Hereditary bleeding disorders in dogs and cats
Marjory Brooks, DVM, DACVIM
Veterinary Medicine, June 1999; pp. 555-564

Guidelines for diagnosing and treating the most common hereditary bleeding disorders in dogs and cats are included in this article. Hereditary bleeding disorders usually cause excessive bleeding from wounds and/or recurrent spontaneous bleeding. Prolonged bleeding along the gingival/tooth margin can also be seen. This type if disorder is caused by a mutation in the genes that code for a specific plasma protein (von Willebrand factor, clotting factors) or for proteins needed for platelet adhesion, aggregation, or intracellular signaling. Spontaneous mutations (non hereditary) can occur in any purebred or mixed-breed animal which can affect that animals progeny if bred to another that is an asymptomatic carrier. The most common hereditary bleeding disorders are von Willebrand's disease and hemophilia in dogs and hemophilia in cats..

Diagnosis:
1. Examine a blood smear, estimate platelet number
a. Low platelet count = thrombocytopenia
b. Normal platelet count = continue testing (BMBT and a coagulation panel)
*BMBT is prolonged/coagulation panel normal = primary hemostatic defect
**BMBT is normal/coagulation panel is abnormal = secondary hemostatic defect

A. Primary hemostatic defects - platelet plug formation failure
*this includes interactions between the vessel wall, platelets, and von Willebrand factor at the vascular injury site
1. Perform von Willebrand factor assays
a. Normal assays = Diagnosis of platelet function defect (thrombasthenia, storage pool defect, signaling defect)
b. Abnormal assays = Diagnosis of von Willebrand's disease (type 1, 2, or 3)

B. Secondary hemostatic defects - fibrin clot formation failure
*this includes reactions in the coagulation cascade that result in a cross-linked fibrin clot assembly
1. Perform the following 4 tests: APTT, prothrombin time, thrombin clotting time, and fibrinogen determination

Clinical Signs:
Primary: bruising (ecchymoses) and mucosal bleeding
Secondary: formation of hematomas, lameness (hemarthrosis), and pleural or peritoneal bleeding
*Severe cases are usually diagnosed by 1 year of age, less severe cases may take longer to diagnose due mild clinical expression or those animals that only show abnormal bleeding after a major surgery or trauma.

Screening Tests:
1. Rule out thrombocytopenia - platelet count
2. If platelet count is normal, then do the following initial screening tests: in vivo bleeding time, coagulation panel, ACT (activated clotting time can be done in house for secondary hemostatic defects). If the ACT is prolonged, run a coagulation panel for further diagnosis and confirmation.

In vivo bleeding time (is the time needed for the blood to stop flowing after making a standard wound)
A. Cuticle or toenail bleeding time - prolonged for primary and secondary hemostatic defects
1. sedate/anesthetize patient (minimize pain and movement)
2. clip hair around nail base
3. use guillotine-type nail clipper to cut just into the quick to obtain free flowing blood (if arterial pulse is present the cut is too high, if only 2 - 3 drops, cut is too low). Multiple nails can be used for range.
4. record length of time it takes for bleeding to stop (reference range = 2 - 6 minutes in dogs and cats)
5. cauterize cuticle with silver nitrate
B. Buccal mucosal bleeding time (BMBT) - prolonged for primary hemostatic defects
1. sedate/anesthetize cats, optional in dogs
2. position patient in sternal recumbency
3. evert the upper lip of the animal and secure with a gauze strip snugly around muzzle with a moderate venous flow reduction
4. begin timing as the spring-loaded device is tripped (use a standardized bleeding time device-single blade for cats/puppies, double blade for dogs). Timing stops when blood stops flowing to filter paper. (reference range = 2 - 4 minutes in dogs and cats)
5. blot blood flow without touching the wounds using filter paper
6. After timing is through apply pressure to wounds until bleeding stops, topical tissue adhesive may be helpful.
C. Coagulation Panel (also called clotting profile) - measures in vitro fibrin clot formation of patient's plasma
1. APTT - activated partial thromboplastin time - measures intrinsic and common system
2. Prothrombin time - measures extrinsic and common system
3. Thrombin clotting time - tests for deficiency or dysfunction of fibrinogen
4. Fibrinogen determination - tests for deficiency or dysfunction of fibrinogen
**Prolonged clotting time in one or more of the above tests = coagulation disorder. Specific pattern is dependent on which test(s) show factors are lacking.

