Structural Disorders

Pulmonary Thromboembolism

Pathophysiology

Systemic diseases that result in stasis of blood flow, hypercoagulability, and disruption of the endothelial layer of the vascular bed can result in the secondary complication of pulmonary thromboembolism (PTE). In dogs, immune-mediated hemolytic anemia, sepsis, neoplasia, amyloidosis, hyperadrenocorticism, and dilated cardiomyopathy are associated with increased risk for PTE, while neoplasia and cardiomyopathy are found most often in cats with PTE (Johnson et al. 1999b, Norris et al. 1999)

PTE results in multiple pathophysiologic events that affect gas exchange. Physical obstruction of large pulmonary arteries by clot material increases intravascular pressure, and release of clot-associated vasoactive factors (e.g., thromboxane) causes reactive pulmonary vasoconstriction. Elaboration of humoral mediators (e.g., serotonin, histamine, calcium, and growth factors) from platelets results in bronchoconstriction and increased airway resistance. Surfactant function is altered leading to loss of elastic recoil and atelectasis, decreased pulmonary compliance, and increased right-to-left shunting. Alveolar dead space is increased because of the presence of nonperfused lung regions, and this leads to increased work of breathing.

History and signalment

PTE is generally a disorder of older animals, and history and clinical signs reflect the underlying disease process. Acute onset of respiratory distress and tachypnea in any seriously ill animal should trigger suspicion for PTE. Recent trauma or surgery might also lead to PTE.

Physical examination

Animals with PTE often display relentless tachypnea and breathlessness that is refractory to supplemental oxygen administration. Harsh lung sounds or loud bronchovesicular sounds can be detected; however, crackles or wheezes are less common. Physical examination abnormalities usually reflect the underlying disease process. For example, pale mucous membranes are present in animals with immune-mediated hemolytic anemia, a heart murmur or gallop in the patient with cardiac disease, or a pot-bellied appearance in the dog with Cushing’s disease.

Diagnostic findings

Diagnostic testing is directed at determining the underlying cause for embolization and assessing the severity of gas exchange abnormalities. Thoracic radiographs can be relatively unremarkable (Figure 8.1); however, a variety of pulmonary infiltrates have been reported in dogs with PTE. Cats may be more likely to exhibit pulmonary vascular abnormalities such as uneven distribution of perfusion or blunted pulmonary vessels (Norris et al. 1999), and this might facilitate early diagnosis of PTE. A coagulation panel is generally indicated in the work-up of suspected PTE to assess the intrinsic pathway (APTT, ACT), the extrinsic pathway (OSPT), and fibrin degradation products (FDPs) or D-dimer (see Figure 7.9). Unfortunately, assay for D-dimer, a breakdown product of cross-linked fibrin, has not proven sensitive or specific in documentation of PTE. Thromboelastography, a technique that can identify hypo- and hypercoagulable states by assessing the speed, efficiency, and strength of clot formation, may prove useful in both the diagnosis and management of patients at risk for PTE.

Figure 8.1. Dorsoventral radiograph from a dog documented to have a pulmonary embolus in the lobar artery to the right caudal lung lobe. Note the lack of pulmonary infiltrates, pleural effusion, or vascular abnormalities.

Figure 8.2. Perfusion scan from the dog depicted in Figure 8.1 indicates a lack of perfusion in the right caudal lung lobe, consistent with major pulmonary embolus affecting the blood supply to that lung lobe.

Confirmation of embolization is difficult and requires perfusion scanning with 99-technetium-labeled macroaggregated albumin (Figure 8.2), ventilation/perfusion scanning, or computed tomography (CT) angiography. Perfusion scanning can be a valuable clinical tool because it can be done in the awake animal. This technique has documented that pulmonary embolization is common in dogs after cemented total hip replacement (Liska and Poteet 2003); however, this technique has not been evaluated for use in patients with cardiopulmonary disease and other risk factors for PTE because of the need for anesthesia to complete the scan. Echocardiography might be helpful in increasing suspicion for the diagnosis, since a clot may be visible in the right atrium, or indirect evidence of right ventricular overload might be seen such as right ventricular dilation, flattening of the right ventricular septum, or pulmonary hypertension.

Treatment

Control of the primary disease process is essential in managing PTE. Oxygen therapy is recommended for animals with PTE, although the respiratory pattern may not improve dramatically because of alterations in central respiratory control. Animals that do not have intrapulmonary shunting will show improved hemoglobin saturation with oxygen while on supplementation; however, not all dogs with PTE are oxygen responsive (Johnson et al. 1999b).

Medical therapy for both treatment and prevention of PTE is aimed at limiting further deposition of fibrin on existing clots. Heparin bound to antithrombin inactivates factors (thrombin factor (IIa), factors Xa, IXa, XIa, and XIIa) and prevents further accumulation of fibrin on a clot. Subcutaneous heparin (200–300 U/kg SQ BID–TID) is administered to prolong the APTT two to three times the normal value. In most hospitals, the use of heparin has been supplanted by low-molecular-weight heparins (LMWH). Examples of LMWH agents include enoxaparin (Lovenox^®) and dalteparin (Fragmin^®). This class of drug acts similarly to heparin in inhibiting further clot formation but has greater inhibition of factor X versus factor II, and therefore does not prolong the APTT. Experimental studies in dogs have revealed improved antithrombotic efficacy of LMWH over unfractionated heparin. In cats, LMWH given at standard doses (enoxaparin at 1 mg/kg SQ BID) resulted in plasma levels that approach the human therapeutic range 4 hours after dosing, while administration of dalteparin (100 IU/kg BID) resulted in less predictable levels (Alwood et al. 2007, Vargo et al. 2009). Also, enoxaparin was rapidly cleared, suggesting that more frequent administration may be required.

