Arterial, venous and lymphatic disorders

Question 1

Describe the differences between an ATE and an arterial thrombosis

Answer 1

• Thromboembolism is the result of arterial infarction from a thrombus derived at a distant site
• The underlying arterial wall at the site of ATE is normal
• Thromboembolism is typically the result of stagnant or reduced blood flow, with infectious (esp. endocarditis) and neoplastic (especially pulmonary neoplasia) thomboembolism also possible.
• Arterial thrombosis occurs secondary to arterial wall damage usually due to high shear flow within a narrowed vessel
• Both diseases cause disruption of the blood flow to an arterial vascular bed.

Question 2

Briefly describe the processes necessary for the development of an arterial thromboembolism

Answer 2

1. Primary haemostasis occures with subendothelial collagen following vascular wall injury
2. Platelet adhesion to the underlying collagen and vWF occurs
3. Platelet activation and aggregation
   
   • pro-aggregation factors are released
   • Localised vasoconstriction occurs
4. Coagulation cascade is triggered and secondary haemostasis begins
5. Haemostatic plug forms and endothelial injury repair commences
6. Pro-fibrinolytic mechanisms are activated to prevent excessive thrombus formation

For pathological thrombosis to form, a combination of the following must be present:

• Epithelial injury
• Blood stasis
• Hyper-coagulable state

Question 3

Note the potential sites of localisation for an arterial thromboembolism and the associated clinical signs

Answer 3

1. Kidney
   
   • Renal pain
   • AKI
2. Mesentery
   
   • Acute abdominal pain
   • Vomiting / diarrhoea
3. Spleen
   
   • Lethargy
   • Anorexia
   • Vomiting / diarrhoea
4. Brain
   
   • Variable neurological impairment depending on site of localisation
5. Distal aorta
   
   • Pelvic limb pain, weakness and neurological deficits
   • Signs are due to ischaemic neuromyopathy
6. Brachial artery
   
   • As for aortic obstruction but to a single forelimb
7. Smaller arteries
   
   • Firm painful muscles locally
   • +/- neurological deficits

Question 4

Discuss the major contributing mechanisms to the development of ischaemic neuromyopathy in the setting of acute aortic ATE.

Answer 4

• There is an extensive network of collateral circulation in the vertebral system and epaxial muscles in the normal cat. In experimental aortic obstruction, this network maintains normal pelvic limb perfusion
• With thromboembolism, vasoactive substances including serotonin are released from platelets
• Serotonin in the descending aorta contributes to vasoconstriction to the collateral circulatory network

Question 5

List the disease known to cause aortic thromboembolism in dogs and cats

Answer 5

1. Cardiac disease
2. Hyperadrenocorticism
   
   • Iatrogenic - corticosteroid excess
3. Protein losing nephropathy
4. Immune mediated haemolytic anaemia
5. Sepsis
6. Endocarditis
7. Pulmonary neoplasia

Question 6

Discuss the major management considerations for dogs of cats with acute thromboembolism

Answer 6

• Preventing further / ongoing thrombus formation
  
  • Note: given most originate elsewhere, identification of the underlying cause is necessary to plan rational treatment
• Improve blood flow to the infarcted region / organ
• Provide pain relief
• Identify and treat concurrent clinical conditions and provide appropriate supportive care.

Question 7

Discuss the evidence around the use of unfractionated and low molecular weight heparin in dogs and cats with arterial thromboembolism

Answer 7

UNFRACTIONATED HEPARIN

• Good evidence of efficacy in prolonging clotting in human medicine
• Dosing for adequate inhibition of clotting is variable and changes over time due to variation in circulating AT levels
• Monitoring of effective dosing is controversial
  
  • Prolongation of baseline APTT by 1.5-2.0 has been proposed
    
    • APTT may not correlate well with ciruclating UH
  • anti-Xa monitoring may be useful
    
    • Not been evaluated with regard to efficacy of thrombus inhibition
• When used in dogs, individual dose adjustment is essential or it should not be used. Helmond et al showed good survival to 6 months with individualised doses (7/8), but poor survival if given a constant dose (1/7)

