Anemia (pt 2/3) Hemostasis & Anti-coagulation, Heparin, Warfarin

Question 1

What are the 4 things an ideal anti-coagulant would do? (Blue Box!)

Answer 1

1) Prevent pathologic thrombosis
2) Limit reperfusion injury
3) Allow a normal response to vascular injury
4) Limit bleeding

Question 2

What is hemostasis?

Answer 2

-How the body maintains fluidity of the blood
-Includes repair of vascular injury
-A balance of minimizing blood loss while preventing inadequate perfusion and thrombosis (vessel occlusion)
-Hemorrhage or thrombosis = a breakdown of hemostatic mechanisms
-Primary Hemostasis – formation of the platelet plug
-Secondary Hemostasis – formation of fibrin (coagulation cascade)

Question 3

What are the 3 steps of Primary Hemostasis?

Answer 3

1) Adhesion
2) Activation
3) Aggregation

Question 4

What occurs during the Adhesion phase of Primary Hemostasis?

Answer 4

When vascular endothelium is damaged and the subendothelium is exposed, vWF anchors platelets to the collagen layer of the subendothelium.
-Collagen binds to GP1a receptor
-vWF binds to GP1b receptor

Question 5

What occurs during the Activation phase of Primary Hemostasis?

Answer 5

1) Prothrombin (Factor II) is converted to Thrombin (Factor IIa)
2) Thrombin combines with the Thrombin receptor on the plt surface to activate the platelet
3) Platelet undergoes a morphological change to increase its surface area, so there is more platelet available to interact with other platelets.
4) Platelet releases mediators necessary for aggregation (Thromboxane A2 and ADP). Serotonin is released as well (causes vasoconstriction to prevent unnecessary bleeding)

Question 6

What occurs during the Aggregation phase of Primary Hemostasis?

Answer 6

1) Thromboxane A2 and ADP uncover the fibrinogen receptors (GP IIb/IIIa), allowing fibrinogen to be able to bind to its receptor.
2) Fibrinogen (I) attaches to its receptor and links the platelets to each other, producing a water-soluble, unstable, and friable clot = “white clot”.

Question 7

Why does blood coagulate?

Answer 7

Due to the transformation of soluble Fibrinogen into insoluble Fibrin by the enzyme Thrombin.

Question 8

What is Secondary Hemostasis?

Answer 8

The Coagulation Cascade

Question 9

What triggers the Extrinsic Pathway?

Answer 9

Damage outside the blood vessels.
1) Damage triggers the release of Thromboplastin (AKA Tissue Factor AKA Factor III) from damaged cells
2) Thromboplastin activates Factor VII → VIIa
3) Factor VIIa + Factor IV (Calcium) on the surface of the platelet activates Factor X → Xa

Question 10

What is the primary physiologic initiator of coagulation? !!

Answer 10

Thromboplastin

Question 11

What triggers the Intrinsic pathway?

Answer 11

Triggered by damage inside the blood itself, or when it gets exposed to collagen.
1) Trauma to the blood itself or exposure of the blood to collagen in a traumatized blood vessel wall activates Factor XII → XIIa
2) XIIa activates factor XI → XIa
3) XIa activates factor IX → IXa
4) IXa combines on the platelet surface with Factors VIII and IV and activates Factor X → Xa

Question 12

What are the steps of the Common Pathway?

Answer 12

1) Factor Xa combines on the platelet surface with activated Factor V → Va and Factor IV = conversion of Prothrombin (II) to Thrombin (IIa). -Factor X + help of others activates Factor II to IIa.
2) Thrombin converts Fibrinogen (I) to Fibrin (Ia)
3) Fibrin (I) cross-linking occurs if/when Fibrin(I) is in the presence of Factor XIII.

Question 13

What does Factor IV (Calcium) Do?

Answer 13

Factor IV (Calcium) helps position clotting factors on the surface of the platelet so biochemical reactions can occur. Calcium is located on the surface of the platelet

Question 14

What is Thrombin’s role in hemostasis?

