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__NOTOC__
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{{ Paroxysmal nocturnal hemoglobinuria }}
{{Paroxysmal nocturnal hemoglobinuria}}
{{CMG}}; {{AE}} {{AEL}}  


{{CMG}}
==Overview==
Paroxysmal nocturnal hemoglobinuria is believed to be caused by a [[genetic mutation]] and [[complement]] mediated [[hemolysis]]. A mutation in [[PIGA|PIGA gene]] ([[PIGA|Posphatidylinositol Glycan anchor]] biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the [[Glycophosphatidylinositol|GPI anchor]] synthesis. The PIGA gene mutation is most common a [[frameshift mutation]] which results in a misfolded protein product which is nonfunctional proteins and degraded by [[proteasomes]]. Other genetic mutation may also cause PNH like TET2, [[SUZ12]], U2AF1, and [[JAK2]]. The [[anemia]] in PNH is due to complement mediated [[Hemolytic anemia|hemolysis of RBCs]] which are defective in the [[CD59]]/[[Decay accelerating factor|/CD55]] markers which are important in inactivating the [[complement system]] and protecting the [[RBCs]]. Paroxysmal nocturnal hemoglobinuria may be associated with [[aplastic anemia]], [[myelodysplastic syndrome]], and [[acute myelogenous leukemia]].


==Overview==
==Pathophysiology==
==Pathophysiology==
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.
===Physiology===
* Normally, Red Blood Cells (RBCs), alike other cells in the body, have surface proteins that acts as a communicating signal between the cells and the environment.
* The signaling proteins are most commonly attached to the surface of the RBCs by [[glycolipids]]. The most common glycolipid is the [[Glycophosphatidylinositol|glycosyl phosphatidylinositols (GPI)]].
* The attached proteins are also protective to the cells against destruction by the [[complement system]].<ref name="pmid16051736">{{cite journal| author=Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R et al.| title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria. | journal=Blood | year= 2005 | volume= 106 | issue= 12 | pages= 3699-709 | pmid=16051736 | doi=10.1182/blood-2005-04-1717 | pmc=1895106 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16051736  }}</ref>
* The RBCs are mainly protected by proteins called [[Decay accelerating factor|decay accelerating factor (DAF/CD55).]] The DAF or CD55 proteins prevent the formation of [[C3-convertase|C3-convertase enzyme]], the [[CD59|protectin (CD59)]], and the C9 which are components of the complement inflammatory system.<ref name="pmid160517362">{{cite journal| author=Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R et al.| title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria. | journal=Blood | year= 2005 | volume= 106 | issue= 12 | pages= 3699-709 | pmid=16051736 | doi=10.1182/blood-2005-04-1717 | pmc=1895106 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16051736  }}</ref>
 
===Pathogenesis===
*It is understood that paroxysmal nocturnal hemoglobinuria is caused by [[genetic mutation]] and complement mediated hemolysis.


It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation').  Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected).  Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC.  The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.   
==== PIGA gene mutation and PNH ====
* The acquired gene mutation of [[PIGA|PIGA gene]] (Posphatidylinositol Glycan anchor biosynthesis, class A) is the main pathogenic factor in developing PNH. The PIGA gene is responible for the [[GPI anchor]] synthesis.<ref name="pmid252372002">{{cite journal| author=Brodsky RA| title=Paroxysmal nocturnal hemoglobinuria. | journal=Blood | year= 2014 | volume= 124 | issue= 18 | pages= 2804-11 | pmid=25237200 | doi=10.1182/blood-2014-02-522128 | pmc=4215311 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25237200  }}</ref><ref name="pmid8306954">{{cite journal| author=Bessler M, Mason PJ, Hillmen P, Miyata T, Yamada N, Takeda J et al.| title=Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. | journal=EMBO J | year= 1994 | volume= 13 | issue= 1 | pages= 110-7 | pmid=8306954 | doi= | pmc=394784 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8306954  }}</ref>  
* The PIGA gene is found on the [[X chromosome]] and that concludes the affection of all males who have the mutation in one [[allele]]. However, the females will be carrier if one allele affected and a second genetic "hit" must take place to develop the disease.<ref name="pmid8500164">{{cite journal| author=Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T et al.| title=Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. | journal=Cell | year= 1993 | volume= 73 | issue= 4 | pages= 703-11 | pmid=8500164 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8500164 }}</ref>
* The PIGA gene mutation is most common a [[frameshift mutation]] which results in a misfolded protein product which is nonfunctional proteins and degraded by [[proteasomes]].
* It is believed the mutation mechanism is caused by exposure to [[radiation]], [[chemotherapy]], or [[DNA repair]] defects.
* Other mutations:
** Lack of the [[CD59]] on the [[RBCs]] surface membrane is strongly related to the clinical signs of PNH. It is related to the [[Hemolysis|intravascular hemolysis]] and [[peripheral neuropathy]].  
 
