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

Pulmonary thromboembolism (PTE) is a general term used to describe an occlusion of pulmonary circulation by a blood clot. The clot may be formed in situ, where it is most appropriately termed a pulmonary thrombus, or it may be formed at a distant area of the body and embolize to the pulmonary circulation, a true PTE. Because PTE can be difficult to diagnose ante- and postmortem, the true incidence in companion animals is not known. It is estimated that the prevalence of PTE in dogs is approximately 1% and that in cats approximately 0.06%. Due to the rapid fibrinolysis that occurs in dogs after death (due to higher tissue plasminogen activity), this prevalence may be underestimated in the general population, even in dogs who underwent necropsy.

Animals that are at risk for development of PTE generally have a predisposition to abnormal clot formation, or suffer from a hypercoagulable condition. These conditions may be caused by diseases that damage or activate the vascular endothelium (neoplasia, sepsis, indwelling venous catheters, pancreatitis, other inflammatory diseases), diseases that strengthen procoagulant tendencies (protein-losing nephropathy, hyperadrenocorticism, dirofilariasis, surgery, immune-mediated hemolytic anemia), or those that cause vascular stasis (cardiac disease, trauma with crush injury, neoplasia). Many of these conditions (e.g., neoplasia) have multiple mechanisms through which they may promote the formation of thrombi. A common theme amongst the diseases associated with endothelial activation (which results in a procoagulant phenotype) is systemic inflammation or the systemic inflammatory response syndrome (SIRS). Many of the above-mentioned diseases can result in SIRS, and in the presence of additional factors (e.g., intravenous catheters), may contribute to the increased incidence of thrombosis (pulmonary or otherwise) in this group of animals.

Diagnostics: Clinical Signs

The diagnosis of PTE remains difficult, both in human and veterinary medicine, and many animals are treated on the basis of clinical signs compatible with a PTE rather than actual documentation of the clot. Some animals may appear completely asymptomatic despite large PTEs. Clinical signs that can be seen in animals with PTE include an acute onset of hypoxemia, accompanied by dyspnea, in patients who may be predisposed to clot formation (see above). The respiratory effort is generally worse for the 2–3 hours following the embolism because of the compensatory reaction of the lungs to an interruption of blood flow. Vasospasm caused by the release of vasoconstrictive agents from activated platelets (e.g., thromboxane) can result in less efficient oxygen exchange to perfused alveoli, and bronchospasm may also occur, which can limit the body's ability to oxygenate appropriately. Pulmonary interstitial edema may also occur, which may impair oxygenation, and circulatory overload to other parts of the lung (in the context of large PTE) can result in pulmonary edema in other areas of lung.

As the clot matures, these acute changes become less pronounced and the majority of the clinical signs are related to the disruption of the normal perfusion pattern of the lungs, which is manifest primarily as hypoxemia but not necessarily dyspnea, depending on the scope of the thrombus and the degree of oxygenation defect. The hypoxemia is generally accompanied by hyperventilation, because affected animals will increase their respiratory minute volume to maintain oxygenation and consequently exhale more CO2. Because CO2 is highly soluble, PTE generally only results in impairment of oxygenation, rather than of ventilation.

Other salient aspects of the physical exam in a patient with PTE may note focal or diffuse crackles on thoracic auscultation. Animals may also develop a cough, cyanosis, or collapse. Cardiac auscultation is usually not notable for any specific finding; tachycardia may be present, as a result of hypoxemia, patient stress, or increased workload for the heart. If pulmonary arterial pressures remain chronically elevated due to PTE, the animal may develop signs of right-sided heart failure, which may be noticed on physical exam as ascites or pleural effusion. Some animals with significant acute increases in right ventricular pressure may develop decreased cardiac output due to a decreased left ventricular lumen size caused by a shift in the interventricular septum as the right heart expands (ventricular interdependence). If cardiac output drops, signs of cardiogenic shock such as prolonged capillary refill time, poor pulse quality, dull mentation, and low blood pressure may be noted on physical exam.

