Jump to content

Paroxysmal nocturnal hemoglobinuria: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
m Added short description
Tags: Mobile edit Mobile app edit iOS app edit App description change
 
(205 intermediate revisions by 87 users not shown)
Line 1: Line 1:
{{Short description|Blood disease in which red blood cells are attacked by the immune system}}
{{Infobox disease
{{Infobox medical condition (new)
| Name = Paroxysmal nocturnal hemoglobinuria
| Image =
| name = Paroxysmal nocturnal hemoglobinuria
| Caption =
| image = Haemolytic Anaemia.jpg
| DiseasesDB = 9688
| caption = Intravascular hemolytic anemia
| ICD10 = {{ICD10|D|59|5|d|55}}
| pronounce =
| ICD9 = {{ICD9|283.2}}
| field =
| synonyms = Paroxysmal nocturnal haemoglobinuria, Marchiafava–Micheli syndrome
| ICDO =
| OMIM = 300818
| symptoms =
| MedlinePlus = 000534
| complications =
| eMedicineSubj = med
| onset =
| duration =
| eMedicineTopic = 2696
| MeshID = D006457
| types =
| causes =
| risks =
| diagnosis =
| differential =
| prevention =
| treatment =
| medication =
| prognosis =
| frequency =
| deaths =
}}
}}
'''Paroxysmal nocturnal hemoglobinuria''' (PNH), sometimes referred to as '''Marchiafava-Micheli syndrome''', is a rare, generally acquired,<ref>PNH from mutations of another PIG gene
Lucio Luzzatto Blood 2013</ref> life-threatening disease of the blood characterized by complement-induced intravascular [[hemolytic anemia]] (anemia due to destruction of [[red blood cell]]s in the bloodstream), red [[urine]] (due to the appearance of [[hemoglobin]] in the urine) and [[thrombosis]]. After diagnosis and with only supportive measures, 35% of patients will be dead within 5 years.<ref>Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. N Engl J Med. 1995;333:1253-1258</ref>


'''Paroxysmal nocturnal hemoglobinuria''' ('''PNH''') is a rare, acquired,<ref name=Luzzatto>{{cite journal | vauthors = Luzzatto L | title = PNH from mutations of another PIG gene | journal = Blood | volume = 122 | issue = 7 | pages = 1099–100 | date = August 2013 | pmid = 23950173 | doi = 10.1182/blood-2013-06-508556 | doi-access = free }}</ref> life-threatening disease of the blood characterized by [[hemolytic anemia|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 [[Decay-accelerating factor|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 [[thrombosis|blood clot formation]].<ref name=":0">{{cite journal | vauthors = Parker CJ | title = Paroxysmal nocturnal hemoglobinuria | journal = Current Opinion in Hematology | volume = 19 | issue = 3 | pages = 141–8 | date = May 2012 | pmid = 22395662 | doi = 10.1097/MOH.0b013e328351c348 | s2cid = 21266914 }}</ref> 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).<ref>Brodsky, R. A. (2014a). Paroxysmal nocturnal hemoglobinuria. Blood, 124(18), 2804–2811. https://doi.org/10.1182/blood-2014-02-522128</ref>
PNH is the only hemolytic anemia which is most often caused by an ''acquired'' (rather than inherited) intrinsic defect in the [[cell membrane]] (deficiency of [[glycophosphatidylinositol]] leading to absence of protective proteins on the membrane).<ref name=Robbins>Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). ''Robbins Basic Pathology'' (8th ed.). Saunders Elsevier. p. 432 ISBN 978-1-4160-2973-1</ref> 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 (26%) have the telltale red urine in the morning.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al.'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717| url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699 | pmc=1895106}}</ref>


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.<ref name=Robbins>{{cite book |author1=Kumar Vinay |author2=Abbas AK |author3=Fausto N |author4=Mitchell RN | year=2007 | title=Robbins Basic Pathology | edition=8th | publisher=Saunders Elsevier | page=652 | isbn=978-1-4160-2973-1}}</ref> 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.<ref name=parker2005>{{cite journal | vauthors = Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G | display-authors = 6 | title = Diagnosis and management of paroxysmal nocturnal hemoglobinuria | journal = Blood | volume = 106 | issue = 12 | pages = 3699–709 | date = December 2005 | pmid = 16051736 | pmc = 1895106 | doi = 10.1182/blood-2005-04-1717 }}</ref>
[[Allogeneic bone marrow transplantation]] is the only curative therapy, but has significant rates of both mortality and ongoing morbidity.


