Arterial Thromboembolic Disease- Ettinger

Question 1

Arterial thromboembolism (ATE) is defined as?

Answer 1

The infarction of one or more arterial beds by embolic material usually derived from a thrombus at a site distant to the infarcted arterial bed.

Question 2

It is important to differentiate ATE from arterial thrombosis for multiple reasons. Why?

Answer 2

1. First, the underlying pathology is usually very different. The endothelial surface of the infarcted vessel is normal in cases of ATE, whereas disruptions to the vascular endothelium and/or vascular wall are hallmarks of arterial thrombosis.

2.Secondly, ATE is usually associated with stagnant flow or blood stasis, whereas arterial thrombosis is associated with high shear flow within a narrowed blood vessel.

3. Thirdly, ATE commonly occurs in veterinary patients, whereas true arterial thrombosis is exceedingly rare.
   In some instances, the site of the initiating thrombus is either known or reliably suspecte

Question 3

With cardiogenic embolism (CE), thrombi are most often found within a dilated left atrium or auricle. The heart is also the source of emboli that develop with endocarditis.

However, many times the source of the thrombus cannot be determined and these include conditions such as …….. and ……………………

Answer 3

With cardiogenic embolism (CE), thrombi are most often found within a dilated left atrium or auricle. The heart is also the source of emboli that develop with endocarditis. However, many times the source of the thrombus cannot be determined and these include conditions such as neoplasia and protein-losing nephropathy.

Question 4

Some have suggested that deep venous thrombi are the source of the embolic material, but this would not explain the arterial location of the embolus in the absence of a right-to-left shunting defect. ……..embolism, thromboembolic stroke resulting from deep venous thrombosis, occurs in humans and is usually associated with an atrial septal defect such as a persistent foramen ovale. This has been reported in veterinary medicine[1] and could be the situation for many more of our domestic animal species because a recent study suggests that atrial septal defects are much more common in the dog than originally suspected. Pulmonary ………. is unique in that thrombosis within a pulmonary vein could generate an embolus that travels through the systemic arterial tree.

Answer 4

Some have suggested that deep venous thrombi are the source of the embolic material, but this would not explain the arterial location of the embolus in the absence of a right-to-left shunting defect. Paradoxical embolism, thromboembolic stroke resulting from deep venous thrombosis, occurs in humans and is usually associated with an atrial septal defect such as a persistent foramen ovale. This has been reported in veterinary medicine[1] and could be the situation for many more of our domestic animal species because a recent study suggests that atrial septal defects are much more common in the dog than originally suspected.[2] Pulmonary neoplasia is unique in that thrombosis within a pulmonary vein could generate an embolus that travels through the systemic arterial tree.

Question 5

PATHOGENESIS

In the normal healthy state, there is a delicate equilibrium between thrombus formation and thrombus dissolution. This delicate balance allows for continuous repair of endothelial injury while preventing the unregulated formation of thrombus development.

Answer 5

In the normal healthy state, there is a delicate equilibrium between thrombus formation and thrombus dissolution. This delicate balance allows for continuous repair of endothelial injury while preventing the unregulated formation of thrombus development.

Question 6

Describe primary hemostasis?

Answer 6

1. Primary hemostasis begins with the exposure of subendothelial collagen and is characterized by adhesion of platelets to the subendothelial site.
2. Platelet activation and aggregation follow with release of agents exhibiting proaggregating and vasoconstrictive properties that, in conjunction with circulating factors within the plasma, initiate the coagulation cascade resulting in secondary hemostasis.
3. As the hemostatic plug is formed and endothelial healing is taking place, profibrinolytic mechanisms are activated to break down the developing hemostatic plug, thereby preventing excessive thrombus formation.

Question 7

Pathologic thrombosis happens when the balance between thrombus formation and fibrinolysis is deranged.
The development of pathologic thrombosis has classically been described through Virchow’s triad; this includes?

Answer 7

Endothelial injury, blood stasis, and the presence of a hypercoagulable state.

Question 8

Endothelial injury could result from a dilated left atrium in a cat with hypertrophic cardiomyopathy, damaged aortic valve in a dog with subaortic stenosis, or tumor invasion of the arterial tree.

Blood stasis can be associated with dilated cardiac chambers or restricted blood flow from tumor growth.

The presence of a hypercoagulable state is much more difficult to specifically identify, especially in our domestic animal species. Known hypercoagulable states in humans include inherited abnormalities in the procoagulant factors IIa (thrombin), Va, and VIIIa, as well as the antithrombotic proteins antithrombin III (AT III ), protein C, and protein S.[3-7] Additional hypercoagulable states have been associated with platelet hypersensitivity and increases in homocysteine, lipoprotein(a), plasminogen activator inhibitor (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI).

Clinical thrombosis in dogs and cats has been associated with?

Answer 8

Increased platelet hypersensitivity,
Decreased AT III and protein C activity
Increases in factors II, V, VII, VIII, IX, X, XII, and fibrinogen.

It seems prudent to view the development of pathologic thrombosis through the concept of cumulative risk where each arm of Virchow’s triad contributes to an increased risk of thrombosis.

Question 9

Early pathologic thrombus composition is platelet rich but progressively becomes more fibrin-rich as the thrombus continues to grow. As the thrombus matures, it will become lamellated where superficial portions can break off, forming emboli that infarct distant arterial beds. The level of infarction is dependent upon the size and stability of the embolus because obstruction occurs where the size of the embolus reliably exceeds vessel diameter.

Answer 9

Early pathologic thrombus composition is platelet rich but progressively becomes more fibrin-rich as the thrombus continues to grow. As the thrombus matures, it will become lamellated where superficial portions can break off, forming emboli that infarct distant arterial beds. The level of infarction is dependent upon the size and stability of the embolus because obstruction occurs where the size of the embolus reliably exceeds vessel diameter.

Question 10

CLINICAL SIGNS

Clinical signs attributable to ATE are dependent upon the degree of infarction and the location of the infarcted vascular bed. The severity of clinical signs is inversely proportional to the amount of arterial blood flow. Many organs have a …………… network that can be recruited to provide blood flow around a site of obstruction to a major artery. However, these networks develop more fully with gradual loss of blood flow and there is strong evidence that the acute infarction caused by ATE is associated with an impaired development of these networks.

Answer 10

Clinical signs attributable to ATE are dependent upon the degree of infarction and the location of the infarcted vascular bed. The severity of clinical signs is inversely proportional to the amount of arterial blood flow. Many organs have a collateral network that can be recruited to provide blood flow around a site of obstruction to a major artery. However, these networks develop more fully with gradual loss of blood flow and there is strong evidence that the acute infarction caused by ATE is associated with an impaired development of these networks.

Question 11

Renal infarction has been associated with renal pain and acute renal failure, whereas mesenteric infarction can result in abdominal pain, vomiting, and diarrhea. Splenic infarction can present with lethargy, anorexia, vomiting and diarrhea.[17] Profound neurologic deficits and seizures have been associated with cerebral infarctions as well as sudden death in severe cases.[1]
Although cerebral, renal, and splanchnic infarction occur occasionally, infarction of the ……………… accounts for the majority of ATE cases in dogs and cats.

Answer 11

Renal infarction has been associated with renal pain and acute renal failure, whereas mesenteric infarction can result in abdominal pain, vomiting, and diarrhea. Splenic infarction can present with lethargy, anorexia, vomiting and diarrhea.[17] Profound neurologic deficits and seizures have been associated with cerebral infarctions as well as sudden death in severe cases.[1]
Although cerebral, renal, and splanchnic infarction occur occasionally, infarction of the aortic trifurcation accounts for the majority of ATE cases in dogs and cats.[18]

Question 12

Infarction of the aortic trifurcation (classic saddle embolus) results in a loss of blood flow to the pelvic limbs, which causes ischemic neuromyopathy (INM) (Web Figure 255-1). Clinical signs of INM include?

