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Also known as: '''''IMHA''' — Autoimmune haemolytic anaemia (AIHA) — Pure red cell aplasia (PRCA)

| Also known as:

| '''IMHA'''<br>

'''Autoimmune haemolytic anaemia (AIHA)'''<br>

'''Pure red cell aplasia (PRCA)'''

==Description==

==Introduction==

Immune-mediated haemolytic anaemia (IMHA) is the result of a [[Type II Hypersensitivity|type II antibody-mediated immune response]] directed against molecules expressed on the surface of erythrocytes.  The clinical presentation of the disease depends on the isotype of antibody produced and the severity of the anaemia.

Immune-mediated haemolytic anaemia (IMHA) is the result of a [[Type II Hypersensitivity|type II antibody-mediated immune response]] directed against molecules expressed on the surface of erythrocytes.  The clinical presentation of the disease depends on the isotype of antibody produced and the severity of the anaemia.

[[IgM]] antibodies are capable of fixing complement on the surface of red blood cells leading to the assembly of a membrane attack complex.  This complex causes the direct lysis of erythrocytes and '''intravascular haemolysis'''. Since IgM antibodies have a high avidity, they are also able to co-ordinate the formation of large numbers of red blood cells into aggregates, a phenomenon known as '''auto-agglutination'''.

[[IgM]] antibodies are capable of fixing complement on the surface of red blood cells leading to the assembly of a membrane attack complex.  This complex causes the direct lysis of erythrocytes and '''intravascular haemolysis'''. Since IgM antibodies have a high avidity, they are also able to co-ordinate the formation of large numbers of red blood cells into aggregates, a phenomenon known as '''auto-agglutination'''.

Some types of [[IgG]] antibody are able to directly activate the complement cascade but, in most cases, these antibodies are not able to cause intravascular haemolysis of agglutination and they are therefore described as '''incomplete''' antibodies.  These antibodies act as opsonins and, through their interaction with Fc receptors expressed by cells of the hepatosplenic monocyte-phagocyte system (MPS), they promote the uptake and destruction of the red blood cells to which they are bound. These types of antibody therefore cause '''extravascular haemolysis'''.

Some types of [[IgG]] antibody are able to directly activate the complement cascade but, in most cases, these antibodies are not able to cause intravascular haemolysis of agglutination and they are therefore described as '''incomplete''' antibodies.  These antibodies act as opsonins and, through their interaction with Fc receptors expressed by cells of the hepatosplenic monocyte-phagocyte system (MPS), they promote the uptake and destruction of the red blood cells to which they are bound. These types of antibody therefore cause '''extravascular haemolysis'''.

IMHA may occur as a '''primary''' disease with no apparent cause or it may be '''secondary''' to another systemic insult. Possible secondary causes of IMHA include bacterial and parasite infections (including ''[[Babesia canis]]'' in dogs and ''[[Mycoplasma haemofelis]]'' in cats), adverse drug reactions, neoplasia (especially myeloproliferative and lymphoproliferative disease) and live vaccines, although the association between vaccination and immune-mediated disease remains controversial.   

IMHA may occur as a '''primary''' disease with no apparent cause or it may be '''secondary''' to another systemic insult. Possible secondary causes of IMHA include bacterial and parasite infections (including ''[[Babesia canis]]'' in dogs and ''[[Mycoplasma haemofelis]]'' in cats), adverse drug reactions, neoplasia (especially myeloproliferative and lymphoproliferative disease) and live vaccines, although the association between vaccination and immune-mediated disease remains controversial.   

The majority of cases of IMHA affect only the circulating red blood cells resulting in a strongly regenerative anaemia as the bone marrow stem cells respond to the disease. In a small number of cases, antibodies are produced that affect the stem cells of the erythroid lineage in the bone marrow, resulting in a non-regenerative anaemia that still bears many of the same clinical features as IMHA. Although the two diseases have been considered separately in the past, they really represent two ends of a spectrum of immune-mediated disease directed at cells of the erythroid line.   

