Anticoagulants

Question 1

warfarin (coumadin)

Answer 1

a vitamin K antagonist

Mechanism: Inhibits the enzymatic reduction of vitamin K epoxide. Vitamin K (in the reduced state) is the coenzyme of a carboxylase responsible for the carboxylation of glutamic acid residues on factors II, VII, IX, X, and proteins C, S, and Z.

slow-acting anticoagulant because the depetion of carboxylated factors from the circulation is a function of their half-life

Question 2

warfarin and reductase

Answer 2

principle modulator of warfarin response

mutations either increase sensitivity to warfarin or cause hereditary warfarin resistance

Vitamin K Epoxide Reductase is the main regulator of the carboxylation reaction

Question 3

coagulation proteins affected by warfarin

Answer 3

FVII

FIX

FX

prothrombin

Protein C

Protein Z

Protein S

Question 4

Describe the Vitamin K cycle

Answer 4

Question 5

monitoring of warfarin effect

Answer 5

prothrombin time, which is sensitive to factors II, VII, and X

Question 6

warfarin metabolism

Answer 6

metabolized by P450

SNPs in CYP2C9 effect the rate of warfarin metabolism

SNPs in VKORC1 leads to resistance and higher doses are required

Question 7

When does warfarin treatment become effective?

Answer 7

warfarin becomes effective when levels of factor IX and X are down to below 20-30%

thsi requires at least 5 days of dosing to achieve therapeutic effect

and INR between 2-3 is therapeutic (8+ indicates too much drug)

Question 8

International Normalization Ratio (INR)

Answer 8

derived from PT

ratio of patient PT to control PT, raised to ISI (international sensitivity index) power

INR = (patient PT/control PT)^ISI

ISI is specific for each thromboplastin reagent

value is used to determine level of warfarin anticoagulation

Question 9

factors that potentiate warfarin therapy

Answer 9

a. **poor oral intake of vitamin K **(patients on restricted diets, anorexic, diarrhea, destruction of bowel flora (a source of vitamin K)
b. polymorphisms of the reductase (VKORC1) are common
c. drugs inhibiting metabolic clearance (CYP 2C9) such as erythromycin, fluconazole, anti-inflammatory agents, H2-blockers
d. liver disease & CYP 2C9 polymorphisms (impaired metabolism)
e. unknown mechanism-other antibiotics, anti-arrhythmic drugs such as amiodarone, some herbals, etc.

Question 10

factors that antagonize warfarin therapy

Answer 10

recent vitamin K therapy, anticonvulsants, and certain antibiotics (enhance CYP 2C9). Foods (broccoli, greens, etc.) rich in vitamin K have minimal effect and should not be restricted from the diet

Question 11

warfarin necrosis

Answer 11

Heterozygotes for Protein C or S deficiency, or persons with low levels of Protein C/S due to poor diet and relative deficiency of vitamin K, may suffer massive skin and subcutaneous fat necrosis if suddenly exposed to full doses of warfarin. This is due to a disproportionate decline in Protein C or S as compared to factors IX, X, and prothrombin

Question 12

adverse reactions of warfarin

Answer 12

increased risk of bleading

teratogenic

necrosis/gangrene

Question 13

factors that increase risk of bleeding while a patient is on warfarin

Answer 13

vitamin K deficiency

drug interactions that alter warfarin binding, metabolism, or elimination

liver disease - decreased synthesis of clotting factors

polymorphisms in metabolism of warfarin

older age - increased risk of trauma or vascular problems

interaction with other medications that increase risk such as aspirin or NSAIDs

Question 14

treatment of elevated INR in cases of no bleeding when on warfarin

Answer 14

hold warfarin

give oral (2.5 or 5 mg) vitamin K

if can’t eat or INR > 9, give vitamin K by injection

Question 15

treatment of elevated INR in cases of bleeding when on warfarin

Answer 15

hold warfarin

give vik K oral or IV (slowly)

fresh frozen plasma (FFP), 20 ml/kg, transiently shortens PT by providing infusion of clotting factors

if bleeding is life-threatening, rVIIa or prothrombin complex concentrates (activated clotting factors