Answer 14

1) Proteolytically cleaves small peptides from Fibrinogen (I) to form Fibrin (Ia) clot.
2) Activates upstream clotting factors leading to more Thrombin (sort of like positive feedback)
-Remember in Primary Hemostasis that Thrombin is responsible for plt activation
3) Activates Factor XIII to cross-link Fibrin(I), stabilizing the clot
4) Potent platelet activator and potentiates platelet growth
5) Anti-coagulant effect through activation of Protein C
-Attenuates the clotting process

Question 15

Under normal circumstances, repair of vascular injury occurs without ________ and _____________ ___________.

Answer 15

Under normal circumstances, repair of vascular injury occurs without thrombosis and downstream ischemia.

Question 16

What is Antithrombin III?

Answer 16

Forms complexes with and neutralizes:
-Final Common Pathway: Factors IIa & Xa
-Intrinsic Pathway: Factors IX, XIa, and XIIa

A required cofactor for Heparin.
Antithrombin deficiency is the most common reason a patient is unresponsive to Heparin.

Question 17

What do All anti-coagulants and fibrinolytic drugs have as their principle toxicity?

Answer 17

Increased risk of bleeding

Question 18

How do Indirect Thrombin Inhibitors cause their effects?

Answer 18

Effect is caused by their interaction with Antithrombin III (to prevent thrombin from actually working).
-Unfractionated Heparin (UFH) a.k.a. High-Molecular-Weight (HMW) Heparin
-Low-Molecular-Weight (LMW) Heparin (Has a higher ratio of anti-10a (against activated factor 10) than activated factor II activity than unfractionated heparin)
-Fondaparinux
-Couramins

Question 19

The combination of AT III with unfractionated heparin increases degradation of both ______ and _______.

Answer 19

The combination of AT III with unfractionated heparin increases degradation of both factor Xa and thrombin.

Question 20

The combination of ATIII with fondaparinux or LMW heparin more selectively increases degradation of ________.

Answer 20

The combination of ATIII with fondaparinux or LMW heparin more selectively increases degradation of Factor Xa.

Question 21

What is Heparin’s MOA?

Answer 21

-Binds tightly to the Antithrombin III and causes a conformational change → exposes the active site for a more rapid interaction with the clotting factors
-Accelerates the actions of Antithrombin III 1000-fold
-Once the antithrombin-clotting factor complex is formed, heparin is released intact to bind with additional antithrombin (and inactivate more thrombin)

Question 22

Unfractionated (HMW) Heparin has a high affinity for AT III and inhibits:

Answer 22

Factors IIa, IXa, and Xa

Question 23

LMW Heparin (Enoxaparin, Dalteparin, etc) inhibits ______, but has less of an effect on _______.

Answer 23

LMW Heparin (Enoxaparin, Dalteparin, etc) inhibits Factor Xa, but has less of an effect on Thrombin (not as much of an effect on Factor IIa).

Question 24

What are the pros of LMW Heparin compared to Unfractionated?

Answer 24

-Equal Efficacy
-Increased bioavailability from SQ site
-Less frequent dosing requirements
-More predictable response, less need for blood monitoring

Question 25

What do you need to check before initiating Heparin therapy?

Answer 25

-Assess pt history of bleeding prior to initiating treatment
-Draw baseline coagulation panel

Check Anti-Xa units in high-risk patients:
-Assesses the heparin concentration but not the integrity of the Intrinsic Pathway
-Available on most automated coagulation instruments

Question 26

Does Heparin break down existing clots?

Answer 26

No; Heparin prevents clots from forming or growing larger

Question 27

Why isn’t Heparin given IM?

Answer 27

Given SQ or IV, never IM due to risk of hematoma at site of IM injection.

Question 28

In what situations is LMW Heparin preferred?

Answer 28

Intermittent heparin administration b/c no monitoring is required in most patients.
-Weight based dosing = predictable pharmacokinetics and plasma levels in patients with normal renal function
-Use with caution in patients with renal insufficiency or body weight > 150kg
-LMW levels not routinely measured EXCEPT in pts with renal insufficiency, obesity and pregnancy
-Measure Anti-Xa units to guide therapy as needed

Question 29

What is Enoxaparin full dose?