[[Allogeneic bone marrow transplantation]] is the only cure, but has significant rates of additional medical problems and death.<ref name=Brodsky/> The [[monoclonal antibody]] [[eculizumab]] reduces the need for [[blood transfusion]]s and improves quality of life for those affected by PNH.<ref name=Brodsky>{{cite journal | vauthors = Brodsky RA | title = How I treat paroxysmal nocturnal hemoglobinuria | journal = Blood | volume = 113 | issue = 26 | pages = 6522–7 | date = June 2009 | pmid = 19372253 | pmc = 2710914 | doi = 10.1182/blood-2009-03-195966 }}</ref> 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.<ref name=":1">{{cite journal | vauthors = Wong EK, Kavanagh D | title = Diseases of complement dysregulation-an overview | journal = Seminars in Immunopathology | volume = 40 | issue = 1 | pages = 49–64 | date = January 2018 | pmid = 29327071 | pmc = 5794843 | doi = 10.1007/s00281-017-0663-8 }}</ref> 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.<ref>{{Cite news |url=https://www.cbc.ca/news/health/solaris-pmprb-1.4310249 |title=Alexion Pharmaceuticals ordered to lower price of $500K a year drug in Canada {{!}} CBC News |work=CBC |access-date=2018-11-29 |language=en-US}}</ref><ref name="Reuters">{{cite news |url= https://www.reuters.com/article/alexion-nice-soliris-idUSL6N0M02RR20140304 |title= British watchdog wants U.S. biotech Alexion to justify cost of drug |newspaper= Reuters |date= March 3, 2014 |access-date= June 6, 2014}}</ref><ref name="Car2014">{{cite journal | vauthors = Martí-Carvajal AJ, Anand V, Cardona AF, Solà I | title = Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD010340 | date = October 2014 | pmid = 25356860 | doi = 10.1002/14651858.CD010340.pub2 }}</ref>
The [[monoclonal antibody]] [[eculizumab]] ([http://en.wikipedia.org/wiki/Eculizumab Soliris]) is effective at reducing the need for blood transfusions, improving quality of life, and reducing the risk of thrombosis.<ref name=Brodsky>{{cite journal |author=Brodsky, RA |title=How I treat paroxysmal nocturnal hemoglobinuria. |journal=Blood |volume=113 |issue=26 |pages=6522–7 |year=2009 |pmid=19372253 |doi=10.1182/blood-2009-03-195966| url=http://bloodjournal.hematologylibrary.org/content/113/26/6522.long | pmc=2710914 }}</ref>


==Signs and symptoms==
==Signs and symptoms==
The classic sign of PNH is [[hemoglobinuria|red discoloration of the urine due to the presence of hemoglobin]] and [[hemosiderinuria|hemosiderin]] from the breakdown of [[red blood cell]]s.<ref>{{cite web |title=Paroxysmal Nocturnal Hemoglobinuria - NORD (National Organization for Rare Disorders) |url=https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/ |website=NORD |access-date=3 July 2017 |date=2016}}</ref> 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]], [[Dyspnea|shortness of breath]], and [[palpitation]]s.<ref name=parker2005/>
When first discovered, PNH was noted to have dark coloured urine which occurred episodically, and most often in the morning. Further understanding and research into the disease has shown that this is in fact a chronic condition which is progressive with episodes where signs, symptoms and laboratory values worsen.


A small proportion of patients report attacks of [[abdominal pain]], [[dysphagia|difficulty swallowing]] and [[odynophagia|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 tissue|smooth muscle]] due to depletion of nitric oxide by red cell breakdown products.<ref name="The clinical sequelae of intravascu">{{cite journal | vauthors = Rother RP, Bell L, Hillmen P, Gladwin MT | title = The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease | journal = JAMA | volume = 293 | issue = 13 | pages = 1653–62 | date = April 2005 | pmid = 15811985 | doi = 10.1001/jama.293.13.1653 | doi-access = free }}</ref>
Most people with "primary PNH" have red urine at some point in their disease course, but they may often have PNH for a considerable time before this. Many of them continue to have low-grade breakdown of red blood cells, which leads to a release of the contents of red blood cells, LDH, hemoglobin and L-arginase. The signs and symptoms are due to this hemolysis.


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 mesenteric vein|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.<ref name=parker2005/>
Free hemoglobin is both directly toxic when not quickly bound to haptoglobin in several different ways.


==Pathophysiology==
1) Scavenging of free nitric oxide. Nitric oxide is a potent antithrombotic (by preventing activation of platelets) as well as smooth muscle relaxant. Removing nitric oxide can cause a variety of symptoms, from abdominal pain, [[dysphagia]] (difficulty swallowing) and [[odynophagia]] (pain during swallowing), as well as [[erectile dysfunction]], as is demonstrated by published data from the PNH registry<ref>Int J Hematol. 2013 Jun;97(6):749-57. doi: 10.1007/s12185-013-1346-4. Epub 2013 May 1.
[[File:Protein CD55 PDB 1h03.png|thumb|CD55 protein/Decay Accelerating Factor structure]]
Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry.</ref>
[[File:Cd59.png|thumb|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 [[glycosylphosphatidylinositol|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.<ref name=parker2005/>


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.<ref name=Luzzatto/> 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.<ref name=parker2005/>
2) Damage to end organs due to deposition of iron. This is especially true in the kidneys where chronic inflammation leads to a worsening of kidney function which if treated early is reversible.


