chapter 7 Bleeding and Hemostasis

Question 1

____is the process that maintains the integrity of a closed, high-pressure circulatory system following vascular damage

Answer 1

Hemostasis is the process that maintains the integrity of a closed, high-pressure circulatory system following vascular damage

Question 2

–% of surgical complications are attributed to coagulation abnormalities, either hemorrhage or thrombosis in the operative or postoperative period.

Answer 2

50%

Question 3

II. Vascular injury provokes a complex response in the endothelium and the blood that culminates in the formation of a thrombus to seal the breach. Divided into two distinct but overlapping phases: ____ hemostasis, involving the interaction between platelets and endothelium resulting in the formation of a platelet plug and _____ hemostasis a system of protoeolytic reactions involving coagulation factors and resulting in the generation of fibrin polymers which stabilize the platelet plug to form a mature thrombus.

Answer 3

II. Vascular injury provokes a complex response in the endothelium and the blood that culminates in the formation of a thrombus to seal the breach. Divided into two distinct but overlapping phases: primary hemostasis, involving the interaction between platelets and endothelium resulting in the formation of a platelet plug and secondary hemostasis a system of protoeolytic reactions involving coagulation factors and resulting in the generation of fibrin polymers which stabilize the platelet plug to form a mature thrombus.

Question 4

i. Platelets are derived and released from bone marrow and circulate for __- __days and provide a source of chemokines that are stored in intracellular storage granules.
1. Synthesize prostanoids (____ _ _) from arachidonic acid.
ii. Following endothelial disruption, platelets adhere to subendothelial collagen via the platelet glycoprotein VI receptor or to collagen-bound von Willebrand factor (vWF) activating the cascade and generation of ____and further recruitment of platelets amplifying the initial response.

Answer 4

i. Platelets are derived and released from bone marrow and circulate for 6-8 days and provide a source of chemokines that are stored in intracellular storage granules.
1. Synthesize prostanoids (Thromboxane A2) from arachidonic acid.
ii. Following endothelial disruption, platelets adhere to subendothelial collagen via the platelet glycoprotein VI receptor or to collagen-bound von Willebrand factor (vWF) activating the cascade and generation of thrombin and further recruitment of platelets amplifying the initial response.

Question 5

secondary hemostasis

i. The cascade model of coagulation
1. Extrinsic pathway – initiated by ____ ____
2. Intrinsic pathway – initiated through contact activation of factor ____
a. Both pathways activate factor __ which with factor __ activate prothrombin to ___which then cleaved fibrinogen to form ___.

Answer 5

b. Secondary hemostasis
i. The cascade model of coagulation
1. Extrinsic pathway – initiated by tissue factor
2. Intrinsic pathway – initiated through contact activation of factor XII
a. Both pathways activate factor X which with factor V activate prothrombin to thrombin which then cleaved fibrinogen to form fibrin.

Question 6

secondary hemostasis

ii. Cell based model of coagulation (initiation, amplification, propagation)
1. Tissue factor is the primary physiologic initiator of coagulation
2. The coagulation is localized to and controlled by cellular surfaces.
3. Initiation phase – tissue-factor initiated (______) pathway that generates small amounts of thrombin. TF is a membrane protein expressed on fibroblasts and other extravascular cells under physiologic conditions. Vascular damage allows plasma and TF cells to bind activating factor VII which activated factor X. Factor X and Factor V produce thrombin.
4. Amplification phase – the platelets are activated and they have activated cofactors V and VIII bound to their surfaces. Thrombin amplifies the initial signal, acting on the platelet to set the stage for ___ complex assembly.
5. Propagation phase – complexes are assembled on the surface of the activated platelet and large-scale ___ generation occurs. Thrombin production activates fibrin production and a stable thrombus.

Answer 6

ii. Cell based model of coagulation (initiation, amplification, propagation)
1. Tissue factor is the primary physiologic initiator of coagulation
2. The coagulation is localized to and controlled by cellular surfaces.
3. Initiation phase – tissue-factor initiated (extrinsic) pathway that generates small amounts of thrombin. TF is a membrane protein expressed on fibroblasts and other extravascular cells under physiologic conditions. Vascular damage allows plasma and TF cells to bind activating factor VII which activated factor X. Factor X and Factor V produce thrombin.
4. Amplification phase – the platelets are activated and they have activated cofactors V and VIII bound to their surfaces. Thrombin amplifies the initial signal, acting on the platelet to set the stage for procoagulant complex assembly.
5. Propagation phase – complexes are assembled on the surface of the activated platelet and large-scale thrombin generation occurs. Thrombin production activates fibrin production and a stable thrombus.

Question 7

1. Clot formation must be localized to the site of injury and be sufficient to impede bleeding but not excessive so as to obstruct blood flow.
2. Inhibitors:
   a. ____ (PGI2) – endothelial cells convert arachidonic acid to PGI2
   b. ____ _____(ecto-APDase) – enzyme metabolizes ADP released from activated platelets thus removing a major agonist and abrogating platelet activation and recruitment.
   c. __ ___ – produced by endothelial cells. Diffuses into platelets and decreases intracellular Calcium flux

Anticoagulant pathways

a. _____(AT) – (ATIII) produced by the liver and inactivates coagulation proteins that escape into circulation from a site of injury (binding and inactivating thrombin and factor X). Also inhibits neutrophil adherence and exerts potent anti-inflammatory effects.
b. ____ _____C – activated by the thrombin-thrombomodulin complex. Enhances fibrinolysis via the inactivation of plasminogen activator inhibitor- 1
c. Tissue factor pathway inhibitor – inhibits tissue factor and abrogates the initiation complex of factor VIIIa-TF as well as factor Xa.

Answer 7

1. Clot formation must be localized to the site of injury and be sufficient to impede bleeding but not excessive so as to obstruct blood flow.
2. Inhibitors:
   a. Prostacyclin (PGI2) – endothelial cells convert arachidonic acid to PGI2
   b. Ectoadenosine diphosphatase (ecto-APDase) – enzyme metabolizes ADP released from activated platelets thus removing a major agonist and abrogating platelet activation and recruitment.
   c. Nitric oxide – produced by endothelial cells. Diffuses into platelets and decreases intracellular Calcium flux
3. Anticoagulant pathways
   a. Antithrombin (AT) – (ATIII) produced by the liver and inactivates coagulation proteins that escape into circulation from a site of injury (binding and inactivating thrombin and factor X). Also inhibits neutrophil adherence and exerts potent anti-inflammatory effects.
   b. Activated protein C – activated by the thrombin-thrombomodulin complex. Enhances fibrinolysis via the inactivation of plasminogen activator inhibitor- 1
   c. Tissue factor pathway inhibitor – inhibits tissue factor and abrogates the initiation complex of factor VIIIa-TF as well as factor Xa.

