A thrombus is an aggregation of platelets and fibrin that may form when certain conditions exist. Historically, these have included some combination of blood stasis (reduced flow), endothelial injury, and an existing hypercoagulable state. A thrombus can develop in a cardiac chamber and be attached (mural) or less likely free-floating (ball), or within a blood vessel where it can cause a partial or complete obstruction. The thrombus can be classified based on its location and the clinical signs it produces (eg, jugular venous thrombosis in large animals associated with prolonged venous catheterization, pulmonary arterial thrombosis associated with heartworm disease in dogs).
All or part of a thrombus may break off and be carried through the bloodstream as an embolus that lodges distally at a point where the size of the embolus exceeds the vascular diameter. Poor injection or catheterization techniques along with inferior catheter material can result in vascular thrombosis. However, clinically significant vascular thrombosis is more commonly encountered in patients with underlying diseases that result in a hypercoagulable state, such as systemic inflammation, endotoxemia, or antithrombin deficiency. If left untreated or uncontrolled, systemic thrombotic conditions can result in hemorrhagic diathesis or disseminated intravascular coagulation (DIC), a life-threatening disorder of hemostasis with deposition of microthrombi and consumption of coagulation factors that result in concurrent hemorrhage.
Thrombus formation can occur in both large and small arteries and veins. Horses and cattle are more likely to develop venous thrombi, while in dogs and cats, arterial thrombi appear to be more clinically important. Arterial thrombosis or embolization results in ischemia of the tissues supplied by the infarcted vessel. Emboli from infective conditions such as endocarditis are classified as septic (bacteria contained in the embolus). Septic emboli can result in bacterial dissemination and infection of distal capillary beds. While arterial thromboembolism is clinically important in domestic animal species, primary arterial occlusive disease (arterial thrombosis) is exceedingly rare. Thrombosis of limb arteries causing lameness and gangrene has been reported in adult horses and foals. This occurs secondary to hypercoagulation and systemic inflammation (eg, septicemia in foals).
An aneurysm is a vascular dilation caused by weakening of the tunica media of blood vessels. The weakness might be primary or caused by degenerative or inflammatory changes progressing from an intimal lesion. False aneurysms are caused by damage to all 3 layers of the arterial wall and result in extravascular accumulation of blood. Disruption of the endothelium associated with a true aneurysm can cause formation of a thrombus with subsequent embolization; thus, aneurysms, thrombi, and emboli may be recognized simultaneously. However, aneurysms are rare to uncommon in domestic animal species.
Clinical Findings and Diagnosis
Acute onset of dyspnea is often associated with pulmonary thrombosis/embolism, while some patients may develop hemoptysis; the latter is most associated with pulmonary arterial disease such as heartworm infection (see Heartworm Disease). Septic cardiac thrombi are associated with endocarditis; nonseptic cardiac thrombi are associated with myocardial disease, most commonly in cats. 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 Respiratory Diseases of Horses: 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.
Thrombosis of the caudal vena cava occurs in association with hepatic abscessation and vascular erosion of the abscess. Embolic pneumonia with secondary pulmonary abscessation, thromboembolism, and pulmonary arterial aneurysms are common sequelae. Affected animals may present with coughing, tachypnea, dyspnea, and abnormal lung sounds. Aneurysms in pulmonary arteries that contain septic emboli may rupture and cause intrapulmonary hemorrhage, or pulmonary abscesses may erode into bronchi and result in hemorrhage into the airways. The sequelae to these disorders may include epistaxis, hemoptysis, and death. Clinical pathologic data usually support a diagnosis of vena caval syndrome, but are not specific. Elevated fibrinogen, anemia, and in cases with an active abscess process, elevated liver enzymes may be seen. Pulmonary arterial embolism and embolic pneumonia are also frequent complications of tricuspid or pulmonic valvular endocarditis in cattle, but aneurysms rarely develop. Intermittent fever and anorexia due to bacteremia at times of embolic showering are often present, and the animal typically has a history of a chronic active infection (eg, foot abscess, reticular abscess). Most cases of right heart endocarditis in cattle are bacterial and are commonly associated with a cardiac murmur, with a point of maximal intensity over the tricuspid valve. Echocardiography and blood cultures are useful in identifying right heart vegetative lesions and the causative bacterial agent, respectively. Thrombosis of the cranial vena cava in cattle produces bilateral jugular engorgement; edema of the head, submandibular area, and brisket; and pronounced oral mucosal hyperemia. However, similar clinical signs are seen with right-sided congestive heart failure, which could be a sequela of tricuspid valve endocarditis. Significant lingual, pharyngeal, or laryngeal edema may develop and result in dysphagia and dyspnea.
