Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Rhodesian Ridgeback

Rhodesian Ridgeback

Haemophilia B

Related terms: Factor IX deficiency; Haemophilia B, coagulation disorder; Christmas disease

VeNom term: Haemophilia (VeNom code: 924)

Related conditions: Haemophilia A

Outline: Haemophilia B is a rare blood disorder in which the blood is unable to clot properly, leading to excessive bleeding. It is caused by a hereditary deficiency of the blood clotting protein, factor IX, one of the substances responsible for blood clotting. Rhodesian ridgebacks are prone to a severe form of haemophilia B, caused by a genetic mutation in the coding region of canine factor IX

Prolonged bleeding can be initiated from injury, trauma and surgery. Internal bleeding may occur in the organs. The clinical signs of haemophilia B include episodes of lameness, swelling and bruising under the skin, weakness, lack of appetite, fever and depression. Anaemia may also occur due to the loss of blood, contributing to weakness, lethargy, irregular heartbeats and shortness of breath. Clinical signs usually appear in affected dogs before 6 months of age.


Summary of Information

(for more information click on the links below)

1. Brief description

Haemophilia B is a rare blood disorder in which the blood is unable to clot properly, leading to excessive bleeding. Coagulation is the process of clot formation, when blood transforms from a free flowing liquid into a thickened gel like state, or clot. This process is critically important to seal open wounds, allowing them to stop bleeding and heal. Haemophilia B is caused by a hereditary deficiency of the blood clotting protein, factor IX, one of the substances responsible for blood clotting, causing prolonged bleeding from sites of injury, trauma and surgery or through gum disease which causes bleeding. Under these circumstances, affected animals show abnormally prolonged bleeding, because clot formation is ineffective.  

The clinical signs of haemophilia B include episodes of lameness, swelling and bruising under the skin that resolve with no treatment, weakness, lack of appetite, fever and depression. Affected dogs may show small spots of bleeding under the skin (only readily apparent in areas that are hairless and unpigmented) or inside the tissues of the mouth. Internal bleeding may occur within organs or body cavities, resulting in bloody vomit or stools, rectal or vaginal bleeding, nose bleeds, breathing difficulties, abnormal heart rhythm, swollen distended abdomen and/or excessive thirst. Bleeding inside the eyes and into the brain can occur, and this can lead to blindness or neurological signs (signs of abnormal brain function). Regular episodes of bleeding may cause regenerative anaemia, due to loss of blood, and this may cause weakness, lethargy, irregular heartbeats and shortness of breath.

Rhodesian ridgebacks have a severe form of haemophilia B, often with factor IX deficiency of <5% and more pronounced clinical signs. Extremely affected dogs (factor activity <1%) usually die at birth or shortly thereafter. Severely affected dogs (<5% activity) bleed spontaneously and are at risk of death due to severe bleeding or anaemia.

2. Intensity of welfare impact

Severely affected animals (those with factor IX activity less than 1%) may die at birth due to excessive umbilical bleeding or they may die shortly after due to body cavity haemorrhage.  

For animals not so severely affected, the clinical signs may be less obvious, but they may suffer intermittently from anaemia, weakness, periodic lameness or fever. Affected dogs may also lose bodyweight as a result of inappetance. If bleeding occurs into confined body cavities, such as within the eyeball, the skull or joints, this can cause severe pain due to the increased pressure within the cavity. Severe bleeding following trauma or surgery and severe anaemia can also be life threatening.

Owners of affected dogs can reduce the risk of trauma and injury in their dog– by avoiding situations where they may injure themselves eg in rough play with other dogs or exercise in potentially harmful environments - and by maintaining good dental hygiene to avoid excessive bleeding of the gums (eg with gingivitis). There is no curative treatment for the condition. Antifibrinolytic agents can be given by a veterinarian to stem bleeding, eg after surgical procedures. If anaemia is severe, transfusions of fresh whole blood transfusions may be required.

3. Duration of welfare impact

Affected dogs are born with defects in haemostasis (blood clotting) and the clinical signs of haemophilia usually appear before 6 months of age. At this time, bleeding and bruising or haematomas at the site of injections may be noticed following routine procedures, such as vaccination, castration, or spaying. Severe cases of haemophilia B are lethal due to severe bleeding (external or internal) or anaemia. For cases which are less severe, animals may still experience clinical signs – such as bruising, nosebleeds or blood-tinged vomit, urine or faeces, weakness, lameness – intermittently throughout their lives.

