Anticoagulant Drugs Overview Flashcards

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Unfractionated Heparin

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UFH consists of long heterogeneous polysaccharide chains that bind antithrombin III to boost its activity. It inactivates both $Xa$ and $IIa$ effectively because the long chain can bridge ATIII to thrombin. UFH is given IV or SC, requires aPTT monitoring, and is readily reversed by protamine sulfate.

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Low-Molecular Weight Heparin

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LMWH are shorter heparin fragments (e.g., enoxaparin, dalteparin) that mainly enhance ATIII inhibition of $Xa$ rather than $IIa$. They are given SC with more predictable pharmacokinetics and usually do not require routine monitoring. LMWH are cleared by the kidneys and can accumulate in renal failure.

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Fondaparinux

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Fondaparinux is a synthetic pentasaccharide that activates ATIII and selectively inhibits $Xa$ without significant $IIa$ inhibition. It is too small to bridge ATIII to thrombin so it does not inhibit thrombin directly. Fondaparinux is renally cleared and should be avoided in severe renal failure.

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Antithrombin III

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Antithrombin III is a natural plasma protein that inhibits clotting enzymes, especially $Xa$ and $IIa$. Heparin and related drugs work by binding ATIII and causing a conformational change that accelerates ATIII activity. Without ATIII, heparin is ineffective (heparin resistance).

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Heparin Mechanism

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Heparin does not directly block clotting enzymes but potentiates antithrombin III to inactivate $Xa$ and, with UFH, $IIa$. UFH’s long chains can simultaneously bind ATIII and thrombin, enabling efficient $IIa$ inhibition; LMWH mainly enhances $Xa$ inhibition. The net effect is reduced thrombin and fibrin formation, limiting clot growth.

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UFH vs LMWH

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UFH has variable effects requiring aPTT monitoring and is preferred in severe renal failure because it is less renally cleared and easier to reverse. LMWH has more predictable dosing, often needs no routine monitoring, has lower HIT risk, but accumulates in renal impairment and is only partially reversible. Choice depends on renal function, monitoring availability, and HIT history.

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Heparin Uses

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Heparins are used for VTE prophylaxis after surgery and in hospitalized immobile or high-risk patients, for treatment of DVT/PE, and as an adjunct in acute coronary syndromes. LMWH is commonly preferred during pregnancy because it does not cross the placenta. They prevent clot propagation while the body breaks down existing thrombi.

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Heparin Side Effects

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The main hazard of heparin therapy is bleeding, ranging from minor bruising to severe internal hemorrhage. Other effects include osteoporosis with long-term use and hypoaldosteronism causing hyperkalemia ($K^+$ rise) during prolonged therapy. Protamine sulfate can reverse UFH and partially reverse LMWH.

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Heparin Reversal

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Protamine sulfate is the antidote that binds and neutralizes heparin, working best for UFH and only partially for LMWH. Reversal is used in major bleeding or when rapid neutralization is needed. Protamine itself can cause hypersensitivity reactions in some patients.

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Heparin-Induced Thrombocytopenia

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HIT is an immune-mediated reaction where antibodies form against the heparin–PF4 complex, activating platelets and paradoxically increasing thrombosis while platelet counts fall. Clinically this causes new thromboses (DVT/PE, stroke, limb ischemia) despite thrombocytopenia. Heparin must be stopped and alternative anticoagulation with a DTI started.

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Monitoring Heparin

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UFH requires aPTT monitoring because of unpredictable anticoagulant effect when given IV or SC. LMWH typically does not require routine monitoring, but if needed anti-$Xa$ levels are measured rather than aPTT. Choice of test depends on the heparin formulation and clinical context.

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Direct Thrombin Inhibitors

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DTIs (e.g., bivalirudin, argatroban, lepirudin) bind thrombin directly at the active site and fibrin-binding site, inhibiting conversion of fibrinogen to fibrin. They do not require antithrombin and therefore work in ATIII deficiency and are safe in HIT. DTIs are administered IV and dosing is usually monitored with aPTT.

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DTI Uses

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DTIs are mainly used as alternatives when heparin cannot be used, especially in HIT, and during certain percutaneous coronary procedures. They stop thrombin activity directly so they prevent further clot stabilization and growth. Use is often hospital-based because administration is IV and monitoring is required.

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Direct Oral Anticoagulants

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DOACs include the oral direct thrombin inhibitor dabigatran and the direct $Xa$ inhibitors rivaroxaban, apixaban, and edoxaban. They act directly on a single clotting enzyme, do not require antithrombin, have predictable pharmacokinetics, fixed dosing, and do not need routine INR monitoring. DOACs have fewer food and drug interactions compared with warfarin.

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Dabigatran

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Dabigatran is an oral prodrug converted to an active direct thrombin inhibitor that prevents fibrin formation. It is used for stroke prevention in atrial fibrillation and for VTE treatment and prevention. Dabigatran is primarily renally cleared and can cause GI upset; severe renal failure is a contraindication.

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Factor Xa Inhibitors

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Rivaroxaban, apixaban, and edoxaban directly inhibit $Xa$, reducing thrombin generation and subsequent fibrin formation. They are used for atrial fibrillation stroke prevention, treatment and prevention of VTE, and perioperative prophylaxis. These agents have rapid onset and predictable effects without routine monitoring.

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DOAC Reversal Agents

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Idarucizumab is a specific reversal agent that binds and neutralizes dabigatran. Andexanet alfa acts as a decoy $Xa$ molecule to bind and sequester $Xa$ inhibitors, reversing their effect; prothrombin complex concentrates (PCC) can also be used to restore clotting. Choice of reversal depends on the anticoagulant involved and clinical availability.

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DOAC Contraindications

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DOACs are contraindicated in active major bleeding and are generally avoided in severe bleeding disorders or recent hemorrhagic stroke. Mechanical heart valves are another key contraindication where warfarin is preferred. Severe renal impairment and pregnancy are important considerations—LMWH is preferred in pregnancy.

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Renal Failure Rule

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LMWH and fondaparinux are predominantly renally cleared and can accumulate in renal failure, increasing bleeding risk. In severe renal impairment, UFH is preferred because it is less dependent on renal clearance and can be tightly controlled and reversed. Renal function must guide anticoagulant selection and dosing.

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Long-term Heparin Effects

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Prolonged heparin therapy can cause osteoporosis due to effects on bone formation and increased bone resorption, which is clinically relevant in long pregnancies. Extended therapy can also reduce aldosterone synthesis leading to hyperkalemia ($K^+$ rise), so potassium may be monitored during long courses. Hypersensitivity reactions to heparin are rare but possible.