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.<ref name=Robbins/> Although red blood cells, white blood cells, and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis.<ref>{{cite web |url= https://www.lecturio.com/concepts/paroxysmal-nocturnal-hemoglobinuria/| title= Paroxysmal Nocturnal Hemoglobinuria
The destruction of red blood cells can often lead to anemia. Typical symptoms of anemia are [[tiredness]], [[shortness of breath]], and [[palpitations]], but the tiredness in PNH is not merely due to the reduction in hemoglobin, and is also due to nitric oxide depletion and the cytokine storm.
|website=The Lecturio Medical Concept Library |access-date= 2 September 2021}}</ref> 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 [[CD59|protectin]] (CD59/MIRL/MAC-IP), which binds the [[membrane attack complex]] and prevents [[Complement component 9|C9]] from binding to the cell.<ref name=parker2005/>


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.<ref name=parker2005/> 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]].<ref name="The clinical sequelae of intravascu"/>
On laboratory examination of the urine, breakdown products of red blood cells ([[hemoglobin]] and [[hemosiderin]]) may be identified.<ref name=parker2005/>


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.<ref>{{cite journal | vauthors = Parker CJ | title = Historical aspects of paroxysmal nocturnal haemoglobinuria: 'defining the disease' | journal = British Journal of Haematology | volume = 117 | issue = 1 | pages = 3–22 | date = April 2002 | pmid = 11918528 | doi = 10.1046/j.1365-2141.2002.03374.x | doi-access = free }}</ref>
The most clinically significant finding [[thrombosis]] (a blood clot) which is responsible for 40% to almost 70% of mortality, and patients with PNH have a massively increased risk of thrombosis compared to the general population - 62 times.<ref name=Hill2006>{{cite journal|last=Hill, Ridley, Esser|first=A, SH, D, et al|title=Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: A new approach to PNH therapy|journal=Blood|year=2006|volume=107|issue=5|pages=2131–2137}}</ref><ref name=DeStefano2002>{{cite journal|last=DeStafano, Rossi, Paciaroni, Leone|first=V, E, K, G|title=Screening for inherited thrombophilia: indications and therapeutic implications|journal=Haematologica|year=2002|volume=107|issue=5|pages=1095–1108}}</ref> These may develop in common sites ([[deep vein thrombosis]] of the leg veins 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 mesenteric vein|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 PNH.<ref name=parker2005/> In some cases a blood clot might be the first clinical manifestation of PNH but can be overlooked if the thrombus is in a common site.

Damage to kidneys is chronic and multifactorial, due to reduced perfusion, chronic inflammation due to hemosiderosis and mocrothrombi. This damage leads to mortality in 8% to 18% of patients.


==Diagnosis==
==Diagnosis==
[[Blood test]]s 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 [[reticulocyte]]s (immature red cells released by the [[bone marrow]] to replace the destroyed cells) if there is no [[iron deficiency]] present. The [[direct antiglobulin test]] (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by [[antibody|antibodies]].<ref name=parker2005/>
[[Blood test]]s in PNH show changes consistent with intravascular [[hemolytic anemia]]: low [[hemoglobin]], raised [[lactate dehydrogenase]], [[Hyperbilirubinemia|raised bilirubin]] (a breakdown product of hemoglobin), and decreased levels of [[haptoglobin]]; there can be raised [[reticulocyte]]s (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 [[antibody|antibodies]].<ref name=parker2005/> 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.<ref name=parker2005/>


Historically,<ref name = Brodsky/> 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 test|Ham's acid hemolysis test]]'' (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation.<ref>{{cite journal|doi=10.1056/NEJM193712022172307|author=Ham TH|title=Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium|journal=N Engl J Med|year=1937|volume=217|pages=915–918|issue=23}}</ref>
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 test|Ham's acid hemolysis test]]'' (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation.<ref name = Brodsky/><ref>{{cite journal|doi=10.1056/NEJM193712022172307|author=Ham TH|title=Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium|journal=N Engl J Med|year=1937|volume=217|pages=915–918|issue=23}}</ref> 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|date=September 2022}}


Today, the gold standard is [[flow cytometry]] for [[CD55]] and [[CD59]] on [[white blood cells|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.<ref name=parker2005/> 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.<ref name = Brodsky/>
Today, the gold standard is [[flow cytometry]] for [[CD55]] and [[CD59]] on [[white blood cells|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.<ref name=parker2005/> 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.<ref name = Brodsky/>


==Classification==
===Classification===
PNH is classified by the context under which it is diagnosed:<ref name=parker2005/>
PNH is classified by the context under which it is diagnosed:<ref name=parker2005/>
* ''Classic PNH''. Evidence of PNH in the absence of another bone marrow disorder.
* ''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 mylodylastic syndrome (MDS)
* ''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.
* ''Subclinical PNH''. PNH abnormalities on flow cytometry without signs of hemolysis.


