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Standards of Care May 2009 (Vol 11, No 4)

Thromboembolism

by Crystal Hoh, DVM, Maureen McMichael, DVM, DACVECC

    CETEST This course is approved for 1.0 CE credits

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    Introduction

    Normal hemostasis depends on a delicate balance between the initiators and inhibitors of coagulation. When this balance is upset, hemorrhage or thrombosis results. Three major risk factors leading to thrombosis, known as Virchow's triad, include stasis of blood flow, endothelial damage, and hypercoagulability. If any of these risk factors are present, thrombosis can occur. In smaller vessels, thrombi may remain localized; in larger vessels, there is a higher risk of fragmentation. If fragmentation occurs, the free thromboembolus will be carried through the body until it becomes lodged in another vessel. Systemic venous thromboemboli may remain within the venous system or return to the heart to pass into pulmonary arteries before becoming lodged as pulmonary thromboemboli. Arterial thrombi may originate within the arterial system or within the left atrium or ventricle before spreading to distal arteries.

    The first two risk factors for thrombosis are intuitive. For example, stasis of blood flow can occur with cardiomyopathy when blood pools in an abnormally contracting heart. Endothelial damage can occur with systemic inflammation such as that seen with immune-mediated hemolytic anemia. The final risk factor, hypercoagulability, can be more difficult to identify. Hypercoagulability results from enhanced activation or decreased removal of coagulation factors, deficiencies in natural anticoagulants such as antithrombin or protein C, defective fibrinolysis, or hyperaggregability of platelets. Hypercoagulability is more difficult than hypocoagulability to recognize and assay.

    Diagnostic Criteria

    Historical Information

    Predisposing Conditions

    • Protein-losing nephropathy.
    • Severe protein-losing enteropathy.
    • Neoplasia.
    • Cardiomyopathy.
    • Immune-mediated hemolytic anemia.
    • Sepsis.
    • Heartworm disease.
    • Hyperadrenocorticism.
    • Polycythemia.
    • Pancreatitis.
    • Disseminated intravascular coagulopathy (DIC).
    • Trauma.
    • Hyperthyroidism.

    Owner Observations

    Any body system can be affected; clinical signs depend on the location of the thromboembolism. The distal aorta (saddle thrombus) is a common location in cats.

    • Distal aortic thromboembolism (may be acute or chronic):
      — Asymmetric or symmetric paresis or paralysis of pelvic limbs.
      — Acute pain and vocalization.
      — Acute renal failure or gastrointestinal signs (if mesenteric blood flow occluded).
    • Venous thromboembolism:
      — Pain and edema of the area associated with the vessel (i.e., limb edema).
    • Other locations:
      — Pulmonary thromboembolism (PTE): acute respiratory distress (coughing, hemoptysis, cyanosis, collapse, sudden death).
      — Central nervous system (CNS): May include behavioral changes, ataxia, and seizures.
      — Brachial artery occlusion: Acutely painful asymmetric forelimb paresis to paralysis.

    Other Historical Considerations/Predispositions

    • One of the highest risks for future thromboembolism is a history of thromboembolic episodes.
    • The degree of clinical signs depends on the development of collateral blood flow, degree and duration of obstruction, and release of vasoactive chemicals causing vasoconstriction.
    • Platelet activation is enhanced under conditions of high shear. Therefore, if systemic hypertension is present along with a disease process leading to hypercoagulability, there may be an increased risk of thromboembolism.

    Physical Examination Findings

    • Clinical signs of thromboembolic disease occur due to decreased or complete lack of perfusion to the area affected. The severity of clinical signs frequently reflects the extent, as well as the location, of the offending clot.
    • Depend on location affected.
      — Distal abdominal aortic thromboembolism:
      • Cold hindlimbs; swollen, painful hindlimb muscles.
      • Weak to absent femoral pulses.
      • Pale or cyanotic pads.
      • Heart murmur or gallop rhythm possible.
      • Tachycardia due to pain or heart failure.
      • Tachypnea or dyspnea.
      • Hypothermia.
      • May retain ability to move tail.
      — PTE: Severe acute respiratory distress that may improve with oxygen therapy.
      — CNS thromboembolism: focal to multifocal brain localization. Signs are acute in onset and can range from behavior changes, ataxia, head turn, or circling to coma or death depending on sites affected. Seizures are uncommon.
      — Other aortic thromboembolism locations:
      • Acute abdomen if mesenteric or renal arteries affected.
      • Cold front limbs with onset of paresis to paralysis similar to that seen in hindlimbs if brachial artery occluded.
    Key To Costs