Question 8

iv. Fibrinolysis
1. The enzymatic dissolution of ___. Plasminogen activators proteolytically convert the proenzyme, plasminogen to plasmin. This then degrades fibrin into soluble degradation products
a. Tissue type plasminogen activator (t-PA) - secreted and synthensized by endothelial cells.
b. Urokinase-type plasminogen activator (u-PA)
2. Fibrinolysis is controlled predominantly by PAI-1, alpha2-antiplasmin and thrombin activatable fibrinolysis inhibitor. PAI-1 is the most important and is stored in platelet alpha granules and is released upon platelet activation.
a. Inhibits both tPA and uPA

Answer 8

iv. Fibrinolysis
1. The enzymatic dissolution of fibrin. Plasminogen activators proteolytically convert the proenzyme, plasminogen to plasmin. This then degrades fibrin into soluble degradation products
a. Tissue type plasminogen activator (t-PA) - secreted and synthensized by endothelial cells.
b. Urokinase-type plasminogen activator (u-PA)
2. Fibrinolysis is controlled predominantly by PAI-1, alpha2-antiplasmin and thrombin activatable fibrinolysis inhibitor. PAI-1 is the most important and is stored in platelet alpha granules and is released upon platelet activation.
a. Inhibits both tPA and uPA

Question 9

b. Buccal mucosal bleeding time
i. The duration of hemorrhage resulting from the infliction of a small standardized injury involving only microscopic vessels. Time from incision to cessation of bleeding.
1. Normal ranges are ___ to ___ minutes in the dog and ___ to ___ minutes in the cat

Answer 9

b. Buccal mucosal bleeding time
i. The duration of hemorrhage resulting from the infliction of a small standardized injury involving only microscopic vessels. Time from incision to cessation of bleeding.
1. Normal ranges are 1.7 to 4.2 minutes in the dog and 1.4 to 2.4 minutes in the cat

Question 10

c. Prothrombin time and activated partial thromboplastin time
i. Assess _____hemostasis via reagents that activate coagulation through the extrinsic or intrinsic pathway respectively.
1. PT prolongation – indicates defective _____and/or common pathway
2. PTT prolongation indicates defective ____and/or common pathways.
3. Decreases occur when decreased to less than 25-30% of normal concentrations.
4. PT is very sensitive to vitamin K deficiency or antagonism.

Answer 10

c. Prothrombin time and activated partial thromboplastin time
i. Assess secondary hemostasis via reagents that activate coagulation through the extrinsic or intrinsic pathway respectively.
1. PT prolongation – indicates defective extrinsic and/or common pathway
2. PTT prolongation indicates defective intrinsic and/or common pathways.
3. Decreases occur when decreased to less than 25-30% of normal concentrations.
4. PT is very sensitive to vitamin K deficiency or antagonism.

Question 11

d. Activated clotting time
i. ACT is performed by collecting whole blood in a _____ ____ tube which serves as a contact activator of factor XII.
ii. Can be influenced by severe thrombocytopenia, throbopathia, anemia, altered blood viscosity, and assay incubation temperature.
e. Fibrin splint products
i. Generated when plasmin lyses fibrinogen, soluble fibrin, or cross-linked fibrin.
ii. Elevated concentrations indicate increased _____ and or fibrinogenolysis.
1. Can inhibit coagulation and induce platelet dysfunction, thus contributing to a bleeding tendency.
2. Clearance occurs via hepatic metabolism and the mononuclear phagocytic system.
iii. Elevated fibrin split products concentrations are commonly detected with ___, but are not specific for the condition; elevated concentrations are also seen in dogs with thromboembolism, neoplasia, immune-mediated hemolytic anemia, hepatic failure, sepsis, and SIRS, heatstroke, trauma, GDV, and heart failure.
f. D-dimer
i. Produced when soluble ____ is cross-linked to fXIIIa.
ii. Indicates the activation of thrombin and plasmin and are specific for active coagulation and fibrinolysis.
iii. D-Dimers are a sensitive indicator of thrombotic conditions, such as DIC and thromboembolism,and are more sensitive to thrombosis than are fibrin split products.

Answer 11

d. Activated clotting time
i. ACT is performed by collecting whole blood in a diatomaceous earth tube which serves as a contact activator of factor XII.
ii. Can be influenced by severe thrombocytopenia, throbopathia, anemia, altered blood viscosity, and assay incubation temperature.
e. Fibrin splint products
i. Generated when plasmin lyses fibrinogen, soluble fibrin, or cross-linked fibrin.
ii. Elevated concentrations indicate increased fibrinolysis and or fibrinogenolysis.
1. Can inhibit coagulation and induce platelet dysfunction, thus contributing to a bleeding tendency.
2. Clearance occurs via hepatic metabolism and the mononuclear phagocytic system.
iii. Elevated fibrin split products concentrations are commonly detected with DIC, but are not specific for the condition; elevated concentrations are also seen in dogs with thromboembolism, neoplasia, immune-mediated hemolytic anemia, hepatic failure, sepsis, and SIRS, heatstroke, trauma, GDV, and heart failure.
f. D-dimer
i. Produced when soluble fibrin is cross-linked to fXIIIa.
ii. Indicates the activation of thrombin and plasmin and are specific for active coagulation and fibrinolysis.
iii. D-Dimers are a sensitive indicator of thrombotic conditions, such as DIC and thromboembolism,and are more sensitive to thrombosis than are fibrin split products.

Question 12

d. Fibrinogen
i. The endpoint of all clotting assays (PT, aPTT, ACT) is based on the formation of a fibrin clot. Nevertheless, these tests usually are not prolonged until fibrinogen is severely decreased (

Answer 12

d. Fibrinogen
i. The endpoint of all clotting assays (PT, aPTT, ACT) is based on the formation of a fibrin clot. Nevertheless, these tests usually are not prolonged until fibrinogen is severely decreased (

Question 13

e. Thromboelastography
i. The ______properties of the blood clot are evaluated, from initiation of coagulation, through amplification and propagation, to fibrinolysis.
ii. TEG analysis is performed using a computerized thromboelastograph (Haemoscope Corporation,Niles, IL).101,371 The apparatus consists of a plastic cup and a pin suspended by a torsion wire. A sample of blood is placed in the cup (at 37° C) and the cup is elevated such that the pin hangs in the sample. The cup is then oscillated through an angle of 4°45” around the vertical axis. When fibrin strands form between the pin and the cup, the pin begins to move with the cup and the torque generated is transmitted to a transducer, which converts the signal data for computer display of the TEG tracing.
iii. Many values can be derived from a TEG tracing (see Figure 7-7).349 The reaction time (R) represents the enzymatic portion of coagulation (secondary hemostasis; represents the time of latency from test initiation until beginning of fibrin formation). The clotting time (K) represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets (is the time to clot formation). The angle (alpha) is dependent largely on fibrinogen, as well as on platelets and factors (represents the rapidity of fibrin accumulation and cross linking). The maximum amplitude (MA) represents the ultimate strength of the fibrin clot, dependent primarily on platelet aggregation (platelet number and function) and, to a lesser extent, on fibrinogen. The MA is used to derive the clot shear elastic modulus G, where G 5000 × MA/(100 MA), and is a measure of the overall coagulant status.
iv. TEG is used in human patients to identify hypocoagulability and hypercoagulability, to predict bleeding or thromboembolism, to guide transfusion therapy, and to monitor the impact of various therapeutic agents.

Answer 13

e. Thromboelastography
i. The viscoelastic properties of the blood clot are evaluated, from initiation of coagulation, through amplification and propagation, to fibrinolysis.
ii. TEG analysis is performed using a computerized thromboelastograph (Haemoscope Corporation,Niles, IL).101,371 The apparatus consists of a plastic cup and a pin suspended by a torsion wire. A sample of blood is placed in the cup (at 37° C) and the cup is elevated such that the pin hangs in the sample. The cup is then oscillated through an angle of 4°45” around the vertical axis. When fibrin strands form between the pin and the cup, the pin begins to move with the cup and the torque generated is transmitted to a transducer, which converts the signal data for computer display of the TEG tracing.
iii. Many values can be derived from a TEG tracing (see Figure 7-7).349 The reaction time (R) represents the enzymatic portion of coagulation (secondary hemostasis; represents the time of latency from test initiation until beginning of fibrin formation). The clotting time (K) represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets (is the time to clot formation). The angle (alpha) is dependent largely on fibrinogen, as well as on platelets and factors (represents the rapidity of fibrin accumulation and cross linking). The maximum amplitude (MA) represents the ultimate strength of the fibrin clot, dependent primarily on platelet aggregation (platelet number and function) and, to a lesser extent, on fibrinogen. The MA is used to derive the clot shear elastic modulus G, where G 5000 × MA/(100 MA), and is a measure of the overall coagulant status.
iv. TEG is used in human patients to identify hypocoagulability and hypercoagulability, to predict bleeding or thromboembolism, to guide transfusion therapy, and to monitor the impact of various therapeutic agents.

