What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?
PNH, or Paroxysmal Nocturnal Hemoglobinuria is a rare bone marrow disease affecting the blood, that causes premature death and impaired production of blood cells. This disorder affects red blood cells, which cary oxygen around the body; white blood cells, which protect the body from infection; and platelets which are important for blood clotting. PNH has also been referred to as Marchiafava-Micheli syndrome.
PNH is a non-hereditary genetic disorder caused by a somatic mutation in the PIG-A gene (phosphatidylinositol N-acetylglucosaminyltransferase subunit A) in one or more hematopoietic stem cell (HSC) clones. An affected stem cell can rapidly divide, and result in many mature red blood cells with the PIG-A mutation. The PIG-A gene is responsible for building the protective protein shield around red blood cell. PNH affected blood cells, lack a protein on the surface of the cell, allowing them to be destroyed by one’s own immune (complement) system. [1, 2, 3]
PNH is a non-hereditary genetic disorder caused by a somatic mutation in the PIG-A gene (phosphatidylinositol N-acetylglucosaminyltransferase subunit A) in one or more hematopoietic stem cell (HSC) clones. An affected stem cell can rapidly divide, and result in many mature red blood cells with the PIG-A mutation. The PIG-A gene is responsible for building the protective protein shield around red blood cell. PNH affected blood cells, lack a protein on the surface of the cell, allowing them to be destroyed by one’s own immune (complement) system. [1, 2, 3]
Figure 1: Bone marrow disease causing destruction of red blood cells
Affected PopulationsPNH is a rare disorder affecting mend and women the same. the prevalence is only between 1 and 5 per million people. It occurs all around the world, affecting people of many ethnic backgrounds. It is thought to be more prevalent in Southeast Asia where rates of aplastic anemia is the greatest. PNH can occur at any age but is most commonly identified in early to middle adulthood. This disorder is acquired and not inherited through generations. [3, 4]
|
|
Symptoms
PNH patients often have sudden and recurring symptoms, which could be triggered by stress on the body, such as infection or physical exertion. During these episodes, the immune system will trigger the destruction of PNH affected cells. There are many symptoms associated with PNH due to the effects it has on blood, platelets, and white blood cells. Each of these factors can lead to varying symptoms observed.
Hemolysis - Breaking apart of red blood cells.
- Low red blood cell count (anemia)
- Muscle spasms - Cause shortage of nitric oxide in the body (cause clots) Thrombocytopenia - Low platelet count - Excessive bleeding of gums, nose, or minor cuts. - Heavier menstrual periods - Tiny flat red spots under skin caused by bleeding or excessive bruising. [1, 3, 5] |
Thrombosis - Blood clot in a vein. Occurs in 15-30% of patients.
It is not entirely sure why PNH patients are more likely to get blood clots, however it is believed to be a combination between abnormal "sticky" platelets that clot too often, and a shortage of nitric oxide which helps prevent blood clots. Symptoms of blood clots depend on the location. - Abdomen and Limbs
Neutropenia - Low white blood cell count Affects a persons ability to fight bacterial infections. - Repeated fevers and infections [1, 3, 4, 5] |
Diagnostics
Anyone with symptoms corresponding to PNH should get tested.
