Both show a mild stomatocytic anaemia with Hb levels of 12-16 g/dl and reticulocyte counts of 4.3-24%, with very marked autohaemolysis at refrigerator temperatures and pseudohyperkalaemia as a result of loss of K from red cells on storage at room temperature. The ouabain + bumetanide-insensitive 'passive leak' K influx showed a 'U'-shaped temperature dependence, with a minimum at 23 degrees C. In one family, there was consistent variation in haematological severity within the pedigree. In the other, the parents of the proposita were normal, but all three of her children were affected, consistent with a new mutation of a dominant condition. Cold storage of the red cells led to a very marked increase in osmotic fragility and macrospherocytosis, explaining why a diagnosis of 'hereditary spherocytosis' can easily be reached in these pedigrees.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Cold Temperature , Anemia, Hemolytic, Congenital Nonspherocytic/metabolism , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Bumetanide , England , Erythrocytes/metabolism , Female , Hemolysis , Humans , Lithium/metabolism , Male , Osmotic Fragility , Ouabain , Pedigree , Potassium/metabolism , Potassium Channels/drug effects , Pregnancy , Splenectomy
10.
Am J Hematol ; 67(3): 197-9, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11391719

ABSTRACT

We report a case of recurrent thromboembolic disease and chronic pulmonary hypertension in an adult patient with pyruvate kinase deficiency who underwent splenectomy as a child. Thromboembolism has been reported as a complication following splenectomy for various hereditary chronic hemolytic anemias. To our knowledge, this association has not been described in patients specifically with pyruvate kinase deficiency. Our patient presented at age 37 with recurrent pulmonary emboli, 36 years after splenectomy for severe hemolytic anemia. Work-up for other hypercoagulable states was negative. The mechanism for hypercoagulability in this condition is unclear but may involve a quantitative or qualitative change in disrupted thrombogenic red blood cell membranes that would normally be removed by the spleen. Clinicians should have a high index of suspicion for thrombotic events in these patients, as early diagnosis and treatment can reduce morbidity and mortality, and chronic anticoagulation may help prevent the sequelae of repeated thromboembolic events.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/complications , Femoral Vein , Iliac Vein , Pulmonary Embolism/etiology , Pyruvate Kinase/deficiency , Splenectomy/adverse effects , Thrombophilia/etiology , Venous Thrombosis/etiology , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Anticoagulants/therapeutic use , Blood Transfusion , Combined Modality Therapy , Dyspnea/etiology , Dyspnea/therapy , Female , Genotype , Humans , Oxygen Inhalation Therapy , Recurrence , Thrombophilia/drug therapy
11.
N J Med ; 92(9): 587-8, 1995 Sep.
Article in English | MEDLINE | ID: mdl-7566675

ABSTRACT

Pyruvate kinase deficiency is a rare cause of congenital hemolytic anemia. Despite a paucity of reports, splenectomy resulted in successful outcomes for two siblings with this disorder. The sisters were diagnosed at birth with profound jaundice and congenital nonspherocytic hemolytic anemia.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Pyruvate Kinase/deficiency , Adolescent , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Female , Humans , Splenectomy
13.
Haematologica ; 78(2): 80-3, 1993.
Article in English | MEDLINE | ID: mdl-8349196

ABSTRACT

BACKGROUND AND METHODS: The clinical and biochemical aspects of two cases of PK deficiency associated with chronic hemolytic anemia in two unrelated patients are reported. The residual erythrocyte PK enzymes in both patients were characterized by the recommended methods of the International Committee for Standardization in Hematology (ICSH). RESULTS AND CONCLUSIONS: Patient (W.Q.) had 60% residual PK activity and may be considered homozygous on the basis of consanguinity in the family. This patient suffered from moderate hemolytic anemia that improved after splenectomy. The enzymatic properties were: low activity, moderate thermal stability, reduced affinity for phosphoenol-pyruvate (PEP), and normal electrophoretic mobility. Patient (E.O.) had 42% residual PK activity and may be considered compound heterozygous since his parents are not related. He suffered from moderate hemolytic anemia. The enzymatic properties were: low activity, moderate thermal stability, reduced affinity for PEP and minimal retardation in electrophoretic migration. Theses two cases of PK deficiency are the first to be discovered in Jordan and probably the first in any Arab country.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Pyruvate Kinase/deficiency , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Anemia, Hemolytic, Congenital Nonspherocytic/ethnology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Consanguinity , Erythrocytes/enzymology , Genes, Dominant , Genotype , Humans , Jordan , Male , Pyruvate Kinase/blood , Pyruvate Kinase/genetics , Splenectomy
15.
Article in German | MEDLINE | ID: mdl-6162731

ABSTRACT

Heinz-body haemolytic anaemia represents a rarely occurring kind of hereditary defect of haemoglobin, G-6-PDH or glutathion reductase. The course of disease observed in two patients with non-spherocytic haemolytic anaemia was very serious as compared with other cases with haemoglobin variants and enzyme defects of G-6-PDH described in literature. The course of disease could not be influenced by splenectomy, substitution therapy, and long-term therapy with desferrioxamin. Exitus occurred at an age 22 or 41 as a consequence of severe haemosiderosis.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Erythrocytes/enzymology , Female , Glucosephosphate Dehydrogenase Deficiency/diagnosis , Heinz Bodies , Hemoglobins, Abnormal/analysis , Humans , Splenectomy
16.
Br J Haematol ; 41(1): 115-24, 1979 Jan.
Article in English | MEDLINE | ID: mdl-154342

ABSTRACT

The patterns of survival of isotope-labelled erythrocytes were examined in patients suffering from two variants of congenital non-spherocytic haemolytic anaemia with decreased erythrocyte pyruvate kinase (PK) activity. In one variant, with primary PK defect (PPKD) random destruction of erythrocytes was predominant in the process of haemolysis. In the second variant, with primary magnesium activated adenosine triphosphatase (ATP-ase) (Mg++) deficiency and a secondary decrease in PK activity, erythrocytes were destroyed by senescence. Two subpopulations of labelled erythrocytes with different destruction rates were observed in all patients examined, except one with the second variant, with very mild haemolysis. Splenectomy, performed on two patient, was successful only in the variant with PPKD.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/blood , Erythrocytes/physiology , Adenosine Triphosphatases/deficiency , Adult , Aged , Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Erythrocyte Aging , Erythrocyte Volume , Female , Humans , Male , Middle Aged , Pyruvate Kinase/deficiency , Splenectomy
19.
J Pediatr ; 85(4): 494-7, 1974 Oct.
Article in English | MEDLINE | ID: mdl-4443856

ABSTRACT

Eight children (5 living, 3 deceased) with severe hereditary nonspherocytic hemolytic anemia caused by glucose phosphate isomerase deficiency have been observed in two Kentucky and Indiana families. All affected children were severely anemic in early life. Three deaths occurred in young patients who did not receive adequate transfusions of blood or whose parents refused to permit splenectomy. Splenectomy generally abolishes the requirement for blood transfusion. No patient has required regular transfusion of blood after puberty. Growth and development have been surprisingly normal and no patient has died of infection. The anemia is expressed as an autosomal recessive trait, but the enzyme variant can be detected in hematologically normal heterozygotes. The abnormal isomerase molecule is heat labile and is contained in neutrophils and lymphocytes as well as in erythrocytes.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic , Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/blood , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Child , Child, Preschool , Erythrocytes/enzymology , Female , Humans , Indiana , Infant , Infant, Newborn , Kentucky , Male , Metabolic Diseases/genetics , Pedigree , Prognosis , Splenectomy
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