Hemophilia A

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Comparative Coagulation


Hemophilia A

Hemophilia A is the most common severe inherited coagulation disorder in animals and human beings. In dogs, as in other species, the disease arises as the result of spontaneous mutation. Once hemophilia appears in a family, the defect can then be transmitted through many generations. This article provides an overview of hemophilia, including information on inheritance pattern, clinical signs, and methods of identifying hemophilia affected and carrier dogs.

Cause

The bleeding tendency of Hemophilia A is caused by specific deficiency of a single clotting factor, Factor VIII. The clotting factors are designated by roman numeral and Factor VIII (factor eight) is critical for normal blood clot formation. Abnormalities, or mutations, in the Factor VIII gene prevent the body's production of a normal, functional coagulation Factor VIII.

Inheritance

The gene for Factor VIII is carried on the X chromosome and the presence of one normal gene is sufficient to prevent hemophilia. This form of inheritance is called sex-linked (or X-linked), recessive. All males have one gene for Factor VIII which they inherit from their dam. All females have two genes for Factor VIII, one inherited from dam and one from sire.

Expression and Transmission

  • Males having one normal gene and females having two normal genes for Factor VIII are clear of the hemophilia A trait and will not transmit this defect to offspring.
  • Males having one abnormal gene are affected with hemophilia and will transmit that abnormal gene to all their daughters, but to none of their sons.
  • Females having one normal and one abnormal gene are asymptomatic carriers and will transmit the abnormal gene, on average, to one half of their sons and one half of their daughters.
  • If an X chromosome carrying a normal gene for Factor VIII is represented as XH, and an X carrying the abnormal or hemophilic gene is represented as Xh then the different possibilities for clinical status (phenotype) and genetic makeup (genotype) can be represented as follows:

Phenotype
Genotype
Normal male
XHY
Normal female
XHXH
Affected male
XhY
Carrier female
XhXH
Affected female
XhXh

 

Hemophilia is most commonly propagated within a line when asymptomatic carrier females are bred to normal males. The male puppies produced from this mating with each have a 50:50 chance of being affected with hemophilia, and the females will each have a 50:50 chance of being a carrier. On average, the following 4 categories of offspring types will occur in equal numbers.

Parental type Offspring types Genotype
Carrier female and normal male normal male XHY
(XhXH and XHY) affected male XhY
  normal female XHXH
  carrier female XhXH

 

Clinical Signs

Hemophiliacs may bleed spontaneously into joints or muscles resulting in lameness and swelling. Severe, often fatal hemorrhage can occur into the chest or abdominal cavity. Bleeding under the skin results in soft swellings called hematoma. If a hemophiliac undergoes trauma or surgery then excessive hemorrhage occurs at the injured site. Different mutations responsible for hemophilia cause variable severity of bleeding tendency. Some forms of hemophilia are so severe that most affected dogs will die within the first few weeks of life. Other forms may be less severe, where affected dogs will survive, but exhibit intermittent signs of bleeding.

Laboratory diagnosis

Coagulation assays performed on a specially prepared blood sample are needed to diagnose hemophilia in dogs. The APTT (activated partial thromboplastin time) is a screening test for coagulation defects, and this test is abnormal in hemophiliacs. A specific diagnosis of hemophilia A must be based on specific measurement of canine coagulation Factor VIII - hemophilic dogs have a marked reduction in Factor VIII activity compared to normal dogs.

In properly prepared samples, using tests validated for dogs, the laboratory diagnosis of hemophilia affected dogs is highly accurate. Unfortunately, coagulation assays may not always distinguish between carrier and clear females. In general, carrier females have low levels of Factor VIII, but there is some overlap between carrier and clear females at the low end of Factor VIII's normal range. The accuracy of carrier detection can be enhanced by measuring another blood protein related to Factor VIII (von Willebrand factor) and then determining a ratio of these two proteins. It is still possible, however, for some carrier females to be misclassified. Pedigree analysis, in combination with laboratory assay, is therefore very important.

Pedigree analysis and breeding recommendations

Evaluation of pedigrees can determine carrier status of some asymptomatic females, allow estimates of risk for carrier status, and help to confirm laboratory diagnosis of affected males or females. All daughters and dams of hemophilic males are obligate carriers of hemophilia and should not be used for breeding. These females can be safely spayed, and are clinically normal. The full sisters and maternal half sisters of hemophilic males have a 50% chance of being carriers of hemophilia. The best policy is not to breed these females. Males can be confirmed clear of hemophilia by laboratory testing, and all sons of obligate or possible carrier females should be screened for hemophilia. Males that are confirmed test clear can safely be used for breeding without further propagation of the defect.

Additional information-Screening for Hemophilia A in purebred dogs

The Comparative Coagulation Section, at Cornell University's Diagnostic Laboratory provides assays for identification of canine hemophilia A, and more specialized tests for carrier detection in females. The test program is confidential, results are released only to the submittor. For the most complete and accurate evaluation, we encourage submission of pedigrees with all samples, and progeny testing (evaluation of offspring and parents) in affected lines. Because sample quality is critical for valid test results, we provide detailed instructions and supplies for drawing and processing canine blood samples. Please feel free to contact our laboratory for more information.