Definition

• Primary hemostatic defect caused by a quantitative or functional deficiency of vWF.
• Clinical expression varies from a mild to severe bleeding diathesis.

Pathophysiology

• vWF is an adhesive plasma protein required for normal platelet binding at sites of small vessel injury. In addition, plasma vWF is a carrier protein for coagulation factor VIII.
• A lack of vWF impairs platelet adhesion and aggregation, especially at sites of high shear stress. The largest molecular weight (MW) forms of vWF demonstrate highest reactivity in supporting platelet-collagen interactions.

Systems Affected

• vWF deficiency may cause spontaneous hemorrhage, prolonged post-traumatic hemorrhage, and ultimately blood loss anemia.
• Spontaneous hemorrhage-typically manifests as bleeding from mucosal surfaces.

Genetics

• An autosomal trait; both males and females express and transmit the defect with equal frequency.
• Expression pattern of severe forms (Types 2 and 3 vWD) is recessive; milder form (Type 1 vWD) appears to be recessive or incomplete dominant.

Incidence/Prevalence

• The most common hereditary hemostatic defect in dogs.
• Rarely reported in cats.

Geographic Distribution

None

Signalment

Signs

Causes

Hereditary vWD is caused by mutations that impair vWF synthesis, release, or stability.

Risk Factors

Acquired disease conditions or drug therapy that impair platelet function may exacerbate clinical signs of vWD.

Differential Diagnosis

• Thrombocytopenia (the first rule-out for any patient with abnormal hemorrhage).
• Acquired coagulation factor deficiency (often associated with liver disease, vitamin K deficiency, or DIC).
• Acquired platelet function defects (often associated with drug therapy, uremia, hyperproteinemia).
• Hereditary coagulation factor deficiencies.
• Hereditary platelet function defects.

CBC/Biochemistry/Urinalysis

• Regenerative anemia develops after blood loss.
• Platelet count is normal unless the patient has experienced acute, massive bleeding.

Other Laboratory Tests

• Coagulation screening tests (ACT, APTT, PT, TCT, fibrinogen)-normal.
• Clinical diagnosis based on specific measurement of plasma vWF concentration (vWF:Ag).
  • vWF:Ag <50% indicates vWF deficiency, but clinical signs of abnormal bleeding typically develop in animals with vWF:Ag <25%.
  • Types 1 and 2 vWD are characterized by low vWF:Ag, whereas Type 3 vWD is defined as the complete absence of detectable protein (vWF:Ag <0.1%).
• Types 1 and 2 vWD are differentiated based on functional and/or structural vWF analyses.
  • vWF:CBA is a functional measure of vWF/collagen affinity. Type 2 vWD dogs have a relative lack of vWF:CBA compared to vWF:Ag, resulting in a protein concentration to function ratio >2:1. Type 1 vWD dogs have proportionate protein concentration and function.
• vWF multimer structure is visualized on Western blots. Type 2 vWD dogs lack the highest MW forms.

Imaging

N/A

Diagnostic Procedures

• BMBT and the platelet function analyzer-100 are point-of-care screening tests whose endpoints are prolonged in patients with platelet aggregation defects, and vWF deficiency. Prolongation is nonspecific and may accompany severe thrombocytopenia, anemia, or changes in blood viscosity.
• BMBT (expected values 2–4 minutes): typical values for Type 1 vWD = 5–10 minutes, Types 2 and 3 vWD >12 minutes.
• PFA-100 closure times (expected ADP/collagen closure time <120 seconds): typical values for Type 1 vWD = 150–300 seconds, Types 2 and 3 vWD >300 seconds.

Pathologic Findings

Hemorrhage is the only associated abnormality. Morbidity and mortality are caused by blood loss or hemorrhage into critical sites (i.e., CNS, respiratory tract).

Surgical Considerations

• Preoperative transfusion should be given just before the procedure. Peak vWF is obtained immediately after transfusion, with values falling to baseline by 24 hours after a single dose.
• Cage rest and close monitoring (serial Hct and examination of surgical site) for 24 hours after surgery are ideal to confirm adequate hemostasis. Management of severe vWD typically requires at least one postoperative transfusion.

Drug(s) Of Choice

• Desmopressin acetate (DDAVP) is a vasopressin analog that can be given preoperatively to dogs with mild to moderate Type 1 vWD to enhance surgical hemostasis. Dosage is 1 µg/kg SC; given 30 minutes before surgery.
• Response is variable; transfusion should be available if DDAVP alone does not prevent bleeding.

Contraindications

Avoid drugs with anticoagulant or antiplatelet effects: NSAIDs, sulfonamide antibiotics, heparin, coumadin, plasma expanders, estrogen, cytotoxic drugs.

Patient Monitoring

Observe closely for hemorrhage associated with trauma or surgical procedures.

Prevention

• Screen dogs preoperatively to determine baseline vWF:Ag in breeds or lines with high prevalence of vWD. The risk of abnormal bleeding is greatest for vWF:Ag <25%.
• Clinically affected dogs should not be bred. Carriers of vWD can be identified based on low vWF:Ag (<50%); however, values for carrier and clear dogs may overlap at the low end of normal range (50–70% vWF:Ag). At present, commercial tests (VetGen) to detect specific vWF mutations in DNA are available for several breed-variants of vWD. Dogs that are heterozygous for a specific mutation are considered vWD “carriers” and homozygotes are considered vWD “affected.”
• Selective breeding practices can reduce or eliminate vWD from an affected pedigree. Breeding two clear parents is ideal because all offspring are expected to be vWD clear. Breeding one clear and one carrier parent may be acceptable, with the clear pups produced from these matings used for subsequent breeding. Carrier-to-carrier matings are inadvisable because they are most likely to produce clinically affected offspring.

Expected Course and Prognosis

• Most dogs with mild to moderate vWD have good quality of life and require minimal or no special treatment.
• Dogs with more severe forms require transfusion for surgery and should be transfused if supportive care fails to control a spontaneous bleed. Most of these dogs can be maintained comfortably in pet homes.

Associated Conditions

• The development of any disease condition that impairs platelet function may exacerbate the bleeding tendency of vWD. Common conditions include thrombocytopenia, endocrinopathy (hypothyroidism, hypocortisolism), hyperproteinemia, and uremia.
• Acquired vWD occurs in humans with aortic stenosis, and features of Type 2 vWD have been reported in Cavalier King Charles spaniels with mitral valve disease.

Pregnancy/Fertility/Breeding

See “Prevention” for breeding recommendations.

Synonyms

vWF protein was formerly referred to as factor VIII–related antigen.

Abbreviations

• ACT = activated clotting time
• APTT = activated partial thromboplastin time
• BMBT = bucccal mucosal bleeding time
• DDAVP = deamino-8-d-arginine vasopressin
• DIC = disseminated intravascular coagulation
• MW = molecular weight
• NSAID = nonsteroidal anti-inflammatory drug
• PT = prothrombin time
• TCT = thrombin clotting time
• vWF = von Willebrand factor
• vWF:Ag = von Willebrand factor antigen
• vWF:CBA = von Willebrand factor collagen binding assay

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