    Laboratory Findings

    • Aortic thromboembolism.
      — Lack of bleeding or dark blood from nail of affected limb cut to the quick or Doppler ultrasonography of affected limbs to confirm poor blood flow. $
      — Decreased glucose and increased lactate in blood samples from mild or moderately affected limb compared with a central venous sample. Blood collection from a severely affected limb is not recommended. $
      — Evidence of thrombus in abdominal aorta on abdominal ultrasonography with color flow Doppler. Evidence of an intracardiac thrombus may also be seen with echocardiography. $-$$
      — Evidence of cardiomegaly or neoplasia on thoracic radiographs. $
      — Enlarged left auricle or atrium with possible spontaneous echocardiographic contrast ("smoke") or other evidence of cardiomyopathy on echocardiography. $$
      — Cats often have hyperglycemia from stress and possibly elevations in ALT, AST, and creatine phosphokinase. $
    • PTE:
      — Decreased PaO2, decreased PaCO2, increased alveolar to arterial gradient. Response to oxygen therapy depends on underlying disease. $
      — Thoracic radiography: Possible cardiomegaly and mild pleural effusion. PTE should be suspected if thoracic radiographs are unremarkable and compatible signs are present. $
      — Echocardiography: Direct visualization of PTE is limited to vessels near the heart, but pulmonary hypertension supports the diagnosis. $$
      — Computed tomography (CT): Can use contrast to visualize filling defects in pulmonary arteries (pulmonary angiography). $$$$
    • CNS thromboembolism.
      — Magnetic resonance imaging (MRI): Signs of infarction, edema, or hemorrhage. $$$$
      — CT: Signs of current hemorrhage. $$$$
      — Thoracic radiography: Evidence of neoplasia or cardiomegaly. $
      — Abdominal ultrasonography: Evidence of neoplasia. $

    Coagulation Testing

    • Prothrombin time (PT): Measures extrinsic (factor VII) and common (tissue factor, fibrinogen, factors V and X) pathway function. May be prolonged with DIC. $
    • Partial thromboplastin time (PTT): Measures intrinsic (factors VIII, IX, XI, XII) and common pathway function. May be prolonged with DIC. $
    • Activated clotting time (ACT): Measures intrinsic and common pathway function. May be prolonged with DIC. $
    • D-dimers: A specific marker for fibrinolysis formed from plasmin degradation of cross-linked fibrin. If negative, hypercoagulablility is unlikely. $
    • Fibrinogen degradation products (FDPs): Breakdown products of fibrin or fibrinogen; less specific for fibrinolysis. If negative, hypercoagulablility is unlikely. $
    • Antithrombin: Low antithrombin levels may increase risk for thromboembolism. $
    • Platelet count: Patients with concurrent hypercoagulability and thrombocytosis are at an increased risk of thromboembolism. May be decreased if platelets are being consumed as part of the hypercoagulable state. $

    Summary of Diagnostic Criteria

    • Aortic thromboembolism: Patient presents with a predisposing disease and acute-onset hindlimb paresis or paralysis; cold, painful extremities; and greatly decreased or absent hindlimb pulses. Further confirmation can include abdominal ultrasonography, absence of Doppler signal, or no bleeding with cut nails.
    • PTE: Patient presents in acute respiratory distress with a predisposing disease. May have radiographic manifestations and be responsive to oxygen therapy. Suspicion may be strengthened if D-dimers are elevated. Confirmation requires advanced diagnostics such as echocardiography, CT, or pulmonary angiography.
    • CNS thromboembolism: Patient presents with a predisposing disease and acute onset of neurologic signs (e.g., behavior changes, circling, hemiparesis, seizures). Suspicion may be strengthened if D-dimers are elevated; confirmation requires MRI.

    Diagnostic Differentials

    • Aortic thromboembolism: Primary neurologic disease, spinal trauma. May be ruled out with diagnostics listed for aortic thromboembolus, evidence of spinal trauma on spinal radiographs, and advanced imaging of the spinal cord. Cats with saddle thrombi tend to show lower motor neuron signs compared with spinal cord lesions that would cause upper motor neuron signs.
    • PTE: Cardiac disease, primary pulmonary disease. May be ruled out with D-dimers, echocardiography, fine-needle aspiration of lung lobe if focal area of disease, or bronchoscopy with bronchoalveolar lavage if the patient is stable.
    • CNS thromboembolism: Inflammatory disease, infectious disease, neoplasia, hydrocephalus, trauma. Advanced imaging with possible cerebrospinal fluid collection can help differentiate. Serology for infectious diseases if indicated.