Blood Tests
Complete blood cell count is done to determine how much of each blood cell you have. LDH test looks at an enzyme called lactate dehydrogenase, and is a common lab that is monitored regularly. High LDH level means red blood cells are breaking apart (hemolysis). Bilirubin (liver function) test measures the amount of substance in the blood, and high levels can indicate hemolysis. Reticulocyte count measures the amount of young red blood cells, and an elevated number means red bone marrow is making more red blood cells to compensate for hemolysis. Urinalysis test can show signs of blood in the urine. Haptoglobin test identifies a protein that eliminates debris caused form damaged blood cells, and low levels can be a sign of increased blood cell damage. Finally, a basic metabolic panel can be used to look for signs of chronic kidney disease and renal dysfunction. [1, 6]
Bone Marrow Tests
This is important to test the quality of the bone marrow, and to see how well or poorly the bone marrow is making blood cells. This identifies the quantity and types of cells the bone marrow is making, levels of iron in the bone marrow, and chromosomal DNA abnormalities. [1]
Flow Cytometry
This is considered the gold standard for PNH diagnostics. This test can identify what proteins, if any are present on the surface of blood cells. The proteins on the surface of blood cells are CD55 and CD59. This can also identify how many cells are missing proteins, which can be grouped into one of three categories. *Note a patient with PNH can have more than one type of blood cell and this varies per person. [1, 6]
Complete blood cell count is done to determine how much of each blood cell you have. LDH test looks at an enzyme called lactate dehydrogenase, and is a common lab that is monitored regularly. High LDH level means red blood cells are breaking apart (hemolysis). Bilirubin (liver function) test measures the amount of substance in the blood, and high levels can indicate hemolysis. Reticulocyte count measures the amount of young red blood cells, and an elevated number means red bone marrow is making more red blood cells to compensate for hemolysis. Urinalysis test can show signs of blood in the urine. Haptoglobin test identifies a protein that eliminates debris caused form damaged blood cells, and low levels can be a sign of increased blood cell damage. Finally, a basic metabolic panel can be used to look for signs of chronic kidney disease and renal dysfunction. [1, 6]
Bone Marrow Tests
This is important to test the quality of the bone marrow, and to see how well or poorly the bone marrow is making blood cells. This identifies the quantity and types of cells the bone marrow is making, levels of iron in the bone marrow, and chromosomal DNA abnormalities. [1]
Flow Cytometry
This is considered the gold standard for PNH diagnostics. This test can identify what proteins, if any are present on the surface of blood cells. The proteins on the surface of blood cells are CD55 and CD59. This can also identify how many cells are missing proteins, which can be grouped into one of three categories. *Note a patient with PNH can have more than one type of blood cell and this varies per person. [1, 6]
Other tests are often required to develop a proper treatment plan.
Types of PNH
Type 1PNH 1 cells are NORMAL and can respond like normal red blood cells to the immune system. They are not missing any CD55 or CD59 proteins. [1]
|
Type 2PNH 2 cells are partially sensitive to the immune system. They are missing some CD55 and CD59 proteins on the cell surface which protect from immune attacks. [1]
|
Type 3PNH 3 cells are extremely sensitive to the immune system. The red blood cells lack all the proteins on the cell surface and break apart the easiest. [1]
|
PNH associated with PIG-T
There is an additional form of PNH that is associated with the PIG-T gene. This variation of PNH is extremely rare, affecting even less individuals than PIG-A associated PNH. The risk of developing the PIG-T related form of PNH follows autosomal dominant inheritance pattern, allowing it to be passed through generations. Like PIG-A, this rare form can also be developed from a somatic mutation. In abnormal cells with PIG-T gene variants, the somatic variant deletes other nearby genes that mediate cell development. It is suggested that the loss of these genes increase the proportion of abnormal blood cells in the body affecting the severity of symptoms. Unlike PIG-A related PNH, the PIG-T variation allows the development of GPI anchored proteins, but prevents the attachment of proteins to the membrane anchor. This rare form involves abnormal inflammation in addition to other typical symptoms observed. Inflammation is a normal immune response to injury and foreign invaders. When the PIG-T gene is mutated, abnormal inflammation occurs in the membranes of the brain and spinal cord, rashes, joint pain, and inflammatory bowel disease. These symptoms are often observed earlier than blood related symptoms. [3]
There is an additional form of PNH that is associated with the PIG-T gene. This variation of PNH is extremely rare, affecting even less individuals than PIG-A associated PNH. The risk of developing the PIG-T related form of PNH follows autosomal dominant inheritance pattern, allowing it to be passed through generations. Like PIG-A, this rare form can also be developed from a somatic mutation. In abnormal cells with PIG-T gene variants, the somatic variant deletes other nearby genes that mediate cell development. It is suggested that the loss of these genes increase the proportion of abnormal blood cells in the body affecting the severity of symptoms. Unlike PIG-A related PNH, the PIG-T variation allows the development of GPI anchored proteins, but prevents the attachment of proteins to the membrane anchor. This rare form involves abnormal inflammation in addition to other typical symptoms observed. Inflammation is a normal immune response to injury and foreign invaders. When the PIG-T gene is mutated, abnormal inflammation occurs in the membranes of the brain and spinal cord, rashes, joint pain, and inflammatory bowel disease. These symptoms are often observed earlier than blood related symptoms. [3]
TreatmentMost treatment options are designed to minimize the effect of symptoms and prevent further complications. Therefore treatment plans vary person to person and is based on the severity of symptoms.