Answer 12

Paresis or paralysis of the pelvic limbs with absence of segmental reflexes, firm and painful pelvic limb musculature, and cold and pulseless limbs with cyanotic nail beds. The changes can be bilateral and symmetric, bilateral and asymmetric, or unilateral depending upon the degree of obstruction and degree of collateral vessel development. Clinical signs develop acutely and can worsen but usually remain stagnant or improve over the next several days to 3 weeks.

Question 13

A major contributing factor to the development of INM appears to be the release of …………… from activated platelets reducing collateral flow around the site of obstruction.
Similar pathophysiologic changes have been identified in humans suffering from thrombotic stroke, CE, cardiogenic thromboembolic stroke, and pulmonary embolism.[19-22] With experimental aortic ligation, blood flow is maintained through an extensive collateral circulation in the vertebral system and epaxial muscles (Web Figure 255-2).[15,16,23] However, this collateral circulation is lost with the presence of a thrombus in the aortic segment and clinical signs of INM are evident. …………, released from activated platelets, appears to be at least one major factor for this finding. Research models have demonstrated that the presence of serotonin in an isolated aortic segment results in loss of the collateral network and signs of INM, whereas pretreatment with serotonin antagonists prevents these changes.[16],[24]

Answer 13

A major contributing factor to the development of INM appears to be the release of vasoactive substances from activated platelets reducing collateral flow around the site of obstruction. Similar pathophysiologic changes have been identified in humans suffering from thrombotic stroke, CE, cardiogenic thromboembolic stroke, and pulmonary embolism.[19-22] With experimental aortic ligation, blood flow is maintained through an extensive collateral circulation in the vertebral system and epaxial muscles (Web Figure 255-2).[15,16,23] However, this collateral circulation is lost with the presence of a thrombus in the aortic segment and clinical signs of INM are evident. Serotonin, released from activated platelets, appears to be at least one major factor for this finding. Research models have demonstrated that the presence of serotonin in an isolated aortic segment results in loss of the collateral network and signs of INM, whereas pretreatment with serotonin antagonists prevents these changes.[16],[24]

Question 14

Infarction of the ………………… artery is the second most common site of ATE, at least in cats with underlying cardiac disease. The clinical signs associated with infarction of this site are essentially identical to those for infarction of the aortic trifurcation, although the signs are confined to the ………………………….

Answer 14

Infarction of the right subclavian artery is the second most common site of ATE, at least in cats with underlying cardiac disease. The clinical signs associated with infarction of this site are essentially identical to those for infarction of the aortic trifurcation, although the signs are confined to the right forelimb.

Question 15

In addition to the clinical signs associated with the infarcted vascular bed, additional clinical signs related to the underlying disease may be present. These could include fever, depression, and dyspnea with sepsis; depression, tachypnea, and pallor with immune-mediated hemolytic anemia; depression and ascites or peripheral edema with nephrotic syndrome; tachypnea, weakness, and polyuria/polydipsia with hyperadrenocorticism; dyspnea; and cardiac murmur or gallop sounds with underlying cardiac disease. In cats with CE, concurrent congestive heart failure (CHF) has been reported in 44% to 66% of cases.

Answer 15

In addition to the clinical signs associated with the infarcted vascular bed, additional clinical signs related to the underlying disease may be present. These could include fever, depression, and dyspnea with sepsis; depression, tachypnea, and pallor with immune-mediated hemolytic anemia; depression and ascites or peripheral edema with nephrotic syndrome; tachypnea, weakness, and polyuria/polydipsia with hyperadrenocorticism; dyspnea; and cardiac murmur or gallop sounds with underlying cardiac disease. In cats with CE, concurrent congestive heart failure (CHF) has been reported in 44% to 66% of cases.

Question 16

TREATMENT

Key elements in the acute management of ATE include preventing continued thrombus formation associated with the embolus, improving blood flow to the infarcted organ, pain management when appropriate, treating concurrent clinical conditions, and supportive care.

Answer 16

Key elements in the acute management of ATE include preventing continued thrombus formation associated with the embolus, improving blood flow to the infarcted organ, pain management when appropriate, treating concurrent clinical conditions, and supportive care.

Question 17

Reduce Thrombus Formation

Unfractionated heparin (UH) is a group of heterogeneous molecules with a mean molecular weight of approximately ….,000 Daltons (range of 3,000 to 30,000 Daltons). Due to the variability in ………………….., the pharmacokinetic and anticoagulant properties can be quite variable.

Heparin molecules contain a pentasaccharide sequence that binds to AT ……, facilitating the inhibition of…………………………………..
There is also an inhibition of thrombin-catalyzed activation of factors …. and ………

Unfractionated heparin also exhibits an ……………. effect in normal humans by inhibiting thrombin-induced platelet aggregation, as well as binding to and inhibiting von …………………(….).

Answer 17

Reduce Thrombus Formation

Unfractionated heparin (UH) is a group of heterogeneous molecules with a mean molecular weight of approximately 15,000 Daltons (range of 3,000 to 30,000 Daltons). Due to the variability in molecular size, the pharmacokinetic and anticoagulant properties can be quite variable.

Heparin molecules contain a pentasaccharide sequence that binds to AT III, facilitating the inhibition of IIa, IXa Xa, and XIIa.
There is also an inhibition of thrombin-catalyzed activation of factors V and VIII.

IIa, V, VIII, IX, Xa och XIIa

Unfractionated heparin also exhibits an antiplatelet effect in normal humans by inhibiting thrombin-induced platelet aggregation, as well as binding to and inhibiting von Willebrand factor (VWF).

Question 18

The most common adverse effect of heparin therapy in humans is ……………, but heparin-induced ………………… can develop in up to 10% of patients. Objective studies evaluating the bleeding risk in dogs and cats receiving heparin therapy do not exist, although bleeding has certainly been reported.

Answer 18

The most common adverse effect of heparin therapy in humans is bleeding, but heparin-induced thrombocytopenia can develop in up to 10% of patients.

Objective studies evaluating the bleeding risk in dogs and cats receiving heparin therapy do not exist, although bleeding has certainly been reported. To the author’s knowledge, there is no clinical report of heparin-induced thrombocytopenia in dogs or cats.

Question 19

Ideally, a coagulation panel including …………….(3) should be submitted prior to heparin therapy. This allows baseline coagulation function to be determined prior to heparin therapy, as well as identifying animals that may have a coagulopathy such as disseminated intravascular coagulation associated with the ATE event.

Answer 19

Ideally, a coagulation panel including platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be submitted prior to heparin therapy. This allows baseline coagulation function to be determined prior to heparin therapy, as well as identifying animals that may have a coagulopathy such as disseminated intravascular coagulation associated with the ATE event.

Question 20

Adequate dosing of heparin in dogs and cats has been shown to be quite variable and dosing requirements may change over time due to a decrease in AT III levels.[28-30] Reasonable dosing regimens include 250 to 375 IU/kg IV initially followed by 150 to 250 IU/kg SQ every 6 to 8 hours for cats and 200 to 300 IU/kg IV initially followed by 200 to 250 IU/kg SQ every 6 to 8 hours for dogs.

Answer 20

Adequate dosing of heparin in dogs and cats has been shown to be quite variable and dosing requirements may change over time due to a decrease in AT III levels.[28-30] Reasonable dosing regimens include 250 to 375 IU/kg IV initially followed by 150 to 250 IU/kg SQ every 6 to 8 hours for cats and 200 to 300 IU/kg IV initially followed by 200 to 250 IU/kg SQ every 6 to 8 hours for dogs.