The majority of cases of IMHA affect only the circulating red blood cells resulting in a strongly regenerative [[Anaemia - Introduction|anaemia]] as the bone marrow stem cells respond to the disease. In a small number of cases, antibodies are produced that affect the stem cells of the [[Erythropoiesis|erythroid lineage]] in the bone marrow, resulting in a non-regenerative anaemia that still bears many of the same clinical features as IMHA. Although the two diseases have been considered separately in the past, they really represent two ends of a spectrum of immune-mediated disease directed at cells of the erythroid line.   

The widespread lysis of red blood cells causes disease in the following ways:

The widespread lysis of red blood cells causes disease in the following ways:

==Signalment==

==Signalment==

Primary IMHA occurs with greater frequency in Cocker spaniels<ref>Weinkle TK, Center SA, Randolph JF, Warner KL, Barr SC, Erb HN. '''Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002).''' ''J Am Vet Med Assoc. 2005 Jun 1;226(11):1869-80.''</ref><ref>McAlees TJ. '''Immune-mediated haemolytic anaemia in 110 dogs in Victoria, Australia.''' ''Aust Vet J. 2010 Jan;88(1-2):25-8.''</ref>, Old English sheepdogs and standard Poodles but any breed of dog may be affected. Middle-aged, entire female animals have been shown to be at increased risk of developing the disease in some studies.

Primary IMHA occurs with greater frequency in Cocker spaniels<ref>Weinkle TK, Center SA, Randolph JF, Warner KL, Barr SC, Erb HN. '''Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002).''' ''J Am Vet Med Assoc. 2005 Jun 1;226(11):1869-80.''</ref><ref>McAlees TJ. '''Immune-mediated haemolytic anaemia in 110 dogs in Victoria, Australia.''' ''Aust Vet J. 2010 Jan;88(1-2):25-8.''</ref>, Old English sheepdogs and standard Poodles but any breed of dog may be affected. Middle-aged, entire female animals have been shown to be at increased risk of developing the disease in some studies.

==Diagnosis==

==Diagnosis==

===Clinical Signs===

===Clinical Signs===

Affected animals often present acutely with sudden-onset collapse or severe exercise intolerance. On exmaination, the following signs may become evident:

Affected animals often present acutely with sudden-onset collapse or severe exercise intolerance. On examination, the following signs may become evident:

*'''Pallor''' and/or '''[[Icterus|icterus]]''' of the mucous membranes as the release of bilirubin from lysed red blood cells may result in pre-hepatic jaundice in severely affected animals.

*'''Pallor''' and/or '''[[Icterus|icterus]]''' of the mucous membranes as the release of bilirubin from lysed red blood cells may result in pre-hepatic jaundice in severely affected animals.

*A '''haemic heart murmur''' and a '''hyperdynamic peripheral pulse''' due to the reduction in viscosity of the blood.

*A '''haemic heart murmur''' and a '''hyperdynamic peripheral pulse''' due to the reduction in viscosity of the blood.

===Laboratory Tests===

===Laboratory Tests===

On presentation, full biochemical and haematological analysis of blood samples are indicated to confirm the diagnosis and to obtain a baseline measurement to assess the efficiacy of future treatment. Several tests are also available that have a higher specificity for the diagnosis of IMHA.

On presentation, full biochemical and haematological analysis of blood samples are indicated to confirm the diagnosis and to obtain a baseline measurement to assess the efficacy of future treatment. Several tests are also available that have a higher specificity for the diagnosis of IMHA.

 

====Haematology====

====Haematology====

Affected animals have a reduced [[Packed Cell Volume|packed cell volume]] (PCV) or haematocrit (HCT) and often a reduced haemoglobin concentration.  IMHA causes a strongly [[Anaemia - Introduction|regenerative anaemia]] and evidence of macrocytosis (increased MCV) should be apparent after 48-72 hours in dogs. A blood smear is extremely useful in evaluating cases of IMHA as '''spherocytes''' are often visible. These small, dense red blood cells are formed due to partial phagocytosis of red blood cells by the MPS. Polychromasia should also be visible on a blood smear from an animal undergoing regeneration and reticulocytosis can be confirmed using a supravital stain such as new methylene blue.