LOW MOLECULAR WEIGHT HEPARIN

• Minimal evidence available
• Clinical trial data not published
• Doses of 100IU/kg SC q 12-24 hrs or 1-1.5 mg/kg SC q 12-24 hours have been reported

Question 8

Discuss the practical and evidence based limitations to using heparin therapy for thromboprophylaxis in small animal practice

Answer 8

1. Good evidence ot support the use of heparin in human medicine
2. Evidence suggests heparin therapy can be effective at prolonging the APTT and inhibiting Factor Xa (measured by assessing anti Xa activity).
3. Dosing in both dogs and cats can be highly variable
4. Dosing needs adjustment over time - likely due to reductions in circulating AT
5. APTT in cats may not correlate well with plasma unfractionate heparin concentration
6. Initially, IV injection is required followed by SC injection each 6-8 hours
7. Long courses of treatment are recommended in humans and small animals
8. LMWH can be administered q 12 hours, but is more expensive
9. Clinical trials demonstrating effective thrombus inhibition are lacking with LMWH in dog/cats

Question 9

List the various thrombolytic therapies that have been assessed or used in small animal medicine

Answer 9

1. Streptokinase
2. Urokinase
3. Tissue Fibrinogen Activator

Question 10

Note when thrombolytic therapy may or may not be indicated in cats or dogs

Answer 10

1. Thrombolytic therapy could be considered in patients with known cerebral, renal or splanchnic infarction
2. Ideally, therapy needs to be commenced within 18 hours of initial clinical signs (or 6 hours if following human literature)
   
   • It is often difficult to achieve a definitive diagnosis within this time frame for all but aortic TE.
3. Treatment of aortic thromboembolism in cats is highly controversial due to the high prevalence of reperfusion injury - reported in 40-70 % of cases and the most common cause of death when thrombolytic therapy is used.
   
   • A study looking at the use of tissue plasminogen activator revealed a similar % of reperfusion injury in treated versus non-treated cats

Question 11

Briefly note the method of action of streptokinase and note available evidence for use in canine/feline patients.

Answer 11

• Streptokinase is derived from streptococci
  
  • Can lead to antigenic stimulation and antibody production
• Complexes with plasminogen to form an activator complex - converts plasminogen to plasmin
  
  • The complex converts both circulating and fibrin-bound plasminogen and is considered a non-specific plasmin activator
• No reports of streptokinase use since 2000?.
• High complication rate reported
  
  • spontaneous bleeding in 24%, with 27% of those requiring blood transfusion
  • Repurfusion injury reported in 40% - no worse than when not used in more recent reports
• Responses showing return of arterial pulse was present in ~50% of cases, with better responses when only a single limb was involved.
  *

Question 12

Briefly detail the method of action and evidence supporting the use of tissue plasminogen activator in cats (and dogs) with thromboembolic disease

Answer 12

• Tissue plasminogen activator is the major activator of plasmin in vivo
• t-PA does not bind to circulating plasminogen, but rather has a high affinity for fibrin.
• t-PA is bound within thrombi as is fibrin-associated plasminogen, resulting in fibrin specific conversion of plasminogen to plasmin and local thrombolysis.
• When administered in high doses, t-PA can cause a systemic proteolytic state and promote bleeding
• t-PA was used in 16 cats and retrospectively compared to SOC treatment in 38 cats with aortic thromboembolism affecting 2 limbs
• Survival and complication rates were similar between the two groups
• Under-powered study to identify a small difference
• Retrospective nature of the study of significant limitation

Question 13

Discuss the therapeutic options for improving collateral circulation following acute arterial thromboembolism

Answer 13

• Collateral circulation appears to be inhibited by constriction secondary to release of vasoactive substances from platelets
  
  • serotonin
  • thromboxane
• Anti-platelet drugs such as aspirin and clopidogrel can inhibit platelet activation and aggregation or prevention of thromboxane production
  