Antiplatelet therapy may also reduce the risk of clotting. A low dose of aspirin is used to inhibit cyclooxygenase activity without reducing endothelial cell production of prostacyclin. Although the precise dosage is not certain in veterinary species, 1–2 mg/kg/day in the dog appears to limit platelet aggregation. It is difficult to achieve this small dose in the cat, and because of its prolonged half-life, aspirin is dosed every 2–3 days. Aspirin therapy can be used concurrently with other drugs to decrease platelet aggregability. A newer class of drugs (thienopyridine class) being used to inhibit platelet function acts at the glycoprotein IIb/IIIa receptor and decreases aggregation as well as fibrin cross-linkage. One such drug, clopidogrel (Plavix^®), has been shown to be safe and effective at inhibiting platelets in healthy cats at dosages of 18.75 to 75 mg once daily (Hogan et al. 2004), and various experimental studies in dogs (2–4 mg/kg/day) have shown that it reduces clotting. Use of these drugs in clinical disease is under investigation.

With increasing certainty of the diagnosis of PTE or worsening condition of the patient, more aggressive therapy with fibrinolytic agents can be considered (tissue plasminogen activator, streptokinase). The efficacy of this therapy has not been established in animals with PTE, and in human medicine, fibrinolytic therapy is reserved for patients with hemodynamic instability.

Prognosis

Development of PTE is associated with a guarded prognosis, and mortality is high. Because of the poor success in treatment of PTE, prophylactic anticoagulant therapy should be considered in animals with diseases that have been shown to predispose to the condition. Low-dose aspirin is advised for platelet inhibition. Various doses of heparin have been recommended for prophylaxis: 10 U/kg SQ TID (mini-dose regimen) or 60–100 U/kg SQ BID–TID (low-dose regimen). These dosages should not prolong APTT. LMWH are more costly but can also be used as prophylaxis against embolization. Monitoring thromboelastography and performing an antifactor Xa assay (Cornell University) can be used to determine the dose that approximates the known therapeutic range in humans.

Infectious Disorders

Figure 8.3. Left lateral (a) and dorsoventral (b) radiographs from an 8-year-old FS Shepherd mix dog with stage 3 heartworm disease. There is severe enlargement of pulmonary arteries, with a bulge at the region of the main pulmonary artery on the dorsoventral projection and rounding of the cranial aspect of the heart on the lateral projection consistent with right-sided cardiomegaly. Diffuse pulmonary infiltrates are noted along with mild enlargement of the caudal vena cava and liver. (Courtesy of Dr. Adonia Hsu, University of California, Davis.)

Radiographic findings in canine heartworm disease vary depending on the severity of disease. Pulmonary arteries become progressively enlarged, blunted, and tortuous, parenchymal infiltrates progress, and right ventricular enlargement develops (Figure 8.3). Echocardiography detects the walls of the heartworm as parallel lines (Figure 8.4) and can demonstrate signs of right ventricular overload including right ventricular dilatation, tricuspid regurgitation, and pulmonary hypertension.

Treatment

Prior to adulticidal treatment, the severity of disease should be staged and clinical signs stabilized as indicated. In addition, owners should be cautioned about the possibility of embolic disease and should understand the need for cage confinement for 1–2 months to limit the occurrence of this complication. Monthly preventive medication is continued in dogs with occult infection. If microfilaria are present, the initial dose of preventive medication should be given to the dog while hospitalized to monitor for adverse effects.

Melarsomine dihydrochloride is the approved adulticidal treatment of canine heartworm disease. The manufacturer provides the following recommendations for treatment based on the severity of disease (although the American Heartworm Society and many clinicians prefer to treat all dogs with the split dose protocol). Class 1 dogs are mildly affected with few clinical signs and normal radiographs and laboratory findings. Class 2 dogs are moderately affected with cough or respiratory difficulty, have right heart enlargement on radiographs, and have abnormal laboratory values such as anemia or elevated liver enzymes. Dogs in these groups are given two deep intramuscular injections of melarsomine (2.5 mg/kg) between the third and fifth lumbar vertebrae on alternate sides of the spine separated by 24 hours. Dogs are kept confined and monitored by respiratory rate and effort for adverse effects. For dogs with persistent clinical signs and positive antigen test, a second treatment can be given in 4 months. Class 3 dogs are severely affected with signs of right heart failure, severe radiographic abnormalities, and marked laboratory abnormalities. These dogs appear to be at higher risk for embolization and should be stabilized prior to treatment with oxygen, diuretics, and angiotensin-converting enzyme inhibitors. Use of anticoagulants is controversial. In these dogs, the split-dose protocol is recommended by using a single deep intramuscular injection of melarsomine followed one month later by two injections given 24 hours apart. Restriction of physical activity is essential for 4–6 weeks after treatment. Class 4 dogs are those with caval syndrome, and melarsomine is not recommended for these dogs. Stabilization and physical removal of worms are required.

Figure 8.4. Echocardiographic image from the dog depicted in Figure 8.3 demonstrates parallel lines in the right pulmonary artery (RPA) characteristic of heartworm infection. AO, aorta; RV, right ventricle; MPA, main pulmonary artery (Courtesy of Dr. Adonia Hsu, University of California, Davis.)

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