By C. Guillermo Couto, DVM, Dipl. ACVIM

Thrombosis

The terms "thrombus' and "embolism" were coined by Rudolph Virchow in the 1850s (reviewed in 46). A thrombus (from the Greek thrombos) is defined as a clot of blood formed within a blood vessel that remains attached to its place of origin; an embolus (from the Greek embolus or wedge-shaped object) is an abnormal particle, such as an air bubble or piece of thrombus, circulating in the blood. Thromboembolism (TE) is defined as formation of a clot (thrombus in a blood vessel) that breaks loose and is carried by the blood stream to occlude another vessel. As a general rule, venous thrombi are low-flow, fibrin-rich structures, whereas arterial thrombi are high-flow, platelet-rich clots (2014). Thrombosis can be due to local factors (e.g. stagnant blood flow) or systemic hypercoagulability.

Numerous hemostatic and hemorrheologic mechanisms can contribute to hypercoagulability (reviewed in 47 and 48). In human medicine, the term "thrombophilia" is used to describe conditions that predispose to venous and arterial thrombosis by impairing hemostasis.⁴⁷ Hyperviscosity due to a high circulating red blood cell mass is one of those factors.^49,50

Shortly after starting a race, greyhounds undergo a massive splenic contraction (due to catecholamine release) that leads to marked increases in the hematocrit (HCT); in some dogs, the HCT during or immediately after a race can be as high as 80 percent.^51,52 Although an optimal increase in HCT (and hence, hemoglobin concentration) typically enhances aerobic performance and buffering during exercise, HCT above this value result in high viscosity^53,54 and markedly decreased cardiac output.^54-56 However, a high HCT also has a beneficial effect on endothelial cells, leading to the release of nitrous oxide (NO), and subsequent vasodilation.^57-59 To my knowledge, there are no published reports of red blood cell deformability in greyhounds; in human athletes, the release of high numbers of young RBCs results in increased deformability and compensates for the higher HCT.⁵⁴

A high HCT and its associated increased viscosity lead to hypercoagulability, due to unknown mechanisms.⁴⁹ As Virchow proposed in 1855, "circulating blood does not clot" (reviewed in 46,60. Hence, it is quite likely that greyhounds and other sighthounds have developed adaptational mechanisms to deal with this risk factor for thrombosis, thus becoming somewhat "hypocoagulable." Interestingly, fibrinogen concentrations decrease in human athletes in association with training.⁴⁹ Most greyhounds have fibrinogen concentrations below the reference intervals for dogs (reference intervals 89-180 mg/dL compared to 100-384 mg/dL in non-greyhound dogs.²

Thrombosis and TE are common in cats with hypertrophic cardiomyopathy, but are uncommon in dogs.⁶¹ However, we reported that almost four percent of greyhounds had hemostatic disorders, including hypo- and hypercoagulability, resulting in eight percent of the deaths in the survey.²⁰ Some reports of greyhounds and other sighthounds with central nervous system (CNS) TE have appeared in the literature^62,63 Several greyhounds with aortic and iliac thrombosis^64-69 and another one with pulmonary TE⁷⁰ were also reported recently. Although some of the non-greyhound dogs in these reports had underlying disorders, such as cancer or heart disease, most of the greyhounds and sighthounds affected were otherwise healthy.

In my experience, CNS TE is common in greyhounds and other sighthounds, and it resembles human ischemic strokes. The typical presentation is that of an older (eight to 10-year-old) dog, with peracute onset of CNS signs consisting of ataxia, salivation, nystagmus, seizures, or any combination of neurologic signs; in my experience, most dogs present with central vestibular signs. Results of magnetic resonance imaging (MRI) typically reveal a well-defined lesion that is hyperintense in T2W and T2W-fluid-attenuated inversion recovery sequences, hypointense in T1W sequences, has minimal to no enhancement after IV administration of paramagnetic contrast agents, results in minimal mass effect, and involves predominantly the gray matter in the vascular territory of main cerebral or cerebellar arteries or a perforating branch of such arteries.⁶³ Figure 3 depicts the MRI image of an infarct 24 hours after the development of clinical signs in a nine-year-old, female spayed greyhound.

Most dogs have a single lesion. In a recent retrospective study of 21 greyhounds with ischemic strokes,⁶³ they were located in the cerebellum (n = 9), caudate, and lentiform nuclei and the intervening internal capsule (3), thalamus (6), or piriform lobe of the cerebrum (1). On the basis of the anatomic location of the lesions, the arterial supply that was presumed disrupted included the rostral cerebellar artery (n = 9), lenticulostriate artery (3), another perforating artery (6), or distal branch of the middle cerebral artery (1). Interestingly, most affected greyhounds we have evaluated and those reported by Kent et al⁶³ have normal parameters of hemostasis, including TEG tracings.