==Pathophysiology==
==Screening==
There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis who
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.<ref name=parker2005/>
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.<ref>{{cite journal | vauthors = Hill A, Kelly RJ, Hillmen P | title = Thrombosis in paroxysmal nocturnal hemoglobinuria | journal = Blood | volume = 121 | issue = 25 | pages = 4985–96; quiz 5105 | date = June 2013 | pmid = 23610373 | doi = 10.1182/blood-2012-09-311381 | doi-access = free }}</ref> Those who have a diagnosis of aplastic anemia should be screened annually.<ref name=parker2005/>


==Treatment==
There are several enzymes that are needed to make [[glycosylphosphatidylinositol]] (GPI), a molecule that anchors proteins to the cell membrane. The most common enzyme that is defective in PNH is [[phosphatidylinositol glycan A]] (PIGA). The gene that codes for PIGA is located on the [[X chromosome]], which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through [[X-inactivation]]). There has recently been a case report of a patient with a PIGT mutation, which led to inherited PNH<ref>PNH from mutations of another PIG gene Lucio Luzzatto, Blood 2013</ref>


===Acute attacks===
If a mutation occurs in this gene then PIGA may be defective, which leads to the GPI anchor not being expressed on the cell membrane. When this mutation occurs in a [[bone marrow]] [[stem cell]] (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect.<ref name=parker2005/>
There is disagreement as to whether [[glucocorticoid|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.<ref name=parker2005>{{cite journal | vauthors = Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G | display-authors = 6 | title = Diagnosis and management of paroxysmal nocturnal hemoglobinuria | journal = Blood | volume = 106 | issue = 12 | pages = 3699–709 | date = December 2005 | pmid = 16051736 | pmc = 1895106 | doi = 10.1182/blood-2005-04-1717 }}</ref>

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.<ref name=Robbins/> Although red blood cells, white blood cells and platelets are targeted by compliment, red blood cells are particularly vulnerable to lysis.

The complement system is part of the innate [[immune system]] and has a variety of functions, from destroying invading microorganisms by opsonisation to direct destabalisation by the Membrane Attack Complex. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins that carry out this function are [[decay-accelerating factor]] (DAF) (CD55), which disrupts formation of C3 convertase, and protectin ([[CD59]]), which binds the [[membrane attack complex]] and prevents [[Complement component 9|C9]] from binding to the cell.<ref name=parker2005/>

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.<ref name=parker2005/> 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]].<ref>{{cite journal |author=Rother RP, Bell L, Hillmen P, Gladwin MT |title=The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease |journal=JAMA |volume=293 |issue=13 |pages=1653–62 |year=2005 |month=April |pmid=15811985 |doi=10.1001/jama.293.13.1653 |url=http://jama.ama-assn.org/cgi/content/full/293/13/1653}}</ref>

==Treatment==


===Long-term===
===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, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref>
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).<ref name=parker2005/><ref>{{cite journal | vauthors = Hall C, Richards S, Hillmen P | title = Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) | journal = Blood | volume = 102 | issue = 10 | pages = 3587–91 | date = November 2003 | pmid = 12893760 | doi = 10.1182/blood-2003-01-0009 | doi-access = free | title-link = doi }}</ref>


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.<ref name=parker2005/>
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.<ref name=parker2005/>


=== Crovalimab ===
A [[monoclonal antibody]], [[eculizumab]], protects blood cells against immune destruction by inhibiting the [[complement system]]. It has been shown to reduce the need for blood transfusion in patients with significant hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al.'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> Sufferers from New Zealand in January 2013 called on the government's medicine buying agency [[Pharmac]] to fund the purchase of [[eculizumab]]. New Zealand is the only country in the [[OECD]] not to fund it.<ref>{{cite news| url= http://www.3news.co.nz/Plea-to-Pharmac-for-pricey-life-saver/tabid/423/articleID/284198/Default.aspx|work=3 News NZ | title= Plea to Pharmac for pricey life-saver| date=January 24, 2013}}</ref>
{{Excerpt|Crovalimab}}


===Acute attacks===
=== Danicopan ===
{{Excerpt|Danicopan}}
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.:<ref name=parker2005/>


==Screening==
=== Eculizumab ===
{{Excerpt|Eculizumab}}
There are several groups where screening for PNH should be undertaken. These include:

Patients with unexplained thrombosis who<refThrombosis in paroxysmal nocturnal hemoglobinuria Anita Hill, Richard Kelly and Peter Hillmen, Blood, 2013></ref>
=== Iptacopan ===
1. are young
{{Excerpt|Iptacopan}}
2. The thrombosis occurs in an unusual site e.g. intra-abdominal veins, cerebral veins, dermal veins
3. have any evidence of hemolysis (i.e. a raised LDH)
4. have any cytopenia