Question 21

Historically, serial measurement of the……….. has been used to monitor heparin therapy with a target of 1.5 to 2.0 times the baseline value and this methodology is readily available to practitioners.[29] However, one study in cats suggests that ……… does not correlate well with plasma UH levels.[28] Therefore, ……….. monitoring may be a more reliable monitoring methodology and this is available through at least one commercial laboratory (Cornell Comparative Coagulation Laboratory).[31]

Answer 21

Historically, serial measurement of the aPTT has been used to monitor heparin therapy with a target of 1.5 to 2.0 times the baseline value and this methodology is readily available to practitioners.[29] However, one study in cats suggests that aPTT does not correlate well with plasma UH levels.[28] Therefore, anti-Xa monitoring may be a more reliable monitoring methodology and this is available through at least one commercial laboratory (Cornell Comparative Coagulation Laboratory).[31]

Question 22

The low-molecular-weight heparins (LMWH) are smaller in size than UH and are discussed in detail within the prevention discussion. However, these agents could be used in lieu of UH. The cost for these agents is considerably more expensive than UH (approximately $3 to $5/dose) but can be administered subcutaneously only twice daily in humans for acute management of thrombotic conditions. ………….. (Fragmin) and enoxaparin (Lovenox) have been used in dogs and cats at 100 IU/kg SQ q 12 to 24 hours and 1.0 to 1.5 mg/kg SQ q 24 to 12 hours, respectively.[32],[33] However, clinical trials do not exist in veterinary medicine for these agents, so the exact dose and clinical response are unknown at this time.

Answer 22

The low-molecular-weight heparins (LMWH) are smaller in size than UH and are discussed in detail within the prevention discussion. However, these agents could be used in lieu of UH. The cost for these agents is considerably more expensive than UH (approximately $3 to $5/dose) but can be administered subcutaneously only twice daily in humans for acute management of thrombotic conditions. Dalteparin (Fragmin) and enoxaparin (Lovenox) have been used in dogs and cats at 100 IU/kg SQ q 12 to 24 hours and 1.0 to 1.5 mg/kg SQ q 24 to 12 hours, respectively.[32],[33] However, clinical trials do not exist in veterinary medicine for these agents, so the exact dose and clinical response are unknown at this time.

Question 23

Arterial Flow—Thrombolytic Therapy

An ideal goal with infarction is to reestablish arterial flow to the infarcted organ. This requires removal of the embolus either through embolectomy or dissolution by using …………….. drugs.

Answer 23

Arterial Flow—Thrombolytic Therapy

An ideal goal with infarction is to reestablish arterial flow to the infarcted organ. This requires removal of the embolus either through embolectomy or dissolution by using thrombolytic drugs.

Question 24

Thrombolytic drugs have been used in dogs and cats to dissolve emboli and reestablish arterial flow. Ideally, thrombolytics should be administered as soon as possible after the embolic event but effective dissolution has been noted as late as 18 hours after initial clinical signs. Severe adverse effects can be associated with thrombolytic therapy, so caution should be exercised when considering these drugs.

Answer 24

Thrombolytic drugs have been used in dogs and cats to dissolve emboli and reestablish arterial flow. Ideally, thrombolytics should be administered as soon as possible after the embolic event but effective dissolution has been noted as late as 18 hours after initial clinical signs.[34] Severe adverse effects can be associated with thrombolytic therapy, so caution should be exercised when considering these drugs.

Question 25

The sudden resumption of arterial flow to infarcted organs can result in the rapid development of life-threatening ..................... and severe metabolic............. This is referred to as ................... injury and it is most likely to occur with aortic infarction.

Answer 25

The sudden resumption of arterial flow to infarcted organs can result in the rapid development of life-threatening hyperkalemia and severe metabolic acidosis. This is referred to as reperfusion injury and it is most likely to occur with aortic infarction. The frequency of reperfusion injury following thrombolytic therapy in cats with CE is from 40% to 70%.[34-36] Reperfusion injury represents the most common cause of death in cats receiving thrombolytics with survival rates reported from 0% to 43%.[34-36] Due to potential adverse effects and cost, thrombolytic therapy should not be used in all cases of ATE. However, thrombolytic therapy should be strongly considered in cases of cerebral, splanchnic, or renal infarction because the reestablishment of arterial flow is of principal importance.

Question 26

Streptokinase Streptokinase (SK) combines with ............. to form an activator complex that converts .............. to the proteolytic enzyme ............. Plasmin degrades?

Answer 26

Streptokinase Streptokinase (SK) combines with plasminogen to form an activator complex that converts plasminogen to the proteolytic enzyme plasmin. Plasmin degrades fibrin, fibrinogen, plasminogen, coagulation factors, and SK.

Question 27

The SK-plasminogen complex converts circulating and fibrin-bound plasminogen and is therefore considered a ................. activator of plasmin.

Answer 27

nonspecific

Question 28

Streptokinase is produced by ............., which can lead to ................stimulation, especially with repeated administrations. These anti-SK .............. may also reduce the efficacy of the drug. For these reasons, SK is usually not administered to human patients more frequently than every 4 years; however, such data and guidelines are absent in veterinary medicine.

Answer 28

Streptokinase is produced by streptococci, which can lead to antigenic stimulation, especially with repeated administrations. These anti-SK antibodies may also reduce the efficacy of the drug. For these reasons, SK is usually not administered to human patients more frequently than every 4 years; however, such data and guidelines are absent in veterinary medicine.

Question 29

Streptokinase (Streptase) is typically administered by giving 90,000 IU IV over 1 hour followed by an infusion of 45,000 IU/hour for up to 12 hours in dogs and cats. Currently, the smallest amount of SK that can be purchased is 750,000 IU, which would provide over 15 hours of infusion time. Once reconstituted, it must be used within 8 hours if stored at 2° to 8° C.

Answer 29

Streptokinase (Streptase) is typically administered by giving 90,000 IU IV over 1 hour followed by an infusion of 45,000 IU/hour for up to 12 hours in dogs and cats. Currently, the smallest amount of SK that can be purchased is 750,000 IU, which would provide over 15 hours of infusion time. Once reconstituted, it must be used within 8 hours if stored at 2° to 8° C.

Question 30

Urokinase Urokinase (UK) is similar in activity to streptokinase but is considered more fibrin specific due to the physical characteristics of the compound. Commercial preparations consist of both high-molecular-weight (HMW) and low-molecular-weight (LMW) fractions. There are many more HMW molecules in the commercial solution, but it is quickly and continuously converted to the LMW form within the circulation. The LMW molecules bind with greater affinity to the lysine-plasminogen form of plasminogen, which preferentially accumulates within thrombi. This confers some of the fibrin-specificity of UK. Urokinase (Abbokinase) is currently available as a lyophilized product in 250,000 IU vials. The manufacturer recommends reconstituting with 5 mL of sterile water and then further diluting the stock solution with 0.9% sodium chloride to a volume of 195 mL. Urokinase has been administered to cats and dogs for ATE with a protocol of 4400 IU/kg loading dose given over 10 minutes followed by 4400 IU/kg/hr for 12 hours.[38],[39] Of the 12 cats treated with UK, 56% regained motor function and only 27% regained pulses. There was no bleeding seen but reperfusion injury was noted in 25% of treated cats. Overall, 5/12 (42%) survived treatment.[38] The clinical experience was much less rewarding in dogs—the mortality rate was 100% in UK-treated dogs.[39]

Answer 30

Urokinase Urokinase (UK) is similar in activity to streptokinase but is considered more fibrin specific due to the physical characteristics of the compound. Commercial preparations consist of both high-molecular-weight (HMW) and low-molecular-weight (LMW) fractions. There are many more HMW molecules in the commercial solution, but it is quickly and continuously converted to the LMW form within the circulation. The LMW molecules bind with greater affinity to the lysine-plasminogen form of plasminogen, which preferentially accumulates within thrombi. This confers some of the fibrin-specificity of UK. Urokinase (Abbokinase) is currently available as a lyophilized product in 250,000 IU vials. The manufacturer recommends reconstituting with 5 mL of sterile water and then further diluting the stock solution with 0.9% sodium chloride to a volume of 195 mL. Urokinase has been administered to cats and dogs for ATE with a protocol of 4400 IU/kg loading dose given over 10 minutes followed by 4400 IU/kg/hr for 12 hours.[38],[39] Of the 12 cats treated with UK, 56% regained motor function and only 27% regained pulses. There was no bleeding seen but reperfusion injury was noted in 25% of treated cats. Overall, 5/12 (42%) survived treatment.[38] The clinical experience was much less rewarding in dogs—the mortality rate was 100% in UK-treated dogs.[39]

