Hemolytic anemia pathophysiology: Difference between revisions

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{{Hemolytic anemia}}
{{Hemolytic anemia}}
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==Overview==
==Overview==
The pathophysiology of most hemolytic anemia involves [[complement]]-activated [[autoantibodies]] or non-[[complement]]-activated [[autoantibodies]], which result in [[Hemolysis|destruction of red blood cells]].<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> The underlying mechanisms is based on immune dysregulation between self and non-self.<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref> Numerous [[drugs]] including novel anti-cancer therapeutics, can result in [[Immune-mediated disease|immune-mediated]] [[hemolysis]]. On the other hand, the pathophysiology of non-immune-mediated hemolysis relates to structural factors, such as [[red blood cell]] membrane and [[enzyme]] defects which confer fragility towards [[red blood cells]]. In the setting of defects of [[red blood cell]] membranes or [[anti-oxidant]] [[enzymes]], there is increased risk for [[red blood cell]] destruction.


==Pathophysiology==
==Pathophysiology==
The pathophysiology of most hemolytic anemia involves complement-activated autoantibodies or non-complement-activated autoantibodies, which result in destruction of [[red blood cells]].<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>
===Drug-Induced Hemolysis===
===Drug-Induced Hemolysis===
Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red cell destruction. Drug-induced hemolytic anemia can occur in an antibody-dependent or antibody-independent manner.
Drug-induced hemolysis has large clinical relevance. It occurs when [[drugs]] actively provoke [[Hemolysis|red blood cell destruction]]. Drug-induced hemolytic anemia can occur in an [[Antibody dependent enhancement|antibody-dependent]] or antibody-independent manner.
*Antibody-mediated hemolysis: This can occur via IgG or IgM binding to red blood cell membranes.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
*Antibody-mediated hemolysis: This can occur via [[IgG]] or [[IgM]] binding to [[red blood cell]] membranes.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref> [[Complement]] proteins then fix (or attach) onto IgG or IgM [[antibodies]]. This eventually results in recruitment of the [[membrane attack complex]] consisting of complement proteins C5-C9.
*Antibody-independent hemolysis: This occurs in the absence of IgG or IgM. It can occur via drug-induced protein adsorption on red blood cells.
*Antibody-independent hemolysis: This occurs in the absence of IgG or IgM. It can occur via drug-induced protein [[adsorption]] on [[Red blood cell|red blood cells]].