Treatment for anemia includes taking folic acid to promote production of red blood cells by the bone marrow. Iron supplements to make more blood cells. As well as different drugs that prevent the breakdown of blood cells. In more severe cases blood transfusions are required to treat anemia. Blood thinners are also common to prevent blood clotting. Further treatments may be used to reduce the impacts of other symptoms observed. Common drugs used treat PNH symptoms:
|
The only cure for PNH is a bone marrow stem cell transplant. This is possible if you have a healthy relative, usually brother or sister, to donate stem cells that can replace the defective hematopoietic stem cells in the bone marrow. The defective bone marrow is destroyed using drugs or radiation. This cure can have serious health risks, and is only offered to patients with a match that are young and have serious PNH. [5, 8]
Symptom Control
To minimize symptoms it is recommended PNH patients maintain a healthy lifestyle. A healthy diet, rich in vitamin C combined with iron rich foods helps absorb the iron and prevent anemia. Exercise is important, but should be skipped when red blood cell count is too low, and activities cause increased heart rate, chest pain, or difficulty breathing. Check with your doctor what exercise options are best. Lastly, it is important PNH patients try to stay healthy and avoid infections and contact with sick individuals. Getting a viral or bacterial infection will initiate an immune response and can cause an increase in destruction of PNH affected red blood cells, worsening ones symptoms. [5]
Symptom Control
To minimize symptoms it is recommended PNH patients maintain a healthy lifestyle. A healthy diet, rich in vitamin C combined with iron rich foods helps absorb the iron and prevent anemia. Exercise is important, but should be skipped when red blood cell count is too low, and activities cause increased heart rate, chest pain, or difficulty breathing. Check with your doctor what exercise options are best. Lastly, it is important PNH patients try to stay healthy and avoid infections and contact with sick individuals. Getting a viral or bacterial infection will initiate an immune response and can cause an increase in destruction of PNH affected red blood cells, worsening ones symptoms. [5]
Risk FactorsPNH can lead to other health complications if not treated. PNH, aplastic anemia, and myelodysplastic syndrome (MDS) are bone marrow failure diseases. Often PNH leads to bone marrow failure which is when the marrow does not produce enough red blood cells, white cells, or platelets to keep up with the damaged cells, and the body cannot supply itself with the blood, oxygen, and nutrients it needs.
Aplastic anemia (AA) is a known risk for developing PNH, which is when the body stops producing enough red blood cells. More than 10/100 people with AA will also develop PNH. On the other hand, it has been identified that patients with PNH develop aplastic anemia. 2/100 PNH patents also have been found to develop MDS which is a group of cancers in which immature blood cells in the bone marrow do not mature into healthy blood cells. [1] |
LifespanThe lifespan for individuals with PNH is continuously increasing with new and better medical technologies. There are currently good treatment options, and new treatments are being developed to help PNH patients live longer. This is dependent on the severity of the disease and how symptoms are managed. Life expectancy is steadily climbing to over 20 years. Hopefully soon, PNH patients will have the same life expectance as the average person of the same age. [1]
|
Function of PIG-A gene
Figure 2: Comparison of normal red blood cell to PNH affected red blood cell.