    Treatment Recommendations

    Initial Treatment

    • Aortic thromboembolism.
      — Extremely painful condition especially for first 24-48 hours. Treat with strong pain medication such as pure opioids (fentanyl, morphine, hydromorphone). Can also consider epidural pain medication if hindlimbs are affected. Butorphanol alone is not recommended due to inadequate pain control.
    • PTE.
      — Provide oxygen therapy immediately (preferably in a low-stress manner such as an oxygen cage, but other means of oxygen delivery are acceptable). Oxygen therapy will be necessary until the patient is breathing comfortably and other measures of oxygenation such as arterial blood gas or pulse oximetry normalize.
    • CNS thromboembolism.
      — Supportive care as needed. If patient is seizing, treat with 0.5-1 mg/kg valium intravenously or rectally. Consider valium CRI or loading with other antiepileptic drugs if seizures persist.

    Antiplatelet and anticoagulant therapies (should be continued as long as the patient is at high risk for thrombus formation).

    • Platelet inhibition:
      • Acetylsalicylic acid (aspirin): Prevents thromboxane A2 production by irreversibly inhibiting COX-1. Antiplatelet doses are much lower than antiinflammatory doses and are associated with fewer gastrointestinal effects. $
        • Dogs: 0.5-1.0 mg/kg PO q24h.
        • Cats: 5 mg/cat PO q72h.
      • Clopidogrel: Irreversible ADP-receptor antagonist that reaches maximal effect in 5-7 days and can cause gastrointestinal effects. Needs to be metabolized with cytochrome P450 system in liver to become active. $
        • Cats: 18.75 mg/cat/day PO.
      • Severe immune-mediated hemolytic anemia: Treat until hematocrit stabilizes near a normal value.
      • Albumin level below 2 g/dL: Treat as long as albumin remains low.
      • Low antithrombin levels (activity less than 75%): Treat while the value remains low.
      •  At-risk cardiomyopathy patients: Treat for life.
        • Consider in patients at high risk of thromboembolism (nephrotic syndrome or severe protein-losing enteropathy, feline cardiomyopathy with left atrial dilation or smoke, sepsis).
    • Inhibition of coagulation (prevention of additional thrombi). Can be combined with primary prophylaxis treatments with careful monitoring for hemorrhage. Continue while the patient is at high risk for thromboembolic disease (e.g., DIC) or if thromboembolism production is suspected.
      — Unfractionated heparin (UFH): At lower doses, combines with antithrombin to inactivate factor Xa and thrombin. At higher doses, combines with antithrombin to inhibit factors IX, X, XI, and XII. Has variable pharmacokinetics and must be closely monitored in the hospital setting. Hemorrhage can occur if the dose is too high. The goal is to prolong PTT by 1.5-2.5 times the baseline value. After several days of treatment, this therapy is usually tapered off over 2-3 days. Abrupt discontinuation without tapering may be associated with transient increased hypercoagulability. $
      • Dogs and cats: 150-250 U/kg IV once followed by 150-250 U/kg SC q6-8h.
      — Low-molecular-weight heparin. Accelerates activity of antithrombin to primarily inhibit factor Xa without prolonging PTT. Factor Xa inhibition can be monitored, but proper level for prevention of thromboembolism is controversial. Has a longer half-life and greater bioavailability than UFH. $
      • Dalteparin: Dogs: 200 U/kg SC q24h from study of venous thromboembolism using healthy dogs as models. Cats: 100 U/kg SC q12h based on article studying anticoagulant effects in healthy cats; dosage extremely variable in pharmacokinetic studies.
      • Enoxaparin sodium: Dogs: 100 U/kg (1 mg/kg) SC q12h from study of venous thromboembolism using healthy dogs as models. Cats: 1 mg/kg SC q12h based on article studying anticoagulant effects in healthy cats; dosage extremely variable in pharmacokinetic studies.
      — Warfarin: Vitamin K antagonist that interferes with synthesis of factors II, VII, IX, and X. Anticoagulant proteins C and S are also vitamin K dependent, so a transient hypercoagulable state occurs when warfarin therapy is started. It is recommended that UFH or low-molecular-weight heparin therapy be given concurrently for the first 4-5 days of treatment. $
      • Monitoring: PT daily for first 3 days, then every other day (twice), then weekly until dose is stable, monthly thereafter. The goal is to maintain PT at 1.5-2 times baseline.
      • Cats: 0.1-0.2 mg/cat PO q24h. Approximately 50% of cats have thromboembolus recurrence while receiving warfarin therapy.
      • Dogs: 0.2 mg/kg PO once, then 0.05-0.2 mg/kg PO q24h.
      • Complications: Hemorrhage necessitating blood product transfusion (plasma and red cells if needed) and vitamin K therapy. Many drug interactions.

    Alternative/Optional Treatments/Therapy

    • Aortic thromboembolism.
      — Streptokinase: Binds with plasminogen to form plasmin, which breaks down fibrin to cause thrombolysis and degrades prothrombin and factors V and VII. Use is controversial; not recommended in cats. $$
      • Dogs: 90,000 IU IV over 30 minutes, then maintenance infusion IV of 45,000 IU over 12 hours. May repeat maintenance infusion for up to 3 days. Complications include reperfusion injury, allergic reactions, and hemorrhage.

