Pyruvate kinase deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymopathy that leaves red cells unable to buffer oxidative stress, producing episodic intravascular hemolysis with bite cells and Heinz bodies after infection, fava beans, or oxidant drugs. Diagnosis rests on a G6PD enzyme activity assay that can be falsely normal during the acute episode and must be repeated 2 to 3 months later, while management centers on trigger avoidance, supportive care, and transfusion for severe hemolysis.

Hereditary spherocytosis is an inherited red cell membrane defect, usually autosomal dominant, that produces rigid spherocytes trapped and destroyed in the spleen. It presents with anemia, jaundice, splenomegaly, and pigment gallstones, is diagnosed by spherocytes with elevated MCHC and a negative direct antiglobulin test, and is confirmed by eosin-5-maleimide binding or osmotic fragility testing, with folic acid and splenectomy as the mainstays of treatment.

Hemolytic anemia is premature red cell destruction confirmed by a high reticulocyte count and LDH with low haptoglobin and high indirect bilirubin. The approach then classifies disease by smear findings and a direct antiglobulin test, separating immune from non-immune and inherited from acquired causes to direct treatment.

Autoimmune hemolytic anemia is antibody-mediated red cell destruction confirmed by a positive direct antiglobulin (Coombs) test, split into warm IgG disease with splenic clearance and spherocytes and cold agglutinin IgM disease with complement-mediated agglutination worse in the cold. Warm disease is treated with glucocorticoids first and cold agglutinin disease with cold avoidance and rituximab, and roughly half have an identifiable secondary cause that must be sought and treated.

Sickle cell disease is an autosomal recessive hemoglobinopathy caused by a beta-globin point mutation that produces hemoglobin S, which polymerizes under deoxygenation to sickle erythrocytes and drive chronic hemolysis and vaso-occlusion. Diagnosis is confirmed by hemoglobin electrophoresis or HPLC showing predominant HbS, and lifelong management centers on hydroxyurea, folic acid, penicillin prophylaxis and vaccination for functional asplenia, transcranial Doppler stroke screening, and, in severe disease, transfusion, hematopoietic stem cell transplant, or gene therapy.

Alpha-thalassemia is an inherited microcytic anemia caused by deletions of one or more of the four alpha-globin genes, ranging from a silent carrier state to fatal hemoglobin Barts hydrops fetalis, and it is distinguished from iron deficiency by a normal or elevated RBC count, a normal RDW, and normal iron studies. Diagnosis of the trait requires excluding iron deficiency and often direct globin gene testing because hemoglobin electrophoresis is typically normal, while hemoglobin H disease shows a detectable beta-globin tetramer and HbH inclusions on supravital stain.

Beta-thalassemia is an inherited hemoglobinopathy caused by point mutations that reduce or abolish beta-globin chain synthesis, producing a spectrum from asymptomatic trait to transfusion-dependent thalassemia major (Cooley anemia) with ineffective erythropoiesis, marrow expansion, and hepatosplenomegaly. Diagnosis rests on hemoglobin electrophoresis showing elevated HbA2 and HbF, and management of major disease centers on chronic transfusion paired with iron chelation, since transfusional iron overload is the leading cause of death.

Paroxysmal nocturnal hemoglobinuria is an acquired clonal stem cell disorder caused by a somatic PIGA mutation that leaves blood cells unprotected from complement, producing intravascular hemolysis, unusual-site venous thrombosis, and cytopenias. Diagnosis rests on flow cytometry showing loss of the GPI-anchored proteins CD55 and CD59, and eculizumab or ravulizumab is used to block terminal complement and reduce both hemolysis and thrombotic risk, while allogeneic stem cell transplant remains the only cure.