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ACVP Phase II - Clinical Pathology > Harvey Chapter 7 Evaluation of Hemostasis PART II: Coag Disorders (with Schalm's) AKG > Flashcards

Harvey Chapter 7 Evaluation of Hemostasis PART II: Coag Disorders (with Schalm's) AKG Flashcards

1
Q

What is the difference between the in-vitro and in-vivo model of the propagation stage of coagulation (aka activation of the intrinsic pathway)?

A
  • In-vitro model –> factor XII comes into contact with anionic wettable surface –> autoactivation occurs to FXIIa –> FXIIa activates FXI and FXIIa interacts with prekallikrein bound to HMK
  • In-vivo model –> thrombin activates FXI
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2
Q

FXIIa + prekallikrein –> ______ + _____

A

active fragment of FXIIa (FXIIf) + kallikrein

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3
Q

FXIIf activates ____ in addition to generating kallikrein.

A

complement (C1r)

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4
Q

Kallikrein converts ___ to ____.

A

HMK to bradykinin

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5
Q

List actions of bradykinin

A
  • Vasodilation
  • Increased vascular permeability
  • Inflammation
  • Stimulates release of tissue plasminogen activator (tPA) from endothelial cells –> promotes fibrinolysis
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6
Q

Which factor catalyzes the formation of covalent bonds between lysine and glutamine residues of different fibrin monomers that results in ‘cross linked fibrin’ that is insoluble?

A

FXIII

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7
Q

List the actions of thrombomodulin that is expressed on endothelial cells

A
  • Anticoagulant mechanisms:
    • Forms thrombin:Thrombomodulin complex that inhibits thrombin’s procoagulant activity –> inhibits coagulation
    • Enhances activation of protein C on surface of endothelium –> inhibits coagulation
  • Procoagulant mechanisms:
    • Activates TAFI (TAFI removes carboxyterminal lysine groups from fibrin –> decreasing binding of plasminogen and tPA to fibrin –> decreased generation of plasmin –> slows down fibrinolysis
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8
Q

Thrombin:thrombomodulin complex enhances activation of protein C on the endothelial surface.

Activated protein C can promote fibrinolysis by inactivating ________–> may increase amount of tPA available for fibrinolysis

Activated protein C –> dissociates from endothelial receptor and interacts with protein S –> protein C:protein S degrade ___ and ___ on surface of activated platelets –> inhibits coagulation.

A

plasminogen activator inhibitor 1 (PAI-1)

FVa and FVIIIa (FV is in the prothrombinase complex and FVIII is in the tenase complex)

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9
Q

Protein S forms a complex with protein C to degrade FV and FVIII. Protein S is also a cofactor for which molecule that is synthesized by endothelial cells and is the key inhibitor of the extrinsic pathway (inhibits FXa and TF-VIIa complex)?

A

Tissue factor pathway inhibitor (TFPI)

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10
Q

List endothelial-secreted inhibitors of thrombus formation

A
  • PGI2 and NO (powerful vasodilators)
  • Ectoenzyme that degrades ADP
  • Antithrombin (inhibits conversion of fibrinogen to fibrin and other proteases/coag factors F9-12) - mostly made by hepatocytes, but some from endothelial cells
  • Thrombomodulin and protein C
  • Tissue factor pathway inhibitor (TFPI)
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11
Q

Antithrombin is mostly made by which cell type?

A

Hepatocytes (a little is made by endothelial cells)

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12
Q

Antithrombin binds to ____ on the surface of endohtelial cells which accelerates inactivation of coagualation factors by antithrombin.

A

Heparan sulfate proteoglycans

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13
Q

What are the functions of antithrombin?

A

Main function: To inhibit conversion of fibrinogen to fibrin.

Other functions: Inhibits F9-12

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14
Q

Fibrinolysis is activated by release of ____ from damaged enothelium. This molecule stimulates fibrinolysis by activation ____ to ____. ____ catalyzes the hydrolysis of firbin and forms fibrin degradation products which have antihemostatic properties.

