It has been known for more than three decades in human medicine that spontaneous echo contrast (SEC) – described as dynamic swirling echoes within the cardiac chambers – is caused by an increased ultrasonographic back‑scatter due to red cell aggregation in conditions of blood stasis.

Its association with low-flow states known to predispose to thromboembolism, such as mitral valve disease and atrial fibrillation, have led to the hypothesis that SEC may be a marker of increased thromboembolic risk¹.

Left atrial (LA) SEC was initially imaged with transthoracic echocardiography (TTE), but interest in it was renewed after the advent of transoesophageal echocardiography (TEE), which improved the detection of LA SEC and LA thrombus (LAT).

The development of transthoracic harmonic imaging (THI) – a novel echocardiographic technique that differs from conventional fundamental imaging in that it involves transmitting ultrasound at one frequency and receiving at twice the transmitted frequency – has enhanced the detection of LA SEC.

The association between SEC and increased risk of thromboembolic events shows a similar specificity using THI compared to TEE^2,3.

Fatkin et al (1995) found that severity of SEC, useful for classification of patients at thromboembolic risk, can be assessed reliably by experienced observers using a semiquantitative method of grading called videodensitometry⁴.

Although the mechanism for the development of SEC is not fully understood, an increase in blood viscosity at low shear rates has been hypothesised to cause SEC and favour development of thrombosis in most studies⁵.

LA SEC has been commonly detected in patients undergoing TEE suffering from conditions favouring blood stasis, such as atrial fibrillation, LA enlargement, mitral stenosis or mitral valve replacement.

Although the link between LA SEC and cardiovascular death is not straightforward, the overall incidence of thromboembolic events has been found to be higher in the presence of SEC, and data from several studies support a likely thromboembolic mechanism as a contributing factor for cardiovascular death in patients with atrial fibrillation^6-10.

Sadanandan and Sherrid (2000) investigated the clinical significance of LA SEC in sinus rhythm and the results revealed that SEC occurred in patients with a significantly dilated left atrium and depressed atrial function. LAT was noted in 13 per cent of such patients and the presence of SEC was associated with a higher prevalence of cerebrovascular accident, indicating that LA SEC in sinus rhythm was a marker of prothrombotic condition¹¹.

Significant cardiovascular and echocardiographic changes – including decreased systolic function and cardiac output, as well as the appearance of “new” valvular regurgitation and SEC – have been observed in healthy dogs sedated with dexmedetomidine.

The presence of SEC, in concert with otherwise normal echocardiographic findings, was interpreted as secondary to dexmedetomidine‑associated bradycardia; however, as SEC is considered suggestive of blood stasis and prothrombotic condition in presence of cardiac abnormalities, caution should be used when considering dexmedetomidine for sedation in patients with – or to be screened for – cardiovascular disease¹².

SEC may be distributed throughout the main body of the LA, but it is usually more intense within the left auricular appendage.

It has been observed that severity of LA SEC was inversely related to blood flow velocity within the left auricular appendage and that the presence of mitral regurgitation was protective against SEC formation, but not against the risk for systemic thromboembolism.

It was hypothesised that turbulent flow produced by significant mitral regurgitation may increase blood share rate and, therefore, disrupt red cell aggregation¹³. However, Castello et al (1990) had different results in their study where 12 (48 per cent) of the 25 patients with LA SEC had mitral regurgitation, and the relative incidence of SEC in patients with significant mitral regurgitation was 28 per cent⁶.

Thromboembolism link

The pathogenesis of SEC and its association with thromboembolism is complex and multifactorial. The ability to identify patients at risk for thrombosis has become increasingly important to institute preventive measures and appropriate therapy.

Virchow’s triad of factors related to thrombogenesis includes decreased blood flow, changes in blood constituents leading to hypercoagulability, and vessel wall damage.

Hypercoagulability describes an imbalance of physiological haemostatic mechanisms that results in a tendency to favour clot formation¹⁴. Such imbalance can be caused by excess of coagulation factors (such as fibrinogen and factor VIII coagulant activity) and deficiency of inhibitors (such as antithrombin), and is characterised by an increase in products formed during thrombin generation or secondary to thrombin activity (such as fibrinopeptide A, thrombin-antithrombin complex and plasma fibrin D-dimer)¹⁵.

