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


{{CMG}}
==Overview==
The mainstay of treatment for paroxysmal nocturnal hemoglobinuria is medical therapy. Treatment includes anticomplement therapy which includes Eculizumab which acts on reducing the hemolysis and possible complications of PNH. Other treatment regimens include hematopoietic cell transplantation and treatment of the anemia.


==Overview==
==Medical Therapy==
==Medical Therapy==
There is no widely accepted evidence-based indication for the treatment of PNH.  In classic PNH it is recommended to treat patients with disabling fatigue, thromboses, transfusion dependence, frequent painful paroxysms, renal insufficiency or other end-organ complications from this disease. Watchful waiting is appropriate for the asymptomatic patient or the patient with mild symptoms. 
* The mainstay of treatment for PNH is medical therapy.  
 
* Treatment of PNH includes the following:  
===Long-term===
** Anti-complement therapy
PNH is a chronic condition. In patients who have 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>  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>{{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>
** Hematopoietic cell transplantation
 
** Treatment of the anemia  
In patients with aplastic anemia / PNH treatment should be directed toward the underlying bone marrow failure with careful monitoring of the PNH clone using flow cytometry.  Patients who meet the criteria of severe aplastic anemia should be managed with either an allogeneic bone marrow transplant or immunosuppressive treatment dependent on the age of the patient and the availability of a bone marrow donor.  Treatment of bone marrow failure in PNH is similar to that for aplasia.  Immunosuppressives can be administered such as antithymocyte globulin or cyclosporine.  Supportive measures in terms of GCSF or erythropoeitin (EPO) can also be given.  An allogeneic bone marrow transplant is the only curative treatment and is an option for younger patients.  A bone marrow transplant is curative but is associated with significant morbidity and mortality.  The 2 year survival with this modality is 56%; the majority of deaths occur within the first year of transplant (International Bone Marrow Registry). 


===Acute attacks===
=== Anti-complement therapy  ===
There is debate as to whether steroids (such as [[prednisolone]]) can be useful in decreasing the severity of hemolytic crises. Steroids can decrease complement activation which, subsequently, decreases hemolysis however high doses are usually necessary. 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. Some sources advocate the use of washed red cell transfusions. Leucocyte-depleted transfusions are also recommended for those requiring chronic transfusion therapy.
* Most of the symptoms and signs of PNH is related to the deficiency of the CD55/CD59 which lead to complement induced hemolysis. Hereby, the anti-complement therapy is considered the mainstay of treatment for PNH.
* The anti-complement therapy includes '''Eculizumab''' which acts on reducing the hemolysis, reducing the risk of thrombosis, and decreasing the need for blood transfusion.
* '''Eculizumab:'''
** A monoclonal antibody against the complement tends to decrease the intravascular hemolysis due to complement attacking the RBCs.  
** Eculizumab acts via binding the C5 component of the complement system preventing its conversion to C5b and eventually no formation of the membrane attack complex (MAC) and no hemolysis takes place.
** Dosage:
*** Preferred regimen (1): Eculizumab 600 mg IV once a week for four weeks. Then 900 mg IV  once a week every two weeks.  
** Adverse effects:
*** Eculizumab is associated with increase risk of Neisseria infections as it inhibits the complement system (especially MAC) which is important in the elimination process of the Neisseria species from the body.  
*** In order to prevent this serious side effects of Eculizumab, patients should receive meningococcal vaccines for two weeks before starting treatment with Eculizumab. Moreover, daily prophylaxis with oral antimicrobial should be prescribed.  
* Other anti-complement therapies not approved yet:
** C5 inhibitors as Ravulizumab
** C1 esterase inhibitor
** Factor D inhibition


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/>  It may be necessary to give folate too in order to augment hematopoiesis.  Erythropoeitin (EPO) can be given (10-20,000 u tiw) to help.  As with steroid therapy tranfusions are given when the iron treatments do not suffice. 
*


Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular 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> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.
=== Hematopoietic cell transplantation ===
* Hematopoietic stem cell transplantation is an important curative therapy for paroxysmal nocturnal hemoglobinuria.
* Stem cell transplantation is usually reserved for the severely affected patients and is indicated for the following type of patients:<ref name="pmid28013015">{{cite journal| author=DeZern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA| title=Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia. | journal=Biol Blood Marrow Transplant | year= 2017 | volume= 23 | issue= 3 | pages= 498-504 | pmid=28013015 | doi=10.1016/j.bbmt.2016.12.628 | pmc=5373094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28013015  }}</ref>
** Patients with severe aplastic anemia who are HLA matched donor.  
** Patients with myelodysplastic syndromes
** Patients who are unresponsive to the anti complement therapy (eculizumab)
* Transplantation related issues:<ref name="pmid22689687">{{cite journal| author=Peffault de Latour R, Schrezenmeier H, Bacigalupo A, Blaise D, de Souza CA, Vigouroux S et al.| title=Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. | journal=Haematologica | year= 2012 | volume= 97 | issue= 11 | pages= 1666-73 | pmid=22689687 | doi=10.3324/haematol.2012.062828 | pmc=3487438 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22689687  }}</ref><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>
** Acute Graft-Versus-Host Disease (GVHD) occurs in almost third of the PNH patients treated with transplant.  
** Survival rate of the PNH patients treated with transplantation is from 50% to 60%.


Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis.  Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.
=== Treatment of the anemia ===
* Management of hemolytic anemia in PNH includes the following steps:
** '''[[Blood transfusion|Transfusion support]]''': [[Packed red blood cell transfusion|Packed red blood cell transfusions]] can be administered to help treat hemolytic anemia in the short-term. This is the most rapid method that raises [[hemoglobin]] level. Transfusions were the mainstay of treatment greater than 50 years ago, prior to the develop of effective [[Immunosuppressive therapy|immunosuppressive therapies]]. However, it is important to note that transfusions are a temporizing measure until a more long-term or disease-modifying medication can be given.<ref name="pmid26696797">{{cite journal| author=Salama A| title=Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 294-301 | pmid=26696797 | doi=10.1159/000438731 | pmc=4678315 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696797 }}</ref>
** Iron supplmentation for patients with low reticulocyte count.
** Folate supplementation to convoy the accelerated erythropoiesis due to blood transfusion.  


Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection.  Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given.  If the patient had already received the vaccine, they may need a booster.  Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination.  Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection.  These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations.  Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards.  Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab. 
Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients.  Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count.  This is manifest clinically with a decrease in the need for transfusions. 
Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab.  This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH.  The LDH usually returns to normal or near normal within days to weeks after Eculizumab.  Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction.  The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis.  If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate.  It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis.  It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis. 
Anticoagulation is only partly effective in preventing thrombosis in PNH.  Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab.  Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady.  Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation.  Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period. 
Pregnant patients with PNH have an even greater need for folate and iron supplementation because of the hemolysis.  Pregnancy, as with oral contraceptive use, increases the risk of thrombosis in PNH.  Anticoagulation with a LMWH is recommended as long as there are no contraindications for full anticoagulation.  Give 1 mg/kg subcutaneously every 12 hours when the pregnancy is confirmed in a PNH patient with a large PNH clone.  Some sources state that it is often necessary to switch to unfractionated heparin around the time of delivery if a C-section is planned. 
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Rare diseases]]
[[Category:Genetic disorders]]
[[Category:Mature chapter]]


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Latest revision as of 06:47, 20 October 2020

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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

The mainstay of treatment for paroxysmal nocturnal hemoglobinuria is medical therapy. Treatment includes anticomplement therapy which includes Eculizumab which acts on reducing the hemolysis and possible complications of PNH. Other treatment regimens include hematopoietic cell transplantation and treatment of the anemia.

Medical Therapy

  • The mainstay of treatment for PNH is medical therapy.
  • Treatment of PNH includes the following:
    • Anti-complement therapy
    • Hematopoietic cell transplantation
    • Treatment of the anemia

Anti-complement therapy

  • Most of the symptoms and signs of PNH is related to the deficiency of the CD55/CD59 which lead to complement induced hemolysis. Hereby, the anti-complement therapy is considered the mainstay of treatment for PNH.
  • The anti-complement therapy includes Eculizumab which acts on reducing the hemolysis, reducing the risk of thrombosis, and decreasing the need for blood transfusion.
  • Eculizumab:
    • A monoclonal antibody against the complement tends to decrease the intravascular hemolysis due to complement attacking the RBCs.
    • Eculizumab acts via binding the C5 component of the complement system preventing its conversion to C5b and eventually no formation of the membrane attack complex (MAC) and no hemolysis takes place.
    • Dosage:
      • Preferred regimen (1): Eculizumab 600 mg IV once a week for four weeks. Then 900 mg IV once a week every two weeks.
    • Adverse effects:
      • Eculizumab is associated with increase risk of Neisseria infections as it inhibits the complement system (especially MAC) which is important in the elimination process of the Neisseria species from the body.
      • In order to prevent this serious side effects of Eculizumab, patients should receive meningococcal vaccines for two weeks before starting treatment with Eculizumab. Moreover, daily prophylaxis with oral antimicrobial should be prescribed.
  • Other anti-complement therapies not approved yet:
    • C5 inhibitors as Ravulizumab
    • C1 esterase inhibitor
    • Factor D inhibition

Hematopoietic cell transplantation

  • Hematopoietic stem cell transplantation is an important curative therapy for paroxysmal nocturnal hemoglobinuria.
  • Stem cell transplantation is usually reserved for the severely affected patients and is indicated for the following type of patients:[1]
    • Patients with severe aplastic anemia who are HLA matched donor.
    • Patients with myelodysplastic syndromes
    • Patients who are unresponsive to the anti complement therapy (eculizumab)
  • Transplantation related issues:[2][3]
    • Acute Graft-Versus-Host Disease (GVHD) occurs in almost third of the PNH patients treated with transplant.
    • Survival rate of the PNH patients treated with transplantation is from 50% to 60%.

Treatment of the anemia

  • Management of hemolytic anemia in PNH includes the following steps:
    • Transfusion support: Packed red blood cell transfusions can be administered to help treat hemolytic anemia in the short-term. This is the most rapid method that raises hemoglobin level. Transfusions were the mainstay of treatment greater than 50 years ago, prior to the develop of effective immunosuppressive therapies. However, it is important to note that transfusions are a temporizing measure until a more long-term or disease-modifying medication can be given.[4]
    • Iron supplmentation for patients with low reticulocyte count.
    • Folate supplementation to convoy the accelerated erythropoiesis due to blood transfusion.

References

  1. ↑ DeZern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA (2017). "Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia". Biol Blood Marrow Transplant. 23 (3): 498–504. doi:10.1016/j.bbmt.2016.12.628. PMC 5373094. PMID 28013015.
  2. ↑ Peffault de Latour R, Schrezenmeier H, Bacigalupo A, Blaise D, de Souza CA, Vigouroux S; et al. (2012). "Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria". Haematologica. 97 (11): 1666–73. doi:10.3324/haematol.2012.062828. PMC 3487438. PMID 22689687.
  3. ↑ 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.
  4. ↑ Salama A (2015). "Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review". Transfus Med Hemother. 42 (5): 294–301. doi:10.1159/000438731. PMC 4678315. PMID 26696797.

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