Affected animals have a reduced [[Packed Cell Volume|packed cell volume]] (PCV) or haematocrit (HCT) and often a reduced haemoglobin concentration.  IMHA causes a strongly [[Anaemia - Introduction|regenerative anaemia]] and evidence of macrocytosis (increased MCV) should be apparent after 48-72 hours in dogs. A blood smear is extremely useful in evaluating cases of IMHA as '''spherocytes''' are often visible. These small, dense red blood cells are formed due to partial phagocytosis of red blood cells by the MPS. Polychromasia should also be visible on a blood smear from an animal undergoing regeneration and reticulocytosis can be confirmed using a supravital stain such as new methylene blue.

Reactive [[Platelet Abnormalities|thrombocytosis]] and leucocytosis may be present with any cause of anaemia.

Reactive [[Platelet Abnormalities|thrombocytosis]] and leucocytosis may be present with any cause of anaemia.

====Biochemistry====

====Biochemistry====

Serum bilirubin concentration will be elevated and this may be usfficiently severe to cause [[Icterus|icterus]]. The serum [[urea]] concentration may also be elevated as the kidneys receive less oxygen than normal causing a pre-renal azotaemia. A similar process of tissue hypoxia may also result in elevations in liver enzymes such as ALT and AST.

Serum bilirubin concentration will be elevated and this may be sufficiently severe to cause [[Icterus|icterus]]. The serum [[urea]] concentration may also be elevated as the kidneys receive less oxygen than normal causing a pre-renal azotaemia. A similar process of tissue hypoxia may also result in elevations in liver enzymes such as ALT and AST.

====Other Tests====

====Other Tests====

An '''in-saline agglutination''' test may be used to diagnose cases of IMHA that involve auto-agglutination. A drop of whole blood is mixed with a drop of plain saline on a glass slide and agitated for 30-60 seconds.  A positive result is recorded if evident aggregates form but the slide should be evaluated under a microscope as rouleaux formation may result in a similar gross appearance.  

An '''in-saline agglutination''' test may be used to diagnose cases of IMHA that involve auto-agglutination. A drop of whole blood is mixed with a drop of plain saline on a glass slide and agitated for 30-60 seconds.  A positive result is recorded if evident aggregates form but the slide should be evaluated under a microscope as rouleaux formation may result in a similar gross appearance.  

A '''Coomb's test''' can be used to diagnose cases of IMHA that are caused by incomplete antibodies. The red blood cells from a patient are mixed with Coomb's antiserum (IgG antiobies directed against IgG) and, in cases where the patient has IMHA with antibodies attached to the surface of the erythrocytes, the antiserum will result in the formation of aggregates of cells. The titre of the test should be evaluated as weakly positive results may occur with other diseases.

A '''Coomb's test''' can be used to diagnose cases of IMHA that are caused by incomplete antibodies. The red blood cells from a patient are mixed with Coomb's antiserum (IgG antiobies directed against IgG) and, in cases where the patient has IMHA with antibodies attached to the surface of the erythrocytes, the antiserum will result in the formation of aggregates of cells. The titre of the test should be evaluated as weakly positive results may occur with other diseases.

In cases of pure red cell aplasia, a Coomb's test may still be positive but, experimentally, a definitive diagnosis can only be made by transfusing the serum of one animal to another and documenting the development of anaemia in the recipient.

In cases of pure red cell aplasia, a Coomb's test may still be positive but, experimentally, a definitive diagnosis can only be made by transfusing the serum of one animal to another and documenting the development of anaemia in the recipient.

==Treatment==

==Treatment==

Affected animals often present acutely and may require intensive care. The ultimate aim of long-term treatment for IMHA is to control the autoimmune response.

Affected animals often present acutely and may require intensive care. The ultimate aim of long-term treatment for IMHA is to control the autoimmune response.