Haemostatic changes have been investigated as potential markers of thrombogenesis to identify high-risk patients for LAT and thromboembolic events.

It has been observed that plasmatic macromolecules – such as α-globulins and β-globulins, and fibrinogen – establish reversible bridges among red blood cells; therefore, they are required for the formation of erythrocytes aggregates¹³.

Data from some studies have shown an increase in von Willebrand factor and platelet factor IV – in particular β-thromboglobulin – in patients with atrial fibrillation compared to sinus rhythm, with higher levels in the presence of enlarged LA and LAT, suggesting that endothelial damage and haemostatic activation are associated with the latter^16,17.

Other studies found a significant increase in plasma fibrin D-dimer in patients with SEC and particularly with LAT. Wan et al (2017), in their systematic review and meta-analysis, found further evidence that D-dimer had moderate to high sensitivity and specificity in identifying the presence of LAT, therefore suggesting that a normal D-dimer value may indicate a low risk for the presence of this or thromboembolism¹⁸.

The platelet:lymphocyte ratio – known to be a marker of inflammation and prothrombotic state – has also been found to be independently associated with SEC in patients with mitral stenosis¹⁹.

Increasing recognition

Thrombosis is one of the main causes of death in critically ill people, and it is increasingly recognised as a cause of morbidity and mortality in veterinary medicine.

Mechanisms that contribute to hypercoagulability – and often result in a prothrombotic tendency – have been identified in several veterinary disorders such as, among others, cardiac disease and immune‑mediated haemolytic anaemia (IMHA)¹⁴.

Aortic thromboembolism (ATE) is a common, frequently fatal, sequel of cardiomyopathy in cats. A sub-analysis of a previously reported population of cats with hypertrophic cardiomyopathy (HCM) – where those presented with congestive heart failure (CHF) or ATE had the shortest survival times – investigated risk factors for different causes of mortality, including CHF death, ATE death and sudden cardiac death. Results showed the most common cause of cardiac mortality was CHF (55.7 per cent), then ATE (29.1 per cent) and sudden death (15.2 per cent)^20,21.

In cats and humans with cardiomyopathy, cardiac thrombi and SEC are observed most frequently in the left atrium and the LA appendage (LAA), and LAA flow velocity determined by TTE has been shown to be an independent factor in predicting SEC²².

In a retrospective study conducted by Peck et al (2016), the incidence and prognostic significance of SEC was evaluated in relation to cardiac disease and CHF in 725 cats. In this study, the presence of SEC was associated with an increased risk for death in cats with underlying acquired cardiac disease. Cats with HCM, dilated cardiomyopathy and unclassified cardiomyopathy were significantly more likely to develop SEC than other types of cardiac disease²³.

Stokol et al (2008) reported on the risk of hypercoagulability associated with feline cardiomyopathy, based on an increase in at least two out of four parameters (fibrinogen, factor VIII coagulant activity, thrombin‑antithrombin complex, D-dimer). They found evidence of hypercoagulability in approximately 50 per cent of cats with ATE, and concurrent presence of SEC in 46 per cent of them²⁴.

SEC is uncommonly reported in dogs. One case series reported the presence of SEC in the left ventricle or all the cardiac chambers of three dogs, which were diagnosed with infective mitral endocarditis, Evans syndrome and sepsis of unknown origin. These dogs had either normal cardiac size or mild cardiomegaly, but it was interestingly noted that all of them exhibited hyperfibrinogenaemia. However, a direct association between SEC and fibrinogen could not be established, likely due to the multifactorial pathophysiology of SEC²⁵.

Trauma associated with abdominal surgery has also been reported to lead to the development of SEC in the caudal vena cava in healthy dogs. The authors of this study hypothesised that SEC was caused by systemic inflammation; however, no diagnostics were performed to investigate potential underlying hypercoagulability²⁶.

Another case report described the development of SEC in the left ventricle of one dog, which occurred the day after occlusion of a previously diagnosed patent ductus arteriosus²⁷. The dog experienced both hypotension and hypertension after ductal occlusion similarly to the dogs that exhibited SEC after sedation with dexmedetomidine reported by Kellihan et al (2015)¹². The patient of this case report was discharged with clopidogrel, and five weeks later the previously documented SEC had resolved²⁷.