==== Anemia ====
* The [[anemia]] in PNH is mainly due to [[complement]] induced [[hemolysis]]. However, other defects can cause anemia in the setting of paroxysmal nocturnal hemoglobinuria. These causes include [[bone marrow failure]] and [[Iron deficiency anemia|iron deficiency]].  
* Different mechanisms of anemia in PNH include the following:
** Complement  mediated anemia:<ref name="pmid2475570">{{cite journal| author=Davies A, Simmons DL, Hale G, Harrison RA, Tighe H, Lachmann PJ et al.| title=CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. | journal=J Exp Med | year= 1989 | volume= 170 | issue= 3 | pages= 637-54 | pmid=2475570 | doi= | pmc=2189447 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2475570 }}</ref>
*** The main cause of anemia in the patients of PNH and it can cause both [[intravascular]] and extravascular hemolysis. This type of hemolysis is non immune so, the patients with PNH will have a negative [[Coombs test]].
*** Intravascular hemolysis: This type of hemolytic anemia in PNH is due to lack of [[CD59|CD59 marker]] as this marker is the main inhibitor of intravascular hemolysis normally. 
*** Extravascular hemolysis occurs due to reduced expression of [[CD55|CD55 marker]].
** Aplastic anemia:<ref name="pmid24612308">{{cite journal| author=DeZern AE, Symons HJ, Resar LS, Borowitz MJ, Armanios MY, Brodsky RA| title=Detection of paroxysmal nocturnal hemoglobinuria clones to exclude inherited bone marrow failure syndromes. | journal=Eur J Haematol | year= 2014 | volume= 92 | issue= 6 | pages= 467-70 | pmid=24612308 | doi=10.1111/ejh.12299 | pmc=4161035 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24612308  }}</ref>
*** [[Aplastic anemia]] is defined as [[pancytopenia]] due to [[stem cell]] defect.
*** It may occur in already diagnosed PNH or before established diagnosis.
 
==Genetics==
Genes involved in the pathogenesis of paroxysmal nocturnal hemoglobinuria include:<ref name="pmid25244093">{{cite journal| author=Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T et al.| title=Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. | journal=J Clin Invest | year= 2014 | volume= 124 | issue= 10 | pages= 4529-38 | pmid=25244093 | doi=10.1172/JCI74747 | pmc=4191017 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25244093  }}</ref>
*[[PIGA|''PIGA'' gene]]
*''TET2''
* ''[[SUZ12]]''
* ''U2AF1''
* ''[[JAK2]]''
 
==Associated Conditions==
* However, paroxysmal nocturnal hemoglobinuria is usually associated with the following diseases:<ref name="pmid25237200">{{cite journal| author=Brodsky RA| title=Paroxysmal nocturnal hemoglobinuria. | journal=Blood | year= 2014 | volume= 124 | issue= 18 | pages= 2804-11 | pmid=25237200 | doi=10.1182/blood-2014-02-522128 | pmc=4215311 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25237200 }}</ref>
** [[Aplastic anemia]]
** [[Myelodysplastic syndrome]]
** [[Acute myeloid leukemia|Acute myelogenous leukemia]]


The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s.  They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells.  The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Rare diseases]]
[[Category:Genetic disorders]]
[[Category:Mature chapter]]


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[[Category: (name of the system)]]

Latest revision as of 23:15, 31 October 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

Pathophysiology

Physiology

Pathogenesis

  • It is understood that paroxysmal nocturnal hemoglobinuria is caused by genetic mutation and complement mediated hemolysis.

PIGA gene mutation and PNH

  • The acquired gene mutation of PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is the main pathogenic factor in developing PNH. The PIGA gene is responible for the GPI anchor synthesis.[3][4]
  • The PIGA gene is found on the X chromosome and that concludes the affection of all males who have the mutation in one allele. However, the females will be carrier if one allele affected and a second genetic "hit" must take place to develop the disease.[5]
  • The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes.
  • It is believed the mutation mechanism is caused by exposure to radiation, chemotherapy, or DNA repair defects.
  • Other mutations:

Anemia

  • The anemia in PNH is mainly due to complement induced hemolysis. However, other defects can cause anemia in the setting of paroxysmal nocturnal hemoglobinuria. These causes include bone marrow failure and iron deficiency.
  • Different mechanisms of anemia in PNH include the following:
    • Complement mediated anemia:[6]
      • The main cause of anemia in the patients of PNH and it can cause both intravascular and extravascular hemolysis. This type of hemolysis is non immune so, the patients with PNH will have a negative Coombs test.
      • Intravascular hemolysis: This type of hemolytic anemia in PNH is due to lack of CD59 marker as this marker is the main inhibitor of intravascular hemolysis normally.
      • Extravascular hemolysis occurs due to reduced expression of CD55 marker.
    • Aplastic anemia:[7]

Genetics

Genes involved in the pathogenesis of paroxysmal nocturnal hemoglobinuria include:[8]

Associated Conditions

References

  1. ↑ Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R; et al. (2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.
  2. ↑ Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R; et al. (2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.
  3. ↑ Brodsky RA (2014). "Paroxysmal nocturnal hemoglobinuria". Blood. 124 (18): 2804–11. doi:10.1182/blood-2014-02-522128. PMC 4215311. PMID 25237200.
  4. ↑ Bessler M, Mason PJ, Hillmen P, Miyata T, Yamada N, Takeda J; et al. (1994). "Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene". EMBO J. 13 (1): 110–7. PMC 394784. PMID 8306954.
  5. ↑ Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T; et al. (1993). "Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria". Cell. 73 (4): 703–11. PMID 8500164.
  6. ↑ Davies A, Simmons DL, Hale G, Harrison RA, Tighe H, Lachmann PJ; et al. (1989). "CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells". J Exp Med. 170 (3): 637–54. PMC 2189447. PMID 2475570.
  7. ↑ DeZern AE, Symons HJ, Resar LS, Borowitz MJ, Armanios MY, Brodsky RA (2014). "Detection of paroxysmal nocturnal hemoglobinuria clones to exclude inherited bone marrow failure syndromes". Eur J Haematol. 92 (6): 467–70. doi:10.1111/ejh.12299. PMC 4161035. PMID 24612308.
  8. ↑ Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T; et al. (2014). "Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria". J Clin Invest. 124 (10): 4529–38. doi:10.1172/JCI74747. PMC 4191017. PMID 25244093.
  9. ↑ Brodsky RA (2014). "Paroxysmal nocturnal hemoglobinuria". Blood. 124 (18): 2804–11. doi:10.1182/blood-2014-02-522128. PMC 4215311. PMID 25237200.

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