    Supportive Treatment

    • Aortic thromboembolism: Pain control with opioids, cage rest, warming of limbs if needed, passive range of motion of limbs if paralyzed.
    • PTE:
      — Oxygen supplementation, positive pressure ventilation.
      — Antioxidant therapy (N-acetylcysteine) may be beneficial in attenuating the fibrotic stage of acute lung injury, but there are no studies in veterinary medicine.
    • CNS thromboembolism: Supportive care varies depending on clinical signs and can range from simple monitoring to intensive support of a comatose patient. If needed, antiseizure medications and walking assistance are given.

    Patient Monitoring

    Depending on the location and extent of tissue damage, monitoring should be directed at the affected underlying body system. Many patients require hospitalization during the initial thromboembolic episodes. While the patient receives anticoagulant or fibrinolytic therapy, monitoring for hemorrhage is recommended. When UFH therapy is used, monitoring PTT should provide adequate therapy without significant risk of hemorrhage. Similarly, warfarin therapy should be closely monitored.

    • Aortic thromboembolism can result in ischemia"reperfusion injury if the embolus is removed rapidly. Signs may include hyperkalemia, increased blood lactate, metabolic acidosis, and release of other metabolites and free radicals, possibly resulting in systemic inflammatory response syndrome.

    Home Management

    • Aortic thromboembolism:
      — Monitor for limb or skin necrosis requiring surgical debridement or amputation.
      — Perform passive range of motion and other rehabilitative exercises, bladder expression if needed; carry to assist with elimination if patient cannot walk.
    • PTE: Monitor respiratory rate.
    • CNS thromboembolism: Monitor for progression of signs, behavior changes, and, if needed, assist with basic needs such as eating, drinking, and elimination.

    Contraindications

    Platelet inhibition with marked thrombocytopenia (<60,000/µL) or anticoagulant therapy in hypocoagulable states with significant prolongation of PT, PTT, or ACT.

    Milestones/Recovery Time Frames

    Depends on disease severity, underlying disease processes, and areas affected. Return to normal blood flow and function may never be achieved. Most animals benefit from (or require) lifelong anticoagulant medication.

    Prognosis

    Depends on the severity of the underlying disease process, extent and location of thromboembolic disease, and response to treatment.

    Favorable Criteria

    • Aortic thromboembolism: No heart failure at time of diagnosis; partial obstruction of blood flow or rapid return of blood flow. Also, single leg involvement, especially if ambulatory, may suggest a better short-term prognosis. However, the overall prognosis is poor to grave, with average survival times from days to as long as 10 months.
    • PTE: No heart failure at time of diagnosis, good response to oxygen therapy.
    • CNS thromboembolism: Nonprogressive neurologic signs that allow the animal to perform basic functions (e.g., eating, drinking, urinating, defecating) without assistance. Improvement in neurologic signs.

    Unfavorable Criteria

    • Aortic thromboembolism: Heart failure, complete obstruction of blood flow, hypothermia, obstruction of renal arteries, recurrence within several months, severe underlying cardiomyopathy.
    • PTE: Presence of severe underlying disorder that alone has a poor prognosis, poor response to oxygen therapy, concurrent heart failure.
    • CNS thromboembolism: Severe neurologic signs, including coma, stupor, uncontrollable seizures, and inability to perform basic functions; evidence of progression or lack of improvement.

    Alwood AJ, Downend AB, Brooks MB, et al. Anticoagulant effects of low-molecular-weight heparins in healthy cats. J Vet Intern Med 2007;21(3):378-387.

    Goncalves R, Penderis J, Chang YP, et al. Clinical and neurological characteristics of aortic thromboembolism in dogs. J Small Anim Pract 2008;49(4):178-184.

    Hackner SG. Antiplatelet drugs: what, when, and how. International Veterinary Emergency and Critical Care Symposium 2007.

    Lunsford KV, Mackin AJ. Thromboembolic therapies in dogs and cats: an evidence-based approach. Vet Clin North Am Small Anim Pract 2007;37(3):579-609.

    Morris TA, Marsh JJ, Konopka R, et al. Anti-thrombotic efficacies of enoxaparin, dalteparin, and unfractionated heparin in venous thromboembolism. Thromb Res 2000;100(3):185-194.

    Nelson OL. Use of the D-dimer assay for diagnosing thromboembolic disease in the dog. JAAHA 2005;41(3):145-149.

    Smith CE, Rozanski EA, Freeman LM, et al. Use of low molecular weight heparin in cats: 57 cases. JAVMA 2004;225(8):1237-1241.

    Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med 2003;17(1):73-83.

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    CETEST This course is approved for 1.0 CE credits

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