Chapter 168 - anticoagulants

Question 1

how does the intact vascular endothelium prevent thrombosis from occurring?

Answer 1

1. endothelial surface is negatively charged - inhibits platelet attachment, antithrombotic
2. TFPI(Tissue factor pathway inhibitor)at endothelium decreased procoagulant interaction of TF with FVIIa
3. endothelial cells actively secrete vasodilators and platelet inhibitors (prostacyclin (prostaglandin I2), ex-adenosine diphosphate, nitric oxide
4. endothelial glycocalyx achors heparan sulfate which promotes ANTITHROMBIN activity
5. provides a physical barrier between circulating proteins (plasma or cellular proteins) and prothrombotic substances such as vWF, collagen, fibroblasts, TF etc
6. activated protein C is generated when thrombin binds with thrombomodulin on the endothelial surface - apC and cofactor protein S inactivate fVa, FVIIIa and bind thrombin, decreasing fibrin formation

Question 2

How does the glycocalyx prevent thrombosis?

Answer 2

It anchors heparan sulphate, which promotes the anticoagulant activity of antithrombin, inhibiting thrombin, fXa, fIXa

Question 3

Describe the initiation phase in the cell-based model of coagulation

Answer 3

TF on various extravascular cell surfaces (also monocytes, neoplastic cells, microparticles, platelets, esp in disease) -> binds small amounts circulating activated FVII –> forms TF-FVIIa complex –> catalyses more FVIIa activation, more TF binding –> complex supports generation of FVa, FIXa, FXa –> FXa-FVa complex (prothrombinase complex) forms a small amount of thrombin –> thrombin and FIXa can diffuse from surface of TF-bearing cell and bind to platelets, initiating amplification

Question 4

describe the amplification phase in the cell-based model of coagulation

Answer 4

thrombin:
1. causes generation of more FXIa and FVa
2. binds to PAR1 receptors on the platelet surface –> triggers shape change –> release of granules w/ procoagulant factors
3. separates cWF from FVIII so they can participate in coagulation

Question 5

Arterial clots?

Answer 5

Arterial clots are generally formed under conditions of high shear and include platelets held together by fbrin strands (also known as white clots)

Question 6

Venous clots?

Answer 6

Clots formed within the venous system and under low-shear conditions consist mostly of brin and red blood cells (red clots).

Question 7

The diagnosis of hypercoagulability is difficult to make in the small animal patient. Which diagnostic would you prefer to decide to use anticoagulants?

Answer 7

TEG has been used to identify hypocoagulability and hypercoagulability in dogs with immune- mediated hemolytic anemia, neoplasia, and disseminated intravascular coagulation (DIC).

Question 8

Warfarin (coumarin, Coumadin, Panwarfin) has been used in humans for prevention of venous and arterial thrombosis for many years and is the most commonly used oral anticoagulant in people. There is little veterinary informa- tion on the optimal dose of warfarin.
How does Warfarin work?

Answer 8

Warfarin inhibits the activity of vitamin K epoxide reductase in the liver.
Vitamin K epoxide reductase is required to reduce vitamin K epoxide back to the active form necessary for coagulation factor formation. In the presence of warfarin, vitamin K cannot be recycled, which causes a rapid depletion of vitamin K and the dependent coagulation factors.

Question 9

Explain heparin’s indirect anticoagulant effect.

Answer 9

Once bound to AT, UFH inhibits FIXa, FXa, FXIa, FXIIa, and FIIa, with its most profound effects on FIIa and FXa. Heparin is considered an indirect anticoagulant since it works by enhancing the preexisting properties of AT.

Question 10

Heparin’s direct anticoagulant effect?

Answer 10

It releases Tissue factor pathway inhibitors from the endothelial cell surface.

Question 11

Low-Molecular-Weight Heparins anticoagulant effect?

Answer 11

Inhibits FXa&raquo_space; FIIa

The lower-molecular-weight heparin molecules are not long enough to bind FIIa but still have affinity for FXa and have a 4:1 ratio of anti-Xa to anti-IIa activity.

Due to their size, they exert their primary effect on FXa, and their use in human patients is associated with fewer major bleeding events than with the use of UFH.

Question 12

Oral Fxa inhibitors?

Answer 12

Unlike UFH and LMWH, these drugs do not require AT for FXa-inhibitory activity.

The ROCKET AF study in humans compared rivaroxaban with warfarin in patients with atrial brillation and found rivaroxaban to be noninferior to warfarin for the prevention of stroke and systemic thromboembo- lism.54 In addition, treatment with rivaroxaban was associated with less risk of intracranial hemorrhage and fatal bleeding episodes.