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{{Autoimmune hemolytic anemia}}
{{Autoimmune hemolytic anemia}}


{{CMG}} '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]; {{shyam}}
{{CMG}} '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]; {{shyam}}, [[User:Irfan Dotani|Irfan Dotani]] [3]
 
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==Overview==
==Overview==
The mainstay of therapy for autoimmune hemolytic anemia is [[immunosuppression]], since the pathophysiology of autoimmune hemolytic anemia involves [[immunological]] activation which leads to the destruction of [[red blood cells]]. Suppression of the [[immunological]] activation via medications has been the cornerstone of therapy for many decades. Medications include [[corticosteroids]], [[azathioprine]], [[rituximab]], [[mycophenolate]] mofetil, [[cyclosporine]] A, and [[cyclophosphamide]].


==Medical Therapy==
==Medical Therapy==
The maintain of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to destruction of [[red blood cells]]. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades.
Medical treatment of autoimmune hemolytic anemia is summarized below:
 
*'''[[Corticosteroids]]''': Corticosteroids is the major class of medications used for treatment. Corticosteroids are the first-line therapy. Efficacy of corticosteroids is approximately 70-85%.<ref name="pmid25271314">{{cite journal| author=Zanella A, Barcellini W| title=Treatment of autoimmune hemolytic anemias. | journal=Haematologica | year= 2014 | volume= 99 | issue= 10 | pages= 1547-54 | pmid=25271314 | doi=10.3324/haematol.2014.114561 | pmc=4181250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271314  }} </ref> The initial dose of prednisone is 1 to 1.5mg/kg orally once daily. After a response is seen, steroids should be tapered over 6-12 months. Rapid taper of steroids can result in adrenal insufficiency, which can manifest as hypotension and fatigue and can be fatal.<ref name="pmid25271314">{{cite journal| author=Zanella A, Barcellini W| title=Treatment of autoimmune hemolytic anemias. | journal=Haematologica | year= 2014 | volume= 99 | issue= 10 | pages= 1547-54 | pmid=25271314 | doi=10.3324/haematol.2014.114561 | pmc=4181250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271314  }} </ref> Of note, steroids are effective only for warm-antibody type autoimmune hemolytic anemia. Steroids are not effective for cold-antibody type autoimmune hemolytic anemia. Given the multiple adverse effects of steroids, it is not ideal for a patient to remain on steroids for long-term management. If long-term immunosuppression is required for control of autoimmune hemolytic anemia, and alternative immunosuppression should be attempted.
**''Adverse effects'': The adverse effects of corticocsteroids include immunosuppression, opportunisitic infection, bone density loss, loss of muscle mass, increased adipose deposition, hypertension, cataracts, glaucoma.
 
*'''[[Splenectomy]]''': Splenectomy, or removal of the spleen, is a second-line option for autoimmune hemolytic anemia. Splenectomy is frequently considered for patients who have steroid-refractory or relapsed disease. The response rate for splenectomy is typically 66%.<ref name="pmid25271314">{{cite journal| author=Zanella A, Barcellini W| title=Treatment of autoimmune hemolytic anemias. | journal=Haematologica | year= 2014 | volume= 99 | issue= 10 | pages= 1547-54 | pmid=25271314 | doi=10.3324/haematol.2014.114561 | pmc=4181250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271314  }} </ref> The ideal candidate for splenectomy is one who has adequate functional status and cardiopulmonary reserve to undergo surgery. The decision to proceed with splenectomy is typically made jointly between the patient and physician, as surgical intervention carries inherent risks. Given the infectious risk for splenectomy, patients should undergo vaccination for ''Hemophilus influenzae'', ''Neisseria meningitides'', and ''Streptococcus pneumoniae.'' The three organisms are encapsulated bacteria which are normally eliminated by the spleen via complement-mediated opsonization.
**''Adverse effects'': The adverse effects of splenectomy include the inherent surgical risk, bleeding, post-operative thrombosis, post-operative pain, systemic infection (asplenic sepsis) with encapsulated organisms, and reactive thrombocytosis.


