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| '''For patient information click [[Autoimmune hemolytic anemia (patient information)|here]]'''
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| {{Infobox_Disease | | | {{Infobox_Disease | |
| Name = Autoimmune hemolytic anemia | | | Name = Autoimmune hemolytic anemia | |
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| MeshID = D000744 | | | MeshID = D000744 | |
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| {{SI}} | | {{Autoimmune hemolytic anemia}} |
| {{CMG}} '''Assosciate Editor(s)-In-Chief:''' [[User: Prashanthsaddala|Prashanth Saddala M.B.B.S]]
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| ==Overview==
| | '''For patient information click [[Autoimmune hemolytic anemia (patient information)|here]]''' |
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| '''Autoimmune hemolytic anemia''' (AIHA) is a type of [[hemolytic anemia]] where the body's immune system attacks its own [[red blood cells]] (RBCs), leading to their destruction ([[hemolysis]]). [[Antibodies]] and associated [[complement system]] components become fixed onto the [[Red blood cell|RBC]] surface. These [[antibodies]] can be detected with the [[Coombs test#Direct Coombs test|direct antiglobulin test]], also known as the direct [[Coombs test]]. AIHA can also be induced by several drugs including methyl-dopa and fluarabine. | | {{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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| [[Autoimmunity]] must not be confused with [[alloimmunity]].
| | {{SK}} AIHA; hemolytic anemia with autoimmune cause. |
| | ==[[Autoimmune hemolytic anemia overview|Overview]]== |
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| The terminology used in this disease is somewhat ambiguous. Although [[Medical Subject Headings|MeSH]] uses the term "autoimmune hemolytic anemia",<ref>{{MeshName|Autoimmune+hemolytic+anemia}}</ref> some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category.<ref name="pmid10387489">{{cite journal |author=Wright MS |title=Drug-induced hemolytic anemias: increasing complications to therapeutic interventions |journal=Clin Lab Sci |volume=12 |issue=2 |pages=115–8 |year=1999 |pmid=10387489 }}</ref><ref name="isbn0-7216-0187-1">{{cite book |author=Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. |title=Robbins and Cotran pathologic basis of disease |publisher=Elsevier Saunders |location=St. Louis, Mo |year=2005 |pages=636 |isbn=0-7216-0187-1 }}</ref>. The [[National Cancer Institute]] considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.<ref>{{cite web |url=http://www.cancer.gov/templates/db_alpha.aspx?CdrID=523291 |title=Definition of immunohemolytic anemia |work=NCI Dictionary of Cancer Terms |accessdate=2009-02-07| archiveurl= http://web.archive.org/web/20090115195213/http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=523291| archivedate= 15 January 2009 <!--DASHBot-->| deadurl= no}}</ref>.
| | ==[[Autoimmune hemolytic anemia historical perspective|Historical Perspective]]== |
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| ==Historical perspective== | | ==[[Autoimmune hemolytic anemia classification|Classification]]== |
| "Blood-induced icterus" produced by the release of massive amounts of a coloring material from blood cells followed by the formation of bile was recognized and described by Vanlair and Masius' in 1871. About 20 years later, Hayem distinguished between congenital hemolytic anemia and an acquired type of infectious icterus associated with chronic splenomegaly. In 1904, Donath and Landsteiner suggested a serum factor was responsible for hemolysis in paroxysmal cold hemoglobinuria. French investigators led by Chauffard stressed the importance of red-cell [[autoagglutination]] in patients with acquired hemolytic anemia. In 1930, Lederer and Brill described cases of acute [[hemolysis]] with rapid onset of anemia and rapid recovery after transfusion therapy. These hemolytic episodes were thought to be due to infectious agents. A clear distinction between congenital and acquired hemolytic anemia was not drawn, however, until Dameshek and Schwartz in 1938, and in 1940, they demonstrated the presence of abnormal hemolysins in the sera of patients with acquired [[hemolytic anemia]] and postulated an [[immunology|immune mechanism]].<br />
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| During the past three decades, studies defining red-cell blood groups and serum antibodies have produced diagnostic methods that have laid the basis for immunologic concepts relevant to many of the acquired hemolytic states. Of these developments, the antiglobulin test described by Coombs, Mourant, and Race in 1945 has proved to be one of the more important, useful tools now available for the detection of immune hemolytic states. This technique demonstrated that a rabbit antibody against human globulin would induce agglutination of human red cells "coated with an incomplete variety of rhesus antibody". C. Moreschlit had used the same method in 1908 in a goat antirabbit-red-cell system. The test was historically premature and was forgotten. In 1946, Boorman, Dodd, and Loutit applied the direct antiglobulin test to a variety of hemolytic anemias, and laid the foundation for the clear distinction of autoimmune from congenital hemolytic anemia.<br />
| | ==[[Autoimmune hemolytic anemia pathophysiology|Pathophysiology]]== |
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| ==Classification== | | ==[[Autoimmune hemolytic anemia causes|Causes]]== |
| Haemolysis can be intravascular or extravascular.