=== Pegcetacoplan ===
Have aplastic Anemia and should be screened annually.
{{Excerpt|Pegcetacoplan}}
Have mylodysplastic Syndrome
Unexplained Hemolytic Anemia
Unexplained cytopenia


==Epidemiology==
==Epidemiology==
PNH is rare, with an annual rate of 1-2 cases per million. Many cases develop in people who have previously been diagnosed with aplastic anemia or [[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.<ref name=parker2005/>
PNH is rare, with an annual rate of 1-2 cases per million.<ref name=parker2005/> The prognosis without disease-modifying treatment is 10–20 years.<ref>{{cite journal | vauthors = Pu JJ, Brodsky RA | title = Paroxysmal nocturnal hemoglobinuria from bench to bedside | journal = Clinical and Translational Science | volume = 4 | issue = 3 | pages = 219–24 | date = June 2011 | pmid = 21707954 | pmc = 3128433 | doi = 10.1111/j.1752-8062.2011.00262.x }}</ref> 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]].<ref name=parker2005/>


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).<ref name=parker2005/>
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).<ref name=parker2005/>


==History==
==History==
The first description of paroxysmal hemoglobinuria was by the [[Germany|German]] physician Paul Strübing ([[Greifswald]], 1852–1915) in 1882.<ref>{{cite journal|author=Strübing P|title=Paroxysmale Hämoglobinurie|language=German|journal=Dtsch Med Wochenschr|year=1882|volume=8|pages=1–3 and 17–21|doi=10.1055/s-0029-1196307}}</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>{{cite journal|author=Marchiafava E, Nazari A|title=Nuovo contributo allo studio degli itteri cronici emolitici|language=Italian|journal=Policlinico [Med] | year=1911|volume=18|pages=241–254}}</ref> with further elaborations by Marchiafava in 1928<ref>{{cite journal|author=Marchiafava E|title=Anemia emolitica con emosiderinuria perpetua|language=Italian|journal=Policlinico [Med] |year= 1928|volume=35|pages=105–117}}</ref> and Dr Ferdinando Micheli in 1931.<ref>{{cite journal|author=Micheli F|title=Uno caso di anemia emolitica con emosiderinuria perpetua|language=Italian|journal=G Accad Med Torino|year=1931|volume=13|pages=148}}</ref><ref>{{Whonamedit|synd|2918|Strübing-Marchiafava-Micheli syndrome}}</ref> The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or ''haemoglobinuria paroxysmalis nocturna'' in Latin) in 1928.<ref>{{cite journal| author=Enneking J | title=Eine neue form intermittierender haemoglobinurie (Haemoglobinuria paroxysmalis nocturia) | language=German | journal=Klin Wochensch | year=1928| volume=7 | pages=2045 | doi=10.1007/BF01846778| issue=43}}</ref>
The first description of paroxysmal hemoglobinuria was by the [[Germany|German]] physician Paul Strübing ([[Greifswald]], 1852–1915) during a lecture in 1881, later published in 1882.<ref>{{cite journal|author=Strübing P|title=Paroxysmale Hämoglobinurie|language=de|journal=Dtsch Med Wochenschr|year=1882|volume=8|pages=1–3 and 17–21|doi=10.1055/s-0029-1196307|s2cid=260089988 |url=https://zenodo.org/record/1429838}}</ref> Later comprehensive descriptions were made by [[Ettore Marchiafava]] and Alessio Nazari in 1911,<ref>{{cite journal|vauthors=Marchiafava E, Nazari A |title=Nuovo contributo allo studio degli itteri cronici emolitici|language=it|journal=Policlinico [Med] | year=1911|volume=18|pages=241–254}}</ref> with further elaborations by Marchiafava in 1928<ref>{{cite journal|author=Marchiafava E|title=Anemia emolitica con emosiderinuria perpetua|language=it|journal=Policlinico [Med] |year= 1928|volume=35|pages=105–117}}</ref> and Ferdinando Micheli in 1931.<ref>{{cite journal|author=Micheli F|title=Uno caso di anemia emolitica con emosiderinuria perpetua|language=it|journal=G Accad Med Torino|year=1931|volume=13|pages=148}}</ref><ref>{{Whonamedit|synd|2918|Strübing-Marchiafava-Micheli syndrome}}</ref>


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.<ref>{{cite journal| author=Enneking J | title=Eine neue form intermittierender haemoglobinurie (Haemoglobinuria paroxysmalis nocturia) | language=de | journal=Klin Wochenschr| year=1928| volume=7 | pages=2045–2047 | doi=10.1007/BF01846778| issue=43| s2cid=30149910 }}</ref>
==References==

{{reflist|2}}
== References ==
{{Reflist}}


== External links ==
== External links ==
{{Medical resources
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
| DiseasesDB = 9688
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
| ICD10 = {{ICD10|D|59|5|d|55}}
| ICD9 = {{ICD9|283.2}}
| OMIM = 300818
| MedlinePlus = 000534
| eMedicineSubj = article
| eMedicineTopic = 207468
| MeshID = D006457
}}