===Stabilisation===

===Stabilisation===

In animals that have lost a large percentage of their [[Packed Cell Volume|PCV]] acutely, it is likely that a [[Blood Products|blood transfusion]] will be required. Since animals with IMHA are not usually hypovolaemic, packed red blood cells are often transfused to replace erythrocytes without significantly expanding the plasma volume. In emergency situations, whole blood or synthetic haemoglobin molcules (such as Oxyglobin [tm]) may be used to support the oxygen carrying capacity of the patient. Oxygen may be provided to tachypnoeic and dyspnoeic patients by facemask, nasal catheter or flow-by.  

In animals that have lost a large percentage of their [[Packed Cell Volume|PCV]] acutely, it is likely that a [[Blood Products|blood transfusion]] will be required. Since animals with IMHA are not usually hypovolaemic, packed red blood cells are often transfused to replace erythrocytes without significantly expanding the plasma volume. In emergency situations, whole blood or synthetic haemoglobin molecules (such as Oxyglobin [tm]) may be used to support the oxygen carrying capacity of the patient. Oxygen may be provided to tachypnoeic and dyspnoeic patients by facemask, nasal catheter or flow-by.  

===Immunosuppressive Therapy===

===Immunosuppressive Therapy===

Whatever supportive measures are taken, the autoimmune response must be controlled to prevent the continuing lysis of red blood cells. The following types of drug are typically used to achieve this goal:

Whatever supportive measures are taken, the autoimmune response must be controlled to prevent the continuing lysis of red blood cells. The following types of drug are typically used to achieve this goal:

*'''Corticosteroids''' such as prednisolone and dexamethasone are used universally as a first-line treatment for IMHA as they are frequently effective, act rapidly and are available in a variety of preparations. Traditionally, very high doses of corticosteroids have been used to try to control the autoimmune response but dose rates beyond 2-3 mg/kg/day may be associated with significant adverse effects. More recently, there has been a move to add further immunosuppressive agents (see below) in a polypharmaceutical approach which allows the clinician to keep the corticosteroid dose rate at a reasonable level. Corticosteroids act to control both the cell- and antibody-mediated immune responses.

*'''Corticosteroids''' such as prednisolone and dexamethasone are used universally as a first-line treatment for IMHA as they are frequently effective, act rapidly and are available in a variety of preparations. Traditionally, very high doses of corticosteroids have been used to try to control the autoimmune response but dose rates beyond 2-3 mg/kg/day may be associated with significant adverse effects. More recently, there has been a move to add further immunosuppressive agents (see below) in a polypharmaceutical approach which allows the clinician to keep the corticosteroid dose rate at a reasonable level. Corticosteroids act to control both the cell- and antibody-mediated immune responses.

*'''Azathioprine''' is frequently used in the management of IMHA and it has effects on both cell- and antibody-mediated immune responses. It may take 3-4 weeks of treatment before the patient experiences the maximal effects of the drug. Azathioprine is a cytotoxic drug and gloves should be worn to administer tablets. Owners or keepers should be made aware that the active drug or its metabolites may be present in the saliva and other secretions of animals receiving the drug.

*'''Azathioprine''' is frequently used in the management of IMHA and it has effects on both cell- and antibody-mediated immune responses. It may take 3-4 weeks of treatment before the patient experiences the maximal effects of the drug. Azathioprine is a cytotoxic drug and gloves should be worn to administer tablets. Owners or keepers should be made aware that the active drug or its metabolites may be present in the saliva and other secretions of animals receiving the drug.

*'''Ciclosporin A''' is a fungal metabolite that inhibits a signaling molecule (ciclophilin) involved in T cell activation. Since B cells require T cell help to become activated, differentiate into plasma cells and produce antibodies, there is a rationale for the use of ciclosporin in cases of IMHA but there are currently no reports of its relative efficacy compared to the other immunosuppressive drugs.   

*'''Ciclosporin A''' is a fungal metabolite that inhibits a signaling molecule (ciclophilin) involved in T cell activation. Since B cells require T cell help to become activated, differentiate into plasma cells and produce antibodies, there is a rationale for the use of ciclosporin in cases of IMHA but there are currently no reports of its relative efficacy compared to the other immunosuppressive drugs.   