Definitive diagnostic tests - after the above tests/history have been compiled - NOTE: sample quality is imperative
1. von Willebrand factor - ELISA (quantitative)
---differentiation into factor structure uses Western blot and cofactor assays for further classification and predicting clinical expression
2. platelet function
3. coagulation factor activity

Sample collection: 0.3ml sodium citrate anticoagulant + 2.7ml whole blood (clean venipuncture) OR use vacutainer needle to draw blood directly into a 3ml sodium citrate vacutainer tube. NOTE: sodium citrate : whole blood ratio is critical.
Tests: best if run with in 1 hour of collection, no need to refrigerate
A. von Willebrand factor and coagulation studies: centrifuge 5 - 10 minutes, aspirate plasma and place in a clean plastic or siliconized glass tube. STORE until assay or SHIP on ice-frozen-to lab. Redraw if there is any hemolysis or clots (=sample activation)
B. platelet function tests include (hematology lab must run these within a few hours of sample collection and same species plasma should be used for referencing):
1. flow cytometry and electron microscopy (detect surface proteins and intraplatelet storage organelles)
2. aggregation studies - measures platelet response to agonists such as collagen, adenosine diphosphate, and thrombin
3. modified APTT and prothrombin time assays check fibrin clot endpoints and show as a percentage of activity

Specific Defects
A. von Willebrand's disease - 3 subtypes
1. Type 1 - partial quantitative von Willebrand factor deficiency (plasma vW factor is low with normal protein structure)
2. Type 2 - low vW factor concentration with an abnormal protein structure
3. Type 3 - complete vW factor deficiency where the concentration of the factor in plasma is undetectable
B. Hemophilia - 2 subtypes (both are X-linked, recessive traits OR can be de novo mutations)
1. hemophilia A - deficiency of coagulation factor VIII
2. hemophilia B - deficiency of coagulation factor IX
C. Hageman trait - deficiency of coagulation factor XII - does not cause bleeding tendency - most common in cats (clinically normal, but show prolonged clotting times)

Therapeutic options - hereditary bleeders suffer lifelong risk of bleeding crisis
A. Transfusion Therapy: - goal: to replace functional platelets or specific plasma factors - most successful when early transfusion of blood products at the high end dosage range are given when there is active bleeding or to prevent intraoperative hemorrhage. Dosage and frequency (additional transfusions) are dependent on the patient's status (i.e. minor wounds = 1 transfusion of platelets or plasma, major wounds = multiple transfusions over 1 - 3 days).
Note: use components (preferable over whole blood products) to minimize body's reaction to WBCs and plasma proteins, and prevent fluid overload). Use blood products (RBCs) if acute or chronic blood loss anemia.
1. Components (shelf life & gt; 1 year if stored below -4F (-20 C): fresh-frozen plasma (good for vW and clotting factor deficiencies), plasma cryoprecipitate (best for vW, fibrinogen deficiency, and hemophilia A), or cryosupernatent (good for other factors deficiencies and treating hemophilia B).
2. Platelet-rich plasma (slow centrifugation of fresh whole blood and stored at room temp, must be used within 48 hours)
3. Blood Types:
Cats: On ALL transfusions: Type A receive from Type A donors; Type B receive only from Type B donors
Dogs: On all subsequent transfusions match blood type to blood type (first transfusion won't matter due to dog's lack of preformed RBC antibodies). If blood type unknown, use DEA (dog erythrocyte antigen) 1 negative (1.1- and 1.2-negative) donors only. Note: DEA 1 dog blood group has the most reactions in transfusions due to 3 types of blood in this group (1.1, 1.2, and null)

Crossmatching (detect AB incompatibilities or increased clotting tendencies between donor and recipient)
1. Place 2 drops of recipient serum on glass slide
2. Add 1 drop of donor blood, rock for 10 seconds
3. Check slide after 1 minute for macroagglutination (if positive = blood is INCOMPATIBLE)

Note: rate of transfusion for cats and puppies = 1 - 2 ml/min; for adult dogs = 3 - 6 ml/min
* 1 U = cryoprecipitate produced from 200ml of fresh-frozen plasma.