Question 31

Tissue Plasminogen Activator (t-PA) Tissue-plasminogen activator (t-PA) is the primary activator of plasmin in vivo; however, it does not readily bind circulating plasminogen and therefore does not induce a systemic proteolytic state. Plasminogen and t-PA both have a high affinity for fibrin, thereby forming an intimate relationship within thrombi, resulting in a fibrin-specific conversion of plasminogen to plasmin. However, the fibrin specificity is relative and when t-PA is given at high doses, a systemic proteolytic state and bleeding can be seen.[40]

Answer 31

Tissue Plasminogen Activator (t-PA) Tissue-plasminogen activator (t-PA) is the primary activator of plasmin in vivo; however, it does not readily bind circulating plasminogen and therefore does not induce a systemic proteolytic state. Plasminogen and t-PA both have a high affinity for fibrin, thereby forming an intimate relationship within thrombi, resulting in a fibrin-specific conversion of plasminogen to plasmin. However, the fibrin specificity is relative and when t-PA is given at high doses, a systemic proteolytic state and bleeding can be seen.[40]

Question 32

There is very little clinical experience with human recombinant t-PA (Activase) in dogs and cats. The drug has been administered intravenously either as a constant rate infusion in cats (0.25 to 1 mg/kg/hr IV for a total dose of 1 to 10 mg/kg) or multiple bolus therapy in dogs (1 mg/kg IV). The success rate has been variable with isolated reports of two dogs treated for ATE.[41],[43] One of the dogs with ATE had gradual return of femoral arterial pulses[43] after multiple boluses of t-PA, whereas the other dog had no response.[41] There has been one reported clinical trial of t-PA therapy in six cats with CE.[34] Complications included minor hemorrhage from catheter sites (50%), fever (33%), and reperfusion injury (33%). The acute survival rate was 50% with deaths attributable to reperfusion injury and cardiogenic shock. Of the cats that survived, 100% had infarction of both limbs. Perfusion was restored within 36 hours and motor function returned within 48 hours in 100% of surviving cats.

Answer 32

There is very little clinical experience with human recombinant t-PA (Activase) in dogs and cats. The drug has been administered intravenously either as a constant rate infusion in cats (0.25 to 1 mg/kg/hr IV for a total dose of 1 to 10 mg/kg) or multiple bolus therapy in dogs (1 mg/kg IV). The success rate has been variable with isolated reports of two dogs treated for ATE.[41],[43] One of the dogs with ATE had gradual return of femoral arterial pulses[43] after multiple boluses of t-PA, whereas the other dog had no response.[41] There has been one reported clinical trial of t-PA therapy in six cats with CE.[34] Complications included minor hemorrhage from catheter sites (50%), fever (33%), and reperfusion injury (33%). The acute survival rate was 50% with deaths attributable to reperfusion injury and cardiogenic shock. Of the cats that survived, 100% had infarction of both limbs. Perfusion was restored within 36 hours and motor function returned within 48 hours in 100% of surviving cats.

Question 33

Improve Collateral Flow If dissolution of the embolus is unsuccessful or not attempted, then increasing perfusion to the infracted organ can be attempted by increasing flow through the collateral network. The use of vasodilators, such as acepromazine, has generally been unsuccessful and clinical hypotension may result, further reducing perfusion.

Answer 33

If dissolution of the embolus is unsuccessful or not attempted, then increasing perfusion to the infracted organ can be attempted by increasing flow through the collateral network. The use of vasodilators, such as acepromazine, has generally been unsuccessful and clinical hypotension may result, further reducing perfusion.

Question 34

The platelet release products ................ and .................have been implicated as potential agents responsible for loss of collateral flow associated with aortic infarction. Therefore, ....................... may help improve collateral flow by reducing the amount of vasoactive substances released from platelets. .............has been shown to reduce the amount of released thromboxane from activated cat platelets and improve collateral flow in an experimental cat model of aortic infarction. However, a very large dose of aspirin was used in that model and the salicylate levels obtained have been associated with clinical toxicity in cats; it is unknown if this effect can be seen with clinical doses of aspirin.

Answer 34

The platelet release products serotonin and thromboxane have been implicated as potential agents responsible for loss of collateral flow associated with aortic infarction. Therefore, antiplatelet agents may help improve collateral flow by reducing the amount of vasoactive substances released from platelets. Aspirin has been shown to reduce the amount of released thromboxane from activated cat platelets and improve collateral flow in an experimental cat model of aortic infarction.[44] However, a very large dose of aspirin was used in that model and the salicylate levels obtained have been associated with clinical toxicity in cats; it is unknown if this effect can be seen with clinical doses of aspirin.

Question 35

Clopidogrel (Plavix) has been shown to reduce .................release from activated platelets in cats, whereas studies in other species have demonstrated reduced production of....................[40],[41] There is also evidence that clopidogrel exerts an ex vivo vasomodulating effect in rats, rabbits, and dogs.[47],[48] This vasomodulating effect has also been seen in an in vivo cat model of aortic infarction.[49] Although maximal antithrombotic effects of clopidogrel are achieved within 72 hours of daily administration of 2 to 4 mg/kg in dogs and cats,[40],[50] an oral loading dose of approximately 10 mg/kg to dogs resulted in comparable antithrombotic effects within 90 minutes with no adverse effects.[50] Additionally, daily administration of 75 mg in cats (approximately 15 mg/kg) has been well tolerated and not associated with adverse effects. Therefore, although there are no objective data to support this assertion, the acute administration of clopidogrel upon presentation for ATE may be helpful in improving collateral flow and should not be associated with adverse effects.

Answer 35

Clopidogrel (Plavix) has been shown to reduce serotonin release from activated platelets in cats, whereas studies in other species have demonstrated reduced production of thromboxane.[40],[41] There is also evidence that clopidogrel exerts an ex vivo vasomodulating effect in rats, rabbits, and dogs.[47],[48] This vasomodulating effect has also been seen in an in vivo cat model of aortic infarction.[49] Although maximal antithrombotic effects of clopidogrel are achieved within 72 hours of daily administration of 2 to 4 mg/kg in dogs and cats,[40],[50] an oral loading dose of approximately 10 mg/kg to dogs resulted in comparable antithrombotic effects within 90 minutes with no adverse effects.[50] Additionally, daily administration of 75 mg in cats (approximately 15 mg/kg) has been well tolerated and not associated with adverse effects. Therefore, although there are no objective data to support this assertion, the acute administration of clopidogrel upon presentation for ATE may be helpful in improving collateral flow and should not be associated with adverse effects.

Question 36

Pain Management ATE can result in severe pain and controlling this pain is a critically important aspect of acute ATE treatment. Narcotic agents are most commonly used and work very well. Butorphanol tartrate (0.1 to 0.4 mg/kg SQ, IM, IV q 1 to 4 hours, dogs and cats), hydromorphone (0.08 to 0.3 mg/kg SQ, IM, IV q 2 to 6 hours, dogs and cats), buprenorphine HCl (0.005 to 0.02 mg/kg SQ, IM, IV q 6 to 12 hours, dogs and cats), and oxymorphone HCL (0.05 to 0.2 mg/kg SQ, IM, IV q 1 to 3 hours, dogs and cats) have been widely used and appear to provide good analgesia with little adverse effects. In severe or refractory cases, fentanyl citrate (4 to 10 µg/kg IV bolus followed by 4 to 10 µg/kg/hr infusion, dogs and cats) can be used. Injections should be given cranial to the diaphragm to assure adequate absorption.