*Other less commonly-used drugs include danazol (a steroid related to testosterone), mycophenolate mofetil and cyclophosphamide.  Cyclophosphamide was used widely in the management of IMHA but two separate studies have shown that its use is associated with higher rates of mortality<ref>Grundy SA, Barton C. '''Influence of drug treatment on survival of dogs with immune-mediated hemolytic anemia: 88 cases (1989-1999).''' ''J Am Vet Med Assoc. 2001 Feb 15;218(4):543-6.''</ref><ref>Burgess K, Moore A, Rand W, Cotter SM. '''Treatment of immune-mediated hemolytic anemia in dogs with cyclophosphamide.''' ''J Vet Intern Med. 2000 Jul-Aug;14(4):456-62.''</ref><ref>Mason N, Duval D, Shofer FS, Giger U. '''Cyclophosphamide exerts no beneficial effect over prednisone alone in the initial treatment of acute immune-mediated hemolytic anemia in dogs: a randomized controlled clinical trial.''' ''J Vet Intern Med. 2003 Mar-Apr;17(2):206-12.''</ref>.

*Other less commonly-used drugs include danazol (a steroid related to testosterone), mycophenolate mofetil and cyclophosphamide.  Cyclophosphamide was used widely in the management of IMHA but two separate studies have shown that its use is associated with higher rates of mortality<ref>Grundy SA, Barton C. '''Influence of drug treatment on survival of dogs with immune-mediated hemolytic anemia: 88 cases (1989-1999).''' ''J Am Vet Med Assoc. 2001 Feb 15;218(4):543-6.''</ref><ref>Burgess K, Moore A, Rand W, Cotter SM. '''Treatment of immune-mediated hemolytic anemia in dogs with cyclophosphamide.''' ''J Vet Intern Med. 2000 Jul-Aug;14(4):456-62.''</ref><ref>Mason N, Duval D, Shofer FS, Giger U. '''Cyclophosphamide exerts no beneficial effect over prednisone alone in the initial treatment of acute immune-mediated hemolytic anemia in dogs: a randomized controlled clinical trial.''' ''J Vet Intern Med. 2003 Mar-Apr;17(2):206-12.''</ref>.

*'''Human gamma globulin''' is a variably popular product that is thought to act by occupying Fc receptors on cells of the MPS and therefore preventing phagocytosis of opsonised red blood cells.  Studies investigating the effects of this drug have produced variable results, with some showing that it makes little difference to outcome<ref>Whelan MF, O'Toole TE, Chan DL, Rozanski EA, DeLaforcade AM, Crawford SL, Cotter SM. '''Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia.''' ''J Vet Emerg Crit Care (San Antonio). 2009 Apr;19(2):158-64.''</ref> and others suggesting that it may be useful in the short-term control of cases that are refractory to other immunosuppressive regimes<ref>Kellerman DL, Bruyette DS. '''Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs.''' ''J Vet Intern Med. 1997 Nov-Dec;11(6):327-32.''</ref>.  Human gamma globulin is not widely available in veterinary practices and it is very expensive.

*'''Human gamma globulin''' is a variably popular product that is thought to act by occupying Fc receptors on cells of the MPS and therefore preventing phagocytosis of opsonised red blood cells.  Studies investigating the effects of this drug have produced variable results, with some showing that it makes little difference to outcome<ref>Whelan MF, O'Toole TE, Chan DL, Rozanski EA, DeLaforcade AM, Crawford SL, Cotter SM. '''Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia.''' ''J Vet Emerg Crit Care (San Antonio). 2009 Apr;19(2):158-64.''</ref> and others suggesting that it may be useful in the short-term control of cases that are refractory to other immunosuppressive regimes<ref>Kellerman DL, Bruyette DS. '''Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs.''' ''J Vet Intern Med. 1997 Nov-Dec;11(6):327-32.''</ref>.  Human gamma globulin is not widely available in veterinary practices and it is very expensive.