{{Diseases of RBCs}}
{{Hematology}}
{{Lymphoid and complement immunodeficiency}}
{{Lymphoid and complement immunodeficiency}}
{{Phospholipid metabolism disorders}}
{{Phospholipid metabolism disorders}}
{{Authority control}}


[[Category:Rare diseases]]
[[Category:Rare diseases]]
[[Category:Phospholipid metabolism disorders]]
[[Category:Vascular-related cutaneous conditions]]
[[Category:Vascular-related cutaneous conditions]]
[[Category:Acquired hemolytic anemia]]
[[Category:Acquired hemolytic anemia]]
[[Category:Complement deficiency]]

Latest revision as of 04:14, 30 October 2024

Paroxysmal nocturnal hemoglobinuria
Other namesParoxysmal nocturnal haemoglobinuria, Marchiafava–Micheli syndrome
Intravascular hemolytic anemia
SpecialtyHematology Edit this on Wikidata

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 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

[edit]

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

[edit]
CD55 protein/Decay Accelerating Factor structure
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

[edit]

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

[edit]

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

[edit]

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

[edit]

Acute attacks

[edit]

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

[edit]

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]

Crovalimab

[edit]
This section is an excerpt from Crovalimab.[edit]

Crovalimab, sold under the brand name Piasky, is a monoclonal antibody used for the treatment of people with paroxysmal nocturnal hemoglobinuria.[18] It is a complement component 5 (C5) inhibitor.[18][19]

Crovalimab was approved for use in China in February 2024,[20] in Japan in April 2024,[21] in the United States in June 2024 and in the European Union in August 2024.[22][23][24] It was developed and is marketed by Roche/Genentech.

Danicopan

[edit]
This section is an excerpt from Danicopan.[edit]

Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.[25][26] 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.[26]

The most common side effects include fever, headache, increased levels of liver enzymes (a sign of possible liver problems) and pain in the extremities (arms and legs).[26]

Danicopan was approved for medical use in Japan in January 2024,[27] in the United States in March 2024,[25][28] and in the European Union in April 2024.[26]

Eculizumab

[edit]
This section is an excerpt from Eculizumab.[edit]

Eculizumab, sold under the brand name Soliris among others, is a recombinant humanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica.[29][30] In people with paroxysmal nocturnal hemoglobinuria, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death.[31] Eculizumab was the first medication approved for each of its uses, and its approval was granted based on small trials.[32][33][34][35] It is given by intravenous infusion.[29] It is a humanized monoclonal antibody functioning as a terminal complement inhibitor.[33] It binds to the complement C5 protein and inhibits activation of the complement system, a part of the body's immune system.[36] This binding prevents the breakdown of red blood cells in the bloodstream (intravascular hemolysis) in people with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.[36]

The most frequently reported adverse reactions for people with paroxysmal nocturnal hemoglobinuria include headache, nasopharyngitis (common cold), back pain and nausea[36] The most frequently reported adverse reactions for people with atypical hemolytic uremic syndrome include headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, swelling of lower legs or hands, nausea, urinary tract infections and fever[36]

Eculizumab (Soliris) is developed, manufactured, and marketed by Alexion Pharmaceuticals.[37]: 6 

Iptacopan

[edit]
This section is an excerpt from Iptacopan.[edit]

Iptacopan, sold under the brand name Fabhalta, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).[38] It is a complement factor B inhibitor that was developed by Novartis.[38] It is taken by mouth.[38]

Iptacopan was approved by the US Food and Drug Administration (FDA) for the treatment of adults with paroxysmal nocturnal hemoglobinuria in December 2023.[39][40] The FDA considers it to be a first-in-class medication.[41]

Pegcetacoplan

[edit]
This section is an excerpt from Pegcetacoplan.[edit]

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria[42][43][44][45][46] and geographic atrophy of the retina.[47][48] Pegcetacoplan is a complement inhibitor.[42][47]

The most common side effects include injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.[42][43]

Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells).[49]

Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to and inhibits complement protein C3.[49] Pegcetacoplan was approved for medical use in the United States in May 2021.[49] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[50]

In 2024, the American Society of Nephrology Annual Kidney Meeting,[51] the study group who investigating pegcetacoplan in the largest multicenter double-blind VALIANT trial, showed its significant benefits in the treatment of patients with C3 glomerulopathy or primary immune complex–mediated membranoproliferative glomerulonephritis [52].C3 glomerulopathy leads to kidney failure in approximately 50% of patients within 5-10 years of diagnosis, and even when patients do receive a kidney transplant, approximately two thirds experience disease recurrence. Pegcetacoplan introduce a potential “kidney- and life-saving option” for patients with C3 glomerulopathy.[53]

Epidemiology

[edit]

PNH is rare, with an annual rate of 1-2 cases per million.[5] The prognosis without disease-modifying treatment is 10–20 years.[54] 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

[edit]