Answer 36

Pain Management ATE can result in severe pain and controlling this pain is a critically important aspect of acute ATE treatment. Narcotic agents are most commonly used and work very well. Butorphanol tartrate (0.1 to 0.4 mg/kg SQ, IM, IV q 1 to 4 hours, dogs and cats), hydromorphone (0.08 to 0.3 mg/kg SQ, IM, IV q 2 to 6 hours, dogs and cats), buprenorphine HCl (0.005 to 0.02 mg/kg SQ, IM, IV q 6 to 12 hours, dogs and cats), and oxymorphone HCL (0.05 to 0.2 mg/kg SQ, IM, IV q 1 to 3 hours, dogs and cats) have been widely used and appear to provide good analgesia with little adverse effects. In severe or refractory cases, fentanyl citrate (4 to 10 µg/kg IV bolus followed by 4 to 10 µg/kg/hr infusion, dogs and cats) can be used. Injections should be given cranial to the diaphragm to assure adequate absorption.

Question 37

SURVIVAL Survival data specific to ATE in dogs are generally absent. The largest body of data relates to CE in cats. The reported survival rates for initial CE events in cats is remarkably similar whether conservative (35% to 39%)[18,26,27] or thrombolytic (33%)[35] therapy is used. Cats with single pelvic limb infarction do dramatically better (68% to 93%)[18,26,27,35] than do cats with bilateral pelvic limb infarction (15% to 36%) regardless of therapy used.[18,26,27,35] Nonsurvival rates range from 61% to 67% with natural death rates (28% to 40%) similar to euthanasia rates (25% to 35%).[18,26,27,35] Nonsurvival has been significantly associated with hypothermia,[27],[35] reduced heart rate,[18] and absence of motor function.[18] Reported long-term median survival times following the initial CE event have ranged from 51 days to 345 days

Answer 37

SURVIVAL Survival data specific to ATE in dogs are generally absent. The largest body of data relates to CE in cats. The reported survival rates for initial CE events in cats is remarkably similar whether conservative (35% to 39%)[18,26,27] or thrombolytic (33%)[35] therapy is used. Cats with single pelvic limb infarction do dramatically better (68% to 93%)[18,26,27,35] than do cats with bilateral pelvic limb infarction (15% to 36%) regardless of therapy used.[18,26,27,35] Nonsurvival rates range from 61% to 67% with natural death rates (28% to 40%) similar to euthanasia rates (25% to 35%).[18,26,27,35] Nonsurvival has been significantly associated with hypothermia,[27],[35] reduced heart rate,[18] and absence of motor function.[18] Reported long-term median survival times following the initial CE event have ranged from 51 days to 345 days

Question 38

PREVENTION Primary prevention of ATE is defined as preventing the first event in an animal at risk for ATE. Although primary prevention would be an ideal and logical goal, there is a poor understanding of thrombotic risk in our patients. We do know that some underlying conditions are associated with ATE, but we cannot accurately predict which animals will actually go on to develop ATE. The greatest body of evidence is associated with CE in cats. Cats appear to be at a greater risk for ATE if they have larger left atrial size or evidence of systolic dysfunction.[52] Similar patterns have been identified in humans. These findings combined with clinical experience have led to the recommendation that prophylactic antithrombotic therapy be considered in cats with echocardiographic measurements of an end-systolic left atrial diameter greater than 1.7 cm or left atrium-to-aortic ratio (LA/Ao) greater than 2.0.[53] Prophylactic antithrombotic therapy is also indicated in cats with spontaneous contrast or “smoke” in the left atrium on echocardiography.[53]

Answer 38

PREVENTION Primary prevention of ATE is defined as preventing the first event in an animal at risk for ATE. Although primary prevention would be an ideal and logical goal, there is a poor understanding of thrombotic risk in our patients. We do know that some underlying conditions are associated with ATE, but we cannot accurately predict which animals will actually go on to develop ATE. The greatest body of evidence is associated with CE in cats. Cats appear to be at a greater risk for ATE if they have larger left atrial size or evidence of systolic dysfunction.[52] Similar patterns have been identified in humans. These findings combined with clinical experience have led to the recommendation that prophylactic antithrombotic therapy be considered in cats with echocardiographic measurements of an end-systolic left atrial diameter greater than 1.7 cm or left atrium-to-aortic ratio (LA/Ao) greater than 2.0.[53] Prophylactic antithrombotic therapy is also indicated in cats with spontaneous contrast or “smoke” in the left atrium on echocardiography.[53]

Question 39

Secondary prevention has received more attention in veterinary medicine and is defined as................................ Again, the largest body of evidence in veterinary medicine is related to CE in cats. However, these data have been based on retrospective, nonplacebo controlled studies of individual antithrombotic agents. Therefore there is no scientific basis for conclusions that any antithrombotic agent is effective for secondary prevention of CE or that any one agent is more effective than another. Reported recurrence rates for cats receiving some antithrombotic agent range from 17% to 75%[18,26,27,34,35] with a 1-year recurrence rate of 25% to 50%.[27],[35] The best way to prevent a CE event is to .............................. process that carries the increased thrombotic risk. This should be attempted in all animals with a history of ATE.

Answer 39

Secondary prevention has received more attention in veterinary medicine and is defined as preventing a subsequent ATE event in an animal with a history of ATE. Again, the largest body of evidence in veterinary medicine is related to CE in cats. However, these data have been based on retrospective, nonplacebo controlled studies of individual antithrombotic agents. Therefore there is no scientific basis for conclusions that any antithrombotic agent is effective for secondary prevention of CE or that any one agent is more effective than another. Reported recurrence rates for cats receiving some antithrombotic agent range from 17% to 75%[18,26,27,34,35] with a 1-year recurrence rate of 25% to 50%.[27],[35] The best way to prevent a CE event is to reverse or effectively treat the underlying disease process that carries the increased thrombotic risk. This should be attempted in all animals with a history of ATE.

Question 40

Antithrombotic Drugs Due to their direct effect on thrombus formation, antithrombotic agents have become a mainstay for primary and secondary prevention of ATE in dogs and cats. However, it should be emphasized that a goal of complete prevention of recurrent embolic events in animals with chronic diseases such as cardiac disease or nephrotic syndrome is probably not realistic. The goal should be to delay the time to the next ATE event or to reduce the clinical signs associated with the event. The two major categories of antithrombotics are .................and....................

Answer 40

Antithrombotic Drugs Due to their direct effect on thrombus formation, antithrombotic agents have become a mainstay for primary and secondary prevention of ATE in dogs and cats. However, it should be emphasized that a goal of complete prevention of recurrent embolic events in animals with chronic diseases such as cardiac disease or nephrotic syndrome is probably not realistic. The goal should be to delay the time to the next ATE event or to reduce the clinical signs associated with the event. The two major categories of antithrombotics are antiplatelet agents and anticoagulants.

Question 41

Antiplatelet Agents These agents inhibit some aspect of platelet...... ...................,................, or ................ (3) reaction and impair the formation of the initial platelet-rich................. at the injured endothelial site. Some of these agents also exhibit some .......................... effects by interfering with vasoactive substances such as serotonin and thromboxane.

Answer 41

Antiplatelet Agents These agents inhibit some aspect of platelet adhesion, aggregation, or release reaction and impair the formation of the initial platelet-rich thrombus at the injured endothelial site. Some of these agents also exhibit some vasomodulating effects by interfering with vasoactive substances such as serotonin and thromboxane.

Question 42

Aspirin Aspirin is the most used and studied antiplatelet agent available today. It ......................... acetylates platelet .............., preventing the formation of .................... which has potent proaggregating and vasoconstrictive properties.