Laboratory Diagnostics

The laboratory diagnosis of PTE can be as generic as the physical exam findings, due to a general lack of specificity for the condition. As noted above, signs of SIRS (which includes a high [> 10%] circulating immature neutrophil [band] count and a total WBC count of less than 5000/μL or greater than 18000/μL) are likely to be diagnosed by complete blood count (CBC) using automated machines or by inspection of a blood smear. Platelet counts may be decreased, but mild to moderate thrombocytopenia is common with SIRS conditions as well, so is a nonspecific finding. Serum chemistry screening is of little use with the exception of assisting in the diagnosis of underlying conditions (e.g., protein-losing disease). Arterial blood gas analysis generally shows hypoxemia (PaO2 < 80 mm Hg at sea level) and hyperventilation (PaCO2 < 30 mm Hg). An increased alveolar-arterial oxygen gradient (A-a gradient) is a common finding amongst dogs with PTE.

Although most patients with PTE have identifiable triggers resulting in the formation of either thrombi or thromboemboli, these conditions are difficult to describe using routine coagulation testing. Unless there is a massive clot and significant consumption of coagulation factors, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are generally not prolonged (unless they become so as a result of the underlying or initiating disease), and a shortened PT or aPTT have not been correlated to a hypercoagulable state. Newer methodologies such as thromboelastography (TEG) may have utility in diagnosing hypercoagulable states in veterinary species, but no correlation between TEG parameters and thrombosis has been identified. D-dimers have been suggested as a general screening tool to indicate the presence of fibrinolysis (and hence prior clot formation) in veterinary patients. D-dimers are formed by the breakdown of fibrin molecules that have been crosslinked into a clot, and have been used in human patients to rule out PTE in patients with a clinical suspicion. Recent studies in canine patients have failed to support the use of d-dimers as a diagnostic test in veterinary medicine, identifying patients with PTE and low d-dimer concentrations as well as patients with increased d-dimers who did not have necropsy-confirmed PTE. A very low d-dimer count does make a diagnosis of PTE unlikely, however.

Survey radiography is frequently performed in patients with acute onset of dyspnea and is useful for ruling out other causes of hypoxemia such as aspiration pneumonia, or volume overload/pulmonary edema. Unfortunately, as with many tests in the context of PTE, pulmonary radiography is neither sensitive nor specific for the presence of PTE. Up to 25% of patients with PTE may have no radiographically apparent changes, while in others the pulmonary patterns are nonspecific. Pulmonary infiltrates (interstitial to alveolar pattern) are the most common pulmonary pattern seen and frequently localized to the caudodorsal lung field(s), although the pattern may be diffuse as well. The areas of pulmonary opacity generally have indistinct borders, as differentiated from neoplastic or infectious infiltrates. The lack of specific radiographic findings does inform clinical decisions, and it is wise, in any patient with an acute onset of dyspnea and normal thoracic radiographs, to suspect PTE.

Because a PTE will change the dynamics of the pulmonary circulation, investigation of the right side of the heart can give some clues as to the overall state of the pulmonary blood flow. A large PTE will result in the development of pulmonary hypertension (PH) because the same amount of blood is being pumped through less area (due to the clot). Pulmonary hypertension may be detected using echocardiography by observing high velocity regurgitation through the tricuspid valve during systole; as the right ventricle ejects against higher pulmonary pressure, some of the blood may be forced back into the right atrium if the tricuspid valve is not completely competent. Echocardiography can also describe increases in the end diastolic volume of the right ventricle that can be associated with PH. High velocity regurgitation through the pulmonic valve during diastole can also be indicative of PH. Other possible causes of PH should be considered as well.

Advanced Diagnostics

Although it is difficult to identify a gold standard diagnostic technique for antemortem diagnosis of PTE, computed-tomography (CT) angiography comes the closest at allowing practitioners to see clots in the pulmonary vasculature. CT-angiography requires a power injector to deliver contrast rapidly enough that the pulmonary vasculature is filled with contrast. Filling defects in the pulmonary vasculature indicate an interruption of blood flow, consistent with a clot or tumor. A recent report documents CT angiography performed in sedated patients for the diagnosis of PTE. Selective or non-selective pulmonary angiography (without the CT aspect) has also been used for diagnosis of PTE in veterinary species, but all of these techniques may not identify small thrombi. Pulmonary perfusion scanning using radiolabeled albumin is another option for documenting segmental interruptions in pulmonary perfusion caused by PTE. MRI may also be a sensitive imaging modality for the pulmonary vasculature, although at this point, few reports exist in the human literature regarding the ability of MRI to identify PTE.