===Immune-Mediated Hemolysis===
===Immune-Mediated Hemolysis===


Immune-mediated hemolysis is characterized by the presence of antibodies that bind to red blood cell membranes and trigger red blood cell destruction. Causes of immune-mediated hemolysis include:
[[Immune-mediated disease|Immune-mediated]] hemolysis is characterized by the presence of [[antibodies]] that bind to [[red blood cell]] membranes and trigger [[red blood cell]] destruction. In warm [[autoimmune hemolytic anemia]], [[antibodies]] bind to the [[red blood cell]] membrane at 37 degrees Celcius (core body temperature for humans).<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref> The antibodies are usually [[Polyclonal antibody|polyclonal]], meaning their specificity is for multiple [[antigens]] on [[Red blood cell|red blood cells]].<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656 }} </ref> Causes of [[Immune-mediated disease|immune-mediated]] [[hemolysis]] include:
*'''Drugs:''' This is one of the most common causes of immune-mediated hemolysis. Of note, there is overlap between drug-induced hemolysis and immune-mediated hemolysis. Specifically, drug-induced hemolysis can be immune-mediated or non-immune-mediated, while immune-mediated hemolysis can be drug-dependent or drug-independent.
*'''Drugs:''' This is one of the most common causes of immune-mediated hemolysis. Of note, there is overlap between [[drug-induced]] [[hemolysis]] and immune-mediated hemolysis. Specifically, drug-induced hemolysis can be immune-mediated or non-immune-mediated, while immune-mediated hemolysis can be drug-dependent or drug-independent.
**'''[[Penicillin]]''': Penicillin is an antibacterial medication that, in high doses, can induce immune-mediated hemolysis via the [[hapten]] mechanism in which antibodies are targeted against the combination of penicillin in association with red blood cells. Complement is activated by the attached antibody leading to the removal of red blood cells by the spleen.
**'''[[Penicillin]]''': [[Penicillin]] is an [[Antibiotic|antibacterial medication]] that, in high doses, can induce [[Immune-mediated disease|immune-mediated]] hemolysis via the [[hapten]] mechanism in which [[antibodies]] are targeted against the combination of [[penicillin]] in association with [[red blood cells]]. [[Complement]] is activated by the attached [[antibody]] leading to the removal of [[red blood cells]] by the [[spleen]].  
**'''[[Nivolumab]]''': This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, and lung cancer. Nivolumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059 }} </ref>
**'''[[Nivolumab]]''': This is an [[antibody]] that binds to the PD-1 [[antigen]] found on [[lymphocytes]]. It is typically used to treat [[cancers]] like squamous cell [[Head and neck cancer|carcinoma of the head and neck]], [[melanoma]], [[Hepatocellular carcinoma|hepatocellular cancer]], and [[lung cancer]]. [[Nivolumab]] can trigger significant [[autoimmune]] reactions. When the hematologic system is affected, hemolytic anemia can result.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
**'''[[Pembrolizumab]]''': This is an antibody that binds to the PD-1 antigen found on lymphocytes. It is typically used to treat cancers like squamous cell carcinoma of the head and neck, melanoma, and lung cancer. Nivolumab can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
**'''[[Pembrolizumab]]''': This is an [[antibody]] that binds to the PD-1 antigen found on [[lymphocytes]]. It is typically used to treat [[cancers]] like [[squamous cell carcinoma]] of the head and neck, [[melanoma]], [[urothelial cancer]], and [[lung cancer]]. [[Pembrolizumab]] can trigger significant autoimmune reactions. When the hematologic system is affected, hemolytic anemia can result.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
**'''[[Ipilimumab]]''': This is an antibody that binds to cytotoxic T lymphocyte antigen-4 (CTLA-4) on T cells. It is commonly used to treat stage III melanoma in the adjuvant setting and stage IV melanoma.
**'''[[Ipilimumab]]''': This is an antibody that binds to cytotoxic T lymphocyte antigen-4 ([[CTLA-4]]) on [[T cells]]. [[CTLA-4]] is normally an inhibitor molecule involved in the regulatory [[T cell]] response.<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref> [[CTLA-4]] functions in maintaining normal [[homeostasis]]. [[Ipilimumab]] is commonly used to treat stage III melanoma in the adjuvant setting and stage IV [[melanoma]].
**Anti-RhD: This is a medication used to treat immune thrombocytopenia purpura (ITP). It works by saturating Fc receptors on splenic macrophages and also inducing a mild hemolysis.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
**Anti-RhD: This is a medication used to treat [[ITP|immune thrombocytopenia purpura]] (ITP). It works by saturating [[Fc receptors]] on [[splenic]] [[macrophages]] and also inducing a mild [[hemolysis]].<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref>
*'''Infections:''' Amongst infectious agents, viruses are most likely to trigger hemolysis, compared to bacteria, parasites, or fungi.
*'''Infections:''' Amongst [[infectious agents]], [[viruses]] are most likely to trigger [[hemolysis]], compared to [[bacteria]], [[parasites]], or [[fungi]].
*'''Autoimmune or rheumatologic disease''': Activation of one's own immune system can result in destruction of red blood cells in an antibody-dependent manner. Females are more likely to develop autoimmune hemolytic anemia.
*'''Autoimmune or rheumatologic disease''': Activation of one's own [[immune system]] can result in destruction of [[red blood cells]] in an [[Antibody dependent enhancement|antibody-dependent]] manner. Females are more likely to develop [[autoimmune hemolytic anemia]].
*'''Lymphoproliferative disorders''': These represent a group of primary bone marrow disorders characterized by rapid proliferation of T cells or B cells. Chronic lymphocytic leukemia (CLL), for example, is a lymphoproliferative disorder that is a known etiology of hemolytic anemia.
*'''Lymphoproliferative disorders''': These represent a group of primary [[bone marrow]] disorders characterized by rapid proliferation of [[T cells]] or [[B cells]]. [[Chronic lymphocytic leukemia]] (CLL), for example, is a [[lymphoproliferative disorder]] that is a known etiology of hemolytic anemia.
The drug itself can be targeted by the immune system, e.g. by IgE in a Type I hypersensitivity reaction to penicillin, rarely leading to anaphylaxis.
*'''Genetic polymorphisms''': [[Mutations]] or [[Genetics|genetic]] variants in certains genes, like [[CTLA-4]], can cause hemolytic anemia. Mutations can contribute to [[autoimmunity]].<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref>
 
