Paroxysmal nocturnal hemoglobinuria

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Paroxysmal nocturnal hemoglobinuria
Other namesParoxysmal nocturnal haemoglobinuria, Marchiafava–Micheli syndrome
Haemolytic Anaemia.jpg
Intravascular hemolytic anemia
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, [1] life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venous blood clot formation. [2] Research suggests that PNH thrombosis (a blood clot) is caused by both the absence of GPI-anchored complement regulatory proteins (CD55 and CD59) on PNH platelets and the excessive consumption of nitric oxide (NO). [3]

Contents

PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol or GPI) leading to the absence of protective exterior surface proteins that normally attach via a GPI anchor. [4] It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority of affected people have the telltale red urine in the morning that originally gave the condition its name. [5]

Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and death. [6] The monoclonal antibody eculizumab reduces the need for blood transfusions and improves quality of life for those affected by PNH. [6] Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to the extent that it may be equivalent to that of the general population. [7] Eculizumab costs at least US$440,000 for a single year of treatment and has been reported as one of the world's most expensive drugs. [8] [9] [10]

Signs and symptoms

The classic sign of PNH is red discoloration of the urine due to the presence of hemoglobin and hemosiderin from the breakdown of red blood cells. [11] As the urine is more concentrated in the morning, this is when the color is most pronounced. This phenomenon mainly occurs in those who have the primary form of PNH, who will notice this at some point in their disease course. The remainder mainly experience the symptoms of anemia, such as fatigue, shortness of breath, and palpitations. [5]

A small proportion of patients report attacks of abdominal pain, difficulty swallowing and pain during swallowing, as well as erectile dysfunction in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm of smooth muscle due to depletion of nitric oxide by red cell breakdown products. [12]

Forty percent of people with PNH develop thrombosis at some point in their illness. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in those with PNH. [5]

Pathophysiology

CD55 protein/Decay Accelerating Factor structure Protein CD55 PDB 1h03.png
CD55 protein/Decay Accelerating Factor structure
CD59 protein/Protectin structure Cd59.png
CD59 protein/Protectin structure

All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding environment. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid-protein structures on the surface of blood cells. [5]

The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. The gene that codes for PIGA is located on the X chromosome. As males have only a single X chromosome and, in females, one is silenced through X-inactivation), only one active copy of the gene for PIGA is present in each cell regardless of sex. [1] A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane. When this mutation occurs in a hematopoietic stem cell in the bone marrow, all of the cells it produces will also have the defect. [5]

Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins. [4] Although red blood cells, white blood cells, and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis. [13] The complement system is part of the innate immune system and has a variety of functions, from destroying invading microorganisms by opsonization to direct destabilization by the membrane attack complex. The main proteins that protect blood cells from destruction are decay-accelerating factor (DAF/CD55), which disrupts formation of C3-convertase, and protectin (CD59/MIRL/MAC-IP), which binds the membrane attack complex and prevents C9 from binding to the cell. [5]

The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. [5] There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure. [12]

Historically, the role of sleep and night in this disease (the "nocturnal" component of the name) has been attributed to acidification of the blood at night due to relative hypoventilation and accumulation of carbon dioxide in the blood during sleep. This hypothesis has been questioned by researchers who note that not all those with PNH have increased hemolysis during sleep, so it is uncertain how important a role sleep actually plays in this disease. [14]

Diagnosis

Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no concurrent problem with production of red cells (such as iron deficiency). The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. [5] If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis. [5]

Historically, the sucrose lysis test, in which a patient's red blood cells are placed in low-ionic-strength solution and observed for hemolysis, was used for screening. If this was positive, the Ham's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation. [6] [15] The Ham test involves placing red blood cells in mild acid; a positive result (increased RBC fragility) indicates PNH or Congenital dyserythropoietic anemia. This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.[ citation needed ]

Today, the gold standard is flow cytometry for CD55 and CD59 on white and red blood cells. Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells. Type I cells have normal levels of CD55 and CD59; type II have reduced levels; and type III have absent levels. [5] The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH. FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than simply for CD59 or CD55. [6]

Classification

PNH is classified by the context under which it is diagnosed: [5]

