Anticoagulants and Blood Tests

Question 1

big picture goal of hemostasis & physiologic thrombosis

Answer 1

*to keep blood within the blood vessel lumen
*the subendothelial matrix should NOT be exposed; when it is, this represents a breach in the lumen of the blood vessel and gets the whole process going

Question 2

4 (big picture) steps of hemostasis

Answer 2

1. vasoconstriction
2. platelet plug formation (primary hemostasis)
3. activation of the coagulation cascade
4. fibrin plug formation (secondary hemostasis)

Question 3

hemostasis step 1: vasoconstriction

Answer 3

*if you narrow the diameter of the blood vessel (vasoconstrict), blood flow slows, so less blood is lost
*this is mediated through:
-activated platelets and injured endothelial cells secreting thromboxane A2, serotonin, and epinephrine
-this causes smooth muscles around the vessels to contract -> vasoconstriction
-this is short-lived (only lasts a few minutes); afterwards, vasodilation occurs to allow for inflammatory response to aid in healing

Question 4

hemostasis step 2: platelet plug formation (primary hemostasis)

Answer 4

*exposed subendothelial matrix represents a breach -> collagen is now exposed
*platelets can bind to collagen directly (via their a2b1 and GP VI receptors), but this is a WEAK bond
*platelets also bind to vWF, which binds to collagen, which is a STRONGER bond
*platelets get ACTIVATED when they bind to collagen/vWF
*activation of platelets allows them to release their granules, which recruit more platelets to the site
*this results in formation of a platelet plug

Question 5

hemostasis step 3: coagulation cascade

Answer 5

1. in vivo, we “enter” the coagulation cascade via the EXTRINSIC pathway:
   *activated by tissue factor (expressed by endothelial cells when they are damaged)
2. intrinsic pathway:
   *acts more as an augmenter of coagulation, rather than an initiator
   *factor XII deficiency results in no bleeding (but a prolonged PTT)

Question 6

hemostasis step 4: fibrin plug formation (secondary hemostasis)

Answer 6

*the fibrin plug forms as a result of the coagulation cascade
*this cross-linked fibrin plug provides a more stabilize solution to the breach and stabilizes the platelet plug

Question 7

PT and PTT help us measure primary or secondary hemostasis?

Answer 7

SECONDARY hemostasis (activation of the coagulation cascade, leading to fibrin clot formation)

note - the PT and PTT tests do have some limitations

Question 8

prothrombin time (PT) lab test

Answer 8

*one component of the reagents added = TISSUE FACTOR
*so, PT measures the EXTRINSIC pathway

Question 9

partial thromboplastin time (PTT) lab test

Answer 9

*one component of the reagents added = a phospholipid platelet substitute
*so, PTT measures the INTRINSIC pathway

Question 10

how are PT and PTT tests done

Answer 10

*add the patient’s plasma (that has their clotting factors)
*add the reagents (different reagents for PT than for PTT)
*measure the time for a clot to form

*both tests are measured in seconds - the number of seconds it takes a clot to form in vitro (in the LAB in a test tube, not the body)

note - PT test is very reagent dependent; lots of variation in results from lab to lab; therefore, we often use the INR instead

Question 11

INR = ?

Answer 11

INR = patient’s PT / control PT
note - INR is a ratio (so no units)

Question 12

which coagulation study measures the EXTRINSIC pathway of hemostasis?

Answer 12

PT (prothrombin time) or the INR

note - this is because tissue factor is used as a reagent, which is part of the extrinsic pathway

Question 13

which coagulation study measures the INTRINSIC pathway of hemostasis?

Answer 13

PTT (partial thromboplastin time)

note - this is because a phospholipid platelet substitute is used as a reagent, and platelets are part of the intrinsic pathway

Question 14

why might someone have a prolonged PT or PTT?

Answer 14

*the patient could have a disorder that is associated with:
-a problem with a significant number of clotting factors
-OR, a problem with one factor critical to coagulation

*OR they might have an iatrogenic reason (ex. if we give them a blood thinner)

Question 15

anticoagulants - overview

Answer 15

*anticoagulants will affect components of the coagulation cascade
*if we have a patient on an anticoagulant, we need to know if we have them on the right dose
*we look at how PT/INR and PTT are affected by different anticoagulants
*we have goal ranges for the PT/INR, PTT depending on the medication used

Question 16

warfarin (coumadin) - MOA

Answer 16

*blocks vitamin K epoxide reductase (an enzyme that reactivates/recycles vitamin K)
*impairs the liver’s ability to synthesize the vitamin K dependent clotting factors (II, VII, IX, and X)
*inhibits protein C and protein S (anticoagulants)

Question 17

what are the vitamin K dependent clotting factors that are affected by warfarin (coumadin)

Answer 17

factors II, VII, IX, and X

Question 18

which lab abnormality is affected by warfarin (coumadin)?

Answer 18

PT/INR (because warfarin primarily affects the extrinsic pathway, not the intrinsic) prolongation

Question 19

why does warfarin (coumadin) not affect the PTT (the intrinsic pathway) if it depletes factor IX?

Answer 19

*factor VII (extrinsic pathway) has the shortest half-life and gets depleted first
*factors II and X (common pathway) get their levels reduced to 20%, which is still sufficient to not prolong the PTT test

Question 20

if protein C and protein S (anticoagulants) are inhibited by warfarin (coumadin), then how is warfarin an anticoagulant?

Answer 20

*protein C levels drop quicker than the vitamin K-dependent clotting factors, resulting in a TEMPORARY HYPERCOAGULABLE STATE
*after 4-5 days, the clotting factor levels drop off, and this results in an overall ANTICOAGULABLE STATE
*therefore, we must use a different anticoagulant (such as heparin) during the first few days of treatment to “bridge” this gap and implement the anticoagulable state

Question 21

management of a patient on warfarin (coumadin)

Answer 21

*goal INR 2-3 (for example)
*very diet dependent (leafy green veggies are high in vitamin K, so the INR might be lower when patients eat them and higher when they don’t)
*sometimes, ADEK is given to minimize dietary changes

Question 22

unfractionated heparin - MOA

Answer 22

*binds to antithrombin 3 and causes a conformational change in AT3
*this leads to more rapid inactivation of II, IXa, and Xa
*UFH is long enough to bind to thrombin as well as antithrombin and further augment this reaction

Question 23

which lab abnormality is associated with unfractionated heparin?

Answer 23

PTT (intrinsic pathway) prolongation

Question 24

administering unfractionated heparin

Answer 24

*goal PTT 70-90 sec
*frequent titrations
*given as a DRIP when used as treatment because of its SHORT HALF-LIFE

Question 25

low molecular weight heparin - MOA

Answer 25

*binds and activates antithrombin III
*BUT it is so much shorter (compared to unfractionated heparin), it ONLY INACTIVATES Xa

examples of low molecular weight heparin: enoxaparin & dalteparin (note - these do NOT prolong PTT)

Question 26

low molecular weight heparin - lab abnormalities?

Answer 26

*PT/INR and PTT are both NORMAL

Question 27

examples of low molecular weight heparins

Answer 27

1. enoxaparin
2. dalteparin

Question 28

enoxaparin

Answer 28

*a low molecular weight heparin
*acts mainly on factor Xa
*does not prolong PT or PTT
*to measure activity, measure anti-factor Xa activity

Question 29

dalteparin

Answer 29

*a low molecular weight heparin
*acts mainly on factor Xa
*does not prolong PT or PTT
*to measure activity, measure anti-factor Xa activity