Question 14

1. thrombocytopenia
   a. ____production: drug-induced disorders, immune mediated megakaryocytic hypoplasia, viral (FeLV, FIV), chronic rickettsial disease (Ehrlichiosis), estrogen secreting neoplasm, myelodysplasia, megakaryocytic leukemia, cyclic thrombocytopenia (anaplasma platys), radiation, idiopathic bone marrow aplasia, post vaccination)
   b. _____destruction: immune mediated thrombocytopenia, primary: idiopathic, Evan’s syndrome, systemic lupus erythematosus, secondary:drugs, live virus vaccination, tick-borne disease, neoplasia, bacterial infection, nonimmune disorders (drug induced, ehrlichiosis, rocky mountain spotted fever, dirofilariasis)
   c. ______and/or sequestration
   i. DIC, microangiopathies, splenic torsion, hypersplenism, sepsis, hepatic disease, severe acute hemorrhage, severe hypothermia, hemolytic uremic syndrome
   d. __________
   i. Inherited macrothromboytopenia (cavalier king Charles spaniel)

Answer 14

1. thrombocytopenia
   a. decreased production: drug-induced disorders, immune mediated megakaryocytic hypoplasia, viral (FeLV, FIV), chronic rickettsial disease (Ehrlichiosis), estrogen secreting neoplasm, myelodysplasia, megakaryocytic leukemia, cyclic thrombocytopenia (anaplasma platys), radiation, idiopathic bone marrow aplasia, post vaccination)
   b. Increased destruction: immune mediated thrombocytopenia, primary: idiopathic, Evan’s syndrome, systemic lupus erythematosus, secondary:drugs, live virus vaccination, tick-borne disease, neoplasia, bacterial infection, nonimmune disorders (drug induced, ehrlichiosis, rocky mountain spotted fever, dirofilariasis)
   c. Consumption and/or sequestration
   i. DIC, microangiopathies, splenic torsion, hypersplenism, sepsis, hepatic disease, severe acute hemorrhage, severe hypothermia, hemolytic uremic syndrome
   d. Nonpathologic
   i. Inherited macrothromboytopenia (cavalier king Charles spaniel)

Question 15

2. Thrombopathia
   a. _____: drugs (NSAID), aspirin, nonaspirin, antibiotics (carbenicillin, cephalothin, moxalactam, sulfonamides), cardiac, respiratory drugs (calcium channel blockers, methylxanthines, beta blockers), miscellaneous (barbiturates, heparin, hetastarch), uremia, anemia, hepatic disease, hypothermia, colloid hemodilution, myeloproliferative disorders and paraproteinemias, ehrlichiosis, snake venom, DIC
   b. _____: vWD, signal transduction disroders, Glanzmann’s thrombasthenia, CHediak-Higashi syndrome, selective adenosine diphosphate deficiency, cyclic hematopoiesis, procoagulant expression disorders, macrothrombocytopenia
   c. ________: acquired; vasculitis, hyperadrenocorticism, atherosclerosis, inherited; ehlers-Danlos syndrome

Answer 15

2. Thrombopathia
   a. Acquired: drugs (NSAID), aspirin, nonaspirin, antibiotics (carbenicillin, cephalothin, moxalactam, sulfonamides), cardiac, respiratory drugs (calcium channel blockers, methylxanthines, beta blockers), miscellaneous (barbiturates, heparin, hetastarch), uremia, anemia, hepatic disease, hypothermia, colloid hemodilution, myeloproliferative disorders and paraproteinemias, ehrlichiosis, snake venom, DIC
   b. Inherited: vWD, signal transduction disroders, Glanzmann’s thrombasthenia, CHediak-Higashi syndrome, selective adenosine diphosphate deficiency, cyclic hematopoiesis, procoagulant expression disorders, macrothrombocytopenia
   c. Vascular disorders: acquired; vasculitis, hyperadrenocorticism, atherosclerosis, inherited; ehlers-Danlos syndrome

Question 16

Acquired (Acquired disorders, which are more common, frequently affect _____ primary and secondary hemostasis to variable degrees):
1. vitamin k deficiency, hepatopathy, DIC, pharmacologic anticoagulants, hemodilution, severe hypothermia, academia, shock, massive trauma.

Inherited disorders are almost invariably a _____defect in primary or secondary hemostasis.
1. Hypofibrinogenemia and dysfibrinogenemia, hypoprothrombinemia, hypoproconvertinemia, hemophilia A, hemophilia B, Stuart power trait, plasma thormboplastin antecedent deficiency, vitamin k dependent factor deficiency, prekallikerein deficiency

Answer 16

iii. Acquired (Acquired disorders, which are more common, frequently affect both primary and secondary hemostasis to variable degrees):
1. vitamin k deficiency, hepatopathy, DIC, pharmacologic anticoagulants, hemodilution, severe hypothermia, academia, shock, massive trauma.
iv. Inherited disorders are almost invariably a single defect in primary or secondary hemostasis.
1. Hypofibrinogenemia and dysfibrinogenemia, hypoprothrombinemia, hypoproconvertinemia, hemophilia A, hemophilia B, Stuart power trait, plasma thormboplastin antecedent deficiency, vitamin k dependent factor deficiency, prekallikerein deficiency

Question 17

ii. A study in human trauma patients identified risk factors for the development of acute coagulopathy of trauma-shock.86 ________was the greatest risk factor, followed by hypothermia (temperature

Answer 17

ii. A study in human trauma patients identified risk factors for the development of acute coagulopathy of trauma-shock.86 Acidemia (pH

Question 18

e. Hemodilution
i. Dilutional coagulopathy refers to the syndrome that results from blood loss, consumption of coagulation factors and platelets, and intravascular volume replacement.
ii. ______ decreases first with hemodilution, the decrease results in decreased thrombin formation as well as fibrin polymerization (decreased speed, strength, and stability of clots). Fibrinogen 90ml/kg/day and cats >66ml/kg/day)

Answer 18

e. Hemodilution
i. Dilutional coagulopathy refers to the syndrome that results from blood loss, consumption of coagulation factors and platelets, and intravascular volume replacement.
ii. Fibrinogen decreases first with hemodilution, the decrease results in decreased thrombin formation as well as fibrin polymerization (decreased speed, strength, and stability of clots). Fibrinogen 90ml/kg/day and cats >66ml/kg/day)

Question 19

Regardless of the cause, new-onset thrombocytopenia is an independent predictor of intensive care unit mortality, and the severity of thrombocytopenia is ______related to survival. Sustained thrombocytopenia for longer than 4 days or a decrease in platelet count >50% correlates with a four- to six-fold increase in mortality.

Answer 19

Regardless of the cause, new-onset thrombocytopenia is an independent predictor of intensive care unit mortality, and the severity of thrombocytopenia is inversely related to survival. Sustained thrombocytopenia for longer than 4 days or a decrease in platelet count >50% correlates with a four- to six-fold increase in mortality.

Question 20

a. the basic coagulogram (platelet count, PT, and aPTT) and/or the buccal mucosal bleeding time. The coagulogram assesses only platelet numbers and secondary hemostasis. It is generally stated that PT and aPTT prolongations that exceed 1.5 times control values pose a hemorrhagic risk, but review of the medical literature has concluded that evidence is insufficient to suggest that that these tests are predictive
b. Defects of ______hemostasis are characterized by ecchymosis and spontaneous bleeding from mucosal surfaces (e.g., epistaxis, gingival bleeding, hyphema, hematuria, melena). Defects of ______hemostasis are usually characterized by single or multiple hematomas, and by bleeding into subcutaneous tissue, body cavities, muscles, or joints.