Screening

There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis who are young, have thrombosis in an unusual site (e.g. intra-abdominal veins, cerebral veins, dermal veins), have any evidence of hemolysis (e.g. a raised LDH), or have a low red blood cell, white blood cell, or platelet count. [16] Those who have a diagnosis of aplastic anemia should be screened annually. [5]

Treatment

Acute attacks

There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia, this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced. [5]

Long-term

PNH is a chronic condition. In patients with only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventive treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III). [5] [17]

Episodes of thrombosis are treated as they would in other patients, but, given that PNH is a persisting underlying cause, it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis. [5]

Eculizumab

In 2007, eculizumab (Soliris) was approved for the treatment of PNH. Prior to eculizumab, the median life expectancy of an individual with PNH was approximately 10 years. Since that time, short and mid-term studies of people on eculizumab demonstrate that the medication returns the patient to a normal life expectancy, improves quality of life, and decreases the need for blood transfusions. [7] [10]

Eculizumab is controversial due to its high cost, as it is among the most expensive pharmaceuticals in the world, with a price of US$440,000 per person per year. [9] Eculizumab is a humanized monoclonal antibody that acts as a terminal complement inhibitor. The drug interferes with the formation of the membrane attack complex in erythrocytes by binding to C5, compensating for the loss of protective function that results from CD59 deficiency. This alleviates the primary source of intravascular hemolysis, but it does not reduce the opsonization of erythrocytes caused by CD55 deficiency, so patients who receive this medication often still experience mild to moderate hemolysis. [18] The U.S. Food and Drug Administration (FDA) has issued a black-box warning as those who take the medication have a 1,000 to 2,000-fold greater risk of invasive meningococcal disease. People on eculizumab are strongly advised to receive meningococcal vaccination at least two weeks prior to starting therapy and to consider preventative antibiotics for the duration of treatment. [19]

Pegcetacoplan

Pegcetacoplan (Empaveli) was approved for medical use in the United States in May 2021. [20] [21]

Iptacopan

Iptacopan (Fabhalta), an oral proximal complement inhibitor that targets factor B in the alternative pathway, was approved for medical use in the United States in December 2023. [22] [23] In 2 small phase 3 trials comparing iptacopan to anti-C5 therapy (eculizumab or ravulizumab), iptacopan treatment was superior to anti-C5 treatments in patients with persistent anemia, and improved improved hematologic and clinical outcomes in patients who had not received complement inhibitors. [24]

Danicopan

Danicopan (Voydeya) was approved for medical use in Japan in January 2024. [25]

Epidemiology

PNH is rare, with an annual rate of 1-2 cases per million. [5] The prognosis without disease-modifying treatment is 10–20 years. [26] Many cases develop in people who have previously been diagnosed with myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia or aplastic anemia. [5]

25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively). [5]

History

The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (Greifswald, 1852–1915) during a lecture in 1881, later published in 1882. [27] Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911, [28] with further elaborations by Marchiafava in 1928 [29] and Ferdinando Micheli in 1931. [30] [31]

The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturna in Latin) in 1928, which has since become the default description. [32]

Related Research Articles

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Aplastic anemia is associated with cancer and various cancer syndromes. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.

Glycosylphosphatidylinositol or glycophosphatidylinositol (GPI) is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles in a wide variety of biological processes. GPI is composed of a phosphatidylinositol group linked through a carbohydrate-containing linker and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The two fatty acids within the hydrophobic phosphatidyl-inositol group anchor the protein to the cell membrane.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere-shaped (spherocytosis), rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia.

<span class="mw-page-title-main">Hemolytic anemia</span> Medical condition

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.

<span class="mw-page-title-main">Decay-accelerating factor</span> Mammalian protein found in Homo sapiens

Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the CD55 gene.

Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis, and neuromyelitis optica. In people with PNH, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death. Eculizumab was the first drug approved for each of its uses, and its approval was granted based on small trials. It is given by intravenous infusion.

<span class="mw-page-title-main">CD59</span> Mammalian protein found in Homo sapiens

CD59 glycoprotein, also known as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is a protein that in humans is encoded by the CD59 gene. It is an LU domain and belongs to the LY6/uPAR/alpha-neurotoxin protein family.

