Thrombosis, Embolism, and Aneurysm: Introduction

A thrombus is an aggregation of blood factors that may form when the blood flow in the arteries or veins is impeded. It frequently causes vascular obstruction at its site of origin. The thrombus can be classified based on its location and the syndrome it produces (eg, 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 of narrowing. Embolization can also occur when foreign material (eg, bacteria, air, fat, catheter piece) is carried into the bloodstream. Thrombi and emboli can be septic or nonseptic. Poor injection or catheterization techniques and inferior catheter material can all result in vascular thrombosis. However, life-threatening vascular thrombosis is more commonly encountered in patients with underlying disease states that result in coagulopathies, such as systemic inflammation, or endotoxemia. The underlying mechanism shared by all disease processes that potentiate thrombus formation is endothelial cell injury with concomitant platelet and coagulation factor activation. If left untreated or uncontrolled, these hypercoagulable conditions can result in hemorrhagic diathesis and/or disseminated intravascular coagulation (DIC), a life-threatening disorder of hemostasis with deposition of microthrombi with concurrent hemorrhage.

Thrombus formation can occur in both large and small arteries and veins. Horses and cattle are more likely to develop thrombi affecting the postcapillary circulation, while in dogs and cats arterial thrombi are more clinically important. Nonseptic arterial thrombosis and downstream embolization generally result in ischemia of affected tissues. In addition, septic emboli can result in bacterial dissemination and localized infection. Primary arterial occlusive events affecting the heart or CNS are uncommon in animals. Systemic hypercoagulation with thrombus formation can result in primary coronary or cerebrovascular arterial occlusion, or emboli can lodge in the vasculature of the CNS or myocardium. The underlying pathophysiologic mechanisms of arterial occlusive events affecting these organ systems in animals differ from those in humans, where atherosclerotic lesions commonly lead to thrombus formation and arterial occlusion. Atherosclerotic lesions as seen in humans are not well described in animals. Thrombosis of limb arteries causing lameness and gangrene has been reported in adult horses and foals. Similar to the pathogenesis of arterial occlusion within the CNS and myocardium, thrombosis of limb arteries 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.

Clinical Findings and Diagnosis:

Acute onset of dyspnea is often associated with pulmonary thrombosis, and some patients may develop hemoptysis. Septic cardiac thrombi are associated with endocarditis; nonseptic cardiac thrombi are associated with myocardial disease. Infarction or embolization within the genitourinary system can present with hematuria, abdominal pain, and splinting. Embolization to the viscera may have similar signs, although small animals may vomit or become incontinent.

In cattle, thrombosis of the caudal vena cava occurs in association with hepatic abscessation and erosion of the abscess into the vein. 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. Ultrasonographic examination may confirm liver abscessation. Pulmonary arterial thromboembolism and embolic pneumonia are also frequent complications of right heart 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 diagnosing showering of bacterial emboli, respectively. Thrombosis of the cranial vena cava in cattle produces bilateral jugular engorgement (usually without a jugular pulse); edema of the head, submandibular area, and brisket; and pronounced oral mucosal hyperemia. Significant lingual, pharyngeal, or laryngeal edema may develop and result in dysphagia and dyspnea. Upper respiratory edema may become life-threatening and necessitate tracheostomy.

Embolic pneumonia, cow

Caudal vena cava thrombosis

In horses, cranial vena cava thrombosis may result from embolization of a jugular thrombus or extension of a right atrial endocarditis lesion. Jugular vein thrombosis in horses is often associated with phlebitis following catheterization or paravenous injection and will cause swelling, heat, and pain of the affected area with palpable thickening of the jugular vein. Bilateral jugular vein thrombosis can cause edema and swelling of the head and neck due to passive congestion. Ultrasonographic examination of the affected vein can determine the extent of the thrombus and degree of occlusion. A septic thrombus should be suspected if cavitary lesions are present within accompanying soft tissue inflammation; a nonseptic thrombus is usually of more homogenous echogenicity. 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 for developing jugular thrombosis; ruminants are much less prone to jugular thrombosis than horses.

Migrating Strongylus vulgaris larvae ( Large Strongyles) 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 passive congestion 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 probable but have not yet been elucidated. 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 venous 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.

In dogs, and less commonly in cats, heartworm disease may lead to pulmonary arterial thrombosis; pulmonary embolism is a major secondary effect. Pulmonary thromboemboli most commonly produce dyspnea and tachypnea, and abnormal lung sounds sometimes can be heard during thoracic auscultation. Affected animals are often reportedly normal until sudden onset of respiratory distress. Secondary pulmonary hypertension may cause a split second heart sound. Chest radiographs may be normal or show changes such as an enlarged main pulmonary artery and right heart, underperfusion of the affected region, pleural effusion, or pulmonary hemorrhage or infarction. Blood-gas determinations most often show hypoxemia with low or normal partial pressure of CO₂. Ventilation/perfusion scanning with radionuclide-labeled albumin and gases or pulmonary angiography can confirm the diagnosis. Ancillary tests are essential for the diagnosis of underlying diseases. In both cats and dogs, bacterial endocarditis can lead to pulmonary thrombembolism and embolic pneumonia. In dogs, other diseases associated with pulmonary thrombembolism include ones that result in systemic or metabolic disorders (eg, diabetes mellitus, glomerulonephropathy, hyperadrenocorticism, immune-mediated hemolytic anemia, neoplasia, renal amyloidosis).

