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Thromboembolism and Antithrombotic Therapy

Created by V’22 cardio group modified from Dr. John Rush

Last Updated 06/29/20

Thrombosis: disease state, abnormal blood clots present in body

Thromboembolism: thrombi have broken free from the site at which they formed → embolize downstream location

Thrombosis

Virchow’s Triad: composed of the following 3 factors. Any one (or multiple) can predispose an individual to thrombosis

• Endothelial injury
• • Surgery
  • Trauma
  • Thermal injury
• Circulatory stasis
  • Polycythemia
  • Intracardiac distension
  • Low cardiac output
• Altered coagulability
  • DIC
  • Depletion of antithrombotic factors

Mechanisms of Thrombosis

• Platelet Adhesion: typically, in area of damaged arterial endothelium or on artificial surface (i.e. implants, prosthetics)
• Platelet aggregation: due to rise in platelet intracellular calcium as a response to collagen exposure, vascular injury, thrombin, serotonin, thromboxane A2
  • Can initiate thromboxane synthesis and platelet activation through arachidonic acid release
• Activation of clotting mechanisms → generation of thrombin after activation of platelet membrane
  • Thrombin enhances activation of platelet membrane & plays a key role in coagulation
• Platelet and vascular contraction: during activation, serotonin (and other vasoactive agents) are released from platelets, promoting formation of a hemostatic plug
  • If endothelium is intact – serotonin will promote vasodilation
  • If endothelium is damaged – serotonin will promote vasoconstriction
  • Other vasoconstrictors include inflammatory mediators (i.e. leukotrienes released from white cells, tissue macrophages) → vascular stasis
• Fibrinolysis: breakdown of fibrin (via plasminogen  plasmin) is initiated at the same time as clotting mechanisms are activated
  • Plasmin = enzyme responsible for hydrolysis of fibrin