A

tPA (tissue plasminogen activator)

plasminogen to plasmin

Plasmin

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15
Q

Inhibitors of fibrinolysis:

______ is produced by endothelial cells and inhibits tPA.

______ removes carboxytermainl lysine groupes from fibrin, which decreases binding of plasminogen and tPA to fibrin –> this decreases the generation of plasmin and slows down fibrinolysis.

A

PAI-1 (plasminogen activator inhibitor)

TAFI (thrombin activatable fibrinolysis inhihbitor)

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16
Q

What is the preferred anticoagualant for coagualatoin and platelet function tests, in additaion to blood collection/stroage for transufsions?

A

Sodium citrate

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17
Q

EDTA and citrate - mechanisms of action

Heparin - mechanisms of action

A

EDTA and citrate are calcium chelators

Heparin binds to antithrombin –> this complex inhibits conversion of fibrinogen to fibrin and inhibits F9, 10, and FVIIa:TF complex

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18
Q

Hypercoagulable state = increased tendency for coagulation to occur without clinical signs or laboratory evidence of thrombosis; ‘prethrombotic state’. List factors than can predipose animals to a hypercoagulable state and that can ultimately result in thromboembbolism.

A
  • Platelet hyperreactivity (e.g., increased IL6 and PAF during inflammation)
  • Increased concentration of coag factors (e.g., hyperfibrinogenemia in response to inflammation)
  • Decreased concentrations of coagulation inhibitors (e.g., decreased antithrombin secondary to nephrotic syndrome)
  • Hypofibrinolysis (e.g., increased plasminogen activator inhibitor – acute-phase response to inflammation)
  • Protein C deficiency in horses
  • Hyperadrenocorticism in dogs
  • Many dogs with neoplasia, IMHA, and parvovirus enteritis
  • Many cats with hypertrophic cardiomyopathy, hyperthyroidism, liver disease
  • Septic foals
  • Glucocorticoid therapy
  • Indwelling IV catheters
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19
Q

To diagnose a localized thrombus, platelet counts, coagulation tests, and FDP values may be normal. The best test that has a high sensitivity (higher than FDP) and high negative predictive value to help rule out thromboembolism and DIC is _____.

A

D-dimer

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20
Q

DIC is most often initiated by the disseminated presentation of ___ in blood.

A

tissue factor (TF)

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21
Q

Disseminated coagulation is promoted by increased #s of ____ released by stimulated platelets, monocytes, endothelial cells, tumor cells, and apoptotic cells. These ____ express procoagulant __ and ___ on their surfaces.

A

Microparticles

Microparticles

PS and TF

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22
Q

Hemorrhage is common some dogs with DIC, but uncommon in what two species?

A

Cats and horses

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23
Q

Is firbinogen always low in DIC?

A

No - inflammatory conditions will increase fibrinogen becuase it is a negative acute phase protein. So it may be normal to increased with DIC. If you have normal fibrinogen which it should be increased due to inflammation - should raise concern for early DIC.

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24
Q

TEG results for DIC patients:

A

Varibale

Some patients are hypercoagulable, normocoagulable, or hypocoagulable

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25
Q

Healthy _____ dogs have a high prevalance of antiphospholipid antibody (aka lupus anticoagulant) in plasma that results in prolonged _____.

A

Bernese Mountain Dog

Prolonged APTT

26
Q

In synthetic liver failure/hepatic insufficiency, which coagulation facot has the shortest half life and is the first to go? Which has the longest half life and is the last to go?

A

FVII - shortest half life

Fibrinogen - longest half life - poor prognosis is hypofibrinogemic

27
Q

Vitamin K is essential for carboxylation reaction that results in the formation of active coagulation factors ….

A

II, VII, IX, and X, and protein C and protein S

28
Q

Vitamin K is recycled by ______ which reduces vamin K so that it can be oxidized again when forming active coagulation factors II, VII, IX, and X, and protein C and protein S

A

VKOR = vitamin K epoxide reductase

29
Q

Other than rodenticide toxicity, what else causes dicumarol toxicity mainly in cattle?

A

Moldy sweet clover and sweet vernal grasses

These plants when exposed to high moisture grow mold that converts coumarin to toxic dicumarol. Dicumarol inhibits VKOR, and vitamin K can no longer be reduced and recycled.