In cats, aortic thrombembolism is a frequent complication of cardiomyopathy ( Cardiomyopathies). Hypertrophic and dilated cardiomyopathy create abnormal circulatory patterns, which predispose to intracavitary thrombus formation. Thrombi may be located in the left atrium, ventricle, or both. Thrombi that dislodge form emboli that may obstruct aortic branches, most commonly at the aortic trifurcation. Such “saddle clots” obstruct the internal and external iliac arteries and the median sacral artery. Clinical signs include paralysis and pain of the extremities, (lack of a palpable femoral pulse, cold distal limbs), and signs related to congestive heart failure. Incomplete occlusion of the aortic bifurcation may cause mild neurologic deficits in both hindlimbs or unilateral paresis. Emboli may also lodge more proximally in the aorta or in other systemic vascular beds. Experimentally, aortic ligation does not reproduce the clinical signs of aortic thromboembolism, while artificial production of a thrombus does, suggesting that factors elaborated by emboli may inhibit collateral circulation. These may include serotonin and thromboxane A₂, both of which are released by activated platelets, causing vasoconstriction and platelet aggregation that likely contribute to development of clinical signs through inhibition of collateral circulation. Inflammation and necrosis of hepatic and skeletal muscle may also occur, leading to elevation of serum CK, AST, and ALT. Echocardiography is the imaging modality of choice to assess cardiac structure and function. Angiocardiography may be used to assess collateral circulation and confirm the diagnosis. However, because it requires general anesthesia, it is often unsafe in cats with cardiomyopathy.

Aneurysms cause no clinical signs unless hemorrhage occurs or an associated thrombus develops. Except for dissecting aneurysm in turkeys ( Dissecting Aneurysm: Introduction), aortic or sinus of Valsalva rupture in horses with sudden death, hemorrhage associated with guttural pouch mycosis in horses (), 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:

Treatment of embolic pneumonia caused by 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, transtracheal wash, or both. The prognosis for recovery is guarded at best, and the performance of recovered horses and cattle is often decreased.

Treatment of venous thrombosis 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 generally does not respond to therapy and the prognosis is poor.

Measures to minimize trauma to, and bacterial contamination of, veins remain the best means to prevent thrombosis. Extreme care should be taken when placing catheters or giving IV injections to patients at risk for hypercoagulation disorders. The effectiveness of antiplatelet aggregation with aspirin (100 mg/kg, sid), anticoagulant therapy with unfractionated heparin (40-80 IU/kg, SC, bid-tid), and use of low-molecular-weight heparin to facilitate thrombolysis is questionable, but will help prevent formation of additional clots.

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, as another would likely form. 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 ( Large Strongyles).

Surgical removal of aortic emboli may be attempted in cats; however, it is difficult and often unrewarding. Most authorities recommend medical therapy only, including analgesics, anticoagulants, careful use of IV fluids (sufficient to maintain hydration and blood pressure but not exacerbate congestive heart failure), and specific therapy for underlying heart disease. Streptokinase (90,000 IU/cat, IV over 20 min followed by 45,000 IU as a continuous infusion for 2-24 hr) can be given to lyse thrombi, but will increase the risk of bleeding. Recombinant tissue-type plasminogen activator (tPA) promotes fibrinolysis by binding to fibrin within thrombi and converting entrapped plasminogen to plasmin. In a study of cats with spontaneous thromboembolism given tPA (0.25-1 mg/kg/hr, IV, up to a total dose of 1-10 mg/kg), 43% survived the therapy and walked within 48 hr of administration. However, 50% of the cats died from reperfusion syndrome, heart failure, or from no obvious cause, suggesting that this therapy should be reserved for cats with serious disease.

Acepromazine (0.2-0.4 mg/kg, SC, tid) and hydralazine (0.5-0.8 mg/kg, PO, tid) have been given to improve vasodilation and collateral circulation, although the benefits are not clear. They may also cause hypotensive side effects or non-uniform arterial dilation. Unfractionated heparin (220 IU/kg, IV initially, followed by maintenance doses of 66 IU/kg, SC, qid) traditionally has been used to prevent further clot formation. Its use for this indication remains controversial, because its efficacy has never been established. Low-molecular-weight heparin may potentially have greater efficacy and safety, but dosages vary widely and are still being investigated. The dosages of both unfractionated and low-molecular-weight heparin should be adjusted to prolong activated partial thromboplastin time to 1.5-2 times pretreatment values. The primary complication is bleeding. Warfarin (0.25-0.5 mg/cat, sid) has been used both to prevent further clot formation after thromboembolism has occurred and prophylactically in cats with cardiomyopathy. The initial oral dosage is adjusted to prolong the prothrombin time to twice the normal reference range. Joint treatment with warfarin and heparin should only be considered for indoor cats that can be monitored frequently, because of the possiblity of serious bleeding; such therapy may have no effect on established thrombi.

Aspirin (25 mg/kg, PO, every 48-72 hr or ¼ of a 5-grain tablet) is the most widely used preventive therapy for feline thromboembolism. It preserves collateral circulation by inhibiting formation of thromboxane A₂ and irreversibly inhibits platelet aggregation. However, evidence that aspirin prevents first time or recurrent thromboembolism is lacking.

Many cats with aortic thromboembolism die despite treatment or fail to regain hindlimb function. Some cats that survive the initial cardiovascular crisis recover the ability to walk after several weeks, but residual deficits, including muscle contracture and peripheral neuropathy, are common. The longterm prognosis often depends on the severity of underlying heart disease.

Treatment recommendations for pulmonary thromboembolism in dogs are the same as for aortic thromboemboli in cats.