Cranial vena cava thrombosis may result from extension of a jugular thrombus. Jugular vein thrombosis in horses is often associated with phlebitis following catheterization or extravasation of injected material and will cause swelling, heat, and pain of the affected area. Bilateral jugular vein thrombosis can cause edema and swelling of the head and neck, mimicking cranial caval thrombosis. Ultrasonographic examination of the affected vein can determine the extent of the thrombus and degree of occlusion. Doppler ultrasound is a more sophisticated method to determine blood flow and vessel patency. If a catheter-associated thrombophlebitis is suspected, blood culture and catheter-tip culture can be performed. Horses with colitis and other GI disorders are at increased risk of developing jugular thrombosis; ruminants are much less prone to jugular thrombosis than horses.
Migrating Strongylus vulgaris larvae (see Gastrointestinal Parasites of Horses: Large Strongyles in Horses) can cause arteritis with development of thrombi and verminous aneurysms in the aorta, cranial mesenteric, or iliac artery. In some horses, emboli develop and partially or completely occlude terminal branches of the mesenteric arteries. Affected intestinal segments show changes ranging from ischemia to hemorrhagic infarction. Clinical signs are those of colic, constipation, or diarrhea. The colic usually is recurrent, and attacks may be severe and prolonged. The recent introductions of newer anthelmintics and improved therapeutic regimens have resulted in verminous arteritis becoming an uncommon disorder.
Thrombosis with or without aneurysm of the terminal aorta and proximal iliac arteries produces a characteristic syndrome in horses. Although associated with parasitism, other causes are possible. Affected horses appear normal at rest; however, graded exercise results in an increasing severity of weakness of the hindlimbs with unilateral or bilateral lameness, muscle tremor, and sweating. Severely affected animals may show signs of exercise intolerance, weakness, and atypical lameness that resolves after a short rest. Subnormal temperature of the affected limbs may be detectable, along with decreased or absent arterial pulsations and delayed and diminished capillary filling. Rectal palpation may show variation in pulse amplitude of the internal or external iliac arteries (or both) and asymmetric vasculature. In severe cases, the hindquarter muscles atrophy, and lameness may become evident with only mild exercise. Complete embolic or thrombotic occlusion of the distal aorta may produce acute bilateral hindlimb paralysis and recumbency in horses. Affected animals are anxious, appear painful, and rapidly go into shock. The hindlimbs are cold, and rectal palpation reveals an absence of pulsation in either iliac artery. Transrectal ultrasound can be helpful in determining bloodflow in the aorta and iliac arteries.
Dogs and Cats
In dogs, and less commonly in cats, heartworm disease may lead to pulmonary arterial thrombosis that commonly results in dyspnea, and tachypnea. Affected animals are often reportedly normal until sudden onset of coughing, respiratory distress, or sudden death. Chest radiographs may be normal or show underperfusion of the affected lung lobe, interstitial to alveolar infiltrates, or pleural effusion. Arterial blood-gas analysis typically demonstrates hypoxemia with a normal or low level of CO2 in the blood. Ventilation/perfusion scanning with radionuclide-labeled macroaggregated albumin and gases or pulmonary angiography can confirm the diagnosis. Other diseases associated with pulmonary embolism in dogs and cats include glomerulonephropathy, hyperadrenocorticism, immune-mediated hemolytic anemia, and neoplasia.
In cats, cardiogenic embolism (arterial thromboembolism) is a devastating complication of cardiomyopathies, including hypertrophic, dilated, restrictive, and unclassified forms (see Heart Disease and Heart Failure: Cardiomyopathies). Intracavitary thrombi typically form in the dilated left atrium where stagnant flow exists or, less commonly, within abnormal areas in the left ventricle. While the condition is poorly understood, these cats most likely possess some underlying hypercoagulable disorder, because all cats with cardiomyopathy do not develop cardiogenic embolism. Portions of these intracavitary thrombi can break off and form emboli that infarct arterial branches, most commonly the aortic trifurcation (saddle emboli). Clinical signs include pain and paresis or lower motor neuron paralysis of the rear limbs. The arterial pulse (either femoral or pedal) is reduced to absent in the affected limbs, which are cooler than normal and have firm, swollen muscle bellies. These clinical signs can be unilateral, bilateral, or bilateral but asymmetric. Emboli may also infarct other arterial beds, including the right forelimb, renal, splanchnic, cerebral, and myocardial. Decompensation of the underlying myocardial disease is not uncommon and may result in congestive heart failure (pulmonary edema or pleural effusion). Ischemia and necrosis of infarcted pelvic limb musculature results in elevation of serum CK and AST. Echocardiography is the imaging modality of choice to assess cardiac structure, function, and presence of an intracardiac thrombus. Nuclear perfusion studies, utilizing the unbound radioisotope99m Tc can give sensitive information regarding the degree of perfusion of the pelvic limbs and areas that may require amputation.
