Overview of Thrombosis, Embolism, and Aneurysm

Acute onset of dyspnea is often associated with pulmonary thromboembolism, although some animals may develop hemoptysis; the latter is most associated with pulmonary arterial disease such as that resulting from heartworm infection (see Heartworm Disease). Septic cardiac thrombi are associated with endocarditis; nonseptic cardiac thrombi are associated with myocardial disease (most commonly in cats), or rarely with cardiac or pulmonary neoplasia. Infarction within the genitourinary system can present with hematuria, abdominal pain, and splinting. Splanchnic infarction usually results in abdominal pain, with vomiting seen in small animals.

Aneurysms cause no clinical signs unless hemorrhage occurs or an associated thrombus develops. Except for dissecting aneurysm in turkeys (see Dissecting Aneurysm in Turkeys), aortic or sinus of Valsalva rupture in horses with sudden death, hemorrhage associated with guttural pouch mycosis in horses (see Guttural Pouch Mycosis), or pulmonary arterial aneurysm in cattle, spontaneous aneurysmal hemorrhage is rare, and clinical signs usually relate to thrombosis. An aneurysm of the abdominal aorta and its branches in large animals may be palpated rectally as a fixed firm swelling with a rough, irregular surface that pulsates with the heart beat. Fremitus may be present. In excess thrombus formation, the pulse may be delayed distally and have a slow rate of rise in pressure, or it may be absent. Other helpful diagnostic modalities include ultrasonography and angiography.

Treatment of endocarditis includes longterm antibiotics (several weeks to months) and in some cases intermittent administration of antipyretic, anti-inflammatory, or antithrombotic drugs. Antibiotic choice should be based on culture and sensitivity results obtained from blood cultures. The prognosis for recovery is poor to guarded at best, and persistent debilitating cardiac disease is common even if the active infection can be controlled.

Treatment of venous thrombosis in horses and cattle is usually limited to supportive care, including hydrotherapy of accessible veins, anti-inflammatory agents, and systemic antimicrobials to control secondary sepsis. Surgical removal of thrombosed jugular veins has been performed successfully in horses, but unless both veins are severely affected, inflammation will resolve with medical treatment, and formation of collaterals will usually result in sufficient venous circulation. Thrombosis of the cranial or caudal vena cava results in more severe clinical signs and requires more aggressive therapy, which could include thrombolytic drugs and/or intravascular/surgical removal followed by aggressive anticoagulation. Response to anticoagulation therapy alone is generally inadequate.

Measures to minimize trauma to, and bacterial contamination of, veins remain the best means to prevent venous thrombosis. Extreme care should be taken when placing catheters or giving IV injections. The effectiveness of antiplatelet therapy (aspirin 0.5–5 mg/kg/day or clopidogrel 1–3 mg/kg/day), anticoagulant therapy (unfractionated heparin, 40–80 IU/kg, SC, bid-tid, or low-molecular-weight heparin [enoxaparin at 1 mg/kg, SC, bid, or dalteparin at 150–200 IU, SC, bid]) to facilitate intrinsic thrombus resolution is unknown but should at least prevent further thrombus formation.

In horses, aneurysms due to Strongylus vulgaris rarely rupture; the chief concern is thromboembolism of intestinal vasculature with subsequent colic. Generally, the arterial wall is sufficiently involved that thrombus removal is impractical. Antibacterial treatment and anthelmintics to kill the migrating larvae are of considerable value. The most rational approach to cranial mesenteric and aortic-iliac thrombosis in horses is prevention and control of strongylosis (see Large Strongyles in Horses).

Acute management of aortic emboli in cats can be approached in several ways. More than 50% of cats that survive a cardioembolic event will regain some function of the hindlimbs over 4–6 wk with conservative medical therapy. More aggressive therapy aimed at dissolution of the thrombus through thrombolytic drugs or rheolytic intervention may result in improved short-term functional outcome, but survival is no better than that from conservative therapy and, in some cases, may actually be worse. Conservative therapy usually consists of initial pain management (hydromorphone, 0.1 mg/kg, SC, IM, or IV every 4–6 hr; or buprenorphine HCl, 0.01–0.03 mg/kg, SC, IM, or IV, every 6–8 hr) and anticoagulant therapy (heparin, 250–300 U/kg with first dose IV if animal is in shock, followed by administration SC, tid-qid; or dalteparin 150–170 IU/kg, SC, bid-tid). The activated partial thromboplastin time can be used to monitor heparin therapy, with a goal of 1.5–1.7 × the pretreatment value. The use of antiplatelet therapy (clopidogrel, 75 mg, PO, once on admission, then 18.75 mg/day, PO) should be considered to further reduce the thrombotic potential; in addition, it may have a beneficial effect on collateral circulation. Thrombolytic therapy, although not routinely recommended, could include streptokinase (90,000 IU/cat, IV over 20 min, followed by 45,000 IU as a continuous infusion for 2–24 hr), recombinant tissue-type plasminogen activator (tPA, 0.25–1 mg/kg/hr, IV, up to a total dose of 1–10 mg/kg), or urokinase (4,400 IU/kg, IV over 10 min, then 4,400 IU/kg/hr for 12 hr). These drugs promote thrombolysis by converting plasminogen to plasmin, which subsequently breaks down fibrin strands. Streptokinase is considered a nonspecific activator of plasminogen, because it activates circulating fibrin as well as fibrin contained within thrombi/emboli, which can lead to a systemic proteolytic state and bleeding. Although urokinase and tPA are more fibrin-specific than streptokinase, bleeding can also be seen with these agents. Moreover, all of these agents are prohibitively expensive and difficult to obtain. The use of antiplatelet agents such as clopidogrel has been shown to hasten thrombus dissolution and reduce acute arterial rethrombosis in experimental studies and human clinical trials, respectively. However, an in vitro feline study did not identify a significant difference in thrombolysis rates. It is not known whether these results can be applied to the natural clinical disease. Thrombolytic therapy appears to have the best response in cats with acute onset of clinical signs and incomplete or unilateral infarction. However, these cats may respond similarly well to conservative therapy, without the risk of reperfusion injury or expense of these agents. Although a severe complete infarction is more likely to develop reperfusion injury with thrombolytic therapy, these cats are also less likely to recover with conservative therapy alone. The reported survival rates for initial aortic infarction events are similar whether conservative (35%–39%) or thrombolytic (33%) therapy is used. Cats with single limb infarction do much better (68%–93%) than cats with bilateral hindlimb infarction (15%–36%) regardless of therapy used. Aspirin (25 mg/kg, PO, every 48–72 hr; or 5 mg/cat, PO, every 48–72 hr) has historically been the most widely used preventive therapy for cardioembolic disease in cats. Although aspirin appears relatively safe in cats (up to 20% GI adverse effects) and is inexpensive unless compounding is done, the antiplatelet efficacy of aspirin in cats has been called into question, and currently there is no evidence that aspirin prevents first-time or recurrent cardioembolism. Clopidogrel may be a more effective antiplatelet drug in this species.