{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
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! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Medication}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Mechanism of action}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Response rate}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Dosing and Administration}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Adverse effects}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Metabolism}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Notable features}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
[[Corticosteroids]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Inhibition of [[IL-2]] Inhibition of [[arachidonic acid]] production
* Inhibition of NF-kappaB signaling
| style="padding: 5px 5px; background: #F5F5F5;" |
* 70-85%
* Response usually occurs within 2 weeks<ref name="pmid25271314">{{cite journal| author=Zanella A, Barcellini W| title=Treatment of autoimmune hemolytic anemias. | journal=Haematologica | year= 2014 | volume= 99 | issue= 10 | pages= 1547-54 | pmid=25271314 | doi=10.3324/haematol.2014.114561 | pmc=4181250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271314  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Prednisone]] 1 to 1.5mg/kg PO daily for 1-3 weeks until hemoglobin improves to 10g/dl; rapid taper down to 20mg PO daily; slow taper over months from 20mg to 0mg
* Treat for 3-4 months with low-dose [[prednisone]]<ref name="pmid25271314">{{cite journal| author=Zanella A, Barcellini W| title=Treatment of autoimmune hemolytic anemias. | journal=Haematologica | year= 2014 | volume= 99 | issue= 10 | pages= 1547-54 | pmid=25271314 | doi=10.3324/haematol.2014.114561 | pmc=4181250 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25271314  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Immunosuppression]]
* [[Opportunistic infection|Opportunisitic infection]]
* [[Bone density loss]]
* Loss of muscle mass
* Increased adipose deposition
* [[hypertension]]
* [[cataracts]]
* [[Glaucoma]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Extensive hepatic metabolism
| style="padding: 5px 5px; background: #F5F5F5;" |
* First-line therapy is co-administer calcium supplementation with vitamin D (for bone protection)
* Co-administer H2 receptor antagonist for GI protection if high risk for gastrointestinal bleeding
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Azathioprine]]<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>
| style="padding: 5px 5px; background: #F5F5F5;" |
* Purine synthesis inhibitor
* Converts to [[6-mercaptopurine]]
* [[Antibody-dependent cell-mediated cytotoxicity]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* 40-60%
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* 1-3  mg/m2 IV weekly for 4 weeks
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Hepatitis B]] reactivation
* Progressive [[Leukoencephalopathy|multifocal leukoencephalopathy]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Hepatic metabolism to [[6-mercaptopurine]] and 6-thiouric acid
| style="padding: 5px 5px; background: #F5F5F5;" |
* Higher cost of therapy than [[corticosteroids]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Rituximab]]<ref name="pmid21547266">{{cite journal| author=Fozza C, Longinotti M| title=Use of rituximab in autoimmune hemolytic anemia associated with non-hodgkin lymphomas. | journal=Adv Hematol | year= 2011 | volume= 2011 | issue=  | pages= 960137 | pmid=21547266 | doi=10.1155/2011/960137 | pmc=3087411 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21547266  }} </ref>
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[CD20]] monoclonal antibody
* [[Antibody-dependent cell-mediated cytotoxicity]]
* Depletion of [[B cell|B cells]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* 83-87% overall response rate
* 54-60% complete response rate
| style="padding: 5px 5px; background: #F5F5F5;" |
* 375 mg/m2 IV weekly for 4 weeks
* 100 mg IV weekly for 4 weeks
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Hepatitis B]] reactivation
* [[Progressive multifocal leukoencephalopathy]]
* Infusion reaction
| style="padding: 5px 5px; background: #F5F5F5;" |
* Unknown
| style="padding: 5px 5px; background: #F5F5F5;" |
* Higher cost of therapy than [[Corticosteroid|corticosteroids]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Mycophenolate]] mofetil
| style="padding: 5px 5px; background: #F5F5F5;" |
* Noncompetitive, selective, reversible inhibitor of [[Inosine monophosphate|inosine monophosphate (IMP)]] dehydrogenase
* Inhibits [[T cell proliferation]] by inhibiting purine synthesis
| style="padding: 5px 5px; background: #F5F5F5;" |
* Variable
| style="padding: 5px 5px; background: #F5F5F5;" |
* 1-1.5 g PO every 12 hours
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Hyperglycemia]]
* [[Hyperlipidemia]]
* [[Leukopenia]]
* [[Infections]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Enterohepatic recirculation to MPA, the active form of [[Mycophenolic acid|mycophenolate mofetil]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Higher cost of therapy than [[Corticosteroid|corticosteroids]]
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Cyclosporine]] A
| style="padding: 5px 5px; background: #F5F5F5;" |
* Inhibits calcineurin-mediated [[NFAT|NFAT dephosphorylation]] and activation (calcineurin inhibitor)
* Inhibits [[T cell proliferation]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Variable
| style="padding: 5px 5px; background: #F5F5F5;" |
* 1 mg/kg PO every 12 hours
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Tremor]]
* [[Nephrotoxicity]]
* [[Hypertension]]
* [[Infection]]
* [[Headache]]
* [[Gingival hyperplasia]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* VIa hepatic CYP3A4 to metabolites AM1, AM9, and AM4N
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Nephrotoxicity]] limits its use in patients with renal dysfunction
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Cyclophosphamide]]<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>
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Alkylating agent|DNA alkylating agent]]
* Inhibits [[T cell proliferation]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Variable
| style="padding: 5px 5px; background: #F5F5F5;" |
* 50 mg/kg daily for 4 days
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Bone marrow suppression]]
* [[Nausea and vomiting]]
* [[Hemorrhagic cystitis]]
* [[Bladder cancer]]
| style="padding: 5px 5px; background: #F5F5F5;" |
* Hepatically metabolized to 4-hydroperoxycyclophosphamide and 4-aldophosphamide
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Chemotherapeutic agent]]
|}


