Thrombosis in Veterinary Medicine

Thrombosis in Veterinary Medicine

• Thrombosis and thromboembolism
  • Obstructive shock
  • Impaired regional oxygen delivery
  • Impaired blood flow
  • Organ dysfunction/failure
  • Primarily microthrombosis
  • Complications of therapy, e.g., catheter associated thrombosis

Diagnosis of Thrombosis

• Physical exam
  • Affected extremity is often colder than others
  • Ischemic muscles are painful and hard (ischemic myopathy)
  • Thrombophlebitis (warmth and swelling over a vein, usually at site of prior venipuncture or catheter)
• Signs of organ failure
• Pulmonary thromboembolism (characterized by acute dyspnea)
• Acute kidney injury
• Hepatic injury
• Stroke or other acute neurologic decline
• Sudden death may occur from massive thrombosis
• Ultrasound or other imaging (e.g. CT) may identify thrombi in situ

Hypercoagulability: Theory

• Virchow (circa 1845)
  • Endothelial damage
  • Hypercoagulable state
  • Blood stasis/ alterations in blood flow

Endothelial Dysfunction

• Alterations of glycocalyx exposing procoagulant triggers
• Inflammation
• Fluid therapy
• Direct injury
• Release of von Willebrand factor (vWF)
• Activated endothelial cell

Hypercoagulable State

• Increased procoagulant proteins
  • Sepsis
  • Inflammation
  • Surgery, including surgery for fibrinogen
  • Hyperadrenocorticism (heredity may be a factor)
  • Increased heritability
• Decreased anticoagulant proteins
  • Sepsis
  • Inflammation
  • Gastrointestinal (GI) disease
  • Renal disease

Blood Stasis

• Activation of intrinsic pathway
• Decreased blood flow
• Abnormal blood flow
• Intravascular foreign material
• Negative charge
• Biofilm production

Arterial vs Venous Thrombosis

• Arterial clots ("white clots")
  • Predominantly platelets
  • Activated with high shear blood flow
  • Antiplatelet agents are the primary therapy
• Venous clots ("red clots")
  • Low pressure/venous stasis
  • Rich in fibrin, erythrocytes
  • Anticoagulant agents are the primary therapy

Cardiac Disease

• Feline cardiac disease
  • Left atrial dilation
  • Spontaneous echocontrast
  • Reduced left atrial appendage flow velocity
  • Thromboembolic sequelae (primarily arterial thromboembolism (ATE)).
• Heartworm (pulmonary artery thrombosis)
• Worm thrombus vs. clot
• Transvenous pacemakers
• Uncommon clot formation on leads

Immune-mediated Hemolytic Anemia (IMHA)

• Strongly associated with thrombosis in dogs
• Anticoagulation is standard therapy component
• Risk factors include:
  • Severe inflammatory response
  • High fibrinogen, decreased antithrombin
  • RBC membranes in the circulation
  • Corticosteroid therapy
  • IV access, sometimes multiple
  • Multiple blood transfusions

Protein Losing Conditions

• Protein losing nephropathy (PLN)
  • Associated with thrombosis
  • Possibly due to loss of antithrombin
• Protein losing enteropathy (PLE)
  • Loss of proteins including antithrombin
  • Small and large animals

Glucocorticoids, Hyperadrenocorticism

• Treatment with corticosteroids is associated with a hypercoagulable state
• Risk of thrombosis with hyperadrenocorticism (dogs)

Infectious Disease

• Dogs with sepsis (especially endocarditis, septic peritonitis, aspiration pneumonia) without coagulopathy are at risk of thrombosis
• Does not support routine anticoagulation in septic dogs
• Neonatal sepsis (foals)
• Presence of coagulopathy worsens prognosis
• EHV-1 infection (adult horses)
• Vasculitis, thrombosis → myeloencephalopathy

Equine Gastrointestinal Disease

• Jugular thrombophlebitis or other thrombosis
• Ischemic/strangulating Gl lesions
• Colitis
• Duodenitis/proximal jejunitis
• Right dorsal colitis
• Jugular thrombophlebitis is more likely in horses with surgically treated colic that develop fever or diarrhea.
• Salmonellosis (also a risk factor)
• Thrombosis may initiate at venipuncture site or on catheter

Other Conditions

• Neoplasia
  • Carcinomas in dogs are associated with a risk of thrombosis.
  • Overall prevalence is unknown.
• Cerebrovascular disease
  • May result from a thrombotic event (rather than cause).
• Pancreatitis (dogs)
• Extracorporeal circuits (e.g., dialysis)
  • Activates coagulation during treatment

Vascular Access/Devices

• Transvenous pacemaker leads
• IV catheters
• Central lines
• Catheter-associated thrombi are common in patients with severe inflammation.
• Consideration of the number and type of venous catheter is important
• Catheter alone is not usually a risk factor.