===Cold Agglutinin-Mediated Hemolysis===
[[Cold agglutinins]] usually bind to the the Ii carbohydrate antigen on [[red blood cells]].<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref> [[Agglutination]] usually occurs in the peripheral [[vasculature]] in distal [[capillary]] beds, where temperature is cool. [[Immunoglobulin M|IgM antibody]] binds to [[red blood cells]] upon exposure to cold, and IgM fixes [[complement]] proteins like C1, initiating the [[classical complement pathway]]. Subsequent [[complement]] proteins include C4, C2, and C3. The [[membrane attack complex]] then forms and results in [[intravascular]] hemolysis.<ref name="pmid25705656">{{cite journal| author=Berentsen S, Sundic T| title=Red blood cell destruction in autoimmune hemolytic anemia: role of [[complement]] and potential new targets for therapy. | journal=Biomed Res Int | year= 2015 | volume= 2015 | issue=  | pages= 363278 | pmid=25705656 | doi=10.1155/2015/363278 | pmc=4326213 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25705656  }} </ref>


===Non-Immune-Mediated Hemolysis===
===Non-Immune-Mediated Hemolysis===


Non-immune hemolysis is characterized by the absence of antibodies in the setting of red blood cell destruction.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref> Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair volume regulatory mechanisms, which become activated during [[hypotonic]] [[red blood cell]] swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. [[ouabain]] at very high doses). Alternatively, non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. Red blood cell enzymatic deficiencies are common causes of non-immune-mediated hemolysis.<ref name="pmid12124266">{{cite journal| author=Wiback SJ, Palsson BO| title=Extreme pathway analysis of human red blood cell metabolism. | journal=Biophys J | year= 2002 | volume= 83 | issue= 2 | pages= 808-18 | pmid=12124266 | doi=10.1016/S0006-3495(02)75210-7 | pmc=1302188 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12124266  }} </ref>
Non-immune hemolysis is characterized by the absence of [[antibodies]] in the setting of [[red blood cell]] destruction.<ref name="pmid19960059">{{cite journal| author=Mintzer DM, Billet SN, Chmielewski L| title=Drug-induced hematologic syndromes. | journal=Adv Hematol | year= 2009 | volume= 2009 | issue=  | pages= 495863 | pmid=19960059 | doi=10.1155/2009/495863 | pmc=2778502 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19960059  }} </ref> Non-immune drug-induced hemolysis can also arise from [[drug-induced]] damage to cell volume control mechanisms; for example [[drugs]] can directly or indirectly impair volume regulatory mechanisms, which become activated during [[hypotonic]] [[red blood cell]] swelling to return the [[cell]] to a normal volume. The consequence of the drugs actions are irreversible cell swelling and [[lysis]] (e.g. [[ouabain]] at very high doses). Alternatively, non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the [[Antioxidants|antioxidant]] defense system of the [[Red blood cell|red blood cells]]. [[Red blood cell]] enzymatic deficiencies are common causes of non-immune-mediated hemolysis.<ref name="pmid12124266">{{cite journal| author=Wiback SJ, Palsson BO| title=Extreme pathway analysis of human red blood cell metabolism. | journal=Biophys J | year= 2002 | volume= 83 | issue= 2 | pages= 808-18 | pmid=12124266 | doi=10.1016/S0006-3495(02)75210-7 | pmc=1302188 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12124266  }} </ref>