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{Hematology}}
[[Category:Hematology]]
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Latest revision as of 11:23, 20 September 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Overview

The mainstay of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to the destruction of red blood cells. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades. Medications include corticosteroids, azathioprine, rituximab, mycophenolate mofetil, cyclosporine A, and cyclophosphamide.

Medical Therapy

Medical treatment of autoimmune hemolytic anemia is summarized below:

Medication Mechanism of action Response rate Dosing and Administration Adverse effects Metabolism Notable features

Corticosteroids

  • 70-85%
  • Response usually occurs within 2 weeks[1]
  • Prednisone 1 to 1.5mg/kg PO daily for 1-3 weeks until hemoglobin improves to 10g/dl; rapid taper down to 20mg PO daily; slow taper over months from 20mg to 0mg
  • Treat for 3-4 months with low-dose prednisone[1]
  • Extensive hepatic metabolism
  • First-line therapy is co-administer calcium supplementation with vitamin D (for bone protection)
  • Co-administer H2 receptor antagonist for GI protection if high risk for gastrointestinal bleeding

Azathioprine[2]

  • 40-60%
  • 1-3 mg/m2 IV weekly for 4 weeks

Rituximab[3]

  • 83-87% overall response rate
  • 54-60% complete response rate
  • 375 mg/m2 IV weekly for 4 weeks
  • 100 mg IV weekly for 4 weeks
  • Unknown

Mycophenolate mofetil

  • Variable
  • 1-1.5 g PO every 12 hours

Cyclosporine A

  • Variable
  • 1 mg/kg PO every 12 hours
  • VIa hepatic CYP3A4 to metabolites AM1, AM9, and AM4N

Cyclophosphamide[2]

  • Variable
  • 50 mg/kg daily for 4 days
  • Hepatically metabolized to 4-hydroperoxycyclophosphamide and 4-aldophosphamide

References

  1. ↑ 1.0 1.1 Zanella A, Barcellini W (2014). "Treatment of autoimmune hemolytic anemias". Haematologica. 99 (10): 1547–54. doi:10.3324/haematol.2014.114561. PMC 4181250. PMID 25271314.
  2. ↑ 2.0 2.1 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.
  3. ↑ Fozza C, Longinotti M (2011). "Use of rituximab in autoimmune hemolytic anemia associated with non-hodgkin lymphomas". Adv Hematol. 2011: 960137. doi:10.1155/2011/960137. PMC 3087411. PMID 21547266.

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