<span class="mw-page-title-main">PIGA</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is the catalytic subunit of the phosphatidylinositol N-acetylglucosaminyltransferase enzyme, which in humans is encoded by the PIGA gene.

Fluorescein-labeled proaerolysin (FLAER) is used in a flow cytometric assay to diagnose paroxysmal nocturnal hemoglobinuria (PNH). The assay takes advantage of the action of proaerolysin, a prototoxin of aerolysin, a virulence factor of the bacterium Aeromonas hydrophila. Proaerolysin binds to the glycophosphatidylinositol(GPI) anchor in the plasma membrane of cells. Cells affected by PNH lack GPI anchoring proteins, and thus are not bound by proaerolysin. Of note, the FLAER-based assay is not suitable for evaluation of erythrocytes and platelets in PNH but flow cytometry assays based on CD55, CD59 and others are suitable.

The Ham test is a blood test used in the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). Patient red blood cells (RBCs) are placed in mild acid; a positive result indicates PNH or congenital dyserythropoietic anemia. This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.

<span class="mw-page-title-main">CD55 deficiency</span> Medical condition

CD55deficiency, also called DAF deficiency or CHAPLE syndrome, is a rare genetic disorder of the immune system. CHAPLE stands for "CD55 deficiency with hyper-activation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (PLE)." The disorder usually manifests in childhood and can be life-threatening. This condition was described by Özen, et al. in 2017.

Ravulizumab, sold under the brand name Ultomiris, is a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. It is designed to bind to and prevent the activation of Complement component 5 (C5).

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria and geographic atrophy of the retina. Pegcetacoplan is a complement inhibitor.

<span class="mw-page-title-main">Iptacopan</span> Chemical compound

Iptacopan, sold under the brand name Fabhalta, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria. It is a complement factor B inhibitor that was developed by Novartis. It is taken by mouth.

<span class="mw-page-title-main">Sucrose lysis test</span>

The sucrose lysis test is a diagnostic laboratory test used for diagnosing paroxysmal nocturnal hemoglobinuria (PNH), as well as for hypoplastic anemias and any hemolytic anemia with an unclear cause. The test works by using sucrose, which creates a low ionic strength environment that allows complement to bind to red blood cells. In individuals with PNH, some red blood cells are especially vulnerable to lysis caused by complement. The test may also produce suspicious results in other hematologic conditions, including megaloblastic anemia and autoimmune hemolytic anemia. False-negative results can occur when complement activity is absent in the serum. A simpler alternative called the sugar water test also involves mixing blood with sugar and observing for hemolysis, using the same principle as the sucrose lysis test.

Crovalimab is an C5 inhibiting monoclonal antibody under investigation by Roche/Genentech for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

<span class="mw-page-title-main">Danicopan</span> Medication

Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria. It is a complement inhibitor which reversibly binds to factor D to prevent alternative pathway-mediated hemolysis and deposition of complement C3 proteins on red blood cells.