Systemic Thrombosis/Thromboembolism

Feline arterial (systemic) thrombosis/thromboembolism

• Associations
  • Feline aortic thromboembolism (ATE/FATE): common, devastating sequelae to feline cardiomyopathy
  • Intracardiac thrombosis with subsequent embolization – major cause
  • Neoplasia (esp. pulmonary carcinoma) – maybe 5% of cases
• Pathophysiology
  • Intracardiac thrombi formation may relate to pathologic changes → exposure of thrombogenic surfaces
  • Chamber dilation, valvular regurgitation, partial outflow obstruction in cases of extreme hypertrophy → alterations in blood flow
  • DIC and other coagulopathies are reported in cats with ATE
  • Feline platelets = more reactive than other species
  • Interrupted blood flow past the distal aorta → ischemic myopathy & neuropathy
  • Humoral agents released from the blood clot (thromboxane, endothelin, serotonin, etc.) play an important role in the pathophysiology
• Clinical presentation
  • Distal aortic thromboembolism (aka “Saddle Thrombus”) occurs in >90% of cases. Common, especially in cats with known myocardial disease
    • Clinical signs
      • Posterior paresis/paralysis
      • Loss of femoral pulses
      • Cool posterior extremities
      • Cyanotic/pale rear-limb paw pads
      • Cyanotic nail beds that do not bleed
      • Firm, painful gastrocnemius muscles
      • Vocalization (presumably due to pain)
    • Simultaneous onset of acute CHF is common
      • Weakness
      • Dyspnea
      • Pulmonary edema
    • Sudden death due to coronary thromboembolism/thrombus occluding LVOT is possible
    • Diagnosis
      • Can be first presenting evidence of cardiovascular disease (heart disease was previously undetected)
      • Usually clinical signs are clear enough to make a diagnosis
      • Differentials
        • IVDD
        • FCE
        • Spinal lymphoma
        • Trauma!!
      • Cardiomyopathy signs may be present
        • Jugular distension
        • Murmur or arrhythmia
        • Gallop sounds
      • CHF signs may be present
        • Dyspnea
        • Tachypnea
        • Weakness
        • Pulmonary crackles
        • Cyanosis
      • Further workup
        • Thoracic radiographs
        • ECG
        • NT-proBNP
        • Echo
      • Nonspecific angiography of aorta is also diagnostic – can localize thrombus and evaluate collateral circulation (is usually NOT necessary/indicated though)
      • Ancillary testing may indicate –
        • Muscle injury → enzyme release: Increased CPK, ALT, AST, LDH
        • Stress: leukogram, hypoglycemia
        • DIC
        • Hypoxemia
      • Therapy
        • Goals: supportive treatment of acute syndrome, relief of CHF, attempt to remove thrombi, establish collateral circulation
        • If CHF present
          • Oxygen
          • Diuretics
          • +/- ACE inhibitors or pimobendan
          • AVOID propranolol and probably other beta-blocker (low cardiac output altered vasomotor tone may reduce blood flow to tissues at risk)
        • Analgesics (i.e. fentanyl, buprenorphine, or other narcotics)
        • Anticoagulation with heparin to prevent additional thrombosis
          • Heparin can also activate plasminogen → enhanced thrombolysis (unproven but suggested)
          • Antiplatelet drugs in acute management
        • Surgical embolectomy = high mortality rate. Reperfusion injury and decompensated condition of the patient at time of surgery. If done should likely be done early, within the first few hours of ATE
        • Vasodilators (i.e. acepromazine or hydralazine) to induce collateral circulation
          • MAP = a KEY determinant of collateral flow!
          • These drugs can drop BP, and might reduce blood flow or limit opening up of collateral vessels
          • Efficacy not established
        • Thrombolytic therapy (streptokinase, urokinase, or tissue plasminogen activator)
          • Common consequences of clot lysis include reperfusion injury (hyperkalemia and metabolic acidosis) and bleeding consequences can also happen with thrombolytics
          • Goal: early return of blood flow to tissues with compromised perfusion that are NOT yet necrotic
          • If thrombolytics are used – should be started within 12 hours, ideally within 1 hour of onset of clinical signs
        • Prevention
          • Optimal therapy = cure underlying disease (i.e. DCM due to taurine deficiency)
          • Aspirin, heparin, LMWH, clopidogrel, Coumadin (warfarin)
        • Prognosis
          • Devastating complication of feline myocardial disease
          • Median survival time = 61 d. – 11 mo. (if cat is not euthanized at time of presentation)
          • Repeated thrombosis is possible
          • Most common cause of subsequent death in treated cats = CHF
        • Other clinical syndromes due to occlusion of –
          • Mesenteric artery
          • Renal artery
          • Hepatic artery
          • Splenic artery
          • Ovarian artery
          • Forelimb arteries (right forelimb may be more common than left forelimb; these often get better and cats usually will walk again)