*'''Glucose-6-phosphate dehydrogenase (G6PD) deficiency''': This is a red blood cell enzyme defect that results in oxidative stress and hemolysis. It is the most common red blood cell enzymatic defect. Antimalarial oxidant drugs like primaquine damages red blood cells in [[glucose-6-phosphate dehydrogenase deficiency]] in which the red blood cells are more susceptible to oxidative stress due to reduced NADPH production consequent to the enzyme deficiency. G6PD is the rate-limiting enzyme in the pentose phosphate pathway, or hexose monophosphate shunt. The normal function of G6PD is to confer reductive potential to erythrocytes via NADPH. Oxidation of NADPH to NADP+ in erythrocytes prevents oxidation of other molecules in these cells and thus prevents hemolysis.<ref name="pmid24372186">{{cite journal| author=Luzzatto L, Seneca E| title=G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. | journal=Br J Haematol | year= 2014 | volume= 164 | issue= 4 | pages= 469-80 | pmid=24372186 | doi=10.1111/bjh.12665 | pmc=4153881 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24372186  }} </ref> Intact G6PD allows for generation of reduced glutathione, which prevents oxidative stress and hemolysis.<ref name="pmid24372186">{{cite journal| author=Luzzatto L, Seneca E| title=G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. | journal=Br J Haematol | year= 2014 | volume= 164 | issue= 4 | pages= 469-80 | pmid=24372186 | doi=10.1111/bjh.12665 | pmc=4153881 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24372186  }} </ref> In the presence of G6PD deficiency, the stores of glutathione are depleted, and the sulfhydryl groups of hemoglobin and other proteins become oxidized. This creates precipitation of denatured hemoglobin known as Heinz bodies. This leads to irreversible membrane damage and thus hemolysis. Drugs that typically cause hemolysis in patients with G6PD deficiency include:
*'''[[Glucose-6-phosphate dehydrogenase]] (G6PD) deficiency''': This is a [[red blood cell]] enzyme defect that results in [[oxidative stress]] and [[hemolysis]]. It is the most common [[red blood cell]] enzymatic defect. [[Antimalarial medication|Antimalarial oxidant drugs]] like [[primaquine]] damages [[Red blood cell|red blood cells]] in [[glucose-6-phosphate dehydrogenase deficiency]] in which the [[red blood cells]] are more susceptible to oxidative stress due to reduced [[NADPH]] production consequent to the enzyme deficiency. [[Glucose-6-phosphate dehydrogenase|G6PD]] is the rate-limiting enzyme in the [[pentose phosphate pathway]], or hexose monophosphate shunt. The normal function of G6PD is to confer reductive potential to [[erythrocytes]] via NADPH. Oxidation of [[NADPH]] to [[NADP|NADP+]] in [[erythrocytes]] prevents [[oxidation]] of other molecules in these [[cells]] and thus prevents [[hemolysis]].<ref name="pmid24372186">{{cite journal| author=Luzzatto L, Seneca E| title=G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. | journal=Br J Haematol | year= 2014 | volume= 164 | issue= 4 | pages= 469-80 | pmid=24372186 | doi=10.1111/bjh.12665 | pmc=4153881 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24372186  }} </ref> Intact G6PD allows for generation of reduced [[glutathione]], which prevents oxidative stress and hemolysis.<ref name="pmid24372186">{{cite journal| author=Luzzatto L, Seneca E| title=G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. | journal=Br J Haematol | year= 2014 | volume= 164 | issue= 4 | pages= 469-80 | pmid=24372186 | doi=10.1111/bjh.12665 | pmc=4153881 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24372186  }} </ref> In the presence of [[G6PD]] deficiency, the stores of [[glutathione]] are depleted, and the [[sulfhydryl]] groups of [[hemoglobin]] and other [[proteins]] become oxidized. This creates precipitation of denatured hemoglobin known as [[Heinz bodies]]. This leads to irreversible membrane damage and thus [[hemolysis]]. Drugs that typically cause hemolysis in patients with [[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]] include:
**primiquine and other anti-malarial agents
**Primiquine and other [[Antimalarial drug|anti-malarial agents]]
**fava beans
**[[Fava bean|Fava beans]]
**sulfa drugs like trimethoprim-sulfamethoxazole
**[[Sulfa drugs]] like [[trimethoprim-sulfamethoxazole]]
**dapsone
**[[dapsone]]