4. Number of animals affected

Haemophilia is rare in dogs, although the exact prevalence is unknown. Haemophilia B is reported to be inherited in Rhodesian ridgebacks. Male dogs are more commonly affected than female dogs, since the genetic defect is on a sex-linked chromosome.

5. Diagnosis

Blood can be tested for platelet count, and activated clotting time; dogs with haemophilia B have a slower clotting time and a deficiency of factor IX protein activity.

6. Genetics

A mutation in the gene that codes for the expression of Factor IX protein is responsible for haemophilia B in Rhodesian ridgebacks. Haemophilia B is a sex-linked recessive disorder, as the mutation is found on the sex chromosome X; males have one X and one Y. If a male, inherits an X chromosome carrying the mutated gene then it will be affected by the haemophilia B disorder. For females to be affected they have to be homozygous for the condition, that is both X chromosomes have to carry the mutated gene; but this is less common. Heterozygous females, which carry one copy of the genetic mutation, are therefore unaffected carriers for the disorder. Mating of a female carrier with a homozygous affected male will result in half of male offspring being affected and the other half of male offspring being clear. Half of female offspring will be affected and the other half will be carriers (unaffected but able to pass on the condition to their offspring).

7. How do you know if an animal is a carrier or likely to become affected?

Haemophilia B can be detected using a genetic test, with DNA from blood or saliva samples. Dogs with haemophilia B can be diagnosed using measures of blood clotting, where abnormal clotting times and a deficiency of factor IX are found.

8. Methods and prospects for elimination of the problem

Although the condition is considered to be rare, breeding from affected dogs should be avoided since it will result in both affected dogs and carriers (females only). Prospective breeders should seek testing for haemophilia B in dogs showing clinical signs, via a veterinarian, before choosing to breed the dog.


For further details about this condition, please click on the following:
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1. Clinical and pathological effects

Haemophilia B is a rare blood disorder in which the blood is unable to clot properly, leading to excessive bleeding. Coagulation is the process of clot formation, when through a series of steps, blood transforms from a free flowing liquid into a thickened gel like state, a clot. This process is critically important to seal open wounds, allowing them to stop bleeding and begin to heal.

Platelets are cell-like particles that start the process of blood clotting. They are produced in the bone marrow and circulate in the blood. When an injury occurs, the wall of the blood vessel breaks and bleeding occurs. The blood vessel narrows so that there is a slower blood supply to the broken vessel. Platelets rush to the broken wall where exposure to certain proteins cause the shape of these cells to change from round to spiny.  This allows the platelets to clump together, and with other blood cells, at the site of damage to blood vessel. Other proteins form fibrin strands, creating a net that holds together the platelets and blood cells, creating a clot that plugs the break in the vessel wall, stopping the loss of blood.

Defects in the blood clotting proteins, usually referred to as factors, cause delayed coagulation and leads to prolonged bleeding (Hutt et al 1948). Haemophilia B is caused by a hereditary deficiency of clotting factor IX, one of the substances responsible for blood clotting under a process called the coagulation cascade. Factor IX forms links between platelets and collagen fibrils and promotes binding of the platelets to the extracellular matrix of the blood vessel wall. Typically haemophilia is noticed after wounds caused by injury, trauma or surgery or through gum disease which causes bleeding. Under these circumstances, affected animals show abnormally prolonged bleeding, because clot formation is ineffective. Affected dogs may show small spots of bleeding under the skin (only readily apparent in areas that are hairless and unpigmented) or inside the tissues of the mouth. These blood spots within the tissues are called petechiae, when small, and purpura or ecchymoses when larger.

Internal bleeding may also occur in organs and body cavities and this may present as blood in the vomit or stools, bleeding from the nose, rectum or vagina, breathing difficulties, abnormal heart rhythm, swollen or enlarged abdomen and/or excessive thirst (Mustard et al 1960). Internal bleeding may cause the formation of haematomas (where blood outside of blood vessels collects locally), bleeding into joint spaces (hemarthrosis) and body cavity haemorrhage. Bleeding inside the eyes and into the brain can occur, and this can lead to blindness or neurological signs (signs of abnormal brain function).