Answer 20

a. the basic coagulogram (platelet count, PT, and aPTT) and/or the buccal mucosal bleeding time. The coagulogram assesses only platelet numbers and secondary hemostasis. It is generally stated that PT and aPTT prolongations that exceed 1.5 times control values pose a hemorrhagic risk, but review of the medical literature has concluded that evidence is insufficient to suggest that that these tests are predictive
b. Defects of primary hemostasis are characterized by ecchymosis and spontaneous bleeding from mucosal surfaces (e.g., epistaxis, gingival bleeding, hyphema, hematuria, melena). Defects of secondary hemostasis are usually characterized by single or multiple hematomas, and by bleeding into subcutaneous tissue, body cavities, muscles, or joints.

Question 21

a. Blood loss of 25% to 30% of blood volume generally results in tachycardia and vasoconstriction, although these compensatory mechanisms can be blunted by anesthesia, medication, or disease.
b. Tachycardia prolonged capillary refill time, pallor, altered pulses, hypotension, reduced urine output, falling central venous pressure, bruising, and swelling are all suggestive of bleeding.
c. __% of hemodynamically unstable human patients had hyperfibrinolysis as the major cause of bleeding.8 Little is known regarding hyperfibrinolysis in small animals. It has been suggested to contribute to postoperative bleeding in some _______.203
i. Hyperfibrinolysis is best detected via ___; markedly elevated D-dimers and low fibrinogen levels are suggestive.213

Answer 21

a. Blood loss of 25% to 30% of blood volume generally results in tachycardia and vasoconstriction, although these compensatory mechanisms can be blunted by anesthesia, medication, or disease.
b. Tachycardia prolonged capillary refill time, pallor, altered pulses, hypotension, reduced urine output, falling central venous pressure, bruising, and swelling are all suggestive of bleeding.
c. 10% of hemodynamically unstable human patients had hyperfibrinolysis as the major cause of bleeding.8 Little is known regarding hyperfibrinolysis in small animals. It has been suggested to contribute to postoperative bleeding in some Greyhounds.203
i. Hyperfibrinolysis is best detected via TEG; markedly elevated D-dimers and low fibrinogen levels are suggestive.213

Question 22

XIII. Platelet transfusion

a. Lack of readily available donors, short shelf-lives of platelet components, and an inability to administer sufficient numbers of platelets to meet the patient’s needs are major difficulties encountered.
b. Platelet containing products: fresh whole blood (transfused within __ hours), platelet-rich plasma, and platelet concentrate.
c. Platelet transfusion is essential in the management of uncontrolled or life-threatening bleeding (bleeding into the brain, lungs, or myocardium) because of severe thrombocytopenia or thrombopathia. Even with immune-mediated thrombocytopenia, where transfused platelets are rapidly destroyed, a negligible increase in platelet count may provide adequate, lifesaving hemostasis.

Answer 22

XIII. Platelet transfusion

a. Lack of readily available donors, short shelf-lives of platelet components, and an inability to administer sufficient numbers of platelets to meet the patient’s needs are major difficulties encountered.
b. Platelet containing products: fresh whole blood (transfused within 8 hours), platelet-rich plasma, and platelet concentrate.
c. Platelet transfusion is essential in the management of uncontrolled or life-threatening bleeding (bleeding into the brain, lungs, or myocardium) because of severe thrombocytopenia or thrombopathia. Even with immune-mediated thrombocytopenia, where transfused platelets are rapidly destroyed, a negligible increase in platelet count may provide adequate, lifesaving hemostasis.

Question 23

a. Desmopressin DDAVP
i. Injectable or intranasal desmopressin is administered at 1 to 4 μg/kg subQ. is a synthetic vasopressin analogue
ii. Desmopressin is used as adjunctive treatment of bleeding associated with canine type 1 ______ _____ disease, as well as for presurgical prophylaxis (administered 30 minutes before surgery).
b. Antifibrinolytics
i. Aprotinin, epsilon-aminocaproic acid (EACA), and tranexamic acid (TEA) are clinically used antifibrinolytics.
ii. Until additional data become available, it is difficult to provide evidence-based guidelines for use. EACA may be considered as adjunctive treatment of unrelenting surgical bleeding, particularly if hyperfibrinolysis is documented via TEG, or is suspected on coagulation testing
c. Recombinant factor VIIa
i. The mechanisms of action of recombinant activated fVII (rFVIIa) are both tissue-factor dependent and tissue-factor independent.
ii. rFVIIa has also been successfully utilized as a universal prohemostatic agent in many human bleeding disorders, including hemophilia, fVII deficiency, quantitative and qualitative platelet disorders, hepatic failure, surgical bleeding, and trauma
iii. Dosage recommendations range from 20 to 100 μg/kg IV, administered q2h until effective hemostasis is achieved.
iv. Implications are that rFVIIa can be used for only a short period in dogs and cannot be repeated; pretreatment with antihistamines may prove useful in prevention of acute hypersensitivity reactions.

Answer 23

a. Desmopressin DDAVP
i. Injectable or intranasal desmopressin is administered at 1 to 4 μg/kg subQ. is a synthetic vasopressin analogue
ii. Desmopressin is used as adjunctive treatment of bleeding associated with canine type 1 von Willebrand disease, as well as for presurgical prophylaxis (administered 30 minutes before surgery).
b. Antifibrinolytics
i. Aprotinin, epsilon-aminocaproic acid (EACA), and tranexamic acid (TEA) are clinically used antifibrinolytics.
ii. Until additional data become available, it is difficult to provide evidence-based guidelines for use. EACA may be considered as adjunctive treatment of unrelenting surgical bleeding, particularly if hyperfibrinolysis is documented via TEG, or is suspected on coagulation testing
c. Recombinant factor VIIa
i. The mechanisms of action of recombinant activated fVII (rFVIIa) are both tissue-factor dependent and tissue-factor independent.
ii. rFVIIa has also been successfully utilized as a universal prohemostatic agent in many human bleeding disorders, including hemophilia, fVII deficiency, quantitative and qualitative platelet disorders, hepatic failure, surgical bleeding, and trauma
iii. Dosage recommendations range from 20 to 100 μg/kg IV, administered q2h until effective hemostasis is achieved.
iv. Implications are that rFVIIa can be used for only a short period in dogs and cannot be repeated; pretreatment with antihistamines may prove useful in prevention of acute hypersensitivity reactions.

Question 24

a. Thrombocytopenia
i. Thrombocytopenia is the most common primary hemostatic defect, occurring through one of four mechanisms: decreased production, increased destruction, increased consumption, or sequestration (see above)
ii. Spontaneous bleeding generally does not occur until platelet counts fall below __,000/μL, but counts as low as 5000/μL can occur without bleeding.
iii. Sequestration thrombocytopenia, such as occurs with hypersplenism and splenic torsion, is not associated with bleeding.307
iv. immune-mediated thrombocytopenia is the most common cause of thrombocytopenia in dogs; can be idiopathic or may occur secondary to drugs, vaccines, or underlying infectious or neoplastic disease
v. thrombocytopenic cats have underlying disease, commonly viral (approximately 30%) and neoplastic (approximately 20%).178

Answer 24

a. Thrombocytopenia
i. Thrombocytopenia is the most common primary hemostatic defect, occurring through one of four mechanisms: decreased production, increased destruction, increased consumption, or sequestration (see above)
ii. Spontaneous bleeding generally does not occur until platelet counts fall below 50,000/μL, but counts as low as 5000/μL can occur without bleeding.
iii. Sequestration thrombocytopenia, such as occurs with hypersplenism and splenic torsion, is not associated with bleeding.307
iv. immune-mediated thrombocytopenia is the most common cause of thrombocytopenia in dogs; can be idiopathic or may occur secondary to drugs, vaccines, or underlying infectious or neoplastic disease
v. thrombocytopenic cats have underlying disease, commonly viral (approximately 30%) and neoplastic (approximately 20%).178