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.[55] Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911,[56] with further elaborations by Marchiafava in 1928[57] and Ferdinando Micheli in 1931.[58][59]

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.[60]

References

[edit]
  1. ^ a b Luzzatto L (August 2013). "PNH from mutations of another PIG gene". Blood. 122 (7): 1099–100. doi:10.1182/blood-2013-06-508556. PMID 23950173.
  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. ^ a b Kumar Vinay; Abbas AK; Fausto N; Mitchell RN (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. p. 652. ISBN 978-1-4160-2973-1.
  5. ^ a b c d e f g h i j k l m n o p q r Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. (December 2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.
  6. ^ a b c d Brodsky RA (June 2009). "How I treat paroxysmal nocturnal hemoglobinuria". Blood. 113 (26): 6522–7. doi:10.1182/blood-2009-03-195966. PMC 2710914. PMID 19372253.
  7. ^ 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.
  9. ^ "British watchdog wants U.S. biotech Alexion to justify cost of drug". Reuters. March 3, 2014. Retrieved June 6, 2014.
  10. ^ Martí-Carvajal AJ, Anand V, Cardona AF, Solà I (October 2014). "Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria". The Cochrane Database of Systematic Reviews. 10 (10): CD010340. doi:10.1002/14651858.CD010340.pub2. PMID 25356860.
  11. ^ "Paroxysmal Nocturnal Hemoglobinuria - NORD (National Organization for Rare Disorders)". NORD. 2016. Retrieved 3 July 2017.
  12. ^ a b 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.
  14. ^ Parker CJ (April 2002). "Historical aspects of paroxysmal nocturnal haemoglobinuria: 'defining the disease'". British Journal of Haematology. 117 (1): 3–22. doi:10.1046/j.1365-2141.2002.03374.x. PMID 11918528.
  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. ^ a b "Piasky- crovalimab injection, solution". DailyMed. 28 June 2024. Retrieved 5 September 2024.
  19. ^ Röth, Alexander; Nishimura, Jun-ichi; Nagy, Zsolt; Gaàl-Weisinger, Julia; Panse, Jens; Yoon, Sung-Soo; Egyed, Miklos; Ichikawa, Satoshi; Ito, Yoshikazu; Kim, Jin Seok; Ninomiya, Haruhiko; Schrezenmeier, Hubert; Sica, Simona; Usuki, Kensuke; Sicre de Fontbrune, Flore; Soret, Juliette; Sostelly, Alexandre; Higginson, James; Dieckmann, Andreas; Gentile, Brittany; Anzures-Cabrera, Judith; Shinomiya, Kenji; Jordan, Gregor; Biedzka-Sarek, Marta; Klughammer, Barbara; Jahreis, Angelika; Bucher, Christoph; Peffault de Latour, Régis (19 March 2020). "The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria". Blood. 135 (12): 912–920. doi:10.1182/blood.2019003399. PMC 7082616. PMID 31978221.
  20. ^ "Crovalimab Approved in China as the First Country, for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)". chugai-pharm.co.jp. 8 February 2024. Archived from the original on 18 April 2024. Retrieved 18 April 2024.
  21. ^ "Japan Becomes Second Market to Approve Roche's Piasky". Navlin Daily. 3 April 2024. Archived from the original on 18 April 2024. Retrieved 21 June 2024.
  22. ^ Cite error: The named reference Crovalimab Piasky EPAR was invoked but never defined (see the help page).
  23. ^ Cite error: The named reference Crovalimab Piasky PI was invoked but never defined (see the help page).
  24. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 21 June 2024. Archived from the original on 30 April 2024. Retrieved 21 June 2024.
  25. ^ a b "Voydeya- danicopan tablet, film coated; Voydeya- danicopan kit". DailyMed. 3 April 2024. Archived from the original on 25 April 2024. Retrieved 25 April 2024.
  26. ^ a b c d "Voydeya EPAR". European Medicines Agency. 22 February 2024. Archived from the original on 23 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. ^ "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. Archived from the original on 24 February 2024. Retrieved 24 February 2024.
  28. ^ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
  29. ^ a b "Soliris- eculizumab injection, solution, concentrate". DailyMed. 20 April 2021. Archived from the original on 9 April 2022. Retrieved 9 April 2022.
  30. ^ "Soliris EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 19 October 2019. Retrieved 9 April 2022.
  31. ^ Martí-Carvajal AJ, Anand V, Cardona AF, Solà I (October 2014). "Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria". The Cochrane Database of Systematic Reviews. 10 (10): CD010340. doi:10.1002/14651858.CD010340.pub2. PMID 25356860.
  32. ^ "FDA approves first treatment for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system" (Press release). U.S. Food and Drug Administration (FDA). 27 June 2019. Archived from the original on 14 September 2019. Retrieved 28 June 2019.