Various coagulation abnormalities have also been documented in dogs with IMHA, including disseminated intravascular coagulation (DIC) and hypercoagulable state, which has been shown to be associated with an increased risk of thromboembolism.

Reported mortality of dogs with primary IMHA ranges from 26 per cent to 70 per cent, with thromboembolism being linked with a poor clinical outcome²⁸.

The pathophysiology of hypercoagulability in IMHA is complex, and several factors have been hypothesised to play a role – such as decreased concentration of fibrinolytic or anticoagulant factors, increased procoagulant factors, enhanced platelet reactivity and presence of antiphospholipid antibodies.

Scott-Moncrieff et al (2001) reported hypercoagulability as a common finding in dogs with IMHA at the time of clinical presentation, and documented decreased antithrombin activity and thrombocytopenia in 50 per cent and 65 per cent of dogs, respectively. Most of these dogs had also increased fibrinogen concentration.

In this study, long-term mortality was 30 per cent, with thromboembolism being the most common cause²⁹.

Clinical outcome prediction

Other studies have reported the use of thromboelastography (TEG) to identify hypercoagulability in dogs with IMHA, and data indicate that coagulation index at hospital admission may be predictive of clinical outcome.

Whereas most of the dogs exhibited TEG profiles consistent with hypercoagulable state, a normal TEG profile was unexpectedly linked with a higher incidence of death – and it was hypothesised that consumptive coagulopathy may be responsible for the poorer outcome in dogs with relative hypocoagulability at initial presentation^30,31.

Intravascular haemagglutination in animals with IMHA has been hypothesised to be the reason for development of SEC due to the increased reflective surface of red blood cells³². The most commonly observed site of thromboembolism in dogs with IMHA is in the lungs, but other sites include the cranial vena cava, heart, spleen and kidney³¹.

SEC is commonly detected in the splenic and portal veins; however, in a recent review of diagnostic imaging for the evaluation of abdominal vascular diseases, Specchi and d’Anjou (2019) reported that in their experience SEC can also be seen in other abdominal veins of small animals affected by IMHA³².

Spontaneous portal vein thrombosis is not a common event in dogs, and diagnosis is rarely made antemortem.

In dogs, it can occur secondarily to several pathological conditions – including autoimmune disease, pancreatitis, renal amyloidosis and hepatic neoplasm; however, the underlying cause is not always identified^32,33.

Lamb et al (1996) reported a case series of portal vein thrombosis detected ultrasonographically in four dogs diagnosed with protein-losing enteropathy (PLN) and probable IMHA, pancreatitis and haemorrhagic gastroenteritis (HGE), chronic ehrlichiosis, and duodenal neoplasm, respectively. Three out of four dogs had decreased portal blood flow and portal hypertension, and hypercoagulability was suspected to be present in two dogs, specifically those diagnosed with pancreatitis/HGE and PLN/IMHA³³.

Splenic vein thrombosis (SVT) is the most common disease that affects the splenic vein in both humans and dogs. SVT is often an incidental finding observed on routine abdominal ultrasonography in dogs, and rarely it leads to clinical symptoms; therefore, investigation of the underlying causes is required to understand the clinical significance of SVT.

In a recent case report, one dog with history of hyperadrenocorticism and concurrent pancreatitis was diagnosed ultrasonographically with acute SVT. Possible hypercoagulable state was not investigated; however, the dog completely recovered after splenectomy³⁴.

Laurenson et al (2010) reported on concurrent conditions in dogs with SVT and found that SVT occurred most commonly as a sequel to neoplastic disease, with lymphoma being the most represented neoplasm. Other causes included immune‑mediated disorders, endocrine diseases, DIC and pancreatitis³⁵.

Conclusion

In conclusion, SEC is considered a marker of increased thromboembolic risk on the basis of its association with low blood flow and hypercoagulable state.

Thrombosis is increasingly recognised as a cause of mortality in veterinary medicine and mechanisms that contribute to development of a prothrombotic tendency have been identified in several disorders, including cardiac disease and IMHA.

The incidence and prognostic significance of SEC in relation to cardiac disease has been thoroughly investigated; however, a lack of knowledge exists about association between SEC and risk of thromboembolism in IMHA; therefore, this may be considered an interesting aspect for future research.