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| '''Intravascular haemolysis'''<br>
| | ==[[Autoimmune hemolytic anemia differential diagnosis|Differentiating Autoimmune hemolytic anemia from other Diseases]]== |
| Red blood cell lysis occurs in the circulation as a result of activation of the [[complement system]] cascade.
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| '''Extravascular haemolysis'''<br>
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| Red Blood Cells that are coated with antibodies are specifically recognised in the [[reticuloendothelial system]] and destroyed by [[macrophages]].
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| ===Subtypes=== | | ==[[Autoimmune hemolytic anemia epidemiology and demographics|Epidemiology and Demographics]]== |
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| *'''[[Warm antibody autoimmune hemolytic anemia]]'''
| | ==[[Autoimmune hemolytic anemia risk factors|Risk Factors]]== |
| :*Idiopathic
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| :*[[Systemic lupus erythematosus]]
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| :*[[Evans' syndrome]] (antiplatelet antibodies and haemolytic antibodies)
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| :*[[Chronic lymphocytic leukemia]]
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| :*Drugs ([[methyldopa]])
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| *'''Cold antibody autoimmune hemolytic anemia'''
| | ==[[Autoimmune hemolytic anemia screening|Screening]]== |
| :*[[Idiopathic cold hemagglutinin syndrome]]
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| :*[[Infectious mononucleosis]]
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| :*[[Paroxysmal cold hemoglobinuria]] (rare)
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| :*[[Lymphoma]]
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| *'''Mixed-type autoimmune hemolytic anemia'''
| | ==[[Autoimmune hemolytic anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| ==Pathophysiology== | |
| A hemolytic state exists whenever the red cell survival time is shortened from the normal average of 120 days. Hemolytic anemia is the hemolytic state in which anemia is present, and bone marrow function is inferentially unable to compensate for the shortened life-span of the red cell. Immune hemolytic states are those, both anemic and nonanemic, which involve immune mechanisms consisting of antigen-antibody reactions. These reactions may result from unrelated antigen-antibody complexes that fix to an innocent-bystander erythrocyte, or from related antigen-antibody combinations in which the host red cell or some part of its structure is or has become antigenic. The latter type of antigen-antibody reaction may be termed "autoimmune", and hemolytic anemias so produced are autoimmune hemolytic anemias.<ref name="pmid5267234">{{cite journal |author=Sawitsky A, Ozaeta PB |title=Disease-associated autoimmune hemolytic anemia |journal=[[Bulletin of the New York Academy of Medicine]] |volume=46 |issue=6 |pages=411–26 |year=1970 |month=June |pmid=5267234 |pmc=1749710 |doi= |url= |accessdate=2012-07-25}}</ref>
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| AIHA can be caused by a number of different classes of antibody, with [[IgG]] and [[IgM]] antibodies being the main causative classes. Depending on which is involved, the [[pathology]] will differ. As IgG is poor at activating [[complement system|complement]] but effectively binds the [[Fc receptor]] (FcR) of [[phagocytosis|phagocytic cells]],<ref>{{cite journal |author=Abramson N, Gelfand EW, Jandl JH, Rosen FS |title=The interaction between human monocytes and red cells. Specificity for IgG subclasses and IgG fragments |journal=J. Exp. Med. |volume=132 |issue=6 |pages=1207–15 |year=1970 |month=December |pmid=5511570 |pmc=2180500 |doi=10.1084/jem.132.6.1207 }}</ref> AIHA involving IgG is generally characterized by phagocytosis of RBCs. IgM is a potent activator of the [[classical complement pathway]], thus, AIHA involving IgM is characterized by complement mediated lysis of RBCs. IgM also leads to phagocytosis of RBCs however, because phagocytic cells have receptors for the bound complement (rather than FcRs as in IgG AIHA). IgG AIHA generally takes place in the [[spleen]], while IgM AIHA takes place in [[Kupffer cells]] – phagocytic cells of the [[liver]]. Phagocytic AIHA is termed extravascular, while complement mediated lysis of RBCs is termed intravascular AIHA. In order for intravascular AIHA to be recognizable it requires overwhelming complement activation, therefore most AIHA is extravascular – be it IgG or IgM mediated.<ref name="pmid11921020">{{cite journal |author=Gehrs BC, Friedberg RC |title=Autoimmune hemolytic anemia |journal=[[American Journal of Hematology]] |volume=69 |issue=4 |pages=258–71 |year=2002 |month=April |pmid=11921020 |doi= |url=http://dx.doi.org/10.1002/ajh.10062 |accessdate=2012-07-25}}</ref>
| | ==Diagnosis== |
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| AIHA cannot be attributed to any single autoantibody. To determine the autoantibody or autoantibodies present in a patient, the [[Coombs test]], also known as the antiglobulin test, is performed . There are two types of Coombs test, direct and indirect; more commonly, the direct antiglobulin test (DAT) is used. Classification of the antibodies is based on their activity at different temperatures and their aetiology. Antibodies with high activity at physiological temperature (approximately 37°C) are termed warm autoantibodies. Cold autoantibodies act best at temperatures of 0–4°C. Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state. Usually, the antibody becomes active when it reaches the limbs, at which point it opsonizes RBCs. When these RBCs return to central regions, they are damaged by complement. Patients may present with one or both types of autoantibodies; if both are present, the disease is termed "mixed-type" AIHA.