  • Clopidogrel - active metabolite irreversibly binds to membrane ADP binding site.
  • Aspirin - inactivates COX-1 prevention thromboxane formation
• Initial high doses of clopidogrel can reduce circulating serotonin and a significant reduction in clinical signs associated with ATE has been demonstrated in experimental models
• Aspirin has been shown to reduce thromboxane release and improve collateral flow in experimental studies, but high doses are required - associated with toxicosis
• Clopidogrel may also reduce thromboxane production
• No objective clinical data to support their use, but clopidogrel could help and should not have significant adverse effects

Question 14

ATE - Prevention

Discuss the difference between primary and secondary prevention of ATE

When might primary or secondary prevention be recommended?

Answer 14

• Primary prevention of ATE refers to administration of medications in a patient considered to be at risk of having an ATE event
• Secondary prevention refers to treatment with medications to limit or reduce the risk of a second or subsequent ATE in a patient having already suffered a known ATE.
• Primary prevention with clopidogrel is recommended in cats with cardiac disease when the left atrium is significantly enlarged (>1.7 cm) or LA:ao ratio of > 2.0.
• Clopidogrel is also recommended if there is evidence of spontaenous echo contrast in the left atrium / left auricle or a noted thrombus within the chamber
• Prevention should also be considered for patients with IMHA and PLN.
• Secondary prevention is recommended for all patients having a known ATE event

Question 15

Detail the major findings to arise from the FAT CAT study:

Secondary prevention of cardiogenic thromboembolism in the cat

Answer 15

• Clopidogrel group: 443 days to recurrence of ATE
  
  • Clopdigrel was dosed at 18.75 mg / cat PO q 24 hours
• Aspirin group: 192 days to recurrence of ATE
  
  • Aspirin was dosef at 81 mg PO / cat q 72 hours
• No placebo group
• Significant reduction in the liklihood of recurrent ATE with clopidogrel versus aspirin
• Both drugs were well tolerated

Question 16

Describe the pharmacological actions of aspirin as it relates to thrombosis prevention

Answer 16

• Aspirin irreversibly acetylates cyclooxygenase (COX1)
  
  • COX1 is necessary for the production of thromboxane A2
    
    • Thromboxane potently stimulates platelet aggregation
    • Thromboxane is a potent vasoconstrictor
• By actions on COX, aspirin inhibits secondary platelet aggregation, not primary aggregation
• Aspirin also inhibits COX in endothelial cells, inhibiting the production of prosacyclin. Other mechanisms help the endothelial cells overcome this inhibition
• Aspirin is considered a modest anti-platelet drug
• Low dose aspirin (5 mg/cat q 72 hours) exerts a similar effect on platelet function (similar thrombosis recurrence) compared with higher dose (>40 mg/cat q 72 hours) with significantly fewer and more mild adverse effects (Smith JVIM 2003)

Question 17

Discuss the pharmacological effects of clopidogrel on platelet function

Answer 17

• A second generation thienopyridine that induces specific and irreversible antagonism of the ADP_2Y12 receptor on the platelet membrane
• By antagonising the ADP membrane, both primary and secondary platelet aggregation are inhibited
• The inhibition expands to effect multiple agonists of platelet aggregation
• Inhibits the ADP-induced conformational change of the glycoprotein IIb/IIIa complex
  
  • inhibits fibrinogen and vWF binding
• Impairs the release of vasoactive substances from the platelets
  
  • including serotonin and ADP
• Hepatic transformation of the parent drug is required for anti-platelets effects

Question 18

Discuss the mechanism of action of low molecular weight heparin

Answer 18

• LMWH contains a pentasaccharide sequence that binds to and ACTIVATES antithrombin III (AT).
  
  • AT normally inactivates thrombin, factor Xa and other proteases.
• LMWH thus enhances the inactivation of factor Xa, a crucial catalyst in the conversion of Prothrombin to thrombin
• LMWH will not bind to both AT and thrombin - at least 18 saccharide units are required to form a ATIII - thrombin - heparin bond.
• LMWH does not inhibit thombin (factor IIa) as unfractionated heparin does
  
  • Therefore, there is negligible effect on aPTT and TEG with LMWH therapy
• Due to predominanting effects on Xa, monitoring of Xa is necessary to assess efficacy.