Clopidogrel (18.75 mg/cat/day, PO) inhibits both primary and secondary platelet aggregation. These effects are more potent than those induced by aspirin. Clopidogrel also impairs the platelet release reaction, decreasing the release of pro-aggregating and vasoconstrictive agents. Adverse effects are rare but can include vomiting in up to 10% of cats; this appears to be ameliorated by giving the drug with food. A combination protocol of aspirin and clopidogrel has been used previously. Although this protocol has not been studied objectively, it seems to be well tolerated despite a theoretical increased risk of bleeding. A multicenter, randomized, prospective study revealed that clopidogrel was associated with a significantly prolonged survival time compared with aspirin in cats that presented with cardiogenic arterial thromboembolism. The time to recurrence of arterial thromboembolism or death in the clopidogrel group was >365 days versus 192 days in the aspirin group.

Warfarin (0.25–0.5 mg/day/cat, PO) has also been used for prevention of primary or secondary cardioemboli. Dosing is adjusted to prolong the prothrombin time to 1.5–1.7 × the pretreatment value. Because warfarin decreases the anticoagulant proteins C and S before reduction in factors II, VII, IX, and X, joint treatment with heparin is recommended for the first 5–7 days of warfarin therapy. Problems with warfarin therapy include large inter- and intra-individual variability, difficult dosing because of tablet size, and bleeding, including fatal hemorrhage. Because of these limitations and lack of objective clinical data demonstrating efficacy, warfarin is not a first-line antithrombotic for cardioembolic prevention in cats.

The low-molecular-weight heparins (LMWHs) are smaller in size than unfractionated heparin but maintain the ability to inhibit factor Xa, with a greatly reduced inhibition of IIa. The reduced anti-IIa activity translates into a negligible effect on the activated partial thromboplastin time, but measurement of anti-Xa activity can be used to monitor dosing efficacy. Enoxaparin (1–1.5 mg/kg, SC, once or twice daily) and dalteparin (150–170 IU/kg, SC, bid-tid ) have both been used in cats. These drugs have been well tolerated with only rare bleeding reported, but objective clinical studies evaluating their efficacy have not been performed. These agents have been frequently combined with clopidogrel in an attempt to provide a more complete antithrombotic effect. This protocol appears to be well tolerated, although some minor bleeding has been seen. Reported recurrence rates for cats receiving some form of antithrombotic prevention are 17%–75%, with a 1-yr recurrence rate of 25%–50%. Long-term median survival times after an initial cardioembolic event have ranged from 51–376 days. Although these numbers may seem daunting, many of these cats can do well. If owners are willing to treat, they should be encouraged to give cats 24–72 hr of supportive care before deciding on euthanasia, unless severe infarction, severe CHF, or reperfusion injury are present.

Arterial thrombosis in dogs is most commonly associated with protein-losing nephropathy and neoplasia, though idiopathic thrombosis is also seen. There is very little clinical experience with arterial thromboembolism in dogs, but thrombolytic therapy using streptokinase, urokinase, and tPA have been reported in isolated cases with variable success. There are no clinical trials evaluating the efficacy of antithrombotic therapy for prevention of arterial thromboembolism in dogs, but dosing protocols for aspirin (0.5–5 mg/kg, PO, once or twice daily), clopidogrel (1–3 mg/kg/day, PO), warfarin (0.1–0.22 mg/kg/day, PO), dalteparin (150 IU/kg, SC,bid-tid), enoxaparin (1–1.5 mg/kg, SC, once or twice daily), and rivaroxaban (0.5–1 mg/kg/day, PO) have been reported.

Treatment recommendations for pulmonary embolism in dogs are similar to those for cardioembolic disease in cats. Aspirin (0.5 mg/kg/day, PO) has improved survival in dogs with immune-mediated hemolytic anemia when added to standard immunosuppressive therapy.