Inherited Platelet Disorders
World Small Animal Veterinary Association World Congress Proceedings, 2014
Benjamin M. Brainard, VMD, DACVAA, DACVECC
University of Georgia, Athens, GA, USA

Normal Platelet Physiology and Activation

As a background to understanding inherited platelet function defects, it is necessary to review the normal platelet response to agonists and how the platelets function when making a clot in vivo. The platelet has myriad receptors that are responsive to procoagulant or proaggregatory elements that are either soluble in the blood, or that are exposed with tissue damage or inflammation. Activation of the platelet receptors initiates a cascade of biochemical events that alter the levels of calcium inside the platelet, resulting in a change in the conformation of the platelet itself as well as of the fibrinogen receptor (GPIIb-IIIa, also known as integrin αIIbβ3). Activation of GPIIb-IIIa is the final common pathway for many platelet activation pathways and allows the platelets to be integrated in to the forming clot. Defects in any step of this pathway can lead to decreased or abolished platelet function, and are both a cause of heritable platelet defects as well as a target for drugs to decrease platelet function.

Typical soluble agonists for platelet aggregation include adenosine diphosphate (ADP), thrombin, serotonin (5HT), and thromboxane (TXA2). Many of these agonists are stored within the platelets themselves, in the alpha or dense granules, the contents of which are released upon platelet activation. Other agonists, such as collagen, are associated with the vascular subendothelium and are exposed in the context of vascular injury. Fibrinogen helps platelets link to each other and plays a role in tethering the platelets to the area of vascular injury, through the GPIIb-IIIa receptor. Von Willebrand factor (vWF) is produced by endothelial cells and also helps to tether platelets to areas of vascular damage, especially in areas of high blood flow (e.g., the arterial circulation).

Clinical Signs, Clinical Pathology of Platelet Dysfunction

Clinical signs of platelet dysfunction can vary depending on the characteristics of the actual disease, but defects in primary hemostasis are generally characterized by bleeding from mucosal surfaces. Affected animals may display epistaxis, hematuria, or gastrointestinal bleeding. Excessive bleeding from the gums may be noted during eruption of permanent teeth in puppies and kittens. Milder platelet function defects may be diagnosed in patients who have prolonged bleeding following surgery. Cutaneous bruising and petechiae may be seen, depending on the circulating platelet number and the characteristics of the actual disease.

In general, patients with platelet function defects have an adequate number of circulating platelets (although the total number may be low if there has been active hemorrhage, or high if there is chronic low-grade hemorrhage), and a normal plasma coagulation profile (prothrombin time [PT], activated partial thromboplastin time [aPTT], activated clotting time [ACT]). The buccal mucosal bleeding time (BMBT), or oral mucosal bleeding time, will be prolonged (normal range 3–5 minutes). Advanced testing can include the platelet function analyzer (PFA-100) which evaluates platelet function under conditions of high flow, platelet aggregometry, which evaluates platelet responses under low flow, or flow cytometry, which can distinguish platelet surface characteristics. Some of these tests can be difficult to perform or may give erroneous results in patients with thrombocytopenia. Other specific testing can include quantification of vWF antigen in the plasma. Reference range for canine vWF antigen (vWF:Ag) at the Cornell comparative coagulation laboratory is 65–150%.

Extrinsic Disorders in Platelet Function

Extrinsic disorders in platelet function involve conditions where the lack of exogenous substances decreases platelet function. The most common extrinsic platelet function disorder in veterinary medicine is von Willebrand's disease (vWD). vWD is characterized by a either a complete lack of vWF, or the lack of appropriate amounts of vWF, and generally is classified into three clinical syndromes on this basis.

 Type I vWD is characterized by a lower total amount of functional vWF and has been reported in numerous breeds of dog, including both purebred and mixed-breed dogs. Doberman pinchers classically have type I vWD. In addition, it has been described in Arabian horses. The clinical severity of type I vWD depends on the quantitative degree of vWF activity present. This is the most common form of vWD reported in dogs.

 Type II vWD describes different 'functional variants' of vWF, and has been infrequently reported in animals. vWD type IIA is characterized by a decrease in primarily the larger vWF molecules, which are more important for coagulation, and these animals have significant defects in primary hemostasis. There is also a net decrease in all circulating vWF in animals with type IIA vWD, which has been reported in German shorthair and wirehair pointers, as well as Simmental cattle, Quarter horses and thoroughbred horses.

 Type III vWD is characterized by complete lack of circulating vWF. It has been reported in many breeds of dog (and a mixed-breed dog), a Himalayan cat, and Poland and China white pigs. Type 3 vWD has the most severe clinical presentation of the vWD variants.