Question 19

For what conditions are LMWHs recommended?

Answer 19

Cats:

• Minimal clinical indication at this stage
• Experimental studies have shown proof of concept with thrombus inhibition demonstrated
  
  • No good correlation between thrombus inhibiton effect and measurement of anti Xa activity.
• Known arterial thrombotic events - to prevent further growth of the thrombus
  
  • Prospective clinical studies are lacking
  • Retrospective studies demonstrated a comparable recurrence rate and median survival time with and without LMWH (conference abstracts - 2003)

Dogs

• Pulmonary thromboembolism
• Immune mediated haemolytic anaemia - controversial with one study showing similar survival with non-treated group.
  
  • Higher doses than have been studied may be required
• May not be effective for PLN due to low AT III levels.

Question 20

Identify the various physiological mechanisms that may contribute to oedema formation?

Answer 20

1. Increased venous hydrostatic pressure
2. Decreased Oncotic pressure
3. Increased vascular permeability
4. Altered lymphatic permeability
5. Altered lymphatic return

Question 21

Describe the physiological mechanisms that serve to control systemic venous return

Answer 21

1. Positive intravascular pressure behind and negative intracardiac pressure in front of the blood column
2. Lateral forces on the veins - especially muscle contraction
3. Gravity
4. Posture
5. Systemic vascular resistance
   
   • mediated by autonomic nervous system, hormones and vasoactive mediators
6. Pressure changes in the thorax during respiration
7. Anatomically, valves in the veins serve to prevent backflow

Question 22

Define the basic physiological roles of the lymphatic system in health and disease

Answer 22

1. Crucial role in regulation of interstital fluid volume\
2. Role in regulation of body cavity fluid volumes
   
   • Includes the trace volume normally present within the pleural and pericardial spaces
3. Modulation of fat absorption from the GIT
4. Removal of inorganic material from the SC space
5. Antigen transport
6. Immune surveillance
7. Route for the metastatic spread of cancerous cells

Question 23

Describe the mechanism by which fluid moves into the lymphatic system from the interstitium, along the lymphatics and ultimately back into the venous circulation.

Answer 23

• Lymphatic vessels contain endothelial cells with many gap junctions. The endothelial cells are anchored to the ECM by collagen and reticular fibres
• When the interstitial pressure increases (with fluid accumulation), the supporting fibres stretch causing the gap junctions to open
• Fluid passively moves from the ECM to the lymphatics along a pressure gradient until pressure is reduced, fibres contract and junctions close
• The junctions act like inlet valves, preventing backflow of fluid from the lymphatics into the ECM
• External forces including muscle contraction together with intrinsic smooth muscle contraction of the lymphatic vessels aids movement of the fluid
• In the lymph node, the lymphatic fluid and blood contact
  
  • ~50% of the fluid is returned to the circulation within the nodes
• The larger lymphatic ducts have fewer gap junctions between endothelial cells
• The thoracic duct drains back into the brachicephalic trunk or left subclavian vein
• The right lymphatic duct drains the right side of the head and neck and right forelimb and is independent of the thoracic duct

Question 24

List the various tests that can help identify venous or lymphatic disease processes and their typical indications

Answer 24

1. Angiography
   
   • traditional test to diagnose peripheral vascular disease
2. Ultrasonography
   
   • Useful for identification and localisation of venous or arterial thrombosis (eg. ATE, CVC thrombosis)
   • Useful for AV fistula diagnosis
   • Duplex imaging enhances the modality by helping define flow abnormalities around thrombosis or stenotic lesions
3. Cross sectional imaging
   
   • CTA
     
     • Largely replaced angiography for diagnosis of PSVA
     • Greater sensitivity for identification of intra-cavitary vascular anomalies when compared to US and traditional angiography
   • MRA
     
     • Contrast may not be required to visualise blood vessels/blood.
4. Lymphoscintigraphy
   
   • Described in sogs with mammary cancer but not commonly used in veterinary medicine
   • Used in people for oncological staging and to evaluate lymphatic drainage

Question 25

List the various diseases of the venous system seen in dogs and cats.

Indicate the relative frequency of each disease process.

Answer 25

1. Venous thrombosis - Common and likely under-diagnosed
   
   • Seconary thromboembolism - primarily pulmonary thromboembolism
2. Phlebitis - Common: IV catheterisation the most likely cause.
   
   • Typically a localised disease process, though sepsis, endocarditis and thromboembolic pneumonia can occur in immunocompromised patients
3. Traumatic injury - Common: typically self-limiting when clotting function is normal
4. Venous aneurism, varicosis, AV fistula.
5. Secondary venous compression due to a mass: Common with investigation and treatment generally directed at the primary process.

Question 26

Describe the conditions required for development of venous thromboembolism.

Note conditions often seen as risk factors for the development of venous thrombosis

Answer 26

• Classical components described by Virchow’s triangle
  
  • Vascular stasis
  • Endothelial injury
  • Hyper-coagulable state
• Venous thrombosis most often seen as a clinical problem in dogs or cats when secondary embolism to the pulmonary vasculature occurs

Predisposing diseases / causes:

1. IMHA - especially dogs
2. PLN
3. PLE
4. Hyperadrenocorticism
5. Corticosteroid use
6. Cardiac disease
7. Sepsis
8. DIC
9. Neoplasia
10. Hepatic disease - potential cause of portal or splenic vein thrombosis
11. Splenic torsion - cause of splenic vein thrombosis

NOTE: in a retrospective post-mortem study of 29 cats with PTE, 47% had multiple predisposing conditions.

Question 27

What is lymphadenitis and lymphangitis?

What are the common causes of inflammatory lymphatic disorders in dogs and cats?

Answer 27

1. Lymphadenitis: inflammation of the lymph node/s typically due to an infectious process
2. Lymphangitis: inflammation of the lymphatic vessel - typically caused by infection distal to the site of inflammation

• Localised infectious diseases are the most common causes of lymphadenitis/lymphangitis
  
  • Infection/inflammation of the skin, subcutaneous tissue or mucous membranes that drain to the affected node/lymphatic vessels
  • Foreign body reaction
  • Fungal infection including coccidiomycosis
  • in association with PLE due to chronic lipogranulomatous lymphangitis

Question 28

Define lymphodema

Describe the various causes of decreases lymphatic drainage

Answer 28

• Lymphoedema is the abnormal accumulation of fluid within the interstitial space resulting from abnormal lymphatic drainage.
• Lyphoedema fluid is protein rich 20-50 g/L, causing a high osmotic gradient which exaccerbates fluid accumulation
• Interstitial fluid accumulates as normal due to movement of fluid from the vascular bed into the interstitium.
• Lymphatic drainage is reduced due to:
  
  • lymphatic obstruction
  • Inadequate collection into the lymphatics
  • abnormal lymphatic vessel contractility
  • Insufficient or “leaky” lymphatics
  • Lymph node obstruction
  • Large lymphatic duct defects
• Primary and secondary lymphatic function defects can contribute to lymphoedema formation
  *

Question 29

Note the mechanisms that help limit the accumulation of lymphodema.

Describe the secondary causes of lymphoedema seen in cats and dogs.

Answer 29

Note: significant damage or obstruction to smaller lymphatics, multiple lymph nodes or larger lymphatic channels must occur to cause lymphoedema due to extensive collateral network and multiple mechanisms for re-routing lymph flow.

• Oppening of collateral vessels
• Re-routing through lymphaticovenous anastomoses
• Perilymphatic routes of drainage
• Increased venous fluid uptake

1. secondary lymphoedema typically forms in the face of concurrent lymphatic and venous obstruction.
2. Blockage of lymphatics / lymph nodes with compressive or invasive neoplasia
3. Post-surgery - including lymph node excision
4. Post radiation