*Due to the risk of thrombo-embolism caused by the release of endogenous procoagulant molecules, low doses of '''heparin''' or '''aspirin''' are often administered to dogs with IMHA to try to prevent the formation of thrombi in the lungs, liver or spleen. There is some evidence to suggest that, if a dose of heparin is used which is individualised for a particular patient, there may be beneficial effects on survival<ref>Helmond SE, Polzin DJ, Armstrong PJ, Finke M, Smith SA. '''Treatment of immune-mediated hemolytic anemia with individually adjusted heparin dosing in dogs.''' ''J Vet Intern Med. 2010 May-Jun;24(3):597-605. Epub 2010 Apr 6.''</ref>. This effect is not observed if a constant dose of heparin is used for all patients<ref>Weinkle TK, Center SA, Randolph JF, Warner KL, Barr SC, Erb HN. '''Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002).''' ''J Am Vet Med Assoc. 2005 Jun 1;226(11):1869-80.''</ref>.

*Due to the risk of thrombo-embolism caused by the release of endogenous procoagulant molecules, low doses of '''heparin''' or '''aspirin''' are often administered to dogs with IMHA to try to prevent the formation of thrombi in the lungs, liver or spleen. There is some evidence to suggest that, if a dose of heparin is used which is individualised for a particular patient, there may be beneficial effects on survival<ref>Helmond SE, Polzin DJ, Armstrong PJ, Finke M, Smith SA. '''Treatment of immune-mediated hemolytic anemia with individually adjusted heparin dosing in dogs.''' ''J Vet Intern Med. 2010 May-Jun;24(3):597-605. Epub 2010 Apr 6.''</ref>. This effect is not observed if a constant dose of heparin is used for all patients<ref>Weinkle TK, Center SA, Randolph JF, Warner KL, Barr SC, Erb HN. '''Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002).''' ''J Am Vet Med Assoc. 2005 Jun 1;226(11):1869-80.''</ref>.

===Adjunctive Therapy===

===Adjunctive Therapy===

Animals with IMHA frequently suffer from concurrent vomiting, regurgitation and diarrhoea while hospitalised. These conditions are frequently managed with [[Gastroprotective Drugs|gastro-protectant drugs]] such as sucralfate, ranitidine and omeprazole to prevent the development of gastro-duodenal ulceration and [[Oesophagitis|oesophagitis]].

Animals with IMHA frequently suffer from concurrent vomiting, regurgitation and diarrhoea while hospitalised. These conditions are frequently managed with [[Gastroprotective Drugs|gastro-protectant drugs]] such as sucralfate, ranitidine and omeprazole to prevent the development of gastro-duodenal ulceration and [[Oesophagitis|oesophagitis]].

Antibiotics are frequently administered to animals which present with acute haemolytic crises but these should be used judiciously on a case-by-case basis.   

Antibiotics are frequently administered to animals which present with acute haemolytic crises but these should be used judiciously on a case-by-case basis.   

==Prognosis==

==Prognosis==

Most mortality occurs in the first two weeks after presentation and, overall, 30-50% of animals would be expected to survive for at least one year after initial treatment for IMHA<ref>'''Idiopathic immune-mediated hemolytic anemia: treatment outcome and prognostic factors in 149 dogs.''' ''Piek CJ, Junius G, Dekker A, Schrauwen E, Slappendel RJ, Teske E.'' J Vet Intern Med. 2008 Mar-Apr;22(2):366-73. Epub 2008 Mar 10.</ref>.  

Most mortality occurs in the first two weeks after presentation and, overall, 30-50% of animals would be expected to survive for at least one year after initial treatment for IMHA<ref>'''Idiopathic immune-mediated hemolytic anemia: treatment outcome and prognostic factors in 149 dogs.''' ''Piek CJ, Junius G, Dekker A, Schrauwen E, Slappendel RJ, Teske E.'' J Vet Intern Med. 2008 Mar-Apr;22(2):366-73. Epub 2008 Mar 10.</ref>.  

==References==

==References==

<references/>

<references/>

[[Category:Antibody Mediated Autoimmune Diseases]]

[[Category:Antibody Mediated Autoimmune Diseases]]

[[Category:Dog]][[Category:Cat]]

[[Category:Dog]][[Category:Cat]]

[[Category:To Do - Review]]

[[Category:Expert Review]]