Background

The most frequent enzyme-related glycolytic deficit that causes red cell hemolysis is PKD (pyruvate kinase deficiency). Medical heterogeneity is a trait of this illness. Variable levels of hemolysis brought on by heterogeneity lead to irreparable cellular damage.

Hereditary non-spherocytic anemia is a constant side effect of PKD. From the neonatal era until adulthood, manifestations take place. Hemolytic anemia may lead to a variety of problems.

Epidemiology

PKD was first identified by Valentine et al. in 1961. Since this discovery, news has spread across the globe. An uncommon condition, PKD. The unknown is the true prevalence of PKD. The estimated prevalence of PKD in Western people is between 3.2 and 8.5 cases per million. A frequency of 1:20,000 has already been noted, though.

The frequency of mutant alleles may be close to 51 in million. Tunisia and Brazil have case clusters. There doesn’t seem to be much data on gender differences in PKD. In other communities, like the Romani and Amish in Pennsylvania, some mutations are more prevalent.

This observation might be explained by a few things. A founding effect shows that mutations are heritable. Specific migrant couples have been linked to certain mutations. Consanguinity also raises the likelihood of homozygosity.

Anatomy

Pathophysiology

RBC ATPases that are membrane-bound protect the cells’ integrity. ATPases swap potassium for sodium. As a result, cellular fluid equilibrium, deformability, and transcellular electrical and chemical neutrality are all preserved. RBC ATP generation is reduced by PK enzyme deficiency, which reduces RBC deformability.

Fluid loss and intracellular potassium toxicity also happen. Damage to RBC is the result. Enzyme concentrations of 25percent or lower cause PKD to emerge. Hepatic and splenic capillaries seize damaged RBCs. Hepatosplenomegaly is caused by extravascular hemolysis. Additionally, hemoglobinuria can be brought on by intravascular hemolysis.

The growing weariness in PKD is caused by anemia. Elevated 2,3-DPG results in tissue oxygen discharge. This causes the oxygen dissociation graph to shift to the right. Increased 2,3-DPG aids in anemia restitution. In patients who are homozygotic, these mechanisms are at work. The majority of heterozygote carriers exhibit no symptoms.

Hemolysis, however, can happen under stressful circumstances. A lack of folate is caused by prolonged hemolysis. Extramedullary hemopoiesis has been documented in PKD. RBCs in newborns use more ATP than adult RBCs. Exchange transfusion may be necessary to avoid kernicterus because the splenic loss of reticulocytes results in hyperbilirubinemia.

Fetal hydrops can be the consequence of extreme anemia in pregnancy. Newborn anemia that requires transfusions may happen. These people get dilutional anemia throughout the second trimester of pregnancy. RBC mass rises more slowly than plasma levels.

It seems likely that maternal hemodilution leads to better fetal results. Additionally, it reduces postpartum loss of blood. PKD may make a pregnant woman’s physiological anemia worse. Periodic hemolysis may call for RBC replacement by transfusion.

Etiology

Glycolysis is crucial to the metabolism of red blood cells (RBCs). The enzyme pyruvate kinase (PK) is essential to this procedure. Phosphoenolpyruvate is changed into pyruvate by PK. This process results in 50 percent of Erythrocyte ATP. For the purpose of reducing methemoglobin, PK controls NADH synthesis.

These metabolites are necessary for RBCs to function properly. Cell energy efficiencies and lifespan are reduced in PKD. In PKD, young RBCs are particularly impacted. The PK-LR gene controls the expression of PK. The gene is found on 1q21 of the chromosome. The inheritance pattern for PKD is autosomal recessive.

Both compound heterozygotes and homozygotes are impacted. Two distinct mutant genotypes are inherited by complex heterozygotes. There have been discovered about 300 mutations that cause PKD. Most of these mutations are missense ones. However, reports of new mutations have been made. Mutations of the frameshift, deletion and insertion types can happen.