|
The PIG-A gene encodes a protein required for the biosynthesis of glycosylphosphatidylinositol (GPI), which attaches dozens of proteins to the surface of red blood cells. Surface GPI-anchored proteins such as CD55, and CD59 sit on the surface of red blood cells to function as complement system regulators. These proteins on the surface of red blood cells allow recognition of the cells by the immune system, preventing destruction. Hematopoietic stem cells are responsible for producing mature red blood cells in bone marrow. When the PIG-A gene is mutated in somatic hematopoietic stem cells (HSCs), the stem cells begin producing mature red blood cells that no longer have surface GPI-anchored proteins (CD55 and CD59) which leads to hemolysis or destruction of one's own blood cells by their immune system, a disease known as PNH. The constant destruction of red blood cells causes severe life threatening symptoms. PNH is more commonly caused from a mutation in the PIG-A gene, but can also develop from mutations in several other genes. Depending on the location of the mutation, different therapies are more effective than others for PNH patients. PNH can result result in several different mutations averaging a mutation load of 3.85 genes per patient. The most common mutations seen in the PIG-A gene include truncation, splicing-site mutations, frame-shift deletion, missense mutation, or additional mutations located in intronic sites or the 3' untranslated region. [10, 11, 12]
|
Chromosomal Location of PIG-A
The PIG-A gene is located on chromosome Xp22. [10]
Figure 3: PIG-A gene is located at position 22 on chromosome X.
Current Knowledge Gap
|
The role of PIG-A in mediating normal blood cell function remains unclear. Especially in the synthesis of GPI-anchored proteins that aid in resistance of immune responses signaling for cellular destruction.
It also is unclear why certain PNH blood cells show different patterns of GPI-anchoring, and how each of these affects cellular sensitivity to immune responses. [1] |
|
Courtney Youngchild |
Recent Visits
References
[1] PNH - paroxysmal nocturnal hemoglobinuria. Aplastic Anemia & MDS International Foundation. (n.d.). Retrieved February 23, 2023, from https://www.aamds.org/diseases/pnh
[2] Hill, A. et al. (2017, May 18). Paroxysmal nocturnal haemoglobinuria. Nature reviews. Disease primers. Retrieved February 23, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879566/
[3] Brodsky et al. (2022, February 24). Paroxysmal nocturnal hemoglobinuria: Medlineplus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/paroxysmal-nocturnal-hemoglobinuria/
[4] Parker, C. J. (2023, January 12). Paroxysmal nocturnal hemoglobinuria - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/
[5] Peri, C. et al. (2021, September 2). Paroxysmal nocturnal hemoglobinuria (PNH): Causes, symptoms, and treatment. WebMD. Retrieved February 23, 2023, from https://www.webmd.com/digestive-disorders/paroxysmal-nocturnal-hemoglobinuria-pnh#091e9c5e80f063fe-3-8
[6] Paroxysmal nocturnal hemoglobinuria (PNH): Symptoms & treatment. Cleveland Clinic. (2022, April 25). https://my.clevelandclinic.org/health/diseases/22871-paroxysmal-nocturnal-hemoglobinuria
[7] Unmet need for PNH patients: EMPAVELI® (pegecetacopan). Empaveli HCP. (2023, March 21). https://empavelihcp.com/pnh/
[8] Arrendell, A. (2022, May 19). Paroxysmal nocturnal hemoglobinuria (PNH): Johns Hopkins Kimmel Cancer Center. Paroxysmal Nocturnal Hemoglobinuria (PNH) | Johns Hopkins Kimmel Cancer Center. https://www.hopkinsmedicine.org/kimmel_cancer_center/cancers_we_treat/blood_bone_marrow_cancers/paroxysmal_nocturnal_hemoglobinuria_PNH.html
[9] Stern RM, Connell NT. Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728. doi: 10.1177/2040620719874728. PMID: 31534662; PMCID: PMC6737867.