B. Nontransfusion therapy:
1. Cauterization, topical tissue adhesive, sutures, pressure wraps at focal injuries
2. Patients with severe disorder should not be subject to unnecessary jugular vein catheterization, abdominocentesis, or other invasive procedures.
3. AVOID sulfonamides, nonsteroidal anti-inflammatory drugs, heparin, dextrans, and any other drug that may hinder hemostasis
4. Treatment with DDAVP (desmopressin acetate) for type 1 vW patients postoperatively: Give 1 microgram/kg SC 1/2 hour before surgery, monitor closely as transfusions may also be required.

Disease control and genetic counseling
1. If a hereditary bleeding disorder is diagnosed, the dam, sire, and siblings should also be evaluated
2. Hemophiliacs are X-linked, therefore a male is either positive or clear of the defect, subsequently a hemophiliac male will transfer the gene to his daughters, but not his sons. These females will be heterozygous for factor VIII or IX mutations and are clinical normal. These females would theoretically transfer the gene to half their sons (who will be bleeders) and to half their daughters (asymptomatic carriers). Carrier females usually produce the most severe hemophiliacs. If a male has a mild form of the disease, he may easily survive to adulthood and reproduce.
3. All platelet function defects, vW disease, and factor deficiencies (not VII and IX) are autosomal trait inherited, transmitted and expressed equally by males and females. Most traits are recessive. Homozygous = marked decrease in concentration and activity of the factor; Heterozygous = clinically normal with an intermediate factor activity or concentration.
4. GOAL: accurately assign genotype to clinically normal animals (heterozygotes) and proper client education relating the disorder.
5. Breed dispositions:
A. Type 1 von Willebrand's Disease = Airedale, Akita, dachshund, Doberman pinscher, German shepherd, golden retriever, greyhound, Irish wolfhound, Manchester terrier, Pembroke Welsh corgi, poodle, mixed breeds, other dog breeds, Himalayan cats.
B. Type 2 von Willebrand's Disease = German shorthaired pointer and German wirehaired pointer
C. Type 3 von Willebrand's Disease = Dutch Kooikerhondje, Scottish terrier, Shetland sheepdog, mixed breeds, and others
D. Thrombasthenia = Great Pyrenees, otter hound
E. Storage pool defects = American cocker spaniel, collie, Persian cats
F. Signal Transduction defects = Basset hound, collie, spitz
G. Fibrinogen (factor I) = Bichon frise, borzoi, collie, viszla, mixed breeds, DSH and DLH cats
H. Prothrombin (factor II) = Boxer, English cocker spaniel
I. Factor VII = Beagle, malamute, DSH cats
J. Hemophilia A (factor VIII) = German shepherd, German shorthaired pointer, golden retriever, Labrador retriever, mixed breeds, many other dog breeds, Abyssinian, DLH, DSH, Havana brown, Himalayan, and Siamese cats
K. Hemophilia B (factor IX) = Airedale, Cairn terrier, Labrador retriever, mixed breeds, and others, British shorthair, DLH, DSH, and Siamese cats
L. Factor X = American cocker spaniel, Jack Russell terrier, DSH cats
M. Factor XI = Kerry blue terrier, springer spaniel
N. Hageman trait (factor XII) = miniature poodle, shar pei, DLH, DSH, and Siamese cats
O. Vitamin K-dependent factors (II, VII, IX, and X) = Devon rex cats..