Therapeutics

In the absence of a gold standard diagnostic test for PTE, the clinician frequently has to treat animals using the most appropriate diagnostics available, and in dyspneic patients, frequently there is strong motivation to initiate therapy on even a strong suspicion of PTE. The three goals of therapy are: treat the underlying condition (if the initiating hypercoagulability is not resolved, more PTEs may occur), prevent further clot formation (to limit the extent of the thrombus), and support normal function (this includes support for oxygenation and therapy for pulmonary hypertension). This will focus primarily on the second two categories.

Limiting further clot extension is best accomplished using anticoagulant drugs. Because it is unknown whether suspected PTE originated on the arterial or the venous side of circulation, anticoagulant therapy is frequently mixed, consisting of both antiplatelet drugs (indicated to prevent arterial thrombi) and anticoagulant drugs (indicated for venous thrombi). In general, thrombolytic agents (e.g., streptokinase, tissue plasminogen activator) are not recommended unless they can be delivered locally to the pulmonary circulation (via pulmonary artery catheter), as systemic administration can result in significant hemorrhage. In patients where the PTE results in significant cardiovascular instability, however, attempts to break down clots might be more strongly indicated. Continuous hemodynamic monitoring and access to blood products is recommended if thrombolysis is considered. Unfractionated heparin (UFH) inactivates coagulation factors IIa and Xa by complexing with antithrombin, is recommended to prevent extension of the existing clot. Unfractionated heparin can be administered as a constant rate infusion IV, or by subcutaneous injection three times daily. Absorption in dehydrated animals or in animals in shock may not be reliable, and the IV route is recommended. Low-molecular-weight heparins (LMWH) can also be used for this and may be associated with less hemorrhagic complications, although veterinary species may require more frequent dosing than in humans (up to four times daily). These anticoagulant drugs may be combined with antiplatelet drugs such as aspirin (in dogs) or clopidogrel (dogs and cats) to broaden the anticoagulant coverage. The combination of more than one anticoagulant drug may increase the chances for hemorrhage, although this aggressive therapy may be necessary to prevent clot extension. Warfarin is not a recommended anticoagulant in dogs or cats due to difficulties associated with monitoring and hemorrhage.

Patient support in the context of PTE consists of supplemental oxygen, administered either by oxygen cage, nasal cannulae, or by mechanical ventilator if severe. The patient's oxygenation can be monitored either by serial arterial blood-gas analysis or by pulse oximetry. To help to alleviate PH, selective vasodilators can be used. The preferred drug for this purpose is sildenafil, which is a phosphodiesterase 5 (PDE5) inhibitor which selectively dilates the pulmonary circulation and which can alleviate PH and clinical signs associated with PH. In dogs, doses of 1–2 mg/kg by mouth two to three times daily can improve clinical signs of PH due to nonspecific causes. Bronchodilation using drugs such as terbutaline or the methylxanthines (aminophylline/theophylline/caffeine) may improve oxygenation and pulmonary blood flow. The methylxanthines may have additional benefit of strengthening diaphragmatic contractions (helpful for patients with fatigue from dyspnea).

References

1.  Epstein SE, Hopper K, Mellema MS, Johnson LR. Diagnostic utility of D-dimer concentrations in dogs with pulmonary embolism. J Vet Intern Med. 2013;27(6):1646–1649.

2.  Goggs R, Chan DL, Benigni L, Hirst C, Kellett-Gregory L, Fuentes VL. Comparison of computed tomography pulmonary angiography and point-of-care tests for pulmonary thromboembolism diagnosis in dogs. J Small Anim Pract. 2014;55(4):190–197.

3.  Goggs R, Benigni L, Fuentes VL, Chan DL. Pulmonary thromboembolism. J Vet Emerg Crit Care. 2009;19(1):30–52.

4.  Johnson LR, Lappin MR, Baker DC. Pulmonary thromboembolism in 29 dogs: 1985–1995. J Vet Intern Med. 1999;13(4):338–345.

5.  Norris CR, Griffey SM, Samii VF. Pulmonary thromboembolism in cats: 29 cases (1987–1997). J Am Vet Med Assoc. 1999;215(11):1650–1654.

  

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


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