30
Q

Ddx for vitamin K deficiency associated with GI issues:

A
  • Malabsorptive syndromes –> bile duct obstruction
  • Sterilization of the intestine by prolonged use of antibiotics
  • Some cats with hepatic lipidosis, severe inflammatory bowel disease, and severe IBD associated with cholangiohepatitis
  • Reports in cats eating commercial canned diets high in salmon or tuna
31
Q

Substances that have been shown to interfere with vitamin K metabolism:

A
  • Vitamin E
  • Beta-lactam antibiotics
  • Salicylates
32
Q

Vitamin K deficiency leads to prolonged …….

A

PT and aPTT

Normal TCT (becuase TCT tests for fibrinogen abnormalities and vitamin k is not responsible in making fibrinogen (aka FI)

33
Q

Elapid snakes (coral snakes, cobras, mambas, sea snakes) primarily produce ___ venom.

VIpers (rattlesnakes, copperheads, cottonmouths) primarily produce ____ venom.

A

Neurotoxic

Hemotoxic

34
Q

Prekallikrein deficiency occurs in dogs, horses and cattle. It does not result in clinical bleeding, but does result in prolonged ____.

A

APTT

35
Q

Factor VIII deficiency is aka ____.

Factor IX deficiency is aka ____.

Both are transmitted as ___ traits, and are therefore mostly recognized in males.

These deficiencies cause prolongation of which coag tests?

A

FVIII –> hemophilia A (dogs, cats, horses, cattle, alpaca)

FVIX –> hemophilia B (dogs and cats)

X chromosome-linked recessive traits

Prolongation of PTT/ACT (normal PT)

36
Q

This deficiency is most common in laboratory beagles and results in prolonged ___. Does it cause severe bleeding?

A

FVII deficiency

PT

Does not cause severe bleeding.

37
Q

Cats and sheep have been documented to have an inherited vitamin K-dependent coagulopathy that invovles a deficiency in the enzyme _____.

A

y-glutamyl carboxylase

38
Q

APTT is used to evaluate coag factors of the intrinsic and common pathways. What are they?

A

Intrinsic (factors VIII, IX, XI, XII)

Common pathways (factor I – fibrinogen, II – prothrombin, V, X)

39
Q

APTT can be artifactually prolonged if the plasma:citrate ratio is too ____ or if _______ is present.

APTT and PT can be shortened by ______ conditions with high ____.

A

Low; erythrocytosis

inflammatory; fibrinogen

40
Q

The PT test is used to evaluate extrinsice and common pathway factors. List the factors.

A

the extrinsic (factor VII) and common pathways (factor I – fibrinogen, II – prothrombin, V, X)

41
Q

Thrombin clotting time (TCT) is based on the addition of thrombin to evaluate _____ disorders.

A

fibrinogen

42
Q

What can decrease fibrinogen?

A
  • Liver failure
  • Some venemous snakes (pit-vipers) that have thrombin-like activities that cleave fibrinogen (defibrinogenation syndrome)
  • Consumption (DIC - but may be increased with DIC too)
43
Q

A common and practical way to estimate fibrinogen values is by the heat precipitation test, however this test is not sensitive enough to differentiate low-normal from low fibrinogen values measured with a refractometer. The most accurate way to test fibrinogen levels is with a _________, which measures the rate of fibrinogen-to-fibrin conversion in diluted samples in the presence of excess thrombin, so that fibrinogen concentration in plasma is the rate limiting step. The fibrinogen concentration will be _____ proportional to the clotting time.

A

thrombin-initiated clotting rate assay (Clauss clotting method)

Inversely

44
Q

Which factors falsely decrease fibrinogen concentrations in the Clauss clotting method?

A

Remember that Clauss clotting method aka thrombin-initiated clotting rate assay - tests firbinogen levels.

Falsely increased by:

  • Hemolysis and lipemia
  • High concentrations of FDPs
45
Q

FDPs have antihemostatic properties that promote hemorrhage by inhibiting ___ function.

A

Platelet

46
Q

Ddx for positive FDP test

A
  • DIC
  • Thromboembolism
  • Fibrinogenolysis
  • Naturally occuring internal hemorrhage
47
Q

Which is a better test for DIC in horses, FDP or D-dimer assays?