[10] Uniprot website fallback message. UniProt. (n.d.). Retrieved February 23, 2023, from https://www.uniprot.org/uniprotkb/P37287/entry#family_and_domains
[11] Chen, F., Hu, S., Ruan, J. et al. Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria. Blood Cancer J. 11, 58 (2021). https://doi.org/10.1038/s41408-021-00451-1
[12] Rasmussen, S. A. (2022, July 21). Entry - #300818 - paroxysmal nocturnal hemoglobinuria 1; PNH1 - OMIM. Human Genetics Knowledge for the World. Retrieved February 24, 2023, from https://www.omim.org/entry/300818
Images
Header: https://www.medpagetoday.com/hematologyoncology/hematology/91681
Transfusion Cartoon: https://www.freepik.com/premium-vector/cute-cartoon-illustration-blood-drop-having-blood-transfusion-with-cute-modern-style-deign_29832875.htm
Figure 1: https://www.hcp.novartis.com/medical/areas-of-research/pnh/a/mechanism-of-disease/
Figure 2: https://www.hcp.novartis.com/medical/areas-of-research/pnh/a/mechanism-of-disease/
Figure 3: https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chrX%3A15319451%2D15335554&hgsid=1577970275_lfrWbR2ALotGUzHDNujMLIaYUzXw
[2] Hill, A. et al. (2017, May 18). Paroxysmal nocturnal haemoglobinuria. Nature reviews. Disease primers. Retrieved February 23, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879566/
[3] Brodsky et al. (2022, February 24). Paroxysmal nocturnal hemoglobinuria: Medlineplus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/paroxysmal-nocturnal-hemoglobinuria/
[4] Parker, C. J. (2023, January 12). Paroxysmal nocturnal hemoglobinuria - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/
[5] Peri, C. et al. (2021, September 2). Paroxysmal nocturnal hemoglobinuria (PNH): Causes, symptoms, and treatment. WebMD. Retrieved February 23, 2023, from https://www.webmd.com/digestive-disorders/paroxysmal-nocturnal-hemoglobinuria-pnh#091e9c5e80f063fe-3-8
[6] Paroxysmal nocturnal hemoglobinuria (PNH): Symptoms & treatment. Cleveland Clinic. (2022, April 25). https://my.clevelandclinic.org/health/diseases/22871-paroxysmal-nocturnal-hemoglobinuria
[7] Unmet need for PNH patients: EMPAVELI® (pegecetacopan). Empaveli HCP. (2023, March 21). https://empavelihcp.com/pnh/
[8] Arrendell, A. (2022, May 19). Paroxysmal nocturnal hemoglobinuria (PNH): Johns Hopkins Kimmel Cancer Center. Paroxysmal Nocturnal Hemoglobinuria (PNH) | Johns Hopkins Kimmel Cancer Center. https://www.hopkinsmedicine.org/kimmel_cancer_center/cancers_we_treat/blood_bone_marrow_cancers/paroxysmal_nocturnal_hemoglobinuria_PNH.html
[9] Stern RM, Connell NT. Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728. doi: 10.1177/2040620719874728. PMID: 31534662; PMCID: PMC6737867.
[10] Uniprot website fallback message. UniProt. (n.d.). Retrieved February 23, 2023, from https://www.uniprot.org/uniprotkb/P37287/entry#family_and_domains
[11] Chen, F., Hu, S., Ruan, J. et al. Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria. Blood Cancer J. 11, 58 (2021). https://doi.org/10.1038/s41408-021-00451-1
[12] Rasmussen, S. A. (2022, July 21). Entry - #300818 - paroxysmal nocturnal hemoglobinuria 1; PNH1 - OMIM. Human Genetics Knowledge for the World. Retrieved February 24, 2023, from https://www.omim.org/entry/300818
Images
Header: https://www.medpagetoday.com/hematologyoncology/hematology/91681
Transfusion Cartoon: https://www.freepik.com/premium-vector/cute-cartoon-illustration-blood-drop-having-blood-transfusion-with-cute-modern-style-deign_29832875.htm
Figure 1: https://www.hcp.novartis.com/medical/areas-of-research/pnh/a/mechanism-of-disease/
Figure 2: https://www.hcp.novartis.com/medical/areas-of-research/pnh/a/mechanism-of-disease/
Figure 3: https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chrX%3A15319451%2D15335554&hgsid=1577970275_lfrWbR2ALotGUzHDNujMLIaYUzXw