| Paroxysmal nocturnal hemoglobinuria | |
|---|---|
| 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 bydestruction of red blood cells by thecomplement system, a part of the body'sinnate immune system. This destructive process occurs due to deficiency of thered blood cell surface proteinDAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of thecirculatory system, the red blood cell destruction (hemolysis) is considered anintravascular hemolytic anemia. There is ongoing research into other key features of the disease, such as the high incidence of venousblood clot formation.[2] Research suggests that PNHthrombosis (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 anacquired (rather than inherited) intrinsic defect in thecell membrane (deficiency ofglycophosphatidylinositol 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 otherbone marrow disorders such asaplastic 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] Themonoclonal antibodyeculizumab reduces the need forblood 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]
The classic sign of PNH isred discoloration of the urine due to the presence of hemoglobin andhemosiderin from the breakdown ofred blood cells.[8] 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 asfatigue,shortness of breath, andpalpitations.[5]
A small proportion of patients report attacks ofabdominal pain,difficulty swallowing andpain during swallowing, as well aserectile dysfunction in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm ofsmooth muscle due to depletion of nitric oxide by red cell breakdown products.[9]
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 resultantpulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: thehepatic vein (causingBudd–Chiari syndrome), theportal vein of the liver (causingportal vein thrombosis), thesuperior orinferior mesenteric vein (causingmesenteric ischemia) and veins of the skin.Cerebral venous thrombosis, an uncommon form ofstroke, is more common in those with PNH.[5]
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 byglycolipids such asglycosyl 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 isphosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. The gene that codes for PIGA is located on theX chromosome. As males have only a single X chromosome and, in females, one is silenced throughX-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 ahematopoietic 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 thecomplement 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.[10] The complement system is part of theinnate immune system and has a variety of functions, from destroying invading microorganisms byopsonization to direct destabilization by themembrane attack complex. The main proteins that protect blood cells from destruction aredecay-accelerating factor (DAF/CD55), which disrupts formation ofC3-convertase, andprotectin (CD59/MIRL/MAC-IP), which binds themembrane attack complex and preventsC9 from binding to the cell.[5]
The symptoms ofesophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact thathemoglobin released during hemolysis binds with circulatingnitric oxide, a substance that is needed to relaxsmooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates orsildenafil (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 ofpulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on theheart and causesheart failure.[9]
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 relativehypoventilation 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.[11]
Blood tests in PNH show changes consistent with intravascularhemolytic anemia: lowhemoglobin, raisedlactate dehydrogenase,raised bilirubin (a breakdown product of hemoglobin), and decreased levels ofhaptoglobin; there can be raisedreticulocytes (immature red cells released by thebone marrow to replace the destroyed cells) if there is no concurrent problem with production of red cells (such asiron deficiency). Thedirect antiglobulin test (DAT, or direct Coombs' test) is negative, as thehemolysis of PNH is not caused byantibodies.[5] If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormalwhite blood cell counts and decreasedplatelet 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, thesucrose 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, theHam's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation.[6][12] 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 isflow cytometry forCD55 andCD59 onwhite andred 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] Thefluorescein-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]
PNH is classified by the context under which it is diagnosed:[5]
There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis whoare 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.[13] Those who have a diagnosis of aplastic anemia should be screened annually.[5]
There is disagreement as to whethersteroids (such asprednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significantanemia, 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]
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 withwarfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).[5][14]
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 withwarfarin or similar drugs needs to be continued long-term after an episode of thrombosis.[5]
Crovalimab, sold under the brand name Piasky, is amonoclonal antibody used for the treatment of people with paroxysmal nocturnal hemoglobinuria.[15] It is acomplement component 5 (C5) inhibitor.[15][16]
Crovalimab was approved for use in China in February 2024,[17] in Japan in April 2024,[18] in the United States in June 2024,[19][20] and in the European Union in August 2024.[21][22] It was developed and is marketed byRoche/Genentech.[citation needed]
Danicopan, sold under the brand name Voydeya, is a medication used for the treatment of paroxysmal nocturnal hemoglobinuria.[23][24] It is acomplement inhibitor which reversibly binds to factor D to prevent alternative pathway-mediatedhemolysis and deposition ofcomplement C3 proteins on red blood cells.[24]
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).[24]
Danicopan was approved for medical use in Japan in January 2024,[25] in the United States in March 2024,[23][26] and in the European Union in April 2024.[24] The USFood and Drug Administration (FDA) considers it to be afirst-in-class medication.[27]Eculizumab, sold under the brand name Soliris among others, is a recombinanthumanized monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria,atypical hemolytic uremic syndrome, generalizedmyasthenia gravis, andneuromyelitis optica.[28][29] In people with paroxysmal nocturnal hemoglobinuria, it reduces both thedestruction of red blood cells and need forblood transfusion, but does not appear to affect the risk of death.[30] Eculizumab was the first medication approved for each of its uses, and its approval was granted based on small trials.[31][32][33][34] It is given byintravenous infusion.[28] It is a humanizedmonoclonal antibody functioning as a terminalcomplement inhibitor.[32] It binds to the complement C5 protein and inhibits activation of the complement system, a part of the body's immune system.[35] 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.[35]
The most frequently reported adverse reactions for people with paroxysmal nocturnal hemoglobinuria include headache, nasopharyngitis (common cold), back pain and nausea[35] 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[35]
Eculizumab (Soliris) isdeveloped, manufactured, and marketed byAlexion Pharmaceuticals.[36]: 6
Iptacopan, sold under the brand name Fabhalta, is amedication used for the treatment of paroxysmal nocturnal hemoglobinuria andproteinuria.[37] It is acomplement factor B inhibitor that was developed byNovartis.[37] It is takenby mouth.[37]
Iptacopan was approved for medical use in the United States in December 2023,[37][38] and in the European Union in May 2024.[39] The USFood and Drug Administration considers it to be afirst-in-class medication.[40]
Pegcetacoplan, sold under the brand name Empaveli among others, is amedication used to treat paroxysmal nocturnal hemoglobinuria[41][42][43][44][45] andgeographic atrophy of the retina.[46][47] Pegcetacoplan is acomplement inhibitor.[41][46]
The most common side effects include injection-site reactions, infections,diarrhea,abdominal pain, respiratory tract infection, viral infection, and fatigue.[41][42]
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).[48]
Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to and inhibitscomplement protein C3.[48] Pegcetacoplan was approved for medical use in the United States in May 2021.[48] The USFood and Drug Administration (FDA) considers it to be afirst-in-class medication.[49]
In 2024, the American Society of Nephrology Annual Kidney Meeting,[50] 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.[51] 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.[52]PNH is rare, with an annual rate of 1–2 cases per million.[5] The prognosis without disease-modifying treatment is 10–20 years.[53] Many cases develop in people who have previously been diagnosed withmyelodysplastic syndrome (MDS). The fact that PNH develops in MDS also explains why there appears to be a higher rate ofleukemia in PNH, as MDS can sometimes transform into leukemia oraplastic 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]
The first description of paroxysmal hemoglobinuria was by theGerman physician Paul Strübing (Greifswald, 1852–1915) during a lecture in 1881, later published in 1882.[54] Later comprehensive descriptions were made byEttore Marchiafava and Alessio Nazari in 1911,[55] with further elaborations by Marchiafava in 1928[56] and Ferdinando Micheli in 1931.[57][58]
The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (orhaemoglobinuria paroxysmalis nocturna in Latin) in 1928, which has since become the default description.[59]
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.[60][61][62]
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