Genetics

Prognostic Factors

In PKD, the prognosis is quite unpredictable. Early intervention and severity of disease affect results. In especially during pregnancy, hemosiderosis and serious anemia are risky and undesirable.

Clinical History

Neonatal Period: 

• In some cases, infants may present with jaundice and anemia shortly after birth. 
• Anemia in the neonatal period can be severe, leading to pallor and lethargy. 

Early Childhood: 

• Children with PKD may exhibit signs of chronic hemolysis, including jaundice, splenomegaly (enlarged spleen), and pallor. 
• Fatigue, irritability, and poor growth may be observed. 
• The severity of symptoms can vary, and some children may have a milder presentation. 

Adolescence and Adulthood: 

• Individuals may continue to experience chronic hemolysis, leading to anemia, jaundice, and splenomegaly. 
• Fatigue, shortness of breath, and palpitations may be more noticeable during physical activity. 
• Some individuals may remain relatively asymptomatic, especially if their PKD is less severe. 

Acute Episodes: 

• Individuals with PKD may experience acute episodes of hemolysis triggered by factors such as infections, medications, or stress. 
• Acute episodes can lead to a sudden worsening of symptoms, including increased jaundice, pallor, and anemia. 

Associated Comorbidities: 

• Splenomegaly: Enlargement of the spleen is a common feature in PKD, and in some cases, splenectomy may be considered to reduce hemolysis. 

• Infections: Individuals, especially those who have undergone splenectomy, are at an increased risk of certain bacterial infections, necessitating preventive measures such as vaccinations and antibiotic prophylaxis. 

Physical Examination

• Jaundice: It is a yellowing of the skin and sclera (the whites of the eyes), is a common feature of hemolytic anemias, including PKD. Healthcare providers will evaluate the degree of jaundice. 
• Pallor: Pallor may be noticeable, reflecting the reduced number of red blood cells and the severity of anemia. 
• Splenomegaly: Enlargement of the spleen (splenomegaly) is a characteristic finding in PKD. The healthcare provider may palpate the abdomen to assess the size of the spleen. 
• Liver Examination: In some cases, the liver may be palpated to check for enlargement. 
• Assessment of Growth and Development: In pediatric patients, healthcare providers may assess growth and development, looking for signs of delayed growth or failure to thrive. 
• Vital Signs: Heart rate, and respiratory rate are routinely measured to assess the overall health and stability of the individual. 
• Cardiovascular Examination: Healthcare providers may listen to the heart for signs of increased heart rate or murmurs associated with anemia. 

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

• Hereditary Spherocytosis (HS): Like PKD, hereditary spherocytosis is a genetic disorder affecting red blood cells, leading to hemolytic anemia. It is characterized by spherical-shaped red blood cells, and patients may present with jaundice, splenomegaly, and anemia. 
• G6PD Deficiency (Glucose-6-Phosphate Dehydrogenase Deficiency): This enzyme deficiency can lead to hemolysis, especially in response to certain triggers such as infection, certain medications, or fava bean ingestion. An X-linked recessive condition called G6PD deficiency can occasionally result in hemolysis. 
• Thalassemia: Both alpha and beta thalassemias can result in hemolytic anemia. Thalassemia is characterized by abnormal hemoglobin production, leading to the destruction of red blood cells. Thalassemias are usually diagnosed through hemoglobin electrophoresis and genetic testing. 
• Autoimmune Hemolytic Anemia (AIHA): Hemolysis results from the immune system’s inadvertent destruction of red blood cells in this scenario. AIHA can be secondary to various underlying conditions or occur idiopathically. 
• Pregnancy-Induced Hemolytic Anemia: In some cases, pregnancy can induce hemolysis, and conditions like glucose-6-phosphate dehydrogenase deficiency or other hemoglobinopathies may become more apparent during pregnancy. 
• Paroxysmal Nocturnal Hemoglobinuria (PNH): It is a rare acquired disorder characterized by complement-mediated hemolysis. It often presents with hemoglobinuria, thrombosis, and bone marrow failure. 
• Malaria: In regions where malaria is prevalent, it can lead to hemolytic anemia. Malaria should be considered, especially in individuals with a history of travel to endemic areas. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• Folate Supplementation: Folate (vitamin B9) supplementation is often recommended. Since PKD leads to increased red blood cell turnover, folate is essential for the production of new red blood cells. Folate supplementation can help support erythropoiesis and reduce the risk of megaloblastic changes in the bone marrow. 