Answer 42

Aspirin Aspirin is the most used and studied antiplatelet agent available today. It irreversibly acetylates platelet cyclooxygenase, preventing the formation of thromboxane A2, which has potent proaggregating and vasoconstrictive properties.

Question 43

Aspirin is considered a modest and indirect ....................agent, which inhibits .......... but not ............platelet aggregation. Aspirin exerts a similar effect on ..................... within endothelial cells reducing .................. production, which exhibits antiaggregating and vasodilating properties. However, endothelial cells are able to overcome this inhibition, unlike platelets, so ................... properties predominate in the clinical setting.

Answer 43

Aspirin is considered a modest and indirect antiplatelet agent, which inhibits secondary but not primary platelet aggregation. Aspirin exerts a similar effect on cyclooxygenase within endothelial cells reducing prostacyclin production, which exhibits antiaggregating and vasodilating properties. However, endothelial cells are able to overcome this inhibition, unlike platelets, so antithrombotic properties predominate in the clinical setting.

Question 44

The pharmacologic, analgesic, and antiplatelet effects of aspirin have been well studied in the dog and cat.[54-57] Aspirin has been used for primary and secondary prevention of CE in cats for over 30 years. Recurrence rates from retrospective studies range from 17% to 75%.[18,26,27,34] Adverse effects are typically gastrointestinal such as ................ and ........................ and have been reported in up to 22% of treated cats.[18] One study evaluating a low-dose aspirin protocol did not see a significant difference in recurrence rates compared with a standard aspirin dose, but there was a reduced rate of adverse gastrointestinal events.[18] There is very little published clinical use of aspirin for the prevention of thrombosis in dogs. However, one study reported an increased survival in dogs with IMHA that received a low dose of aspirin in addition to immunosuppressive therapy.[58] Healthy dogs receiving aspirin have been reported to have uniformly developed moderate gastroduodenal endoscopic lesions including erosions and submucosal hemorrhages.[59] In that study vomiting was noted in approximately 7% of the dogs during the treatment period with no evidence of diarrhea.

Answer 44

The pharmacologic, analgesic, and antiplatelet effects of aspirin have been well studied in the dog and cat.[54-57] Aspirin has been used for primary and secondary prevention of CE in cats for over 30 years. Recurrence rates from retrospective studies range from 17% to 75%.[18,26,27,34] Adverse effects are typically gastrointestinal such as anorexia and vomiting and have been reported in up to 22% of treated cats.[18] One study evaluating a low-dose aspirin protocol did not see a significant difference in recurrence rates compared with a standard aspirin dose, but there was a reduced rate of adverse gastrointestinal events.[18] There is very little published clinical use of aspirin for the prevention of thrombosis in dogs. However, one study reported an increased survival in dogs with IMHA that received a low dose of aspirin in addition to immunosuppressive therapy.[58] Healthy dogs receiving aspirin have been reported to have uniformly developed moderate gastroduodenal endoscopic lesions including erosions and submucosal hemorrhages.[59] In that study vomiting was noted in approximately 7% of the dogs during the treatment period with no evidence of diarrhea.

Question 45

Clopidogrel (Plavix) Clopidogrel is a second-generation .................... that induces specific and irreversible antagonism of the ................. receptor along the platelet membrane. Clopidogrel is a direct antiplatelet drug inhibiting both ....... and .......... platelet aggregation in response to multiple agonists. These effects are more potent than those induced by ............. The ADP-induced conformational change of the ................. complex is also inhibited, which reduces binding of ...............and............. Clopidogrel also impairs the platelet release reaction decreasing the release of proaggregating and vasoconstrictive agents such as................and............... .............. effects have also been seen through in vitro and in vivo studies. The parent compound does not possess ............effects; instead, it must undergo hepatic biotransformation to form an active metabolite.

Answer 45

Clopidogrel (Plavix) Clopidogrel is a second-generation thienopyridine that induces specific and irreversible antagonism of the ADP2Y12 receptor along the platelet membrane. Clopidogrel is a direct antiplatelet drug inhibiting both primary and secondary platelet aggregation in response to multiple agonists. These effects are more potent than those induced by aspirin. The ADP-induced conformational change of the glycoprotein IIb/IIIa complex is also inhibited, which reduces binding of fibrinogen and VWF.[60] Clopidogrel also impairs the platelet release reaction decreasing the release of proaggregating and vasoconstrictive agents such as serotonin and ADP. Vasomodulating effects have also been seen through in vitro and in vivo studies. The parent compound does not possess antiplatelet effects; instead, it must undergo hepatic biotransformation to form an active metabolite.

Question 46

Unlike aspirin, clopidogrel is not associated with gastroduodenal ulceration. In a short-term pharmacodynamic study in healthy cats, when clopidogrel was administered at 18.75 mg/cat orally, maximal antiplatelet effects were seen by....... days of drug administration and were lost within 7 days after drug discontinuation.[45] There has been a similar pharmacodynamic study of clopidogrel in dogs with similar results to those seen in cats when dosed from 2 to 3 mg/kg orally once a day.[50] Stimulation of the hepatic ..........enzyme system in dogs resulted in ................effects at lower doses of clopidogrel (1 mg/kg). Although there were no adverse effects noted during either study, there are empirical reports of sporadic cats experiencing some vomiting while receiving clopidogrel clinically. Administering clopidogrel in a gel capsule or with food appears to dramatically reduce this occurrence. Currently, there are no published efficacy studies evaluating clopidogrel in dogs or cats, but the Feline Arterial Thromboembolism: Clopidogrel vs. Aspirin Trial (FAT CAT) is currently under way. To date, there are no reported cases of agranulocytosis or thrombotic thrombocytopenic purpura (TTP), possible adverse effects in humans receiving clopidogrel, occurring in dogs or cats.

Answer 46

The parent compound does not possess antiplatelet effects; instead, it must undergo hepatic biotransformation to form an active metabolite. Unlike aspirin, clopidogrel is not associated with gastroduodenal ulceration. In a short-term pharmacodynamic study in healthy cats, when clopidogrel was administered at 18.75 mg/cat orally, maximal antiplatelet effects were seen by 3 days of drug administration and were lost within 7 days after drug discontinuation.[45] There has been a similar pharmacodynamic study of clopidogrel in dogs with similar results to those seen in cats when dosed from 2 to 3 mg/kg orally once a day.[50] Stimulation of the hepatic P450 enzyme system in dogs resulted in antiplatelet effects at lower doses of clopidogrel (1 mg/kg). Although there were no adverse effects noted during either study, there are empirical reports of sporadic cats experiencing some vomiting while receiving clopidogrel clinically. Administering clopidogrel in a gel capsule or with food appears to dramatically reduce this occurrence. Currently, there are no published efficacy studies evaluating clopidogrel in dogs or cats, but the Feline Arterial Thromboembolism: Clopidogrel vs. Aspirin Trial (FAT CAT) is currently under way. To date, there are no reported cases of agranulocytosis or thrombotic thrombocytopenic purpura (TTP), possible adverse effects in humans receiving clopidogrel, occurring in dogs or cats.

Question 47

Anticoagulant Agents This group of drugs inhibits the coagulation cascade by interfering with the .......... of one or more active coagulation factors. Some of these drugs also exhibit relatively minor ..................effects.

Answer 47

Anticoagulant Agents This group of drugs inhibits the coagulation cascade by interfering with the formation of one or more active coagulation factors. Some of these drugs also exhibit relatively minor antiplatelet effects.

Question 48

Warfarin Warfarin inhibits the formation of the vitamin K–dependent coagulation factors ..........,......,.......,....... as well as the anticoagulant proteins ... and .....

Answer 48

Warfarin Warfarin inhibits the formation of the vitamin K–dependent coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S.