Question 25

b. von Willebrand disease i. von Willebrand disease is the most common ______bleeding disorder of dogs ii. vWF is a multimeric plasma glycoprotein that facilitates _____adhesion to exposed subendothelium iii. Three types of von Willebrand disease are described. 1. Type 1 von Willebrand disease is characterized by the presence of all multimers, but in reduced concentrations. It is the most common (______, poodles, Shetland sheepdogs, German shep, airdales) 2. Type 2 von Willebrand disease is characterized by a disproportionate loss of high-molecular-weight multimers. (uncommon) 3. Type 3 is a quantitative deficiency, with an almost complete absence of vWF (

Answer 25

b. von Willebrand disease i. von Willebrand disease is the most common congenital bleeding disorder of dogs ii. vWF is a multimeric plasma glycoprotein that facilitates platelet adhesion to exposed subendothelium iii. Three types of von Willebrand disease are described. 1. Type 1 von Willebrand disease is characterized by the presence of all multimers, but in reduced concentrations. It is the most common (Dobermans, poodles, Shetland sheepdogs, German shep, airdales) 2. Type 2 von Willebrand disease is characterized by a disproportionate loss of high-molecular-weight multimers. (uncommon) 3. Type 3 is a quantitative deficiency, with an almost complete absence of vWF (

Question 26

2. Factor ___ deficiency is an asymptomatic condition of dogs and cats. It is the most common factor deficiency in cats, with a reported prevalence of 2.1% of samples submitted.

Answer 26

2. Factor XII deficiency is an asymptomatic condition of dogs and cats. It is the most common factor deficiency in cats, with a reported prevalence of 2.1% of samples submitted.

Question 27

a. Vitamin K deficiency i. Vitamin K is required for the activation of factors __,__,___,___, as well as for the synthesis of proteins C and S ii. compounds (Vitamin K antagonism occurs with warfarin therapy or anticoagulant rodenticide toxicity)inhibit vitamin K epoxide reductase, leading to a relative vitamin K deficiency. iii. Spontaneous bleeding is universal with anticoagulant rodenticide toxicity, whereas subclinical hemostatic defects are common with disease- or drug-related deficiency. iv. __ prolongation occurs first, reflecting the short half-life of fVII (4 to 6 hours). Prolongation of the____ follows when other factors are depleted (approximately 2 days). v. Treatment includes vitamin K1 administration, management of the underlying condition, and, in the actively bleeding patient, transfusion. Vitamin K1 therapy is initiated at 2.5 to 5.0 mg/kg SC or IM, followed by 1.25 to 2.5 mg/kg SC or PO q12h. Oral supplementation is preferable in the nonvomiting patient with adequate gastrointestinal absorption.

Answer 27

a. Vitamin K deficiency i. Vitamin K is required for the activation of factors II, VII, IX, and X, as well as for the synthesis of proteins C and S ii. compounds (Vitamin K antagonism occurs with warfarin therapy or anticoagulant rodenticide toxicity)inhibit vitamin K epoxide reductase, leading to a relative vitamin K deficiency. iii. Spontaneous bleeding is universal with anticoagulant rodenticide toxicity, whereas subclinical hemostatic defects are common with disease- or drug-related deficiency. iv. PT prolongation occurs first, reflecting the short half-life of fVII (4 to 6 hours). Prolongation of the aPTT follows when other factors are depleted (approximately 2 days). v. Treatment includes vitamin K1 administration, management of the underlying condition, and, in the actively bleeding patient, transfusion. Vitamin K1 therapy is initiated at 2.5 to 5.0 mg/kg SC or IM, followed by 1.25 to 2.5 mg/kg SC or PO q12h. Oral supplementation is preferable in the nonvomiting patient with adequate gastrointestinal absorption.

Question 28

a. Hepatic disease i. The liver plays a pivotal role in hemostasis by synthesizing ______factors (with the exception of fVIII), coagulation inhibitors (AT, protein C), and fibrinolytic proteins, as well as by clearing activated factors, enzyme-inhibitor complexes, and fibrin split proteins. Occurs only with significantly decreased functional hepatic mass (>__%), with fVII showing earliest reduction. ii. Hyperfibrinolysis can result from impaired clearance of t-PA, together with decreased hepatic synthesis of thrombin activatable fibrinolysis inhibition. iii. Spontaneous hemorrhage occurs in less than 2%, but bleeding is common in response to a hemostatic challenge such as surgery, liver biopsy, or gastrointestinal ulceration. iv. In disseminated intravascular coagulation, fibrinogen levels tend to be lower and D dimers higher, compared with hepatic disease. v. Because coagulation tests do not distinguish between vitamin K deficiency and coagulation factor deficiency, a vitamin K trial is valid, particularly in the patient with cholestatic disease.

Answer 28

a. Hepatic disease i. The liver plays a pivotal role in hemostasis by synthesizing clotting factors (with the exception of fVIII), coagulation inhibitors (AT, protein C), and fibrinolytic proteins, as well as by clearing activated factors, enzyme-inhibitor complexes, and fibrin split proteins. Occurs only with significantly decreased functional hepatic mass (>70%), with fVII showing earliest reduction. ii. Hyperfibrinolysis can result from impaired clearance of t-PA, together with decreased hepatic synthesis of thrombin activatable fibrinolysis inhibition. iii. Spontaneous hemorrhage occurs in less than 2%, but bleeding is common in response to a hemostatic challenge such as surgery, liver biopsy, or gastrointestinal ulceration. iv. In disseminated intravascular coagulation, fibrinogen levels tend to be lower and D dimers higher, compared with hepatic disease. v. Because coagulation tests do not distinguish between vitamin K deficiency and coagulation factor deficiency, a vitamin K trial is valid, particularly in the patient with cholestatic disease.

Question 29

XVI. Thromboembolism a. refers to ________obstruction by a thrombus that develops locally (primary thrombosis), or that translocates from a distant site (embolism). Thromboembolism is classified as arterial or venous, according to the vasculature involved. b. _____ thromboembolism most commonly involves the aorta and/or its branches, or the cerebral vasculature; myocardial infarction is less common. _______ thromboembolism usually manifests as pulmonary thromboembolism; thrombosis of the portal, splenic, hepatic, vena caval, and mesenteric veins also occurs. c. Thrombotic tendency i. Pathophysiology 1. Thrombotic tendency (prothrombosis, thrombophilia) depends on three major risk factors, as described by Virchow's triad: abnormalities of the vessel wall (endothelial injury), abnormalities of blood flow (vascular stasis), and abnormalities of blood constituents (hypercoagulability). a. Hypoalbuminemia increases TxA2 synthesis, resulting in hyperaggregability. (protein losing nephropathy – favor coagulation, but not PLE) b. Activated protein C deficiencies are described in human beings with sepsis, malignancy, or pancreatitis, and postoperatively,108,146 as well as in dogs with sepsis contribute to hypercoagulability. ii. Causes 1. The term hypercoagulable state refers to an underlying disorder that poses a risk for thrombosis. 2. Conditions associated with canine thromboembolism include protein-losing nephropathy, neoplasia, immune-mediated hemolytic anemia, necrotizing pancreatitis, hyperadrenocorticism, corticosteroid therapy, cardiac disease (primarily infective endocarditis and dirofilariasis), atherosclerosis, sepsis, and diabetes mellitus a. Protein-losing enteropathy parvoviral enteritis, trauma, and surgery are less commonly described. b. thromboembolic risk is cumulative, and that the likelihood of thromboembolism is increased when multiple prothrombotic conditions occur. c. Arterial thromboembolism is well documented, occurring secondary to ____disease and, less commonly, neoplasia in the cat i. Fewer reports have described venous thromboembolism, generally resulting from neoplasia or cardiac disease; less frequently, pancreatitis, IMHA, corticosteroid therapy, sepsis, protein-losing nephropathy, and PLE 3. A majority of hypercoagulable patients have normal coagulograms 4. Fibrinogen is an acute phase reactant and is an independent risk factor for thromboembolism in humans a. Hyperfibrinogenemia has been suggested to contribute to hypercoagulability in dogs, but as yet, no correlation has been established between hyperfibrinogenemia and thrombotic risk 5. Of currently available tests, TEG demonstrates greatest utility for the diagnosis of hypercoagulability in the individual patient.184,349