References

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  2. ↑ Parker CJ (May 2012). "Paroxysmal nocturnal hemoglobinuria". Current Opinion in Hematology. 19 (3): 141–8. doi:10.1097/MOH.0b013e328351c348. PMID   22395662. S2CID   21266914.
  3. ↑ Brodsky, R. A. (2014a). Paroxysmal nocturnal hemoglobinuria. Blood, 124(18), 2804–2811. https://doi.org/10.1182/blood-2014-02-522128
  4. 1 2 Kumar Vinay; Abbas AK; Fausto N; Mitchell RN (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. p. 652. ISBN   978-1-4160-2973-1.
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  7. 1 2 Wong EK, Kavanagh D (January 2018). "Diseases of complement dysregulation-an overview". Seminars in Immunopathology. 40 (1): 49–64. doi:10.1007/s00281-017-0663-8. PMC   5794843 . PMID   29327071.
  8. ↑ "Alexion Pharmaceuticals ordered to lower price of $500K a year drug in Canada | CBC News". CBC. Retrieved 2018-11-29.
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  11. ↑ "Paroxysmal Nocturnal Hemoglobinuria - NORD (National Organization for Rare Disorders)". NORD. 2016. Retrieved 3 July 2017.
  12. 1 2 Rother RP, Bell L, Hillmen P, Gladwin MT (April 2005). "The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease". JAMA. 293 (13): 1653–62. doi: 10.1001/jama.293.13.1653 . PMID   15811985.
  13. ↑ "Paroxysmal Nocturnal Hemoglobinuria". The Lecturio Medical Concept Library. Retrieved 2 September 2021.
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  15. ↑ Ham TH (1937). "Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium". N Engl J Med. 217 (23): 915–918. doi:10.1056/NEJM193712022172307.
  16. ↑ Hill A, Kelly RJ, Hillmen P (June 2013). "Thrombosis in paroxysmal nocturnal hemoglobinuria". Blood. 121 (25): 4985–96, quiz 5105. doi: 10.1182/blood-2012-09-311381 . PMID   23610373.
  17. ↑ Hall C, Richards S, Hillmen P (November 2003). "Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)". Blood. 102 (10): 3587–91. doi: 10.1182/blood-2003-01-0009 . PMID   12893760.
  18. ↑ Brodsky, Robert A. (2014-10-30). "Paroxysmal nocturnal hemoglobinuria". Blood. 124 (18): 2804–2811. doi:10.1182/blood-2014-02-522128. ISSN   0006-4971. PMC   4215311 . PMID   25237200.
  19. ↑ "Patients Receiving Eculizumab (Soliris) at High Risk for Invasive Meningococcal Disease Despite Vaccination". Centers for Disease Control and Prevention Health Alert Network. 7 July 2017.
  20. ↑ "FDA approves new treatment for adults with serious rare blood disease". U.S. Food and Drug Administration (FDA). 14 May 2021. Retrieved 14 May 2021.
  21. ↑ "Apellis Announces U.S. Food and Drug Administration (FDA) Approval of Empaveli (pegcetacoplan) for Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH)" (Press release). Apellis Pharmaceuticals. 14 May 2021. Retrieved 14 May 2021– via GlobeNewswire.
  22. ↑ "Novartis receives FDA approval for Fabhalta (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH". Novartis (Press release). Retrieved 2023-12-06.
  23. ↑ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration (FDA). 6 December 2023. Retrieved 10 December 2023.
  24. ↑ Peffault de Latour, Régis; Röth, Alexander; Kulasekararaj, Austin G.; Han, Bing; Scheinberg, Phillip; Maciejewski, Jaroslaw P.; Ueda, Yasutaka; de Castro, Carlos M.; Di Bona, Eros; Fu, Rong; Zhang, Li; Griffin, Morag; Langemeijer, Saskia M.C.; Panse, Jens; Schrezenmeier, Hubert (2024-03-14). "Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria". New England Journal of Medicine. 390 (11): 994–1008. doi:10.1056/NEJMoa2308695. ISSN   0028-4793.
  25. ↑ "Voydeya (danicopan) granted first-ever regulatory approval in Japan for adults with PNH to be used in combination with C5 inhibitor therapy". AstraZeneca (Press release). 19 January 2024. Retrieved 24 February 2024.
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  27. ↑ Strübing P (1882). "Paroxysmale Hämoglobinurie". Dtsch Med Wochenschr (in German). 8: 1–3 and 17–21. doi:10.1055/s-0029-1196307. S2CID   260089988.
  28. ↑ Marchiafava E, Nazari A (1911). "Nuovo contributo allo studio degli itteri cronici emolitici". Policlinico [Med] (in Italian). 18: 241–254.
  29. ↑ Marchiafava E (1928). "Anemia emolitica con emosiderinuria perpetua". Policlinico [Med] (in Italian). 35: 105–117.
  30. ↑ Micheli F (1931). "Uno caso di anemia emolitica con emosiderinuria perpetua". G Accad Med Torino (in Italian). 13: 148.
  31. ↑ Strübing-Marchiafava-Micheli syndrome at Who Named It?
  32. ↑ Enneking J (1928). "Eine neue form intermittierender haemoglobinurie (Haemoglobinuria paroxysmalis nocturia)". Klin Wochenschr (in German). 7 (43): 2045–2047. doi:10.1007/BF01846778. S2CID   30149910.
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