A

D-dimer - I think it detects about 50% of cases

FDP assays are not sensitive enough to be used for a diagnostic test in horses.

48
Q

Ddx for positive D-dimer values

A
  • DIC
  • Neoplasia
  • Immune-mediated disease
  • Inflammation
  • Liver disease
  • Renal failure
  • Post-op
  • Internal hemorrhage
49
Q

FDP and D-dimer assays are 100% specific for DIC. T/F

A

False - they can be positive due to a wide variety of diseases that are assoaited with fibrinolysis. So these tests indicate fibrinolysis, but are not disease-specific.

50
Q

What does PIVKA stand for and what is it?

Is it specific for vitamin K deficiency?

A

Proteins induced by vitamin K absence or antagonism

PIVKA is a modified PT test that is recommended for the use in the diagnosis of anticoagulant toxicity in dogs. It utilizes a tissue thromboplastin and diluted plasma to result in longer clotting times than the standard PT test. PIVKA test is not specific for vitamin K deficiency (2, 7, 9 , 10) and may be prolonged with other defects along the extrinsic and/or common pathways.

51
Q

Does PIVKA have any advantagnes over PT in identifying rodenticide toxicities?

A

No

52
Q

Interpret:

  1. Thrombocytopenia + normal APTT and PT and FDP tests
A
  1. Lack of production –> bone marrow biopsy to r/o production
  2. Enhanced destruction à MC; primary vs secondary
53
Q

Interpret:

  1. Thrombocytopenia + prolonged APTT and PT + positive FDP tests
A
  1. Consumption of both platelets and coagulation factors à DIC
  2. Plasma antithrombin is probably low
  3. All four abnormalities often do not occur in one animal with DIC – PT is most likely to be normal
54
Q

Interpret:

  1. Normal platelet count + prolonged APTT and PTT + negative FDP test
A
  1. Multiple coagulation defects (e.g., rodenticide toxicity or liver disease) or less likely inherited defect in the common pathway
  2. Platelet counts may be decreased with rodenticide toxicity due to massive hemorrhage
  3. FDP may be increased in dogs with rodenticide toxicity
  4. *if blood is collected via a heparinized IV?
55
Q

Interpret:

  1. Normal platelet count + normal PT + prolonged APTT + negative FDP test
A
  1. Inherited defect in intrinsic pathway
  2. Inappropriately low plasma to anticoagulant ratio
  3. Hemoconcentration
56
Q

Interpret:

  1. Normal platelet count + prolonged PT + normal APTT + negative FDP test
A
  1. Inherited defect in extrinscic pathway (e.g., FVII deficiency)
  2. Early anticoagulant toxicity
57
Q

Interpret:

  1. Normal platelet count + normal PT and APTT + negative FDP in the presence of bleeding diathesis
A
  1. Platelet function defect or vascular injury à perform BMBT or PFA100 and look for VWF antigen
  2. Inherited platelet abnormalities or vWD
  3. **rare cases of vWF deficiency have slightly prolonged APTT due to mildly decreased FVIII in plasma
58
Q

TEG - what does R, K, α, MA, LY60/A60/CL60 stand for?

A
  • R (rxn time) –> time from start to initial fibrin formation (reflects intrinsic activity)
  • K (kinetics) –> time taken to reach a specific level of clot strength
  • alpha (angle) –> measure of the speed of firbin build-up and cross linking/clot strength
  • MA (max amplitude) –> represents the ultimate strength of the clot (fibrinogen concentration and activity)
  • LY60/CL60 –> % lysis 60 minutes after MA
59
Q

TEG - what would cause a decrease in MA?

A
  • Decreased platelet #s/thrombocytopenia
  • Reduced platelet function
  • Hypofibrinogenemia
60
Q

What would cause an increase in LY60 (%)?

A

premature or excessive fibrinolysis (e.g., early DIC)

61
Q

What would increase R time for TEG?

A

Coagulopathy/factor deficiency (e.g., hemophilia, late DIC)

Anticoagualant

62
Q

What would shorten R time on TEG?

A
  • Hypercoagulable state (e.g., early DIC)
  • Anemic patients (decreased HCT)

ACVP Phase II - Clinical Pathology (14 decks)

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