Answer 29

XVI. Thromboembolism a. refers to macrovascular obstruction by a thrombus that develops locally (primary thrombosis), or that translocates from a distant site (embolism). Thromboembolism is classified as arterial or venous, according to the vasculature involved. b. Arterial thromboembolism most commonly involves the aorta and/or its branches, or the cerebral vasculature; myocardial infarction is less common. Venous thromboembolism usually manifests as pulmonary thromboembolism; thrombosis of the portal, splenic, hepatic, vena caval, and mesenteric veins also occurs. c. Thrombotic tendency i. Pathophysiology 1. Thrombotic tendency (prothrombosis, thrombophilia) depends on three major risk factors, as described by Virchow's triad: abnormalities of the vessel wall (endothelial injury), abnormalities of blood flow (vascular stasis), and abnormalities of blood constituents (hypercoagulability). a. Hypoalbuminemia increases TxA2 synthesis, resulting in hyperaggregability. (protein losing nephropathy – favor coagulation, but not PLE) b. Activated protein C deficiencies are described in human beings with sepsis, malignancy, or pancreatitis, and postoperatively,108,146 as well as in dogs with sepsis contribute to hypercoagulability. ii. Causes 1. The term hypercoagulable state refers to an underlying disorder that poses a risk for thrombosis. 2. Conditions associated with canine thromboembolism include protein-losing nephropathy, neoplasia, immune-mediated hemolytic anemia, necrotizing pancreatitis, hyperadrenocorticism, corticosteroid therapy, cardiac disease (primarily infective endocarditis and dirofilariasis), atherosclerosis, sepsis, and diabetes mellitus a. Protein-losing enteropathy parvoviral enteritis, trauma, and surgery are less commonly described. b. thromboembolic risk is cumulative, and that the likelihood of thromboembolism is increased when multiple prothrombotic conditions occur. c. Arterial thromboembolism is well documented, occurring secondary to cardiac disease and, less commonly, neoplasia in the cat i. Fewer reports have described venous thromboembolism, generally resulting from neoplasia or cardiac disease; less frequently, pancreatitis, IMHA, corticosteroid therapy, sepsis, protein-losing nephropathy, and PLE 3. A majority of hypercoagulable patients have normal coagulograms 4. Fibrinogen is an acute phase reactant and is an independent risk factor for thromboembolism in humans a. Hyperfibrinogenemia has been suggested to contribute to hypercoagulability in dogs, but as yet, no correlation has been established between hyperfibrinogenemia and thrombotic risk 5. Of currently available tests, TEG demonstrates greatest utility for the diagnosis of hypercoagulability in the individual patient.184,349

Question 30

d. Postoperative thromboembolism i. Highest risk is seen in patients undergoing major orthopedic or trauma surgery (arthroplasty, hip fracture surgery), followed by major urologic and gynecologic surgery. ii. A study in dogs revealed that as many as __% of patients undergoing total hip arthroplasty have evidence of pulmonary thromboembolism postoperatively. Pulmonary thromboembolism has also been reported in hyperadrenocorticoid dogs following adrenalectomy Among renal transplantation dogs, 50% (5 of 10) of those that did not receive anticoagulant prophylaxis developed thromboembolism.

Answer 30

d. Postoperative thromboembolism i. Highest risk is seen in patients undergoing major orthopedic or trauma surgery (arthroplasty, hip fracture surgery), followed by major urologic and gynecologic surgery. ii. A study in dogs revealed that as many as 82% of patients undergoing total hip arthroplasty have evidence of pulmonary thromboembolism postoperatively. Pulmonary thromboembolism has also been reported in hyperadrenocorticoid dogs following adrenalectomy Among renal transplantation dogs, 50% (5 of 10) of those that did not receive anticoagulant prophylaxis developed thromboembolism.

Question 31

________ thromboembolism is the most common postoperative thromboembolic complication, with manifestations ranging from clinically insignificant to profound respiratory compromise. b. Pulmonary thromboembolism should be considered in any patient with an acute onset of respiratory signs, particularly if the patient has no prior evidence of respiratory disease. assessment includes thoracic radiography, arterial blood gas analysis, and routine hematologic and biochemical testing c. Initial assessment i. Most patients with pulmonary thromboembolism have abnormal thoracic radiographs, but findings are nonspecific. usually are alveolar, but can be interstitial or mixed alveolar-interstitial. ii. thoracic radiographs that underestimate the degree of clinical respiratory compromise are an important diagnostic clue. iii. Arterial blood gas analysis can be useful in diagnosis and is relevant to patient management, but findings are not pathognomonic.

Answer 31

a. Pulmonary thromboembolism is the most common postoperative thromboembolic complication, with manifestations ranging from clinically insignificant to profound respiratory compromise. b. Pulmonary thromboembolism should be considered in any patient with an acute onset of respiratory signs, particularly if the patient has no prior evidence of respiratory disease. assessment includes thoracic radiography, arterial blood gas analysis, and routine hematologic and biochemical testing c. Initial assessment i. Most patients with pulmonary thromboembolism have abnormal thoracic radiographs, but findings are nonspecific. usually are alveolar, but can be interstitial or mixed alveolar-interstitial. ii. thoracic radiographs that underestimate the degree of clinical respiratory compromise are an important diagnostic clue. iii. Arterial blood gas analysis can be useful in diagnosis and is relevant to patient management, but findings are not pathognomonic.

Question 32

ii. Antiplatelet drugs (aspirin, thienopyridines) inhibit platelet activation and/or aggregation, and generally are prescribed for arterial ___________

Answer 32

ii. Antiplatelet drugs (aspirin, thienopyridines) inhibit platelet activation and/or aggregation, and generally are prescribed for arterial thromboprophylaxis

Question 33

iii. Anticoagulants (heparins, warfarin) inhibit secondary hemostasis and are used for ______ thromboprophylaxis.

Answer 33

iii. Anticoagulants (heparins, warfarin) inhibit secondary hemostasis and are used for venous thromboprophylaxis.