• Blood Transfusions: Blood transfusions could be required to maintain appropriate hemoglobin levels in situations of severe anemia or during times of increased hemolysis. Transfusions can provide temporary relief from symptoms but are not a cure for PKD. 
• Splenectomy: In extreme hemolysis situations, splenectomy—the surgical removal of the spleen—may be considered. In PKD, the spleen may also capture and kill healthy red blood cells in addition to its normal function of filtering and eliminating damaged red blood cells. Splenectomy can reduce hemolysis and improve anemia but increases the risk of infections, particularly with encapsulated bacteria. Vaccination and prophylactic antibiotics may be recommended after splenectomy. 
• Chelation Therapy: For individuals who undergo regular blood transfusions, iron overload can become a concern. Chelation therapy may be considered to remove excess iron from the body and prevent complications associated with iron overload. 
• Supportive Care: Patients with PKD may benefit from general supportive care measures such as maintaining good hydration, avoiding triggers that can exacerbate hemolysis (such as certain medications or infections), and managing complications like gallstones or iron overload. 
• Genetic Counseling: Hereditary counseling is a crucial part of the therapy paradigm for Parkinson’s disease (PKD) because it is a hereditary ailment. Family planning, the inheritance pattern, and the possibility of passing the disease on to future generations are all topics that genetic counseling may address. 
• Disease Monitoring: Regular monitoring of blood counts, reticulocyte counts, and other relevant laboratory parameters is important to assess the effectiveness of treatment and to identify and manage complications promptly. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

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Dietary Considerations: 

• Folate-Rich Diet: Ensuring an adequate intake of folate-rich foods can support red blood cell production. Good sources of folate include legumes, fortified cereals, and leafy green vegetables. 
• Hydration: Staying well-hydrated is essential to prevent dehydration, especially during periods of increased hemolysis. 

Avoiding Triggers: 

• Infections: Since infections can trigger hemolysis, practicing good hygiene and promptly treating infections is important. Regular vaccinations, including those for encapsulated bacteria, may be recommended. 
• Certain Medications: Avoiding medications that can exacerbate hemolysis or cause oxidative stress is crucial. Individuals with PKD should consult their healthcare provider before taking new medications. 

Regular Exercise: 

• Moderate Physical Activity: Regular, moderate exercise can promote overall health and well-being. However, excessive physical stress should be avoided, as it may contribute to increased hemolysis. 

Avoiding Oxidative Stress: 

• Environmental Factors: Minimizing exposure to environmental factors that can induce oxidative stress, such as certain chemicals or pollutants, may be beneficial. 

Genetic Counseling and Family Planning: 

• Family Planning: Genetic counseling is crucial for individuals with PKD who are considering having children. Understanding the inheritance pattern and potential risks can inform family planning decisions. 

Psychosocial Support: 

• Counseling and Support Groups: Living with a chronic condition can be challenging, and psychological well-being is an integral part of overall health. Counseling or joining support groups can provide emotional support and practical advice. 

Regular Monitoring: 

• Health Check-ups: Regular follow-up with healthcare providers for routine monitoring of blood counts, reticulocyte counts, and other relevant parameters is essential. 

Splenectomy Considerations: 

• Careful Evaluation: If splenectomy is considered, careful evaluation of the risks and benefits, along with appropriate preoperative and postoperative care, is crucial. 