Answer 29

1mg/kg SQ every 12 hours

Question 30

What is Heparin used in the prevention and treatment of?

Answer 30

Venous thromboembolic disease
Arterial thrombosis
Thrombus prevention in cardiac or arterial surgery

Question 31

What do you want your lab values to be for a aPTT in a patient receiving Heparin therapy?

Answer 31

1.5-2.5 baseline

Question 32

What lab test is used to measure both LMW and UFH?

Answer 32

Partial Thromboplastin Time (PTT)
-Measures the intrinsic pathway

Question 33

What lab tests are specific to UFH?

Answer 33

-Protamine titration
-Anti-Xa units

Question 34

What is the loading dose for UFH?

Answer 34

80-100 units/kg - use actual body weight

Question 35

What is the Maintenance Dose for UFH?

Answer 35

15-22 units/kg per hour

Question 36

What is the low dose for prophylaxis with UFH?

Answer 36

5000U SQ every 8-12 hrs

Question 37

What are the symptoms of Heparin Toxicity?

Answer 37

-Bleeding!!! Inc risk in elderly women & pts with renal failure
-Allergy
-Alopecia (reversible)
-Osteoporosis/Fractures
-Mineralocorticoid Deficiency
-HIT

Question 38

What is Heparin-Induced Thrombocytopenia (HIT)?

Answer 38

-Systemic hypercoagulable state
-Incidence = 1-4% of patients treated with UFH
-M&M associated with thrombotic events, venous > arterial
-Skin necrosis
-Monitor platelet counts
-New thrombi after Heparin initiation ↑ suspicion of HIT
-Treat by discontinuing Heparin and starting Argatroban (direct thrombin inhibitor)

Question 39

Which patients are at increased risk for HIT?

Answer 39

-Surgical patients are at greatest risk
-Higher risk in pts with UFH (bovine > porcine) versus LMW heparin

-Incidence is lower in pediatric pts outside of the critical care unit
-Rare in pregnant women

Question 40

Peripheral incidence of a thrombosis increases when?

Answer 40

In an extremity with an indwelling catheter

Question 41

Why do you monitor platelet counts when suspecting HIT?

Answer 41

Thrombocytopenia appearing in a time frame consistent with an immune response (first few days of therapy) to heparin should be considered suspicious for HIT

Question 42

What do you do for Heparin Reversal?

Answer 42

1) Stop the Heparin
2) Administer Protamine Sulfate

-Heparin 100 U = Protamine 1 mg IV (no more than 50mg in 10 min)
-Enoxaparin 1mg = Protamine 1 mg IV (Not Fondaparinux or Danaparoid)

Question 43

What does Protamine Sulfate do?

Answer 43

A positively charged molecule that combines with Heparin (negatively charged) to form a stable complex.
-NO Anticoagulant actions
-Only partial reversal of Enoxaparin (LMWH)

Question 44

What are C/Is to Heparin therapy?

Answer 44

HIT
Hypersensitivity
Active bleeding
Hemophilia
Significant thrombocytopenia
Purpura
Severe hypertension
Intracranial hemorrhage
Infective endocarditis
Active TB
Ulcerative lesions of the GI tract
Threatened spontaneous abortion
Visceral carcinoma
Advanced hepatic or renal disease
Pts who have recently had surgery of the brain, spinal cord or eye
Pregnancy unless clearly indicated as there is no apparent placental transfer

Question 45

What pathway does Coumadin work on?

Answer 45

Extrinsic Pathway

Question 46

What are the Pharmacokinetics about Coumadin?

Answer 46

-Racemic mixture (S-warfarin is 4x more potent than R-warfarin)
-Sodium salt with 100% bioavailability
-99% bound to plasma albumin
-Small volume of distribution
-Half-life = 36 hours (difficult to initially become therapeutic)

Question 47

What is the MOA of Warfarin? (Blue Box!)

Answer 47

Blocks the y-carboxylation of glutamate residues in:
-Factors II, VII, IX, & X
-Anticoagulant Protein C & S

Results in biologically inactive coagulation factors.

Question 48

How does Warfarin inhibit Vitamin K?