Question 16

indicatsions for warfarin therapy

Answer 16

chronic anticoagulation of patients with thromboses

artificial heart valves

atrial fibrillation (to prevent embolization)

and other conditions predisposing to thrombosis (antithrombin, Protein C or S deficiency)

Question 17

contraindications of warfarin

Answer 17

pregnancy, especially 1st and 3rd trimester

Question 18

drugs given concurrently with warfarin

Answer 18

unfractionated or low molecular weight heparin

fondparinux

argatroban

**this is necessary because of the lag time before warfarin takes effect

**patients may be hypercoagulable to start because protein C and S levels fall first before many of the other clotting factors

Question 19

heparin

Answer 19

polymeric, highly sulfated glycosaminoclycan

30-50 saccharide units

binds to antithrombin

heparin-antithrombin complex inhibits FXa and thrombin equally

Question 20

higher versus lower molecular weight heparin

Answer 20

lower mostly inhibits FXa, and higher inhibits thrombin and binds to platelets

all enhance the activity of antithrombin

Question 21

heparin half-life

Answer 21

dose-dependent - 56 min after 100 U/kg and 156 min after 400 U/kg

reduced in patients with extensive thrombotic disease, and thrombin bound to fibrin is protected from heparin-antithrombin complex

Question 22

unfractionated heparin

Answer 22

inactived if given orally

administered IV, subcutaneous

heparin-AT complex inhibits IXa, Xa, XIIa, VIIa-tissue factor as well as thrombin

inhibits smooth muscle proliferation, angiogenesis

Question 23

metabolism of heparin

Answer 23

done in the liver and kidney

binds to endothelium, taken up by macrophages

30% inactivated by liver heparinase, and 70% excreted as uroheparin

neutralized by platelet factor 4

Question 24

therapeutic uses of heparin

Answer 24

a. In the acute treatment of deep vein thrombosis, pulmonary thromboembolism, sudden arterial occlusion, consumption coagulopathy (DIC) associated with malignancy, and to prevent clotting in extracorporeal circuits (renal dialysis, heart-lung machine, etc.)

Complications: bleeding in approximately 20% of patients, especially women > 60. Contraindications (all relative): thrombocytopenia (platelet factor 4 neutralizes heparin), peptic ulcer, liver and renal disease. Antagonist: protamine sulfate - 5 mg for each 1000 u of heparin given.

b. Prophylaxis to prevent deep vein thrombosis and pulmonary embolism in patients on prolonged bed rest (post-operative, after myocardial infarction, etc.), or for chronic intravascular coagulation syndromes

Complication: osteoporosis and vertebral collapse when given for > 6 months.

c. In patients in whom warfarin is not appropriate (pregnant, non-compliant, etc.)

Question 25

Heparin-induced thrombocytopenia

Answer 25

immunologic basis (antibodies to neoepitopes on platelet factor 4 induced by heparin-binding). Associated with **paradoxical thromboses**. When recognized, heparin must be _discontinued immediately_, and alternative anticoagulants started (direct thrombin inhibitors-discussed below)

Question 26

monitoring of unfractionated heparin

Answer 26

aPTT monitoring check after 4 hours and then every 6 hours therapeutic range is dependent on aPTT reageant _alternative monitoring_: anti-Xa levels

Question 27

adverser reactions of unfractionated heparin

Answer 27

bleeding (more frequent in elderly and underweight) in wound/soft tissue, lungs, GI, GU, nasal, retroperitoneal region, CNS rarely heparin induced thrombocytopenia osteoporosis - enhances bone resorption, inhibits bone formation mild inhibition of aldosterone increases potassium

Question 28

advantages of unfractonated heparin

Answer 28

immediate effect readily reversed by protamine use in patients with renal insufficiency