Role of Water-soluble vitamins in the treatment of Pyruvate Kinase Deficiency

Water-soluble vitamins, particularly vitamin B9 (folate), play a significant role in the treatment of Pyruvate Kinase Deficiency (PKD). PKD is a genetic disorder that affects red blood cells and leads to hemolytic anemia. Folate is essential for various cellular processes, including DNA synthesis and repair, and it has a specific relevance in the context of PKD. 

Folate is critical for the production and maturation of red blood cells. Since individuals with PKD experience increased red blood cell turnover due to hemolysis, ensuring an adequate supply of folate is crucial to support erythropoiesis and prevent megaloblastic changes in the bone marrow. Folate supplementation can help improve anemia symptoms and contribute to maintaining normal blood cell production rates. 

Folate is necessary for the synthesis of DNA, and its deficiency can lead to impaired DNA synthesis, resulting in enlarged and immature red blood cell precursors (megaloblasts). Folate supplementation helps prevent or correct megaloblastic anemia. 

Folic acid: Red blood cell-producing enzymes require folic acid as a cofactor in their activity. 

Role of Pyruvate Kinase-R Activators in the treatment of Pyruvate Kinase Deficiency

PK-R is an isoenzyme of pyruvate kinase, and activating this isoform could potentially compensate for the reduced activity of pyruvate kinase in individuals with PKD. 

The rationale behind developing PK-R activators is to stimulate the remaining functional pyruvate kinase enzyme in red blood cells, promoting glycolysis and reducing hemolysis. However, it’s important to note that specific medications or treatments targeting PK-R activation were not yet widely available or approved for clinical use. 

Mitapivat:  It is a novel pyruvate kinase (PK) activator, and it has shown promise in the treatment of hemolytic anemia associated with Pyruvate Kinase Deficiency (PKD). Mitapivat is a first-in-class small molecule that specifically targets the underlying defect in PKD by activating pyruvate kinase, an enzyme crucial for glycolysis in red blood cells. It works by promoting the active, tetrameric form of pyruvate kinase, increasing its enzymatic activity. By enhancing the function of pyruvate kinase, Mitapivat helps improve the energy metabolism of red blood cells, reducing hemolysis and potentially increasing the lifespan of these cells.  

Role of antibiotics in the treatment of Pyruvate Kinase Deficiency

Individuals with PKD may be more susceptible to infections due to the increased turnover of red blood cells and potential spleen dysfunction. Infections can exacerbate hemolysis in these individuals. Antibiotics are used to treat bacterial infections promptly and prevent complications. It’s important to choose antibiotics that cover the specific bacteria causing the infection.In cases where splenectomy (removal of the spleen) is performed, individuals become more susceptible to certain bacterial infections, particularly those caused by encapsulated bacteria. Antibiotic prophylaxis, along with vaccination against these bacteria, may be recommended to reduce the risk of infections post-splenectomy. 

Pencillin Vk: Cell wall mucopeptide production is inhibited by penicillin VK. 

Erythromycin: By preventing the peptidyl ribonucleic acid transfer (tRNA) from dissociating from ribosomes and so arresting RNA-dependent protein synthesis, this antibiotic suppresses the development of bacteria. 

Role of Vaccines in the treatment of Pyruvate Kinase Deficiency

Vaccines play a crucial role in the overall management of Pyruvate Kinase Deficiency (PKD), especially in individuals who have undergone splenectomy. Splenectomy is sometimes performed in patients with PKD to reduce hemolysis and alleviate symptoms.  

Vaccines are administered to individuals with PKD, especially those who have undergone splenectomy, to prevent infections by providing immunity against specific pathogens. The most common vaccines recommended for individuals with PKD include: 

Pneumococcal Vaccines: 

• Pneumococcal Conjugate Vaccine (PCV13): Defends against 13 different strains of the bacteria Streptococcus pneumoniae, which is known to cause diseases such as meningitis and pneumonia. 
• Pneumococcal Polysaccharide Vaccine (PPSV23): Provides additional coverage against additional strains of Streptococcus pneumoniae. 