Question 49

After warfarin administration in humans, the levels of .......fall prior to the coagulation factors, resulting in a theoretic hypercoagulable state for 4 to 6 days. For this reason, ......is typically administered during this period. Warfarin is indicated in multiple diseases in humans with a risk for ATE including atrial fibrillation and prosthetic heart valves. Numerous studies have demonstrated the efficacy of warfarin for primary and secondary prevention of CE with atrial fibrillation even when lower-intensity anticoagulation protocols are used. Bleeding is the most common complication in humans.[61] Warfarin has numerous interactions with other medications that may increase or decrease the anticoagulation effect.

Answer 49

After warfarin administration in humans, the levels of protein C fall prior to the coagulation factors, resulting in a theoretic hypercoagulable state for 4 to 6 days. For this reason, UH is typically administered during this period. Warfarin is indicated in multiple diseases in humans with a risk for ATE including atrial fibrillation and prosthetic heart valves. Numerous studies have demonstrated the efficacy of warfarin for primary and secondary prevention of CE with atrial fibrillation even when lower-intensity anticoagulation protocols are used. Bleeding is the most common complication in humans.[61] Warfarin has numerous interactions with other medications that may increase or decrease the anticoagulation effect. Warfarin therapy is adjusted by monitoring the International Normalized Ratio (INR). The INR is normalized for different thromboplastin reagents used in different laboratories by the equation [(patients PT/control PT)ISI], where ISI is the international sensitivity index for the thromboplastin. Medium anticoagulation intensity (INR of 2 to 3) is recommended for most conditions in humans.

Question 50

The pharmacokinetics and pharmacodynamics of warfarin have been evaluated in dogs and cats.[62],[63] Pharmacokinetic studies of warfarin in cats demonstrate that absorption after oral administration is rapid and undergoes ................................., which may contribute to the known wide interindividual and intraindividual variable anticoagulant response.

Answer 50

The pharmacokinetics and pharmacodynamics of warfarin have been evaluated in dogs and cats.[62],[63] Pharmacokinetic studies of warfarin in cats demonstrate that absorption after oral administration is rapid and undergoes enterohepatic recirculation, which may contribute to the known wide interindividual and intraindividual variable anticoagulant response.

Question 51

It has been demonstrated that warfarin is not evenly distributed throughout the tablet, so the tablet should be crushed and compounded by a pharmacist. Due to the wide interindividual and intraindividual variation in anticoagulation response, close and careful monitoring is required and owners should be aware of this prior to beginning therapy because it requires dedication and expense for the owner. It is generally recommended that animals on warfarin should avoid activity that could result in trauma and potentially fatal hemorrhage. It has been recommended that adjustments to warfarin dosing should be done by changing the total weekly dose and not daily dose in response to INR monitoring.[64] Although unsubstantiated, an INR of 2 to 3 has been considered as adequate anticoagulation in dogs and cats. Objective clinical trials evaluating the efficacy of warfarin in the prevention of thrombotic events in dogs and cats do not exist. Published CE recurrence rates for cats receiving warfarin from retrospective studies range from 42% to 53% with estimated mean survival times of 210 to 471 days.[26],[35] Bleeding (both major and minor) is the most common complication seen in 13% to 20% of cats with fatal hemorrhage reported in up to 13% of cats.[26,33,35]

Answer 51

63] It has been demonstrated that warfarin is not evenly distributed throughout the tablet, so the tablet should be crushed and compounded by a pharmacist. Due to the wide interindividual and intraindividual variation in anticoagulation response, close and careful monitoring is required and owners should be aware of this prior to beginning therapy because it requires dedication and expense for the owner. It is generally recommended that animals on warfarin should avoid activity that could result in trauma and potentially fatal hemorrhage. It has been recommended that adjustments to warfarin dosing should be done by changing the total weekly dose and not daily dose in response to INR monitoring.[64] Although unsubstantiated, an INR of 2 to 3 has been considered as adequate anticoagulation in dogs and cats. Objective clinical trials evaluating the efficacy of warfarin in the prevention of thrombotic events in dogs and cats do not exist. Published CE recurrence rates for cats receiving warfarin from retrospective studies range from 42% to 53% with estimated mean survival times of 210 to 471 days.[26],[35] Bleeding (both major and minor) is the most common complication seen in 13% to 20% of cats with fatal hemorrhage reported in up to 13% of cats.[26,33,35]

Question 52

Low-Molecular-Weight Heparins The LMWH are smaller in size than UH (.............to ......... Daltons) but maintain the pentasaccharide sequence that binds to .................., inhibiting factor .......a, with a greatly reduced inhibition of ........a. Due to their smaller size, the LMWH have a higher bioavailability and longer plasma half-life than UH in humans, allowing once- or twice-daily administration. The reduced anti-IIa activity translates into a negligible effect on the aPTT with LMWH therapy. For this reason, the only clinical way to evaluate LMWH treatment is through measurement of anti-....a activity through a chromogenic assay.

Answer 52

Low-Molecular-Weight Heparins The LMWH are smaller in size than UH (4000 to 5000 Daltons) but maintain the pentasaccharide sequence that binds to AT III, inhibiting factor Xa, with a greatly reduced inhibition of IIa. Due to their smaller size, the LMWH have a higher bioavailability and longer plasma half-life than UH in humans, allowing once- or twice-daily administration. The reduced anti-IIa activity translates into a negligible effect on the aPTT with LMWH therapy. For this reason, the only clinical way to evaluate LMWH treatment is through measurement of anti-Xa activity through a chromogenic assay.

Question 53

Human studies have demonstrated that anti-Xa levels peak around .... hours after administration and then decline until approximately ...hours after administration where they become undetectable. Although anti-Xa levels generally do not correlate to antithrombotic effect, clinical trials in humans have demonstrated that peak anti-Xa levels of 0.5 to 1.0 U/mL (4 hours postadministration) are correlated with reduced ................................. and achieved in a majority of patients considered effectively treated.

Answer 53

Human studies have demonstrated that anti-Xa levels peak around 4 hours after administration and then decline until approximately 8 hours after administration where they become undetectable. Although anti-Xa levels generally do not correlate to antithrombotic effect, clinical trials in humans have demonstrated that peak anti-Xa levels of 0.5 to 1.0 U/mL (4 hours postadministration) are correlated with reduced thrombotic events and achieved in a majority of patients considered effectively treated.

Question 54

The most common adverse effect of the LMWH is .............. with the frequency of minor bleeding reported from 5% to 27% and major bleeding from 0% to 6.5%, which is similar to UH.

Answer 54

The most common adverse effect of the LMWH is bleeding with the frequency of minor bleeding reported from 5% to 27% and major bleeding from 0% to 6.5%, which is similar to UH.

Question 55

Two pharmacokinetic studies have evaluated the LMWH dalteparin and enoxaparin in healthy cats. The first study demonstrated that cats appeared to be similar to humans where peak ........... levels with dalteparin were reached at ..... hours after administration, then gradually reduced until undetectable after approximately .....hours.[32] The second study evaluated dalteparin and enoxaparin through measurement of multiple hemostatic markers including anti-Xa levels and thromboelastography (TEG).[67] The pattern for anti-Xa mirrored the first study where peak levels were reached at 4 hours and then declined until they became undetectable around 8 hours for both drugs. Based on these data, a pharmacokinetic model was created and the authors concluded that dalteparin and enoxaparin should be administered at higher doses and more frequently than currently published to maintain anti-Xa levels within the human peak therapeutic range over the entire treatment period. However, the peak anti-Xa levels in people are not meant to be maintained throughout the dosing period.