Question 34

Anticoagulants Unfractionated heparin i. The primary mechanism of action is the potentiation of ____ activity, leading to the inactivation of coagulation factors, notably thrombin and fXa. Other effects of unfractionated heparin include the release of tissue factor pathway inhibitor, decreased blood viscosity, decreased platelet function, and increased vascular permeability.153,284 ii. heparin binding proteins can be increased in patients with inflammation, resulting in relative heparin resistance. Low-molecular weight heparin i. Manufactured from unfractionated heparin to yield smaller molecules (4000-6500 daltons). The smaller size translates to far greater inhibition of _____than of thrombin (2:1 to 4:1). For this reason, anticoagulant effect cannot be monitored by PTT, but is assessed by anti-facotr Xa assay. 1. Ability to inhibit platelet bound factor Xa, and lesser effects on platelet function and vascular permeability. 2. Examples: dalterparin, enoxaparin, and tinzaparin Warfarin i. Vitamin K antagonist that alters the synthesis of ___ _dependent coagulation factors II, IV, IX, X as well as anticoagulant proteins C and S. ii. Initiated at a dosage of 0.05-0.1mg/kg PO q 24 hours in dogs and cats iii. Therapeutic ranges are achieved in 5-7 days. iv. Bleeding tendencies exist and should be monitored for. Therapy is monitored via PT or international normalization ratio, and the dosage adjusted to achieve a PT 1.25-1.5 times baseline or an international normalization ration of 2.0-3.0

Answer 34

XIX. Anticoagulants a. Unfractionated heparin i. The primary mechanism of action is the potentiation of AT activity, leading to the inactivation of coagulation factors, notably thrombin and fXa. Other effects of unfractionated heparin include the release of tissue factor pathway inhibitor, decreased blood viscosity, decreased platelet function, and increased vascular permeability.153,284 ii. heparin binding proteins can be increased in patients with inflammation, resulting in relative heparin resistance. b. Low-molecular weight heparin i. Manufactured from unfractionated heparin to yield smaller molecules (4000-6500 daltons). The smaller size translates to far greater inhibition of fXa than of thrombin (2:1 to 4:1). For this reason, anticoagulant effect cannot be monitored by PTT, but is assessed by anti-facotr Xa assay. 1. Ability to inhibit platelet bound factor Xa, and lesser effects on platelet function and vascular permeability. 2. Examples: dalterparin, enoxaparin, and tinzaparin c. Warfarin i. Vitamin K antagonist that alters the synthesis of vitamin K dependent coagulation factors II, IV, IX, X as well as anticoagulant proteins C and S. ii. Initiated at a dosage of 0.05-0.1mg/kg PO q 24 hours in dogs and cats iii. Therapeutic ranges are achieved in 5-7 days. iv. Bleeding tendencies exist and should be monitored for. Therapy is monitored via PT or international normalization ratio, and the dosage adjusted to achieve a PT 1.25-1.5 times baseline or an international normalization ration of 2.0-3.0

Question 35

Antiplatelet Drugs Aspirin i. Induces an ______functional defect in platelets by inactivating COX -1, thus suppressing the synthesis of TxA2 1. Effects is maintained for the life of the platelets 2. Unlike platelets, endothelial cells have the capacity to synthesize new COX-1. So an endothelial sparing dose should be used. 3. 0.5mg/kg PO q 12-24 hours to inhibit platelet function in dogs (ultra-low dose) 4. Adverse effects: gastrointestinal and are dosage related. 5. Cats 5mg/cat P q 72 hours has been shown to compare favorably with traditional doses (81mg/cat PO q 72 hours) for cats with arterial thromboembolism Clopidogrel i. Requires hepatic metabolism to aquire antiplatelet activity. Active metabolites ______block ADP binding to its P2y12 receptor on the platelet surface. Platelet inhibition occurs by 2 days and reaches a steady state after 5-7 days. The effects persist for the life of the platelet. ii. Also inhibits serotonin release, which may have a vasomodulating effect, reducing the ischemic impact of thromboembolism events. iii. Small proportion of cats developed self-limiting diarrhea

Answer 35

XX. Antiplatelet Drugs a. Aspirin i. Induces an irreversible functional defect in platelets by inactivating COX -1, thus suppressing the synthesis of TxA2 1. Effects is maintained for the life of the platelets 2. Unlike platelets, endothelial cells have the capacity to synthesize new COX-1. So an endothelial sparing dose should be used. 3. 0.5mg/kg PO q 12-24 hours to inhibit platelet function in dogs (ultra-low dose) 4. Adverse effects: gastrointestinal and are dosage related. 5. Cats 5mg/cat P q 72 hours has been shown to compare favorably with traditional doses (81mg/cat PO q 72 hours) for cats with arterial thromboembolism b. Clopidogrel i. Requires hepatic metabolism to aquire antiplatelet activity. Active metabolites irreversibly block ADP binding to its P2y12 receptor on the platelet surface. Platelet inhibition occurs by 2 days and reaches a steady state after 5-7 days. The effects persist for the life of the platelet. ii. Also inhibits serotonin release, which may have a vasomodulating effect, reducing the ischemic impact of thromboembolism events. iii. Small proportion of cats developed self-limiting diarrhea

Question 36

Treatment for thromboembolism a. Extrapolations from human medicine, on pathophysiologic rationale, and on anecdotal recommendations from experts in the field i. Initial therapy 1. Patient support, prevention of thrombus propagation and/or recurrence, and in rare cases thrombolysis 2. In dogs, thrombi begin to lyse spontaneously within hours. 3. _______ supplementation is indicated when dyspnea is evident and/or when the arterial partial pressure of oxygen (PaO2) decreases to below 70mmHg a. Has also been shown to dilate pulmonary vessels, improve hemodynamics, reduce pulmonary hypertension, and improve right ventricular function. 4. Anticoagulation is the mainstay of initial management of venous thromboembolism in human beings. 5. ______ ____in the dog: a bolus of 80-100U/kg is administered IV followed by a CRI of 18U/kg/hr. A PTT is evaluated in 6 hours after initiation of therapy and adjustments are made as indicated. a. PTT 3 x mean normal, stop infusion for 1 hour, recheck pTT in 6 hours. 6. The role of thrombolytic agents in animals with venous thromboembolism remains to be investigated. a. Plasminogen activators (streptokinase, urokinase, and t-PA) augment fibrinolysis and carry an appreciable risk of systemic hemorrhage. i. t-PA is more clot-specific and has proved to be clinically superior.

Answer 36

XXI. Treatment for thromboembolism a. Extrapolations from human medicine, on pathophysiologic rationale, and on anecdotal recommendations from experts in the field i. Initial therapy 1. Patient support, prevention of thrombus propagation and/or recurrence, and in rare cases thrombolysis 2. In dogs, thrombi begin to lyse spontaneously within hours. 3. Oxygen supplementation is indicated when dyspnea is evident and/or when the arterial partial pressure of oxygen (PaO2) decreases to below 70mmHg a. Has also been shown to dilate pulmonary vessels, improve hemodynamics, reduce pulmonary hypertension, and improve right ventricular function. 4. Anticoagulation is the mainstay of initial management of venous thromboembolism in human beings. 5. Unfractionated heparin in the dog: a bolus of 80-100U/kg is administered IV followed by a CRI of 18U/kg/hr. A PTT is evaluated in 6 hours after initiation of therapy and adjustments are made as indicated. a. PTT 3 x mean normal, stop infusion for 1 hour, recheck pTT in 6 hours. 6. The role of thrombolytic agents in animals with venous thromboembolism remains to be investigated. a. Plasminogen activators (streptokinase, urokinase, and t-PA) augment fibrinolysis and carry an appreciable risk of systemic hemorrhage. i. t-PA is more clot-specific and has proved to be clinically superior.

Question 37

ii. Ambulation and adequate hydration are important for prophylaxis of thromboembolism. iii. For moderate and high risk cases, unfractionated heparin 500U SC hour preoperatively , then q 8-12 hours following surgery or low molecular weight heparin (initiated 12 hours before or after surgery).

Answer 37

ii. Ambulation and adequate hydration are important for prophylaxis. iii. For moderate and high risk cases, unfractionated heparin 500U SC hour preoperatively , then q 8-12 hours following surgery or low molecular weight heparin (initiated 12 hours before or after surgery).