Canine systemic thrombosis/thromboembolism

• Much less common in dogs
• Many cases are NOT of cardiogenic origin (rather due to systemic disease, develop in situ)
• Associations
  • Vascular disease
    • Arteriosclerosis
    • Vasculitis
    • Trauma
    • IV injection of an irritating/hypertonic substance
    • Neoplastic invasion
    • Bacterial endocarditis
  • Vascular stasis
    • Hypovolemia
    • Shock
    • Cardiac failure
    • Vascular compression
  • Hypercoagulability
    • Antithrombin III deficiency
    • Platelet disorders
    • Dehydration
    • Hyperviscosity
    • IMHA
    • Being a greyhound
  • Thrombotic events from sources in the veins (if ASD), cardiac valves/chambers
  • Introduction of foreign substances by trauma or iatrogenically
• Clinical presentation
  • Signs dependent on site of thrombosis, degree/duration of occlusion, and composition of thrombus
  • Some thrombi will NOT → clinical disease
  • In the dog – saddle thrombus can → posterior weakness/lameness ONLY (especially if partial or intermittent obstruction occurs; common when the thrombus develops in situ in the distal aorta)
  • Femoral pulses = weak to absent, hind limbs may be cool
  • Front limb thrombosis = LESS dramatic, unilateral
  • Endocarditis may → septic embolization of 1+ organ beds (kidneys, gut, liver, spleen, heart, spinal cord, brain)
    • Clinical signs are dependent upon which site is affected
  • Diagnosis
    • Radiographs of thorax/abdomen may suggest underlying disease
      • Dirofilariasis
      • Neoplasia
      • Cardiomegaly
      • Radiopaque foreign object
    • Laboratory tests may suggest systemic disease
      • Elevated hepatic/pancreatic enzymes
      • Azotemia
      • Proteinuria
      • Hematuria
      • Leukocytosis
      • Hypoproteinemia
      • Microfilaremia
    • Echo or abdominal ultrasound may be useful, based upon clinical signs
      • i.e. visible thrombus in abdominal aorta or iliac arteries
    • Angiography or CT of selected area could reveal lesions
  • Treatment: newer anticoagulants and Coumadin MAY be most effective!
    • Correct underlying abnormality
    • Supportive therapy
      • Rehydration
      • Analgesics
    • Prevent thrombus enlargement
      • Heparin
      • Antiplatelet drugs
      • Coumadin or newer drugs like direct acting Factor anti-Xa inhibitors like rivaroxaban or apixaban may be the best approach!!
    • Thrombolytic therapy
    • Surgical embolectomy
  • Prognosis is dependent upon underlying disease (usually guarded). Thrombosis recurrence is common

Pulmonary Thrombosis/Thromboembolism

• Associations
  • Dirofilariasis: heartworm is a well-documented cause of PTE
  • Nephrotic syndrome: proteinuria → loss of antithrombin
  • Autoimmune hemolytic anemia: many patients will succumb to PTE
  • Other causes of antithrombin deficiency
    • Hyperadrenocorticism
    • Hypothyroidism
    • Pancreatitis
    • DIC
    • Etc.
  • Deep vein thrombosis (esp. in people): thrombi embolize to the pulmonary circulation
• Clinical Presentation
  • Signs are nonspecific, mimic other cardiorespiratory diseases
  • Acute onset of dyspnea common***
• Diagnosis = difficult at best
  • Acutely ill patient, could succumb from diagnostic testing alone
  • Suggestive findings
    • Arterial hypoxemia (PaO2 < 80 mmHg)
    • Thoracic radiographs are NOT always suggestive of cardiorespiratory disease
      • Sometimes normal
      • Changes that MAY be seen include –
        • Pulmonary vessel size change
        • Lobar lucency
        • Small vessels in area that is affected by thrombus
        • RVE
        • Pulmonary infiltrates
        • Pleural effusion
      • Pulmonary angiography: injection of contrast may demonstrate filling defect in pulmonary artery OR a complete interruption of blood flow
        • Negative study = significant disease is NOT present
      • CT scan of thorax with contrast: currently the best diagnostic test for PTE. Can see the thrombus in the PA.
    • Prevention: prophylactic therapy may be initiated if patient is predisposed to PTE (sepsis, neoplasia, prolonged recumbency, IMHA). Treat underlying disease/condition
    • Treatment
      • Support with oxygen
      • Fluid support to maintain circulation
      • Heparin or LMWH
      • Antiplatelet drugs
      • Coumadin
      • +/- Newer anticoagulants like direct acting Factor anti-Xa inhibitors (rivaroxaban or apixaban), Thrombolytics in acute setting
    • Prognosis: poor – guarded in severely ill patients requiring oxygen supplementation

Therapeutic Modalities for Thrombotic Diseases

Antiplatelet therapy: reduces platelet aggregation  altered thrombus formation. Prevention of vasoconstriction due to platelet release of substances (i.e. serotonin, PDGF)

