Anticoagulants

Question 1

Hemostasis

Answer 1

Hemostasis is the arrest of blood loss from damaged vessels.

This process involves platelet adhesion and activation as well as blood coagulation (fibrin formation).

Question 2

Thrombosis

Answer 2

Thrombosis is a pathological condition resulting from inappropriate activation of hemostatic mechanisms.

Venous thrombosis is usually associated with stasis of blood. A venous thrombus has a small platelet component and a large component of fibrin. Use anticoagulants for tx

Arterial thrombosis is usually associated with atherosclerosis, and the thrombus has a large platelet component. Use antiplatelet medications to tx

Question 3

Vascular Injury Cascade Steps

Answer 3

Exposure of collagen and vWF to cause platelet adhesion and granule release, which then recruits more platelets and soon platelet aggregation to form a primary plug thrombus

TF exposure causes activation of coagulation and thrombin generation leading to fibrin formation and secondary plug thrombus

Adhesion: platelets + non-platelet components like collagen
Aggregation: platelets stick to each other (primary plug)

Question 4

Antithrombotic Drugs: Antiplatelet, Anticoagulant, and Fibrinolytic

Answer 4

Antiplatelet: for arterial thrombi; stops the primary plug from forming
Anticoagulant: for venous system; inhibits coagulation reaction to prevent fibrinogen conversion to fibrin
Fibrinolytic: once the plug is formed, the other two medications will not work, so use this one

Question 5

Parenteral Anticoagulants + Target

Answer 5

Thrombin fXa- IV or IM; inhibit thrombin generation (IIa) and Xa; increase rate of anti-thrombin reactions; include Heparin and LMWH

Thrombin: direct thrombin inhibitors, will not do anything to factors 10, 11, and 12; they will not inhibit anything before thrombin in the pathway

fXa: newer drug; neutralizes Xa ONLY

Question 6

Unfractionated Heparin vs. LMWH vs. Fondaparinux

Answer 6

Length of heparin molecule is important

Unfractionated heparin: inhibits/neutralizes thrombin and Xa

LMWH: you can inhibit both thrombin and factor Xa (18 or greater)
If you only have 5 units, it works on Xa ONLY
If you have 5, and less than 13 (less than 18), will not work on thrombin; sometimes will if 5+13 or close to it

If you have fondaparinux, only 5 will work with Xa

Overall you need unfractionated or LMWH to involve both thrombin and Xa
Therefore, you can limit where you want the action to take place

Question 7

Heparin: Vascular, Surgical, Prophaylaxis, and Critical Care Uses

Answer 7

Vascular:
Acute-phase myocardial infarction
Venous and arterial thrombo-embolism
Pulmonary embolism
Atherosclerosis
Atrial fibrillation with embolization
Acute ischemic stroke
Deep vein phlebitis

Surgery: open-heart surgery

Prophylaxis: pulmonary embolism, deep vein thrombosis

Critical care: Heparin-coated central venous and pulmonary arterial catheters. Heparin flushes in arterial and central venous lines

Question 8

Heparin-Induced Thrombocytopenia

Answer 8

Non-immune mediated HIT type I: in 4 days they will have HIT; no complications because if you stop meds nothing will happen except tiny platelet aggregates; recovery in 1-3 days once med stopped

Immune mediated HIT type II: 5-14 days or sooner get reaction onset; complications include thromboembolism via IgG mediated platelet activation; recovery in 5-7 days once med stopped

Question 9

Heparin-PF4-IgG Induced Thrombotic State

Answer 9

When you give patient heparin, platelet factor 4 (H-PF4) protein that combines with heparin and will not be able to work
Ab generation that works on platelets to cause more factor 4 to be released and more platelet activation
When platelets are activated by the Ab, it will cause more clotting reactions leading to thromboembolism

Question 10

Management of Heparin Induced Thrombocytopenia

Answer 10

When someone has HIT, stop all heparin and give alternative anticoagulant such as lepirudin, argatroban, bivalirudin, or fondaparinux

DO NOT give warfarin until platelet count returns to baseline and DO NOT give platelet transfusions

When warfarin is administered, give vitamin K to restore the INR (internalized normalized ratio) to normal because you don’t want clot formation, but don’t want bleeding from warfarin either

Evaluate for thrombosis, particularly DVT

Question 11

Limitations of Heparin

Answer 11

Unpredictable anticoagulant response- heparin binds to plasma proteins, the levels of which vary between patients
Reduced activity in the vicinity of thrombi- heparin is neutralized by platelet factor 4 and high molecular- weight multimers of vWF released from activated platelets
Unable to inactivate Xa bound to platelets or thrombin bound to fibrin

Question 12

LMWH Drugs

Answer 12

Exoxaprin
Dalteparin
Danaparoid

Question 13

Direct FXa Inhibitors

Answer 13

Fondaparinux

Rivaroxaban

Question 14

Unfractionated Heparin vs. LMWH

Answer 14

Binds to proteins: heparin must work in the blood (given IV) and biggest protein in blood is albumin, so lots of drug interactions happen because they bind to plasma proteins (have to worry about drug-drug interaction with unfractionated, but not with LMWH because will not have to compete with other drugs to bind)