Answer 48

-Vit K moves through an oxidation-reduction cycle in order to first donate an electron to y-glutamyl carboxylase and then receive one so it can be recycled to make more factors
-y-glutamyl carboxylase is needed to convert factors II, VII, IX, & X to their functional forms
-Warfarin prevents the reduction reaction that allows Vit K to be recycled
-Warfarin is INDIRECT (not acting directly on 2,7,9,10). Actually works on Vit K that is needed for these factors.

Question 49

Why does Warfarin take awhile to onset?

Answer 49

Blocks creation of more factors, not breaking down existing factors. Takes awhile to onset. Have to wait for existing factors to die naturally.
-Inhibits synthesis, but does not alter degradation.

Question 50

List the Vitamin K Dependent Factors from shortest to longest half-lives.

Answer 50

1) VII = 6 hrs
2) Protein C = short, like Factor VII
3) IX = 24 hrs
4) X = 40 hrs
5) II = 60 hrs

Lose function of Factor VII and Protein C first.

Question 51

Why is there a potential hypercoagulable state with initial Warfarin therapy?

Answer 51

Potential for transient, hypercoagulable state as Protein C is inhibited and 2,9,10 are not yet inhibited due to their long half-lives

Question 52

What do you also start patients on immediately when starting Warfarin for the first time? (Blue Box!)

Answer 52

Start patients on Heparin to achieve immediate anti-coagulation in the acute PE or DVT.
-Overlapping therapy between Heparin and Warfarin is generally 5-7 days.

Question 53

How does Warfarin effect the Prothrombin Time (PT)?

Answer 53

-The PT takes approximately 1 wk to adjust to a therapeutic level and then maintenance doses of 5-7 mg can be started
-PT should be increased to a level indicating 25% of normal PT activity
-If PT activity < 20% therapy should be stopped or reduced until > 20%

Question 54

How do you calculate INR?

Answer 54

patient PT time/mean of normal PT times for the lab

Question 55

How does Warfarin effect the INR?

Answer 55

-Therapeutic INR for prophylaxis and treatment of thrombotic disease is 2-3
-High risk (ex. Artificial heart valves) = 2.5-3.5
-For a patient with Warfarin Resistance, the INR may need to be raised or anticoagulation therapy changed to a different agent

Question 56

What is Warfarin resistance?

Answer 56

-Resistance is defined as experiencing an event despite being within the designated therapeutic range
-Seen in pts with advanced cancers typically GI in origin
LMW is superior to Warfarin in preventing venous thrombosis in pts with cancer

Question 57

How do you reverse Warfarin?

Answer 57

1) Stop warfarin therapy and establish normal activity of clotting factors
3) Administer agents based on severity. Drug cessation may be enough in stable pts that are not bleeding
-Oral or parenteral Vitamin K1 (phytonadione)
-FFP
-Recombinant factor VII (rFVIIa)
-4F PCC (Prothrombin Complex Concentrate) = concentrate of II, VII, IX & X

Note the long half-life of Warfarin → reversal may need to be repeated

Question 58

When is Warfarin contraindicated?

Answer 58

Pregnancy:
-Crosses the placenta →hemorrhagic disorders in the fetus
-Can affect the y-carboxyglutamate in fetal bone and blood → abnormal bone
-Heparin is safer choice in pregnancy

Inherited Deficiency of Protein C:
-Develop cutaneous necrosis within the first few weeks of therapy
-Can cause infarction of breast, fatty tissue, intestines and extremities
-Venous thrombosis develops due to the hypercoagulable state from Warfarin induced ↓ Protein C

Question 59

What Drugs increase PT with Warfarin?

Answer 59

Pharmacokinetics:
-Amiodarone
-Fluconazole
-Cimetidine
-Disulfiram

Pharmacodynamics:
-ASA at high doses
-Cephalosporins
-Heparin, Argatroban, etc

Question 60

What Drugs decrease PT with Warfarin?

Answer 60

Pharmacokinetics:
-Barbituates
-Rifampin
-Cholestyramine

Pharmacodynamics:
-Diuretics
-Vit K