Question 29

disadvantages of unfractionated heparin

Answer 29

heterogenous mixture - only a fraction has anticoagulant activity binds to a number of plasma proteins and vessel wall neutralized by platelet factor not effective in neutralizing clot-boud thrombin minority of patients are therapeutic in the first 12 hours heparin induced thrombocytopenia (HIT)

Question 30

low molecular weight heparin

Answer 30

depolymerization of porcine heparin: 13-22 saccharide units anti-Xa but little antithrombin activity administered subcutaneously

Question 31

advantages of low-molecular weight heparins

Answer 31

better bioavailability - less beinding to endothelium predictable anticoagulant effect - less binding to plasma proteins reliability of achieving therapeutic target convenient dosint - based on weight lower incidence of thrombocytopenia routine lab monitoring unnecessary lower bleeding rate - less inhibition of platelet function, less interference with platelet-vessel interaction, less binding to platelets and vWF less osteoporosis

Question 32

protamine sulfate

Answer 32

reverses the effect of heparin, but has only limited effect on LMWHs

Question 33

three types of LMWHs

Answer 33

dalteparin, enoxaparin, tinzaparin enoxaparin has the highest antiXa/antiIIa ratio and is the most bioavailable all have renal clearance except enoxaparin which also has liver clearance

Question 34

clinical use of LMWH

Answer 34

used for prophylaxis, superior to heparin in treatment of deep vein thrombosis/pulmonary embolism, unstable angina can be used in pregnancy as it does not cross placenta or appear in breast milk

Question 35

major adverse effects of LMWH

Answer 35

**bleeding**, often in the epidural space after epidural catheter placements don't give too soon after invasive procedures

Question 36

fondaparinux

Answer 36

totally synthetic, consisting of the pentasaccharide sequence that serves as the binding site for antithrombin enhances the ability of antithrombin to inhibit factor Xa, but has no anti-thrombin activity

Question 37

advantages of fondaparinux

Answer 37

greater than 90% absorption from subcutaneous depots very little binding to plasma proteins half-life of 17-21 hours (once daily subcutaneous injection) does not form complexes with platelet factor 4

Question 38

uses of fondaparinux

Answer 38

somewhat more effective than LMWH for the prevention of thromboembolism safe and effect for thromboembolism treatment effective for pulmonary embolism and deep vein thrombosis

Question 39

contraindications of fondaparinux

Answer 39

patients with renal failure because this drug is completely cleared by the kidneys

Question 40

direct Xa inhibitors

Answer 40

oral anticoagulants rivaroxaban - used for orthopedic prophylaxis, atrial fibrillation, and venous thrombosis apixiban - used for othropedic prophylaxis and atrial fibrillation

Question 41

direct thrombin inhibitors

Answer 41

thrombin has an exosite that binds to fibrinogen and a catalytic site that cleaves fibrinogin to fibrin these inhibitors bind to one or both of these sites

Question 42

parenteral direct thrombin inhibitors and their uses

Answer 42

desirudin - DVT prophylaxis in surgical patients bivalirudin - thrombus prevention in coronary interventions argatroban - approved for heparin-induced thrombocytopenia

Question 43

dabigatran

Answer 43

oral direct thrombin inhibitor prodrug, converted to dabigatran after absorption from the gut approved for atrial fibrillation eliminated by the kidneys food has minimal effect on absorption

Question 44

advantages of direct thrombin inhibitors

Answer 44

_biophysical advantage over heparins_ inactivate clot-bound thrombin in addition to soluble thrombin inhibit thrombin directly, without requiring antithrombin as a cofactor not activated by platelet factor 4 or heparinase

Question 45

IV direct thrombin inhibitors

Answer 45

lepirudin - HIT bivalirudin - coronary angioplasty agratroban

Question 46

argatroban

Answer 46

synthetic direct thrombin inhibitor reversibly binds to catalytic site of thrombin given IV for HIT monitor with aPTT conversion to warfarin problematic because argatroban also prolongs prothrombin time