• Aspirin (acetylsalicylic acid): blocks PG synthesis by irreversibly acetylating & inactivating COX.
  • The production of thromboxane is blocked
  • Prostacyclin synthesis (a vasodilator) is blocked simultaneously  potential consequences of vasoconstriction & vascular stasis
    • BUT – endothelial cells are able to produce prostacyclin within hours, so the antithrombotic effects predominate. Platelet inhibition = low doses
  • Used in cats with significant myocardial disease to prevent thromboembolic events
  • Side effects
    • GI distress
    • Potential for gastric ulceration/bleeding
  • Clopidogrel (Plavix): good antiplatelet therapy in most animals, less SE than aspirin

Anticoagulation therapy: prevent thrombus formation

• Heparin (IV or SC): enhances the activity of antithrombin
  • Antithrombin = protease inhibitor found in normal plasma
  • Heparin-antithrombin complex will neutralize proteases formed during coagulation – i.e. thrombin(IIa)
  • Increases plasminogen activator → activation of fibrinolysis
  • Must give parenteral via IV CRI or frequent SC injections
  • Can use prior to starting a long-term therapy (i.e. warfarin) to initiate anticoagulation
  • Therapeutic dosage monitored via PTT levels
    • PTT increase 1.5X baseline or normal indicates the drug is working
  • Bleeding is a significant complication
  • Protamine sulfate = antidote
    • High side effect potential in dogs
  • Low-Molecular weight heparin: prevent thrombus formation
    • i.e. enoxaparin (Lovenox) and dalteparin (Fragmin)
    • Require SC injection of small volumes
    • Longer half-life than unfractioned heparin – only give 1-3X daily
    • Much more expensive than unfractioned heparin
    • Used for more chronic use (mo. – yr.)
    • Low MW fragments have a HIGH affinity for antithrombin III, inhibit factor X strongly, do NOT inhibit thrombin, and do NOT have a strong tendency to cause hemorrhage
  • Coumadin (Warfarin derivative): vitamin K-dependent anticoagulant
    • Prothrombin = coagulation factor dependent on vitamin K for synthesis
    • Can give orally, long-term prevention of thromboembolism
    • Inhibit the synthesis of coagulation factors – are NOT immediately active in vivo
    • Also decreases levels of protein C (antithrombotic agent) – so give with heparin for immediate therapy and to avoid an initial hypercoagulable state
    • PT is suggestive of drug efficacy – 2X increase from baseline. Monitor every 3-5 d. for 4-6 wk., then every few weeks while administering this drug
  • Newer anticoagulants: i.e. Rivaroxaban or apixaban – these drugs will likely replace Coumadin in the future

Thrombolytic therapy: treatment of acute thrombosis and arterial occlusion

• Dependent on presence of circulating plasminogen
• Plasmin = protease which cleaves circulating proteins, including fibrinogen, plasminogen, and also plasmin.
  • Fibrinogen degradation → fibrin degradation products (FDPs), which are anticoagulants
  • Excess concentration of plasmin due to generalized fibrinolysis activation (systemic fibrinolytic state) can → accumulation of plasmin, excessive fibrinolysis, bleeding
• Streptokinase: produced by Beta-hemolytic Streptococcus
  • Must be given in animals with plasminogen or plasmin BEFORE it can activate plasmin
  • Currently unavailable
• Urokinase: enzyme produced by human kidney cells, cleaves plasminogen
  • Theoretical advantages: preferential affinity for tissue plasminogen
  • Administered systemically or locally (intra-arterially)
  • Currently unavailable
• Tissue plasminogen activator (t-PA): an intrinsic (nonantigenic) protein of all mammals
  • Low affinity for circulating plasminogen – BIG advantage because it may allow systemic administration without induction of a systemic fibrinolytic state (will ONLY act on clots theoretically, but bleeding side effects are still possible)
  • Complications in cats with ATE
    • “Reperfusion syndrome” with hyperkalemia and metabolic acidosis
    • Bleeding complications
    • Neurologic signs
  • Surgery (embolectomy): not common in vet med
    • Is not stated to improve clinical outcome
    • One recent case report