Haemophilus influenzae Type b (Hib) Vaccine: 

• Protects against the bacteria Haemophilus influenzae, also known as type b, which can cause invasive infections including meningitis and pneumonia. 

Meningococcal Vaccines: 

• Meningococcal Conjugate Vaccine (MenACWY): Offers defense against the bacteria Neisseria meningitidis, which can result in septicemia and meningitis. 
• Meningococcal B Vaccine (MenB): Targets specific serogroup B strains of Neisseria meningitidis. 

Influenza (Flu) Vaccine: 

• Seasonal influenza vaccines are recommended annually to protect against the flu virus, which can cause respiratory infections 

use-of-intervention-with-a-procedure-in-treating-pyruvate-kinase-deficiency

• Blood Transfusions: Individuals with severe anemia due to PKD may require regular blood transfusions to increase their red blood cell count and improve oxygen transport. 
• Medication: Folic acid supplementation is often recommended to support red blood cell production. In some cases, other medications may be prescribed to manage symptoms and complications associated with PKD. 
• Splenectomy: Surgical removal of the spleen is considered for individuals with PKD. The spleen is involved in the destruction of red blood cells, and removing it can help to reduce the rate of hemolysis (breakdown of red blood cells). 
• Stem Cell Transplant: A possible therapy for Parkinson’s disease (PKD) has been investigated: stem cell transplantation, specifically hematopoietic stem cell transplantation. This procedure aims to replace defective stem cells with healthy ones that can produce normal red blood cells. 
• Gene Therapy: As of my last update, gene therapy is an area of active research for treating genetic disorders, including PKD. The goal of gene therapy is to fix the underlying genetic flaw that causes the enzyme shortage. 

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Diagnostic Phase: 

• Accurate diagnosis is crucial for effective management. This phase involves obtaining a thorough medical history, conducting physical examinations, and performing diagnostic tests such as blood tests, hemoglobin electrophoresis, enzyme assays, and genetic testing to confirm the presence of PKD. 

Symptom Management Phase: 

Once diagnosed, the focus shifts to managing symptoms associated with PKD, particularly hemolytic anemia. This may involve: 

• Folate supplementation to support red blood cell production. 
• Transfusions of blood to keep hemoglobin levels at a healthy level and treat anemia symptoms. 
• Monitoring for complications such as gallstones and iron overload, and addressing them as needed. 
• Avoiding triggers that can exacerbate hemolysis, such as certain medications or infections. 

Preventive Phase: 

This phase aims to prevent complications and optimize overall health. Key strategies include: 

• Regular monitoring of blood parameters to assess treatment effectiveness and detect any changes. 

• Vaccination against infections, especially for individuals who have undergone splenectomy. 
• Genetic counseling and family planning for affected individuals and their families. 
• Education about the condition and lifestyle modifications to minimize risks. 

Advanced Treatment Phase: 

For individuals with severe symptoms or complications that are not adequately controlled with supportive measures, more advanced treatments may be considered. These may include: 

• Splenectomy: Surgical removal of the spleen to reduce hemolysis, although it carries risks of increased susceptibility to certain infections. 
• Emerging therapies: Investigational treatments such as pyruvate kinase activators (e.g., Mitapivat) that target the underlying defect in PKD. 

Long-Term Management Phase: 

PKD is a chronic condition that requires ongoing monitoring and management. Long-term management involves: 

• Routine follow-up appointments with medical professionals to evaluate the effectiveness of the therapy and modify the plan as necessary. 
• Continuation of supportive measures to maintain stable hemoglobin levels and overall health. 
• Management of any new symptoms or complications that may arise over time. 

Medication

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References

https://www.ncbi.nlm.nih.gov/books/NBK560581/

Pyruvate Kinase Deficiency:ncbi.nlm.nih.