Answer 55

Two pharmacokinetic studies have evaluated the LMWH dalteparin and enoxaparin in healthy cats. The first study demonstrated that cats appeared to be similar to humans where peak ........... levels with dalteparin were reached at ..... hours after administration, then gradually reduced until undetectable after approximately .....hours.[32] The second study evaluated dalteparin and enoxaparin through measurement of multiple hemostatic markers including anti-Xa levels and thromboelastography (TEG).[67] The pattern for anti-Xa mirrored the first study where peak levels were reached at 4 hours and then declined until they became undetectable around 8 hours for both drugs. Based on these data, a pharmacokinetic model was created and the authors concluded that dalteparin and enoxaparin should be administered at higher doses and more frequently than currently published to maintain anti-Xa levels within the human peak therapeutic range over the entire treatment period. However, the peak anti-Xa levels in people are not meant to be maintained throughout the dosing period.

Question 56

A recent study evaluated the pharmacodynamic effect of enoxaparin in a modified venous stasis model in healthy cats.[68] That study demonstrated that enoxaparin administered at 1 mg/kg SQ q 12 hours resulted in 100% thrombus inhibition at 4 hours and 91.4% thrombus inhibition at 12 hours after drug administration. Additionally, there was no correlation found between the antithrombotic effect of enoxaparin and the anti-Xa level because there was no measurable anti-Xa activity at 12 hours after drug administration. In the author's opinion, enoxaparin exhibits an antithrombotic effect at the current reported dosing regimen of 1 mg/kg q 12 to 24 hours and peak anti-Xa levels need to be correlated to reduced thrombotic events through clinical trials before more accurate dosing regimens can be recommended. There is one retrospective study comparing dalteparin to warfarin for the prevention of recurrent CE in cats, which demonstrated a comparable recurrence rate and median survival time between treatment groups.[33] None of the cats receiving dalteparin experienced any bleeding complications and infrequent bleeding was noted with dalteparin therapy in another study in cats.[69] A similar pharmacokinetic study of enoxaparin was performed in dogs where a model was determined to maintain anti-Xa levels throughout the dosing period.[70] Because this is not the goal of LMWH therapy, current dose recommendations of 1 mg/kg SQ q 12 to 24 hours could be followed until clinical trials provide a more accurate dosing information.

Answer 56

A recent study evaluated the pharmacodynamic effect of enoxaparin in a modified venous stasis model in healthy cats.[68] That study demonstrated that enoxaparin administered at 1 mg/kg SQ q 12 hours resulted in 100% thrombus inhibition at 4 hours and 91.4% thrombus inhibition at 12 hours after drug administration. Additionally, there was no correlation found between the antithrombotic effect of enoxaparin and the anti-Xa level because there was no measurable anti-Xa activity at 12 hours after drug administration. In the author's opinion, enoxaparin exhibits an antithrombotic effect at the current reported dosing regimen of 1 mg/kg q 12 to 24 hours and peak anti-Xa levels need to be correlated to reduced thrombotic events through clinical trials before more accurate dosing regimens can be recommended. There is one retrospective study comparing dalteparin to warfarin for the prevention of recurrent CE in cats, which demonstrated a comparable recurrence rate and median survival time between treatment groups.[33] None of the cats receiving dalteparin experienced any bleeding complications and infrequent bleeding was noted with dalteparin therapy in another study in cats.[69] A similar pharmacokinetic study of enoxaparin was performed in dogs where a model was determined to maintain anti-Xa levels throughout the dosing period.[70] Because this is not the goal of LMWH therapy, current dose recommendations of 1 mg/kg SQ q 12 to 24 hours could be followed until clinical trials provide a more accurate dosing information.

Question 57

Synthetic Xa Inhibitors A relatively new class of antithrombotic drugs, the synthetic ............ inhibitors, selectively inhibit ..... through the potentiation of ......... These drugs have no known effect on ...... or ............ function. Therefore, they have no effect on routine coagulation tests such as the activated clotting time, ........ or ...... However, given their selective ........ inhibition, measurement of ................ activity levels is an acceptable and clinically proven method for monitoring the clinical use of these drugs. Unlike the LMWH, these agents are homogeneous preparations of synthetic pentasaccharide units that bind exclusively to ........ so that they have nearly complete bioavailability when administered subcutaneously and with less interpatient variability.

Answer 57

Synthetic Xa Inhibitors A relatively new class of antithrombotic drugs, the synthetic Xa inhibitors, selectively inhibit Xa through the potentiation of ATIII. These drugs have no known effect on IIa or platelet function. Therefore, they have no effect on routine coagulation tests such as the activated clotting time, aPTT or PT. However, given their selective Xa inhibition, measurement of anti-Xa activity levels is an acceptable and clinically proven method for monitoring the clinical use of these drugs. Unlike the LMWH, these agents are homogeneous preparations of synthetic pentasaccharide units that bind exclusively to AT III so that they have nearly complete bioavailability when administered subcutaneously and with less interpatient variability.

Question 58

The most common adverse effect of Synthetic Xa Inhibitors is?

Answer 58

Bleeding, occurring with a similar frequency as that of the LMWH. However, there are no known antidotes for these agents, so the antithrombotic effect is only lost through excretion of the drug.

Question 59

Synthetic Xa Inhibitors: Fondaparinux (Arixtra) is currently approved for clinical use in humans and potentiates the innate neutralizing ability of AT III on Xa by approximately 300-fold. Fondaparinux is a catalytic inhibitor of AT III that, after initiating the formation of the AT III/Xa complex, dissociates from the complex and is available for binding to additional AT III molecules. There does not appear to be any appreciable metabolism of fondaparinux with elimination of unchanged drug within the urine, so careful monitoring is required in patients with renal insufficiency. The elimination half-life is approximately 17 to 21 hours in normal healthy humans, allowing once-daily dosing.[72] There is currently no clinical experience with fondaparinux in dogs or cats. However, a recent pharmacokinetic study in healthy cats demonstrated that fondaparinux will achieve peak and trough anti-Xa levels that approximate recommended human levels when dosed at 0.06 mg/kg SQ q12h (Hogan DF, unpublished data). Idraparinux is a second-generation synthetic pentasaccharide developed to compete with warfarin therapy for chronic antithrombotic therapy. Idraparinux binds to AT III with much greater affinity than fondaparinux, resulting in a plasma half-life similar to AT III (80 hours) allowing once-a-week dosing.[73] Idraparinux is similar to fondaparinux in most other properties. Idraparinux appears to be as effective as warfarin but has been associated with unacceptably high bleeding rates.[74],[75] Because of the bleeding complications seen with idraparinux and lack of specific antidote, the future for this drug remains to be determined. There is no clinical experience with idraparinux in veterinary medicine.

Answer 59

Synthetic Xa Inhibitors Fondaparinux (Arixtra) is currently approved for clinical use in humans and potentiates the innate neutralizing ability of AT III on Xa by approximately 300-fold. Fondaparinux is a catalytic inhibitor of AT III that, after initiating the formation of the AT III/Xa complex, dissociates from the complex and is available for binding to additional AT III molecules. There does not appear to be any appreciable metabolism of fondaparinux with elimination of unchanged drug within the urine, so careful monitoring is required in patients with renal insufficiency. The elimination half-life is approximately 17 to 21 hours in normal healthy humans, allowing once-daily dosing.[72] There is currently no clinical experience with fondaparinux in dogs or cats. However, a recent pharmacokinetic study in healthy cats demonstrated that fondaparinux will achieve peak and trough anti-Xa levels that approximate recommended human levels when dosed at 0.06 mg/kg SQ q12h (Hogan DF, unpublished data). Idraparinux is a second-generation synthetic pentasaccharide developed to compete with warfarin therapy for chronic antithrombotic therapy. Idraparinux binds to AT III with much greater affinity than fondaparinux, resulting in a plasma half-life similar to AT III (80 hours) allowing once-a-week dosing.[73] Idraparinux is similar to fondaparinux in most other properties. Idraparinux appears to be as effective as warfarin but has been associated with unacceptably high bleeding rates.[74],[75] Because of the bleeding complications seen with idraparinux and lack of specific antidote, the future for this drug remains to be determined. There is no clinical experience with idraparinux in veterinary medicine.