Regular episodes of bleeding may cause regenerative anaemia, due to the loss of blood. New blood cells are produced by the bone marrow to replace those that are lost, but anaemia will occur when the speed at which the red blood cells are lost is greater than they can be replaced. This can be measured by an increased presence of immature red blood cells in the blood. The clinical signs of anaemia include weakness, lethargy, irregular heartbeats and shortness of breath. Other possible signs include episodes of lameness, swelling and bruising under the skin that resolve with no treatment, weakness, lack of appetite, fever and depression (Mustard et al 1960, Holmes et al 2011).

The severity of the bleeding disorder is related to how active the factor IX is (Holmes et al 2011, Mischke et al 2011). Animals with extremely low Factor IX activity (less than 1%) usually die at birth or shortly thereafter. If the factor IX activity is very low (<5%), affected dogs usually bleed spontaneously and will have a poor prognosis. If affected dogs have adequate factor IX activity (eg 25-30%), they may have no symptoms until surgery or injury where prolonged bleeding occurs, though this can still be life-threatening. Rhodesian ridgebacks have a severe form of haemophilia B, often with factor IX deficiency of <5% and more pronounced clinical signs (Mischke et al 2011). Carriers of the condition (those with only one copy of the genetic mutation) may show moderately reduced factor IX activity (48%-69%), and are not likely to show clinical signs (Mischke et al 2011).

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2. Intensity of welfare impact

Severely affected dogs may suffer from severe bleeding after injuries and occasional spontaneous bleeding, and severe blood loss may be life-threatening.

For other affected animals, ie with factor IX activity between 5 and 10%, the clinical signs may be less obvious, but they may suffer intermittently from anaemia, weakness, periodic lameness or fever. Where bleeding occurs into confined body cavities, such as within the eyeball, the skull or joints, this can cause severe pain due to the increased pressure within the cavity. Affected dogs may also lose bodyweight as a result of inappetance. Excessive blood loss causes weakness, malaise, nausea, and in severe cases it can cause collapse, seizures and death.

There is no curative treatment for the condition. Antifibrinolytic agents can be given by a veterinarian to stem bleeding, eg after surgical procedures. Owners of affected dogs can reduce the risk of trauma and injury in their dog - by avoiding situations where they may injure themselves eg rough play with other dogs or exercising them in potentially harmful environments - and maintain good dental hygiene to avoid excessive bleeding of the gums (gingivitis). If anaemia is severe, transfusions of fresh whole blood transfusions may be required. Intramuscular injections and certain drugs can impair haemostasis and should be avoided, and so appropriate veterinary care may be hindered.

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3. Duration of welfare impact

Affected dogs are born with defects in haemostasis (blood clotting) and the clinical signs of haemophilia usually appear before 6 months of age. At this time, bleeding and bruising or haematomas at the site of injections may be noticed for routine procedures, such as vaccination, castration, or spaying. Severe cases of haemophilia B are lethal due to severe bleeding (external or internal) or anaemia. For cases which are less severe, animals may not be diagnosed until they show abnormal bleeding after major surgery or trauma. However, these animals may still experience clinical signs – such as bruising, nosebleeds or blood-tinged vomit, urine or faeces, weakness, lameness – intermittently throughout their lives.Return to top

4. Number of animals affected

Haemophilia B is reported to be inherited in Rhodesian ridgebacks (Mischke et al 2011). Male dogs are more commonly affected than female dogs, since the genetic defect is on a sex-linked chromosome. Haemophilia is rare in dogs, occurring sporadically or within families of various dog breeds (Brooks 1999), and is caused by different genetic mutations in different breeds. The exact prevalence is unknown. Haemophilia A, which has similar clinical signs to haemophilia B but is caused by a deficiency of factor VIII is the more common type in dogs, with a ratio of 4:1 (Brooks 1999).

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5. Diagnosis

A diagnosis of haemophilia B is suspected when an animal has apparently abnormal and excessive bleeding eg from the mouth or elsewhere that is beyond what might be expected, or when there is excessive bleeding during surgery. The diagnosis can be confirmed by various blood tests that assess primary and secondary haemostasis (clotting) and by measurement of the concentration factor IX in the blood. An atraumatic venepuncture can be used to draw blood without excessive bleeding. Activated partial thromboplastin time is used as a measure of the time it takes for blood to clot; this is prolonged in dogs with haemophilia B whereas other blood clotting parameters are normal (prothrombin time, thrombin clotting time, fibrinogen determination). Definitive diagnosis of the exact disorder depends on measurement of Factor VIII (haemophilia A) or Factor IX (haemophilia B) activity.