  33. ^ a b Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L (November 2007). "Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria". Nature Biotechnology. 25 (11): 1256–1264. doi:10.1038/nbt1344. PMID 17989688. S2CID 22732675.
  34. ^ Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R (September 2008). "FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria". The Oncologist. 13 (9): 993–1000. doi:10.1634/theoncologist.2008-0086. PMID 18784156. S2CID 21972428.
  35. ^ Keating GM (December 2013). "Eculizumab: a review of its use in atypical haemolytic uraemic syndrome". Drugs. 73 (18): 2053–2066. doi:10.1007/s40265-013-0147-7. PMID 24249647. S2CID 36682579.
  36. ^ a b c d "FDA Approves First Interchangeable Biosimilar for Two Rare Diseases". U.S. Food and Drug Administration. 28 May 2024. Archived from the original on 30 May 2024. Retrieved 31 May 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  37. ^ Bourgoin AF, Nuskey B (April 2015). An Outlook on Biosimilar Competition (PDF) (Report). Archived from the original (PDF) on 13 May 2015. Retrieved 29 June 2015.
  38. ^ a b c "Fabhalta- iptacopan capsule". DailyMed. 5 December 2023. Archived from the original on 10 December 2023. Retrieved 10 December 2023.
  39. ^ "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). Archived from the original on 12 December 2023. Retrieved 6 December 2023.
  40. ^ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration (FDA). 6 December 2023. Archived from the original on 21 January 2023. Retrieved 10 December 2023.
  41. ^ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
  42. ^ a b c "Empaveli- pegcetacoplan injection, solution". DailyMed. 13 April 2023. Archived from the original on 13 July 2021. Retrieved 5 June 2023.
  43. ^ a b "Aspaveli EPAR". European Medicines Agency (EMA). 6 September 2022. Archived from the original on 18 February 2023. Retrieved 18 February 2023.
  44. ^ Heo YA (December 2022). "Pegcetacoplan: A Review in Paroxysmal Nocturnal Haemoglobinuria". Drugs. 82 (18): 1727–1735. doi:10.1007/s40265-022-01809-w. PMC 10234880. PMID 36459381. S2CID 254149706.
  45. ^ Wong RS (28 July 2022). "Safety and efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria". Therapeutic Advances in Hematology (Review). 13. SAGE Publishing: 20406207221114673. doi:10.1177/20406207221114673. eISSN 2040-6215. PMC 9340389. PMID 35923770.
  46. ^ Xu B (July 2023). "Novel targeted C3 inhibitor pegcetacoplan for paroxysmal nocturnal hemoglobinuria". Clinical and Experimental Medicine. 23 (3): 717–726. doi:10.1007/s10238-022-00830-3. PMID 35441351. S2CID 248245151.
  47. ^ a b "Syfovre- pegcetacoplan injection, solution". DailyMed. 23 February 2023. Retrieved 6 June 2023.
  48. ^ Liao DS, Metlapally R, Joshi P (September 2022). "Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study". Immunotherapy. 14 (13): 995–1006. doi:10.2217/imt-2022-0078. PMID 35860926. S2CID 250731980.
  49. ^ a b c "FDA approves new treatment for adults with serious rare blood disease". U.S. Food & Drug Administration (FDA). 18 May 2021. Archived from the original on 17 October 2021. Retrieved 18 February 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  50. ^ Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  51. ^ "Kidney Week 2024". Medscape. Retrieved 2024-12-05.
  52. ^ "Novel Drug Shows Benefits in Rare C3G and Primary immune complex MPGN, with high safty margin". Medscape. Retrieved 2024-12-05.
  53. ^ Apellis Pharmaceuticals, Inc. (2024-07-25). A Phase 3, Randomized, Placebo-Controlled, Double-Blinded, Multicenter Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis (Report). clinicaltrials.gov.
  54. ^ Pu JJ, Brodsky RA (June 2011). "Paroxysmal nocturnal hemoglobinuria from bench to bedside". Clinical and Translational Science. 4 (3): 219–24. doi:10.1111/j.1752-8062.2011.00262.x. PMC 3128433. PMID 21707954.
  55. ^ Strübing P (1882). "Paroxysmale Hämoglobinurie". Dtsch Med Wochenschr (in German). 8: 1–3 and 17–21. doi:10.1055/s-0029-1196307. S2CID 260089988.
  56. ^ Marchiafava E, Nazari A (1911). "Nuovo contributo allo studio degli itteri cronici emolitici". Policlinico [Med] (in Italian). 18: 241–254.
  57. ^ Marchiafava E (1928). "Anemia emolitica con emosiderinuria perpetua". Policlinico [Med] (in Italian). 35: 105–117.
  58. ^ Micheli F (1931). "Uno caso di anemia emolitica con emosiderinuria perpetua". G Accad Med Torino (in Italian). 13: 148.
  59. ^ Strübing-Marchiafava-Micheli syndrome at Who Named It?
  60. ^ 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.
[edit]
Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Paroxysmal_nocturnal_hemoglobinuria&oldid=1254259003"