When are Anticoagulant Drugs Indicated?

• Animals with existing thrombi/thromboembolism
• Animals with a single strong risk factor
• Animals with multiple moderate risk factors
• Always indicated for dogs with IMHA, cats with heart disease

Disease Risk Factor Summary

• Table summarizes conditions, thrombosis risk levels, and recommended anticoagulation use.

Anticoagulant Drugs

• Absence of clear evidence for any single drug/class superiority
• Specific mechanisms (e.g., platelet vs factor)
• Ease of administration; cost

Acetylsalicylic Acid (ASA; Aspirin)

• Inhibits cyclooxygenase (COX)
  • Prevents production of AA metabolite thromboxane (TXA2)
  • Thromboxane is a potent platelet agonist, vasoconstrictor
  • Irreversible COX inhibition
• Decreases platelet aggregation in dogs
• Does reliably impact platelet aggregation in cats or horses

FAT-CAT: Aspirin vs Clopidogrel

• Prevention of recurrent ATE in cats
• 42 dogs, 18.75 mg po q24
• 43 ASA, 81mg po q72h
• Recurrent TE in:
• 19/39 clopidogrel (49%)
• 27/36 ASA (75%)
• Median time to recurrence
• 443 days, (7-990 days) clopidogrel
• 192 days, (6-883 days) ASA

Heparin

• Potentiates AT inhibition (unfractionated heparin (UFH))
• Binds antithrombin (AT) and Flla, FXa
• Low-Molecular weight heparin (LMWH)
  • Binds Xa
    • Dalteparin
    • Enoxaparin
• Can measure anti-Xa activity to dose either directly
• Directly correlated to drug

Types of Heparins

• Unfractionated Heparin (UFH)
  • In dogs/cats/horses with risk of thrombosis
  • Variability in optimal UFH dose
  • Interactions with plasma proteins, endothelial cells, macrophages
  • Bleeding - less specific binding to clotting factors (esp. lla)
  • Erythrocyte agglutination and thrombocytopenia (horses)
• Low molecular weight heparin (LMWH)
  • Used in dogs, cats, and horses with variable dosing regimens
  • More frequent dosing is often needed to achieve similar efficacy compared to humans
  • More predictable PK/PD
  • Not associated with RBC agglutination in horses

Other Uses for Heparin in Horses

• Hyperlipemia
  • Increased release of lipoprotein lipase
  • Increased release of hepatic lipase
  • LMWH may prevent platelet activation from EHV-1
  • Adhesion prevention: effective

Direct Xa Inhibitors

• Rivaroxaban (Xarelto); apixaban (Elliquis)
  • Inhibit Factor Xa directly
  • No need for antithrombin
  • Predictable pharmacokinetics
  • Irreversible inhibition of Factor Xa
  • Well-tolerated in dogs and cats

Antiplatelet Agents vs Anticoagulants for ATE

• Dogs
  • Antiplatelet agents may be more effective
  • Anticoagulants also effective
• Cats
  • Clopidogrel recommended for ATE prevention.

Combination Therapy

• Combination associated with high incidence of bleeding complications
• Especially GI (PPI is recommended)
• Clopidogrel preferred over ASA
• Deescalate therapy (often antiplatelet drug) after acute need, based on risk
• Coadministration of rivaroxaban/clopidogrel (rare)
• Bleeding in one dog (0.8mg/kg RVX, 4mg/kg clopid)
• 0.5 mg/kg RVX, 2mg/kg clopidogrel is successful treatment
• Coadministration of apixaban/clopidogrel
  • Apixaban up to 1 mg/kg PO q12h; clopidogrel 1.875 mg/kg PO q24h
• Appears safe in healthy dogs

Fibrinolytic Drugs

• Tissue plasminogen activator (tPA)
  • Injectable activator of plasmin
  • Rapid effect: may cause reperfusion injury
  • Breaks down all clots
  • Catheter-delivered
  • May be superior