Treatment of endocarditis includes longterm antibiotics (several weeks) and in some cases intermittent administration of antipyretic and anti-inflammatory 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 or intravascular/surgical removal. Response to chronic oral therapy is generally inadequate, resulting in a poor prognosis.
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, 100 mg/kg, sid), anticoagulant therapy (unfractionated heparin, 40–80 IU/kg, SC, bid-tid), and low-molecular-weight heparin 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 Gastrointestinal Parasites of Horses: Large Strongyles in Horses).
Acute management of aortic emboli in cats can be approached in several ways. Over 50% of cats that survive a cardioembolic event will regain some function of the pelvic limbs over 4–6 wk if no specific therapy is instituted. More aggressive therapy aimed at dissolution of the thrombus through thrombolytic drugs or rheolytic intervention results in improved functional outcome, but survival is no better than that from conservative therapy. Conservative therapy usually consists of pain management (hydromorphone, 0.08–0.3 mg/kg SC, IM, or IV every 2–6 hr; or buprenorphine HCl, 0.005–0.01 mg/kg SC, IM, or IV, bid-qid) and anticoagulant therapy (heparin, 250–375 IU/kg IV, then 150–250 IU/kg, SC, tid-qid). 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, PO, sid) should be considered to further reduce the thrombotic potential; in addition, it may have a beneficial effect on collateral circulation. Thrombolytic therapy 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. While urokinase and tPA are more fibrin-specific than streptokinase, bleeding can also be seen with these agents. 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 if these results can be applied to the natural clinical disease. Thrombolytic therapy appears to have the best response in cats with incomplete or unilateral infarction. However, these cats may respond well to conservative therapy without the risk of reperfusion injury or expense of these agents. While a severe complete infarction is more likely to develop reperfusion injury with thrombolytic therapy, these cats are very unlikely to recover with conservative therapy alone, so this may be the best option for survival. The reported survival rates for initial aortic infarction events are similar whether conservative (35–39%) or thrombolytic (33%) therapy is used. Cats with single pelvic limb infarction do much better (68–93%) than cats with bilateral pelvic limb 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. It irreversibly inhibits platelet aggregation through the prevention of thromboxane A2 production. However, currently there is no evidence that aspirin (or any antithrombotic drug) prevents first-time or recurrent cardioembolism. Aspirin appears relatively safe in cats (up to 20% GI adverse effects) and is inexpensive unless compounding is done.
Clopidogrel (18.75 mg/cat, PO, sid) 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. As with aspirin, there is no objective clinical evidence that clopidogrel prevents primary or secondary cardioembolic events. A combination protocol of aspirin and clopidogrel has been used previously. While this protocol has not been studied objectively, it seems to be well tolerated despite a theoretical increased risk of bleeding.
Warfarin (0.25–0.5 mg/cat, PO, sid) has also been used for prevention of primary or secondary cardioemboli. Dosing is adjusted to prolong the prothrombin time to 1.5–1.7× 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 due to tablet size, and bleeding including fatal hemorrhage. Because of these limitations and lack of objective clinical data demonstrating efficacy, warfarin is usually a second-choice antithrombotic for cardioembolic prevention in cats.
The low-molecular-weight heparins (LMWH) 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, so measurement of anti-Xa activity can be used. Enoxaparin (1.0–1.5 mg/kg, SC, sid-bid) and dalteparin (100 IU/kg, SC, sid-bid) have 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 infrequently combined with aspirin or clopidogrel in an attempt for 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%. Longterm median survival times following an initial cardioembolic event have ranged from 51–376 days. While these numbers may seem daunting, many of these cats can do well. Euthanasia during the acute event should be limited to those with severe infarction, and only after 48–72 hr of therapy in the absence of severe CHF or reperfusion injury.
Arterial thromboembolism is most commonly associated with protein-losing nephropathy and neoplasia in dogs. 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 the prevention of arterial thromboembolism in dogs, but dosing protocols for aspirin (0.5 mg/kg, PO, bid), clopidogrel (1–3 mg/kg, PO, sid), warfarin (0.22 mg/kg, PO, sid), dalteparin (100 IU/kg, SC, sid-bid), and enoxaparin (1.0–1.5 mg/kg, SC, sid-bid) are reported.
Treatment recommendations for pulmonary embolism in dogs are similar to those for cardioembolic disease in cats. However, thrombolytic therapy has not been reported in dogs. Aspirin (0.5 mg/kg, PO, sid) has improved survival in dogs with immune-mediated hemolytic anemia when added to standard immunosuppressive therapy.
Last full review/revision July 2011 by Daniel F. Hogan, DVM, DACVIM (Cardiology)