*'''Pyruvate kinase deficiency''': This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis. It is an autosomal recessive disorder. It is the second most common red blood cell enzymatic defect, after G6PD deficiency. Pyruvate kinase is the final enzyme in the glycolysis pathway and converts phosphoenolpyruvate to pyruvate.
*'''[[Pyruvate kinase]] deficiency''': This is a [[red blood cell]] enzymatic defect that can result in [[oxidative stress]] and [[hemolysis]]. It is an [[autosomal recessive]] disorder. It is the second most common red blood cell enzymatic defect, after [[G6PD deficiency]]. [[Pyruvate kinase]] is the final [[enzyme]] in the [[glycolysis]] pathway and converts [[phosphoenolpyruvate]] to [[pyruvate]].


*'''Glucose phosphate isomerase deficiency''': This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.
*'''[[Glucose phosphate isomerase]] deficiency''': This is a [[red blood cell]] enzymatic defect that can result in [[oxidative stress]] and [[hemolysis]].


*'''Triose phosphate isomerase deficiency''': This is a red blood cell enzymatic defect that can result in oxidative stress and hemolysis.<ref name="pmid16980388">{{cite journal| author=Celotto AM, Frank AC, Seigle JL, Palladino MJ| title=Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. | journal=Genetics | year= 2006 | volume= 174 | issue= 3 | pages= 1237-46 | pmid=16980388 | doi=10.1534/genetics.106.063206 | pmc=1667072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16980388  }} </ref> This enzyme normally functions to convert dihydroxyacetone phosphate to glyceraldehyde-3-phosphate, which is a critical step in glycolysis. In addition to causing hemolytic anemia, this condition can cause neuromuscular disease and increased risk for infections.<ref name="pmid16980388">{{cite journal| author=Celotto AM, Frank AC, Seigle JL, Palladino MJ| title=Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. | journal=Genetics | year= 2006 | volume= 174 | issue= 3 | pages= 1237-46 | pmid=16980388 | doi=10.1534/genetics.106.063206 | pmc=1667072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16980388  }} </ref>
*'''[[Triose phosphate isomerase]] deficiency''': This is a [[red blood cell]] enzymatic defect that can result in oxidative stress and hemolysis.<ref name="pmid16980388">{{cite journal| author=Celotto AM, Frank AC, Seigle JL, Palladino MJ| title=Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. | journal=Genetics | year= 2006 | volume= 174 | issue= 3 | pages= 1237-46 | pmid=16980388 | doi=10.1534/genetics.106.063206 | pmc=1667072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16980388  }} </ref> This enzyme normally functions to convert [[dihydroxyacetone phosphate]] to [[glyceraldehyde-3-phosphate]], which is a critical step in [[glycolysis]]. In addition to causing hemolytic anemia, this condition can cause [[neuromuscular disease]] and increased risk for [[infections]].<ref name="pmid16980388">{{cite journal| author=Celotto AM, Frank AC, Seigle JL, Palladino MJ| title=Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. | journal=Genetics | year= 2006 | volume= 174 | issue= 3 | pages= 1237-46 | pmid=16980388 | doi=10.1534/genetics.106.063206 | pmc=1667072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16980388  }} </ref>


==Compensatory response==
==Compensatory response==
[[Hemolytic anemia]] causes a compensatory increase in [[erythropoetin]] that in turn causes an increase in [[reticulocyte percentage]] and [[absolute reticulocyte count]]. This results in increased [[hemoglobin]] and RBC production.
[[Hemolytic anemia]] causes a compensatory increase in erythropoetin that in turn causes an increase in [[Reticulocyte count|reticulocyte percentage]] and [[absolute reticulocyte count]]. This results in increased [[hemoglobin]] and [[red blood cell]] production.