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| When DAT is performed, the typical presentations of AIHA are as follows. Warm-type AIHA shows a positive reaction with [[antiserum|antisera]] to IgG antibodies with or without complement activation. Cases may also arise with complement alone or with [[IgA]], IgM or a combination of these three antibody classes and complement. Cold type AIHA usually reacts with antisera to complement and occasionally to the above antibodies. This is the case in both cold agglutinin disease and cold paroxysmal hematuria. Mixed warm and cold AIHA generally shows a positive reaction to IgG and complement, sometimes IgG alone and sometimes complement alone. Mixed type can, like the others, present unusually with positive reactions to other antisera.<ref name=Sokol81>{{cite journal |author=Sokol RJ, Hewitt S, Stamps BK |title=Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre |journal=Br Med J (Clin Res Ed) |volume=282 |issue=6281 |pages=2023–7 |year=1981 |month=June |pmid=6788179 |pmc=1505955 |doi=10.1136/bmj.282.6281.2023 }}</ref>
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| ==Causes==
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| The causes of AIHA are poorly understood. The disease may be primary, or secondary to another underlying illness. The primary illness is [[idiopathic]] (the two terms being used synonymously). Idiopathic AIHA accounts for approximately 50% of cases.<ref>{{cite journal |author=Gupta S, Szerszen A, Nakhl F, ''et al.'' |title=Severe refractory autoimmune hemolytic anemia with both warm and cold autoantibodies that responded completely to a single cycle of rituximab: a case report |journal=J Med Case Reports |volume=5 |pages=156 |year=2011 |pmid=21504611 |pmc=3096571 |doi=10.1186/1752-1947-5-156 |url=http://www.jmedicalcasereports.com/content/5//156}}</ref> Secondary AIHA can result from many other illnesses. Warm and cold type AIHA each have their own more common secondary causes. The most common causes of secondary warm-type AIHA include lymphoproliferative disorders (e.g. [[chronic lymphocytic leukemia]], [[lymphoma]]) and other autoimmune disorders (e.g. [[systemic lupus erythematosis]], [[rheumatoid arthritis]], [[scleroderma]], [[ulcerative colitis]]). Less common causes of warm-type AIHA include neoplasms other than lymphoid, and infection. Secondary cold type AIHA is also primarily caused by lymphoproliferative disorders, but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis and other respiratory infections. Less commonly, it can be caused by concomitant autoimmune disorders.<ref name=Sokol81/>
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| Drug-induced AIHA, though rare, can be caused by a number of drugs, including [[methyldopa|α-methyldopa]] and [[penicillin]]. This is a [[type II hypersensitivity|type II immune response]] in which the drug binds to [[macromolecule|macromolecules]] on the surface of the RBCs and acts as an antigen. Antibodies are produced against the RBCs, which leads to complement activation. Complement fragments, such as C3a, C4a and C5a, activate granular leukocytes (e.g. neutrophils), while other components of the system (C6, C7, C8, C9) can either form the membrane attack complex (MAC) or can bind the antibody, aiding phagocytosis by [[macrophage|macrophages]] (C3b). This is one type of "penicillin allergy".
| | [[Autoimmune hemolytic anemia diagnostic study of choice|Diagnostic Study of Choice]] | [[Autoimmune hemolytic anemia history and symptoms|History and Symptoms ]] | [[Autoimmune hemolytic anemia physical examination|Physical Examination]] | [[Autoimmune hemolytic anemia laboratory findings|Laboratory Findings]] | [[Autoimmune hemolytic anemia electrocardiogram|Electrocardiogram]] | [[Autoimmune hemolytic anemia chest x-ray|X-ray]] | [[Autoimmune hemolytic anemia echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Autoimmune hemolytic anemia CT|CT]] | [[Autoimmune hemolytic anemia MRI|MRI]] | [[Autoimmune hemolytic anemia other imaging findings|Other Imaging Findings]] | [[Autoimmune hemolytic anemia other diagnostic studies|Other Diagnostic Studies]] |
| ==Epidemiology and Demographics==
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| AIHA is a relatively rare condition, affecting one to three people per 100,000 per year <ref>{{cite journal |author=Böttiger LE, Westerholm B |title=Acquired haemolytic anaemia. I. Incidence and aetiology |journal=Acta Med Scand |volume=193 |issue=3 |pages=223–6 |year=1973 |month=March |pmid=4739592 }}</ref>.