We have also identified a subset of young actively racing greyhounds that develop peracute spinal cord signs within 50 to 75 m of starting the race. Most trainers and veterinarians refer to them as fibrocartilaginous emboli (FCE), despite the fact that, to my knowledge, no imaging or pathologic studies have documented the lesions. Although we have limited data from advanced imaging, most affected dogs that underwent MRI had evidence of arterial thrombosis. In most dogs, the response to antiplatelet agents (see below) is rapid (hours), suggesting a thrombus as opposed to FCE. Interestingly, these episodes seem to coincide with the purported splenic contraction secondary to catecholamine release that rapidly increases the hematocrit to almost 80 percent.⁷¹ In addition to the arterial thrombosis mentioned above, we have seen peracute thrombosis of the spinal venous sinuses in pet greyhounds as young as 18 months of age.

I manage affected dogs with antiplatelet agents, since they are likely arterial (i.e. platelet-rich) thrombi. In my experience, aspirin at a dosage of 40.5 mg (half of an 81-mg aspirin) per dog, PO, q24h, is effective in most dogs treated shortly after the development of clinical signs. Indeed, in some dogs, administration of aspirin at home by their owners frequently results in marked improvement or even resolution of most neurologic signs by the time the patient arrives at the clinic. We continue this treatment indefinitely, and thus far, I have documented only two dogs who relapsed. Interestingly, in the largest study of CNS infarcts in greyhounds, response to therapy was not reported.⁶³

Using platelet function analysis (PFA-100) and TEG platelet-mapping, we documented that 40.5 mg of aspirin given PO once daily significantly decreases platelet aggregation in greyhounds (data not shown). We were unable to demonstrate decreases in platelet aggregation in a small number of greyhounds in which we used clopidogrel (Plavix); this may be due to the fact the latter is a cytochrome P450- (CYP-) dependent drug. Anecdotally, however, clopidogrel may be beneficial in greyhounds (S. Shropshire, DVM, DACVIM, Colorado State University, personal communication). Greyhounds have lower activity of selected CYP enzymes than other dogs,^72,73 so these drugs should be used with caution in the breed.

In a recent study of 100 dogs with aortic thrombosis, greyhounds represented the second most common breed, with 14 percent of the cases; Labrador retrievers were the most common breed, representing 16 percent of the cases.⁷⁴ Most greyhounds did not have clear underlying causes of hypercoagulability.

Greyhounds with aortoiliac thromboembolism (AITE) usually present for intermittent, progressive unilateral rear limb lameness that frequently starts in one limb and gradually becomes bilateral. In most dogs, the distal aorta and/or the external iliac arteries are involved; internal iliac arterial thrombosis is uncommon. Swelling and bruising of the affected limb are common (Figure 4).

In most dogs, physical examination also reveals disparity in the femoral pulses between both limbs. Ultrasonography is the preferred imaging method of diagnosis, as it reveals and echogenic intra-arterial structure with decreased blood flow, as determined by Doppler (Figure 5).^68,69

In dogs with AITE who do not respond to aspirin therapy or who have severe edema/bruising, I have successfully used warfarin (0.05-0.2 mg/kg, q24h), adjusting dosages as reported by Winter et al⁶⁹; as discussed above, warfarin is also a CYP-dependent drug, so it should be used with caution in greyhounds. The rationale behind using heparin is to decrease additional clot formation, and hopefully allow for the endogenous fibrinolytic (and other clot-opposing mechanisms) to work.

In most patients I have managed, underlying hypercoagulable syndromes were not identified. Affected greyhounds had results of OSPT, APTT, fibrinogen concentration, and TEG within the reference interval for the breed. Interestingly, old studies have suggested greyhounds and other sighthounds may have tortuous arteries or arteriosclerosis, or they may develop atheromas.^75-78 This could explain the high prevalence of AITE in these breeds.

In summary, greyhounds (and likely other sighthounds) do not follow the rules when it comes to hemostasis; some bleed and some thrombose, despite having normal test results. Fortunately, the recognition of the delayed postoperative bleeding and the clinical studies of EACA, and better knowledge of the fact greyhounds are at risk for thrombosis, along with implementation of aspirin therapy, have led to decreased morbidity and mortality.

Guillermo Couto, DVM, dipl. ACVIM, specializes in internal medicine and oncology. He has coauthored the bestselling textbook, Small Animal Internal Medicine (Elsevier), now on its sixth edition, has published more than 150 scientific articles in peer-reviewed journals, as well as 150 book chapters. Dr. Couto has 40 years' experience in clinical and comparative hematology, oncology, transfusion medicine, and clinical pathology, and is an expert in greyhound and sighthound medicine.  

Acknowledgements: to Drs. Ana Lara, Liliana Marín, Paulo Vilar Saavedra, and Sara Zaldivar who worked tirelessly to perform these studies

Supported in part by grants by the American College of Veterinary Internal Medicine Foundation, the Morris Animal Foundation, the American Kennel Club, and the Kindy French Foundation.

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