==References==
==References==

Latest revision as of 17:35, 30 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Overview

The pathophysiology of most hemolytic anemia involves complement-activated autoantibodies or non-complement-activated autoantibodies, which result in destruction of red blood cells.[1] The underlying mechanisms is based on immune dysregulation between self and non-self.[2] Numerous drugs including novel anti-cancer therapeutics, can result in immune-mediated hemolysis. On the other hand, the pathophysiology of non-immune-mediated hemolysis relates to structural factors, such as red blood cell membrane and enzyme defects which confer fragility towards red blood cells. In the setting of defects of red blood cell membranes or anti-oxidant enzymes, there is increased risk for red blood cell destruction.

Pathophysiology

Drug-Induced Hemolysis

Drug-induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. Drug-induced hemolytic anemia can occur in an antibody-dependent or antibody-independent manner.

Immune-Mediated Hemolysis

Immune-mediated hemolysis is characterized by the presence of antibodies that bind to red blood cell membranes and trigger red blood cell destruction. In warm autoimmune hemolytic anemia, antibodies bind to the red blood cell membrane at 37 degrees Celcius (core body temperature for humans).[2] The antibodies are usually polyclonal, meaning their specificity is for multiple antigens on red blood cells.[2] Causes of immune-mediated hemolysis include:

Cold Agglutinin-Mediated Hemolysis

Cold agglutinins usually bind to the the Ii carbohydrate antigen on red blood cells.[2] Agglutination usually occurs in the peripheral vasculature in distal capillary beds, where temperature is cool. IgM antibody binds to red blood cells upon exposure to cold, and IgM fixes complement proteins like C1, initiating the classical complement pathway. Subsequent complement proteins include C4, C2, and C3. The membrane attack complex then forms and results in intravascular hemolysis.[2]

Non-Immune-Mediated Hemolysis

Non-immune hemolysis is characterized by the absence of antibodies in the setting of red blood cell destruction.[3] Non-immune drug-induced hemolysis can also arise from drug-induced damage to cell volume control mechanisms; for example drugs can directly or indirectly impair volume regulatory mechanisms, which become activated during hypotonic red blood cell swelling to return the cell to a normal volume. The consequence of the drugs actions are irreversible cell swelling and lysis (e.g. ouabain at very high doses). Alternatively, non-immune drug induced hemolysis can occur via oxidative mechanisms. This is particularly likely to occur when there is an enzyme deficiency in the antioxidant defense system of the red blood cells. Red blood cell enzymatic deficiencies are common causes of non-immune-mediated hemolysis.[4]

Compensatory response

Hemolytic anemia causes a compensatory increase in erythropoetin that in turn causes an increase in reticulocyte percentage and absolute reticulocyte count. This results in increased hemoglobin and red blood cell production.

References

  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.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Berentsen S, Sundic T (2015). "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy". Biomed Res Int. 2015: 363278. doi:10.1155/2015/363278. PMC 4326213. PMID 25705656.
  3. 3.0 3.1 3.2 3.3 3.4 Mintzer DM, Billet SN, Chmielewski L (2009). "Drug-induced hematologic syndromes". Adv Hematol. 2009: 495863. doi:10.1155/2009/495863. PMC 2778502. PMID 19960059.
  4. Wiback SJ, Palsson BO (2002). "Extreme pathway analysis of human red blood cell metabolism". Biophys J. 83 (2): 808–18. doi:10.1016/S0006-3495(02)75210-7. PMC 1302188. PMID 12124266.
  5. 5.0 5.1 Luzzatto L, Seneca E (2014). "G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications". Br J Haematol. 164 (4): 469–80. doi:10.1111/bjh.12665. PMC 4153881. PMID 24372186.
  6. 6.0 6.1 Celotto AM, Frank AC, Seigle JL, Palladino MJ (2006). "Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy". Genetics. 174 (3): 1237–46. doi:10.1534/genetics.106.063206. PMC 1667072. PMID 16980388.

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