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| ==Natural history, Complications and Prognosis==
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| ===Complications===
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| Infection is a serious concern in patients on long-term immunosuppressant therapy, especially in very young children (less than two years).<ref>{{cite journal |author=Zecca M, Nobili B, Ramenghi U, ''et al.'' |title=Rituximab for the treatment of refractory autoimmune hemolytic anemia in children |journal=Blood |volume=101 |issue=10 |pages=3857–61 |year=2003 |month=May |pmid=12531800 |doi=10.1182/blood-2002-11-3547 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12531800}}</ref>
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| ===Prognosis===
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| AIHA in children generally has a good prognosis and is self-limiting. However, if it presents within the first two years of life or in the teenage years, the disease often follows a more [[chronic disease|chronic course]], requiring long term [[immunosuppression]], with serious developmental consequences.
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| ==Diagnosis==
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| Diagnosis is made by first ruling out other causes of hemolytic anemia, such as [[glucose-6-phosphate dehydrogenase deficiency|G6PD]], [[thalassemia]], [[sickle-cell disease]], etc. Clinical history is also important to elucidate any underlying illness or medications which may have led to the disease.
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| ===Laboratory tests===
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| Lab findings are
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| *Positive direct [[Coombs test]]
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| *[[Anaemia]]
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| ==Treatment== | | ==Treatment== |
| Much literature exists regarding the treatment of AIHA. Efficacy of treatment depends on the correct diagnosis of either warm or cold type AIHA.
| | [[Autoimmune hemolytic anemia medical therapy|Medical Therapy]] | [[Autoimmune hemolytic anemia surgery |Surgery]] | [[Autoimmune hemolytic anemia primary prevention|Primary Prevention]] | [[Autoimmune hemolytic anemia secondary prevention|Secondary Prevention]] | [[Autoimmune hemolytic anemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Autoimmune hemolytic anemia future or investigational therapies|Future or Investigational Therapies]] |
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| The aim of therapy may sometimes be to lower the use of steroids in the control of the disease. In this case, [[splenectomy]] may be considered, as well as other immunosuppressive drugs. Infection is a serious concern in patients on long-term immunosuppressant therapy, especially in very young children (less than two years).<ref>{{cite journal |author=Zecca M, Nobili B, Ramenghi U, ''et al.'' |title=Rituximab for the treatment of refractory autoimmune hemolytic anemia in children |journal=Blood |volume=101 |issue=10 |pages=3857–61 |year=2003 |month=May |pmid=12531800 |doi=10.1182/blood-2002-11-3547 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12531800}}</ref>
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| Warm type AIHA is usually a more insidious disease, not treatable by simply removing the underlying cause. First line therapy for this is usually with [[corticosteroid|corticosteroids]], such as [[prednisolone]]. Following this, other immunosuppressants are considered, such as [[rituximab]], [[danazol]], [[cyclophosphamide]], [[azathioprine]] or [[cyclosporine]].
| | ==Case Studies== |
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| Cold agglutinin disease is treated by avoiding the cold or sometimes with rituximab. Removal of the underlying cause is also important.
| | [[Autoimmune hemolytic anemia case study one|Case #1]] |
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| Paroxysmal cold hematuria is treated by removing the underlying cause, such as infection.
| | ==Related Chapters== |
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| ==Related chapters== | |
| *[[Haematology]] | | *[[Haematology]] |
| *[[Haemolytic anaemia]] | | *[[Haemolytic anaemia]] |
| ==References==
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| {{Reflist|2}}
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| {{WH}} | | {{WH}} |
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| {{Hematology}} | | {{Hematology}} |
| {{SIB}}
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| [[de:Autoimmunhämolytische Anämie]] | | [[de:Autoimmunhämolytische Anämie]] |
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| {{WikiDoc Sources}} | | {{WikiDoc Sources}} |
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| [[Category:Mature chapter]]
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| [[Category:Disease]] | | [[Category:Disease]] |
| [[Category:Autoimmune diseases]]
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| [[Category:Coagulation system]]
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| [[Category:Blood disorders]]
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| [[Category:Hematology]] | | [[Category:Hematology]] |