Question 38

DIC disseminated intravascular coagulation a. Syndrome characterized by the systemic activation of coagulation, leading to widespread microvascular thrombosis that compromises organ perfusion and can contribute to organ failure. i. The ongoing activation of coagulation may exhause platelet and coagulation factors, resulting in a hypocaoagulable state and bleeding, particularly in patients at risk for blood loss, such as surgical patients. b. Thrombosis and bleeding can occur separately or concurrently and the diverse clinical characteristics of this disorder make diagnosis and management challenging. c. Mortality rates of ___ - ___% in dogs and ____% in cats d. Conditions associated with DIC Infections/inflammatory 1. Bacterial – bacterial sepsis, severe, localized infection 2. Viral – infectious canine hepatitis, canine distemper, canine parvovirus, feline infectious peritonitis, feline panleukopenia 3. Protozoal – severe systemic protozoal disease 4. Fungal – fulminating systemic fungal disease, candida sepsis Non-infectious inflammatory 1. Neoplasia -solid tumors ( hemangiosarcoma, mammary gland carcinoma, pulmonary adenocarcinoma…), myeloproliferative/lymphoproliferative malignancies 2. Tissue trauma, ischemia – severe shock, heatstroke, pancreatitis, massive crushing injury, severe burns, envenomation (snake, insect), GDV, severe gastrotenteritis, heartworm disease, 3. Immune mediated - IMHA, hemolytic transufion reaction Etiopathogenesis i. Sepsis and SIRS are the most common causes in human beings and dogs. 1. In human sepsis cases, DIC occurs in __-__% of cases ii. Leukocytes release cytokines, TNF- alpha, IL-1 and IL-6 which are pathophysiologic initiators of DIC. Cytokines damage microvascular endothelium and induce the expression of tissue factor on mononucleare, endothelial, and tumor cells, activating the tissue factor fVIIa pathway. Platelets also activated by leukocyte secreted palatelet activating factor. Plasma levels of AT are reduced as a result of comsumption, degradation by neutrophil elastase, and impaired hepatic synthesis. Activated protein C levels decline as a result of consumption, cytokine mediated downregulation of endothelial thrombomodulin, oxidative injury of thrombomodulin by neutrophils, impaired hepatic synthesis, and decreased concentrations of protein S. Given the anti-inflammatory functions of AT and activated protein C, decreased activities result not only in unchecked coagulation but also in the unopposed escalation of inflammation. f. Diagnosis i. Evidence of bleeding (minority of cases) and organ dysfunction. Ischemic manifestation of organ failure, renal failure, respiratory insufficiency, hepatic failure, and gastrointestinal compromise. ii. Laboratory testing 1. D-dimers in cats. 2. No gold standard nor consensus has been reached for the diagnosis of DIC In animals. a. Usually diagnosed based on the presence of a known condition and 3 or more of the following: thrombocytopenia, PT and or PTT prolongation, elevated fibrin split proteins or D-dimers, hypofibrinogenemia, reduce AT activity, and or RBC fragmentation. g. Management i. Outcome is improved by early and aggressive therapy. Cornerstone of DIC management is specific and vigorous treatment of the underlying condition. 1. Specific therapy may involve surgical or medical management of neoplasia, or immunosuppressive therapy for immune-mediated disease. ii. Adequate perfusion must be restored and mainteained via appropriate fluid therapy, to alleviate vascular stasis, hypoxia, and acidosis that promote coagulation activation. iii. Close monitoring of susseptible organs such as the respiratory, kidneys, and GI tracts. 1. Oliguria or renal insufficiency should prompt early fluid and possibly diuretic or dopamine administration. 2. Respiratory – oxygen supplementation or mechanical ventilation. 3. Early enteral nutrition, antacid therapy iv. Fresh frozen plasma may be of benefit in DIC by supplying AT to bolster the sagging anticoagulant pathways, no evidence supports this. v. The past decade has produced sufficient evidence to cast reasonable doubt regarding the role of heparin in DIC therapy. vi. Only studies of activated protein C supplementation has demonstrated a survival benefit, but animal trials have yet to be evaluated.

Answer 38

XXIII. DIC disseminated intravascular coagulation a. Syndrome characterized by the systemic activation of coagulation, leading to widespread microvascular thrombosis that compromises organ perfusion and can contribute to organ failure. i. The ongoing activation of coagulation may exhause platelet and coagulation factors, resulting in a hypocaoagulable state and bleeding, particularly in patients at risk for blood loss, such as surgical patients. b. Thrombosis and bleeding can occur separately or concurrently and the diverse clinical characteristics of this disorder make diagnosis and management challenging. c. Mortality rates of 50-77% in dogs and 93% in cats d. Conditions associated with DIC i. Infections/inflammatory 1. Bacterial – bacterial sepsis, severe, localized infection 2. Viral – infectious canine hepatitis, canine distemper, canine parvovirus, feline infectious peritonitis, feline panleukopenia 3. Protozoal – severe systemic protozoal disease 4. Fungal – fulminating systemic fungal disease, candida sepsis ii. Non-infectious inflammatory 1. Neoplasia -solid tumors ( hemangiosarcoma, mammary gland carcinoma, pulmonary adenocarcinoma…), myeloproliferative/lymphoproliferative malignancies 2. Tissue trauma, ischemia – severe shock, heatstroke, pancreatitis, massive crushing injury, severe burns, envenomation (snake, insect), GDV, severe gastrotenteritis, heartworm disease, 3. Immune mediated - IMHA, hemolytic transufion reaction e. Etiopathogenesis i. Sepsis and SIRS are the most common causes in human beings and dogs. 1. In human sepsis cases, DIC occurs in 25-50% of cases ii. Leukocytes release cytokines, TNF- alpha, IL-1 and IL-6 which are pathophysiologic initiators of DIC. Cytokines damage microvascular endothelium and induce the expression of tissue factor on mononucleare, endothelial, and tumor cells, activating the tissue factor fVIIa pathway. Platelets also activated by leukocyte secreted palatelet activating factor. Plasma levels of AT are reduced as a result of comsumption, degradation by neutrophil elastase, and impaired hepatic synthesis. Activated protein C levels decline as a result of consumption, cytokine mediated downregulation of endothelial thrombomodulin, oxidative injury of thrombomodulin by neutrophils, impaired hepatic synthesis, and decreased concentrations of protein S. Given the anti-inflammatory functions of AT and activated protein C, decreased activities result not only in unchecked coagulation but also in the unopposed escalation of inflammation. f. Diagnosis i. Evidence of bleeding (minority of cases) and organ dysfunction. Ischemic manifestation of organ failure, renal failure, respiratory insufficiency, hepatic failure, and gastrointestinal compromise. ii. Laboratory testing 1. D-dimers in cats. 2. No gold standard nor consensus has been reached for the diagnosis of DIC In animals. a. Usually diagnosed based on the presence of a known condition and 3 or more of the following: thrombocytopenia, PT and or PTT prolongation, elevated fibrin split proteins or D-dimers, hypofibrinogenemia, reduce AT activity, and or RBC fragmentation. g. Management i. Outcome is improved by early and aggressive therapy. Cornerstone of DIC management is specific and vigorous treatment of the underlying condition. 1. Specific therapy may involve surgical or medical management of neoplasia, or immunosuppressive therapy for immune-mediated disease. ii. Adequate perfusion must be restored and mainteained via appropriate fluid therapy, to alleviate vascular stasis, hypoxia, and acidosis that promote coagulation activation. iii. Close monitoring of susseptible organs such as the respiratory, kidneys, and GI tracts. 1. Oliguria or renal insufficiency should prompt early fluid and possibly diuretic or dopamine administration. 2. Respiratory – oxygen supplementation or mechanical ventilation. 3. Early enteral nutrition, antacid therapy iv. Fresh frozen plasma may be of benefit in DIC by supplying AT to bolster the sagging anticoagulant pathways, no evidence supports this. v. The past decade has produced sufficient evidence to cast reasonable doubt regarding the role of heparin in DIC therapy. vi. Only studies of activated protein C supplementation has demonstrated a survival benefit, but animal trials have yet to be evaluated.