Therapy for patients with hemorrhage due to vWD frequently involves transfusion, both of red blood cells (RBC) to increase oxygen-carrying capacity, as well as plasma products such as fresh frozen plasma (FFP) or cryoprecipitate. Cryoprecipitate is made from FFP and contains a concentrated amount of vWF and coagulation factor VIII (FVIII). Cryoprecipitate is particularly useful for prophylactic therapy of known vWD patients prior to surgery or other invasive procedures. Desmopressin acetate (DDAVP; 1 mcg/kg, given subcutaneously) has been used in humans and dogs with vWD, and in humans with type I vWD is associated with a 2- to 4-fold increase in circulating levels of vWF and FVIII. Patients with type II vWD show a variable response, depending on the degree and functional characterization of the defect. In dogs with type I vWD, DDAVP resulted in an improvement of clinical characteristics (decreased BMBT and improved PFA-100 closure time) as well as a small but significant increase in circulating vWF. In patients who may have vWD and require emergent surgery (e.g., a Doberman pinscher with a gastric dilatation/volvulus), it is safe to assume that the patient may be a vWD-affected animal, and the administration of at least DDAVP is recommended. Although BMBT or other platelet function testing may be performed in these animals, thrombocytopenia due to systemic inflammation may affect the interpretation of the results.

Intrinsic Platelet Defects

Glanzmann's thrombasthenia (GT) is caused by a defect in the GP IIb-IIIa receptor on the platelet surface. This receptor interacts with fibrinogen and is critically important to stabilize clots once they have formed in vivo. In dogs, a mutation associated with the IIb subunit is responsible for all of the reported cases of GT. Glanzmann's thrombasthenia has been reported in Great Pyrenees and Otter hound dogs, and also in a thoroughbred-cross and an Oldenburg horse. Clinical signs in patients with GT can be variable but are frequently associated with hemorrhage, either in the postoperative period or secondary to wounds.

A mutation of the P2Y12 ADP receptor has been reported in a Greater Swiss mountain dog in Canada who showed excessive bleeding following ovariohysterectomy (but who had no prior signs of hemorrhage or bruising). This mutation, hypothesized to exist in the ADP binding site of the receptor, was subsequently identified in a number of other Greater Swiss mountain dogs that were both related and unrelated to the dog in the report.

The internal signaling pathway in platelets responding to an agonist includes a sequence or activation pathway toward the final expression of GPIIb-IIIa. An important part of this sequence is the calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI), and mutations in the gene that encodes this factor can result in impaired GPIIb-IIIa activation, impairing the platelet response to multiple agonists that use this pathway. A thrombopathia caused by defects in CalDAG-GEFI has been reported in Bassett hound, Spitz, and Landseer dogs, and Simmental cattle.

Coagulation factors that contribute to secondary hemostasis are serine proteases and work best when held in close proximity to each other on a charged cell membrane. Following activation, platelet membranes experience a rearrangement of their phospholipids that allows them to support secondary hemostasis, thus localizing coagulation to the area of vascular injury. Scott syndrome results from an inability of the platelets to generate an appropriate procoagulant surface to support coagulation, and has been described in German shepherd dogs.

The alpha and dense granules of the platelets contain procoagulant molecules that help to recruit and activate additional platelets and also support secondary hemostasis. Lack of alpha granules "gray platelet syndrome" and lack of dense granules "Chediak-Higashi syndrome (CHS)" have been reported in some veterinary species. Gray platelet syndrome has not been reported in veterinary species, while CHS has been recognized in Persian cats with a "blue flame" hair color, 3 breeds of cattle, and mice. Collies with cyclic hematopoiesis also lack platelet dense granules. A defect in dense granule function has been reported in American Cocker spaniels.

Diagnosis for these intrinsic platelet defects can be difficult, especially because specialized equipment is generally necessary to fully characterize the location. In general, these patients may have signs of impaired primary hemostasis (petechiae, epistaxis, mucosal bleeding) and normal secondary hemostasis (PT, aPTT, ACT). The BMBT may be prolonged, and in patients with GT, platelet retraction may be decreased or absent. In patients with CalDAG-GEFI defects, platelet retraction remains normal (thrombin is an agonist that does not need this pathway), but bleeding is common.

Therapy for hemorrhage from intrinsic platelet defects may require replacement of RBCs and clotting factors, if hemorrhage is severe or protracted. In addition, because the intrinsic defects affect all circulating platelets in an animal, transfusion therapy with functional platelets may be necessary, and these may be given in the form of platelet concentrates or platelet-rich plasma, if available, or through whole blood transfusions. Animals with longer-term mild bleeding may eventually experience iron deficiency and may need dietary supplementation.


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Speaker Information
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Benjamin M. Brainard, VMD, DACVAA, DACVECC
University of Georgia
Athens, GA, USA

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