Anticoagulants Flashcards
Hemostasis
Hemostasis is the arrest of blood loss from damaged vessels.
This process involves platelet adhesion and activation as well as blood coagulation (fibrin formation).
Thrombosis
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
Vascular Injury Cascade Steps
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)
Antithrombotic Drugs: Antiplatelet, Anticoagulant, and Fibrinolytic
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
Parenteral Anticoagulants + Target
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
Unfractionated Heparin vs. LMWH vs. Fondaparinux
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
Heparin: Vascular, Surgical, Prophaylaxis, and Critical Care Uses
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
Heparin-Induced Thrombocytopenia
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
Heparin-PF4-IgG Induced Thrombotic State
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
Management of Heparin Induced Thrombocytopenia
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
Limitations of Heparin
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
LMWH Drugs
Exoxaprin
Dalteparin
Danaparoid
Direct FXa Inhibitors
Fondaparinux
Rivaroxaban
Unfractionated Heparin vs. LMWH
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
Direct Thrombin Inhibitors
Lepirudin: HIT + thrombosis Argtroban: reversible; HIT + thrombosis Bivalirubin: reversible; angioplasty Dabigatran Hirudin: leech protein and slowly reversible
Advantages of Direct Thrombin Inhibitors vs. Heparin
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
Oral Anticoagulants with Targets
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
Warfarin
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
Mechanism of Action: Warfarin
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
Heparin vs. Warfarin
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
Antagonists for Heparin vs. Warfarin
Heparin: protamine sulfate, a strongly basic protein
1mg protamine for 100 units of heparin
Warfarin: vitamin K, fresh plasma
Drug Interactions with Warfain Resulting in Increased PT Time
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
Drug Interactions with Warfain Resulting in Decreased PT Time
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
Warfarin, Dabigatran, Rivaroxaban, Apixaban Oral Anticoagulant Comparison
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
Anticoagulants: Clinical Use
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