A diagnosis of haemophilia B is suspected when an animal has apparently abnormal and excessive bleeding eg from the mouth or elsewhere that is beyond what might be expected, or when there is excessive bleeding during surgery. The diagnosis can be confirmed by various blood tests that assess primary and secondary haemostasis (clotting) and by measurement of the concentration factor IX in the blood. An atraumatic venepuncture can be used to draw blood without excessive bleeding. Activated partial thromboplastin time is used as a measure of the time it takes for blood to clot; this is prolonged in dogs with haemophilia B whereas other blood clotting parameters are normal (prothrombin time, thrombin clotting time, fibrinogen determination). Definitive diagnosis of the exact disorder depends on measurement of Factor VIII (haemophilia A) or Factor IX (haemophilia B) activity.

A genetic test can detect the mutation responsible for Haemophilia B in Rhodesian ridgebacks.

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6. Genetics

A mutation in the gene that codes for the expression of factor IX protein is responsible for haemophilia B in Rhodesian ridgebacks (Mischke et al 2011). Haemophilia B is is a sex-linked recessive disorder, as the mutated gene is found on the sex chromosome X (Hutt et al 1948). Females have two X chromosomes, males only one X and another sex chromosome Y. For males, inheritance of an X chromosome carrying the mutated gene causes haemophilia B to be expressed, since they only have one X chromosome, and therefore only require one copy of the gene mutation to be affected. For females to be affected, they have to inherit two copies of the mutated gene – ie they have to inherit one copy  of the mutation from the mother and the father, but this occurs much less commonly as  breeding from affected dogs is unusual). Females are therefore more usually unaffected carriers (heterozygous) for the disorder, that is, they carry one copy of the genetic mutation on one of their X chromosomes. Mating of a female carrier with a hemizygous affected male will result in half of male offspring being affected and the other half of male offspring being clear. Half of female offspring will be affected and the other half will be carriers (unaffected but able to pass on the condition to their offspring).

Female carriers of the condition (those with one copy of the genetic mutation) may show moderately reduced factor IX activity (48%-69% versus the normal lower boundary of 75%), but are not likely to show clinical signs (Mischke et al 2011).

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7. How do you know if an animal is a carrier or likely to become affected?

A genetic test is available which can detect the mutation responsible for Haemophilia B in Rhodesian ridgebacks. The test uses DNA from blood or saliva, and can detect hemizygous (male) or homozygous (female) affected dogs, carriers (female) and clear dogs.

Dogs with haemophilia B can be diagnosed using measures of blood clotting, where abnormal clotting times and a deficiency of factor IX are found.

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8. Methods and prospects for elimination of the problem

Although the condition is considered to be rare, breeding from affected dogs should be avoided since it will result in both affected dogs and carriers (females only). Without a known genetic background, diagnosis of female carriers of a defect is difficult. Assessment of littermates and relatives showing clinical signs may identify potential carrier status in females, and genetic screening for the mutation should be conducted. Female carriers should not be bred from since they are likely to produce affected male offspring.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

 

Brooks M (1999) A review of canine inherited bleeding disorders: biochemical and molecular strategies for disease characterization and carrier detection. Journal of Heredity 90: 112–118

Holmes PH, Jain NC, Waltisbuhl DJ, Bernstein M, Campbell K, Fan TM, Jorgenson W. and Payne SL (2011) Bleeding disorders of dogs. Merck Veterinary Manual. Accessed: 17/03/2016 http://www.merckvetmanual.com/pethealth/dog_disorders_and_diseases/blood_disorders_of_dogs/bleeding_disorders_of_dogs.html

Hutt FB, Rickard CG and Field RA (1948) Sex-linked haemophilia in dogs. Journal of Heredity 39: 3–9

Mischke R, Kühnlein P, Kehl A, Langbein-Detsch I, Steudle F, Schmid A, Dandekar T, Czwalinna A and Müller E (2011) G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Veterinary Journal 187: 113–8

Mustard JF, Rowsell HC, Robinson GA, Hoeksema TD and Downie HG (1960) Canine Haemophilia B (Christmas Disease). British Journal of Haematology 6: 259–266

© UFAW 2016


Credit for main photo above:

By Gulik (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons