256 Arterial Thromboembolic Disease

Question 1

What is the pathogenesis of thromboembolic disease?

Answer 1

The development of pathologic thrombosis is described through Virchow’s triad: endothelial injury, blood stasis, and presence of hypercoagulable state.

• endothelial injury can result from dilated LA, damaged aortic valve with subaortic stenosis, or tumour invasion of arterial tree
• blood stasis: associated with dilated cardiac chambers or restricted blood flow from tumour growth
• hypercoagulable state is difficult to identify specifically, especially in our domestic animal species.
• Additional hypercoagulable states associated with platelet hypersensitivity, and increase homocysteine, lipoprotein, plasminogen activator inhibitor (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI).
• clinical thrombosis in dogs and cats associated with increased platelet hypersensitivity, decreased AT and protein C activity, and increased factors II, V, VII, VIII, IX, X, XII and fibrinogen.

Question 2

What are the clinical signs of ATE...
Renal infarction?
Splenic?
Neurological?
Aortic trifurcation?

Clinical signs associated with vascular bed infarction

Answer 2

• Depends on degree of infarction and location of infarction vascular bed.
• Severity of clinical signs is inversely proportional to amount of arterial blood flow around a site of obstruction to major artery.
• Renal infarction = signs of renal pain and AKI while mesenteric infarction result in evidence of abdominal pain, vomiting, and diarrhoea
• Splenic infarction associated with lethargy, anorexia, vomiting, and diarrhoea.
• Neurologic deficits an seizures associated with cerebral infractions as well as sudden death in severe cases
• Aortic trifurcation infarction accounts for majority of ATE cases in dogs and cats. Result in loss of blood flow to pelvic limbs and ischemic neuromyopathy (INM). This causes paresis or paralysis of pelvic limbs with absent segmental reflexes, firm and painful pelvic limb musculature, and cold and pulse less limbs with cyanosis nail beds.
• Clinical signs associated with infarction vascular bed= fever, depression and dyspnea with sepsis;
  depression, tachypnoea and pallor with IMHA;
  depression and ascites or peripheral oedema with nephrotic syndrome, tachypnoea, weakness and polyuria/olydipsia with hyperA, dyspnea, and cardiac murmur, or gallop sounds with underlying cardiac disease.

Question 3

How is ATE treated?

Answer 3

• Prevent continued thrombus, - improve blood flow to infarcted organ
• pain management when appropriate
• treat concurrent clinical conditions
• supportive care.

Question 4

What can be administered tor reduce thrombus formation?

Answer 4

Reduce thrombus formation….
- unfractionated heparin - contains pentasaccharide sequence that binds to AT, facilitating the inhibition of IIa, Xa, IXa, and XIIa. There is also inhibition of thrombin, catalysed activation of factors V and VIII.

• low molecular weight heparin (LMWH):daleparin and enoxaparin has been used in dogs and cats 100 IU/kg sc q 12-24h and 1-1.5mg/kg SC q 24-12 respectively, but no clinical trials done.

Question 5

What can be administered to improve the arterial blood flow?

Answer 5

Arterial flow - thrombolytic therapy

• To re-establish arterial flow to the infarcted organ requires removal of the embolus either through embolectomy or dissolution with thrombolytic drugs.
• consider in cases of cerebral, splanchnic or renal infarction, as re-establishment of arterial flow is important.
• start asap within 18hrs of event
• adverse effects: sudden resumption of arterial flow to infarcted organ result in rapid development of life-threatening hyperkalemia and severe metabolic acidosis (reperfusion injury). 40-70% frequency in cats, and common cause of death.

Streptokinase (SK)

• combines with plasminogen to form activator complex that converts plasminogen to proteolytic enzyme plasmin
• plasmin degrades fibrin, fibrinogen, plasminogen, coagulation factors and SK. SK-plasminogen complex converts circulating and fibrin-bound plasminogen and is considered nonspecific activator of plasmin.
• streptokinase is produced by streptococci which leads to antigenic stimulation especially after repeated administrations.
• given 90,000 IU IV over 1 hour followed by 45,000 IU/hr for u to 12 hours in dogs and cats.
• Spontanteous bleeding occurred form oral, rectal, or catheter items in 24% of cats and reperfusion injury in 40%
• 33% survival rate

Urokinase

• more fibrin specific due to physical characteristics.
• commercial preparations consist of HMW and LMW fractions.
• HMW are more concentrated but convert to LMW in circulation.
• LMW bind with greater affinity to lysine-plasminogen form of plasminogen which accumulate in them I.
• administered IV to cats and dogs for ATE with 4,400 IU/kgloading dose over 10 minutes followed by 4,400 IU/kg/h for 12 hours..
• no spontaneous bleeding, but reperfusion injury seen in 255 of treated cats.

Tissue plasminogen activator

• t-PA is primary activator of plasmin; however does not bind to circulating plasminogen.
• plasminogen and t-PA have high affinity for fibrin, thereby forming an relationship with thromboembolic result in in fibrin-specific conversion of plasminogen to plasmin.
• little clinical experience. Administered IV as CRI in cats 0.25-1m/kg/h IV for total dose of 1-10mg/kg) or multiple bolus therapy in dogs 1mg/kg IV.
• complications include minor haemorrhage from catheter site, fever, and reperfusion injury. 50% survival rate due to reperfusion injury, and cardiogenic shock.

Question 6

How can collateral flow be improved?

Answer 6

• Platelets releasing serotonin and thrombocytes have been implicated as potential agents responsible for loss of collateral flow associated with aortic infarction.
• Therefore antiplatelet agents improve collateral flow by reducing vasoactive substances released from platelets
• aspirin reduces amount of thromboxane from cat platelets and improves collateral flow in experimental model, but very high levels (i.e. toxic) was used.
• clopidegrol reduces serotonin release in cats, and reduced thromboxane production in other species.

Question 7

What pain management can be utilised?

Answer 7

Narcotics (give cranial to diaphragm for adequate absorption)

• butorphanol 0.1-0.4 mg/kg SC, IM, IV q 1-4h dogs and cats
• hydromorphone 0.08-0.3 mg/kg SC, IM, IV q2-6h dogs and cats
• buprenorphine 0.005-0.02 mg/kg SC, IM, IV q 2-6h dogs and cat
• oxymorphone 0.05-0.2 mg/kg SC, IM, IV q 1-3h; dogs and cats
• fentanyl 4-10mcg/kg IV followed by 4-10 mcg/kg/h IV infusion; dogs and cats

Question 8

What is the reported survival rate for CE events in cats?

Answer 8

• conservative: 35-39% or thrombolytic 33%
• single pelvic limb do better 68-93% and bilateral pelvic limb infarction 15-36%.
• nonsurival rates from 61-67% with natural death rates 28-40% similar to euthanasia rate 25-35%.
• nonsurvial rate are significantly associated with hypothermia, reduced heart rate, and absent motor function.
• MST ranged from 51d-345days

Question 9

What is primary and secondary prevention and when is it applied?

Answer 9

Primary prevention = reduce risk of first thromboembolic event

• cats at greater risk if large left atrial size or evidence of systolic dysfunction.
• prophylactic echocardiography of end-systolic eft atrial diameter >1.7cm or left atrium-to-aortic ration (LA/Ao)>2.0.
• prophylactic anithombotic therapy indicated in cats with spontaneous contrast in left atrium on echo

Secondary prevention = defined as preventing subsequent ATE in animal with history of ATE

• FAT CAT study was double-blind, randomised, and positive controlled multicenter study that enrolled 75 cats after they survived a CE event.
• clopidegrol 18.75 mg/cat PO q 24h associated with reduced likelihood of recurrent CE compared to aspirin and longer median time to recurrence (443d V 192 d). Clopidegrol also reduced likelihood of composite endpoint of recurrent CE or cardiac death with a longer median time to even (346d V 128 d)

Question 10

What is the action of aspirin?

Answer 10

• antiplatelet agent
• irreversibly acetylates platelet cycoloxygnase, preventing formation of thromboxane A2, which has potent pro-aggregating vasoconstrictive properties.
• aspirin also exerts similar affect on cyclooxygenase in endothelial cells, reduces prostacyclin production, which is a substance that exhibits anti-aggregation and vasodilation properties. Endothelial cells overcome this inhibition so antithrombotic properties predominate in the clinical setting.
• recurrence rate is 17-75%
• adverse effects: GIT (anorexia, vomiting) reported in 22% of treated cats. FAT CAT study used gelatin capsules which was less irritating on the stomach and does not cause ulcers. Healthy dogs receiving aspirin reported uniformly moderate gastroduodenal endoscopic lesions including erosions and submucosal haemorrhages.

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Question 11

What is the mode of action of clopidegrol?

Answer 11

• second generation thienpyridine induces specific and irreversible antagonism of the ADP(2YI2) receptor along the platelet membrane.
• inhibits primary and secondary platelet aggregation in response to multiple agonists
• more potent than aspirin.
• ADP-induced conformational change of glycoproteins IIb/IIIa complex is inhibited, which reduces binding of fibrinogen and von Willebrand factor
• Also impairs platelet release reaction, decreasing release of pro-aggregating and vasoconstrictive agents such as serotonin and ADP
• cats: 18.75mg/cat PO q 24h, max antiplatelet effect after 3 days and lost within 7 days.
• Similar in dogs 1-3 mg/kg PO q 24h. Hepatic P450 enzyme systems results in antiplatelet effects at lower dosages, presumably due to increased bio transformation of parent molecule .

Question 12

How does warfarin work, what is the MOA?

Answer 12

• inhibits vitamin K dependent coagulation factors II, VII, IX, and X as well as anticoagulant proteins C and S.
• protein c levels fall prior to decrease coagulation factors, theoretically resulting in hypercoagulable state for 4-6 days. UH is typically administered during this period.
• bleeding is common complication
  Enterohepatic circulation contributes to widely variable inter- and intra- individual anticoagulant response.

Question 13

What are The low molecular weight heparin? How do they work?

Answer 13

• 4-5k Daltonsbut maintain pentasaccharide sequence that binds to AT, inhibiting factor Xa, with greatly reduced inhibition of IIa.
• reduced anti-IIa activity translates into negligee effect on aPTT and thromboelastography (TEG) with LMWH therapy. Monitoring is measured through anti-Xa activity.
• dalteparin and enoxaparin produced similar results: peak anti-Xa levels at 4 hours that decrease below limit of detection at 8 hours in cats.
• bleeding complications are rare.