Unfractionated: binds both Xa and IIa (thrombin), so lower ratio; risk of drug interactions; when given, must require monitor to adjust dose appropriately

LMWH: binds more Xa than Iia because must be greater than 18 to bind thrombin (Iia), so higher ratio; low risk of drug interactions; fixed dose with weight adjustment so little monitoring

Question 15

Direct Thrombin Inhibitors

Answer 15

Lepirudin: HIT + thrombosis
Argtroban: reversible; HIT + thrombosis
Bivalirubin: reversible; angioplasty
Dabigatran
Hirudin: leech protein and slowly reversible

Question 16

Advantages of Direct Thrombin Inhibitors vs. Heparin

Answer 16

No binding to plasma proteins, so predictable anticoagulant response

Activity is unaffected by proteins released or vWF from activated platelets, so good activity in vicinity of thrombi

Access and inactivate fibrin-bound thrombin and free thrombin

Question 17

Oral Anticoagulants with Targets

Answer 17

Thrombin: dabigatran etexilate

fXa: Rivaroxaban and Apixaban

Other – if you have coagulation pathway, factor 2, 7, 9, and 10 are inhibited by warfarin (established anticoagulant), which is a vitamin K antagonist

Question 18

Warfarin

Answer 18

Oral Anticoagulant

Inhibits gamma caboxylation of glutamates in coagulation factors 2, 7, 9, and 10

Also inhibits protein C and S, but do not want this because it can cause complications for a short period of time

Question 19

Mechanism of Action: Warfarin

Answer 19

The enzyme gamma carboxylase depends on reduced vitamin K to convert non-functional prozymogens to functional ones

When vitamin K is oxidized, then no more reduced form and the reaction does not occur

When you give warfarin, it inhibits vitamin K reductase so clotting proteins 2, 7, 9, 10, C, and S will be blocked

Two isomers of warfarin: are eliminated by two different pathways

Question 20

Heparin vs. Warfarin

Answer 20

Heparin: high negative charge, naturally occurring, activates antithrombin, subcutaneously and IV administration, and immediate onset; hospital/surgical use; works for 4 hours, does not bind to proteins (LMWH) but unfractionated binds proteins, metabolized in liver and excreted by kidney

Warfarin: vitamin K analogue, synthetic, inhibits synthesis of factors 2, 7, 9, and 10, oral administration, and onset takes about 2 days; long term use; works for 2-10 days, bound to albumin (worry about drug-drug interactions), metabolized in liver via side chain reduction to alcohol and oxidation

Question 21

Antagonists for Heparin vs. Warfarin

Answer 21

Heparin: protamine sulfate, a strongly basic protein
1mg protamine for 100 units of heparin

Warfarin: vitamin K, fresh plasma

Question 22

Drug Interactions with Warfain Resulting in Increased PT Time

Answer 22

Pharmacokinetic: amiodarone, cimetindine, disulfiram, metronidazole, phenylbutazone, and sulfinpryazone

Pharmacodynamic: aspirin (high doses), cephalosporins (3rd gen), and heparin

PT time increased (extrinsic pathway)
Inhibit metabolism of the drug – some of the drugs do this so more anticoagulant affect, so it takes more time to clot
First three (kinetic): inhibit R and S isomer
Last three (kinetic): inhibit only S warfarin, which is the part that is more effective
Antibiotics: can alter GI flora and there is where metabolism takes place for some of these drugs, so alters that

Question 23

Drug Interactions with Warfain Resulting in Decreased PT Time

Answer 23

Pharmacokinetic: Barbiturates, cholestyramine, rifampin

Pharmacodynamic: drugs, diuretics, vitamin K, body factors, hereditary resistance, and hypothyroidism

Barbituates: induce the enzyme cP450 so more enzyme inhibiting, so breaks down warfarin so less effect (clot will form faster because less anticoagulant)
Hypothyroidism: decreased turnover of the clotting proteins

Question 24

Warfarin, Dabigatran, Rivaroxaban, Apixaban Oral Anticoagulant Comparison

Answer 24

Warfarin: vitamin K epoxide reductase target, longest half life, no renal clearance, has vitamin K antidote (or plasma), requires monitoring

Dabigatran: thrombin target, renal clearance, no monitoring, no antidote

Rivaroxaban: FXa target, renal clearance, no monitoring or antidote

Apixaban: FXa target, renal clearance, no monitoring or antidote

Question 25

Anticoagulants: Clinical Use

Answer 25

Prevents:
DVT
Extension of established DVT or recurrence of pulmonary embolus
Thrombosis and embolization in patients with atrial fibrillation
Thrombosis on prosthetic heart valves
Clotting of extracorporeal circulations during hemodialysis or bypass surgery

*Heparin (often LWMH) is used acutely and Warfarin for prolonged therapy