Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria | |
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Other names | Paroxysmal nocturnal haemoglobinuria, Marchiafava–Micheli syndrome |
Intravascular hemolytic anemia | |
Specialty | Hematology |
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]
PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the
Signs and symptoms
The classic sign of PNH is
A small proportion of patients report attacks of
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 (
Pathophysiology
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
The most common defective enzyme in PNH is
Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the
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
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
Classification
PNH is classified by the context under which it is diagnosed:[5]
- Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
- PNH in the setting of another specified bone marrow disorder such as aplastic anemia and myelodysplastic syndrome (MDS).
- Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.
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.
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]
References
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- ^ Brodsky, R. A. (2014a). Paroxysmal nocturnal hemoglobinuria. Blood, 124(18), 2804–2811. https://doi.org/10.1182/blood-2014-02-522128
- ^ ISBN 978-1-4160-2973-1.
- ^ PMID 16051736.
- ^ PMID 19372253.
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- ^ "Alexion Pharmaceuticals ordered to lower price of $500K a year drug in Canada | CBC News". CBC. Retrieved 2018-11-29.
- ^ a b "British watchdog wants U.S. biotech Alexion to justify cost of drug". Reuters. March 3, 2014. Retrieved June 6, 2014.
- ^ PMID 25356860.
- ^ "Paroxysmal Nocturnal Hemoglobinuria - NORD (National Organization for Rare Disorders)". NORD. 2016. Retrieved 3 July 2017.
- ^ PMID 15811985.
- ^ "Paroxysmal Nocturnal Hemoglobinuria". The Lecturio Medical Concept Library. Retrieved 2 September 2021.
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- ^ "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.
- ^ "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.
- ^ "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.
- ^ "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.
- ^ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration (FDA). 6 December 2023. Retrieved 10 December 2023.
- ISSN 0028-4793.
- ^ "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.
- PMID 21707954.
- S2CID 260089988.
- ^ Marchiafava E, Nazari A (1911). "Nuovo contributo allo studio degli itteri cronici emolitici". Policlinico [Med] (in Italian). 18: 241–254.
- ^ Marchiafava E (1928). "Anemia emolitica con emosiderinuria perpetua". Policlinico [Med] (in Italian). 35: 105–117.
- ^ Micheli F (1931). "Uno caso di anemia emolitica con emosiderinuria perpetua". G Accad Med Torino (in Italian). 13: 148.
- Who Named It?
- S2CID 30149910.