Anticoagulants and Heparin

Anticoagulants: Key Points

• Anticoagulant drugs treat hemostatic disorders and prevent blood clot formation in various conditions.
• They interfere with coagulation factors during secondary hemostasis.
• Healthcare professionals should monitor anticoagulant use due to their side effects.
• Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are anticoagulants.
• LMWHs are made through chemical depolymerization of UFH.

Heparin: Mechanism, Uses, and Effects

• Heparin potentiates antithrombin III (ATIII), reducing the action of factors IIa (thrombin) and Xa, preventing fibrinogen conversion to fibrin.
• Short-term and immediate anticoagulation addresses acute problems such as venous thromboembolism (VTE), acute coronary syndromes (ACS), and myocardial infarction (MI).
• Also serves as an adjunct to percutaneous coronary intervention (PCI) or as the primary reperfusion strategy in patients with ST-elevation myocardial infarction (STEMI).
• Heparin is safe for use during pregnancy because it does not cross the placenta.
• Activated partial thromboplastin time (aPTT) needs to be monitored during heparin therapy.
• The reversal agent for heparin is protamine sulfate, which is a ⊕ charged peptide that binds ⊝ charged heparin.
• Bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis (long-term use), and type 4 renal tubular acidosis are potential adverse effects.

Heparin-Induced Thrombocytopenia (HIT)

• In HIT type 2, heparin binds to platelet factor 4 (PF4), triggering the development of IgG antibodies.
• The antibody-heparin-PF4 complex activates platelets, which are then removed by splenic macrophages, leading to thrombosis and reduced platelet count.
• HIT type 2 typically arises 5-10 days after heparin administration.
• The risk of HIT is lower with LMWH than with unfractionated heparin, with unfractionated heparin affecting 5–10% of patients.
• Heparin should be discontinued and replaced with a different anticoagulant, such as direct coagulation factor inhibitors Bivalirudin, Argatroban, or Dabigatran.
• Fondaparinux does not interact with PF4 and is a safe alternative.
• HIT type 1 is mild (platelets > 100,000/mm3), characterized by a transient, non-immunologic drop in platelet count, typically occurring within the first 2 days of heparin administration and is not clinically significant.

Warfarin: Mechanism, Uses, and Effects

• Warfarin inhibits vitamin K epoxide reductase (VKOR), preventing the conversion of vitamin K back to its active form and inhibiting vitamin K-dependent gamma-carboxylation of clotting factors II, VII, X, and proteins C and S.
• Prophylaxis of VTE and prevention of stroke in atrial fibrillation are therapeutic uses.
• Warfarin is contraindicated in pregnant patients because it crosses the placenta.
• Prothrombin time (PT) and international normalized ratio (INR) are monitored.
• Vitamin K (slow) and fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) (rapid) may reverse effects.
• Bleeding, teratogenic effects, increased risk of hypercoagulation, and skin/tissue necrosis are potential adverse effects.

Pharmacokinetics: Heparin vs. Warfarin

• Heparin is administered parenterally (IV, SC), while warfarin is administered orally.
• Heparin acts in the blood, while warfarin acts in the liver.
• Heparin has a rapid onset of action (seconds), while warfarin's is slow and limited by the half-life of normal clotting factors.
• Heparin lasts for hours whereas warfarin lasts for days.
• Heparin is 25-50% unchanged, and is eliminated by the reticuloendothelial system. Warfarin is 92% metabolized by the kidneys.
• Heparin is monitored by PTT (intrinsic pathway), while warfarin is monitored by PT/INR (extrinsic pathway).
• Heparin does not cross the placenta, while warfarin does (teratogenic).
• Protamine sulfate reverses heparin, while Vitamin K (slow) +/- FFP or PCC (rapid) reverses warfarin.

Low Molecular Weight Heparin (LMWH)

• Enoxaparin and Dalteparin are LMWHs.
• LMWH consists of fragments of standard unfractionated heparin (UFH).
• The key pentasaccharide sequence, that binds to and activates ATIII, is included.
• ATIII binds to and inactivates factor Xa and factor IIa (thrombin).
• LMWH predominantly inactivates factor Xa rather than thrombin, unlike UFH.
• HIT and thrombosis occur less frequently (~0.6%) with LMWH than with UFH (3%).
• LMWH is given as a weight-adjusted subcutaneous (SC) injection with predictable and stable bioavailability.
• LMWH, unlike UFH, does not affect aPTT, making routine monitoring unnecessary due to greater pharmacokinetic predictability.
• LMWH, similarly to UFH, should not be given intramuscularly (IM).
• Many patients begin warfarin at the same time as LMWH.

Enoxaparin: Mechanism, Uses, Contraindications

• Enoxaparin increases ATIII-mediated inhibition of factor Xa (mainly) and factor IIa.
• Anti-factor Xa activity is much greater than the anti-factor IIa activity.
• Until long-acting anticoagulants take effect, enoxaparin can be used.
• It is used for prophylaxis of DVT, acute DVT treatment (inpatient and outpatient), treatment of unstable angina and non–Q-wave myocardial infarction (UA/NSTEMI), and treatment of acute ST-segment elevation myocardial infarction (STEMI).
• Bleeding and anemia are adverse effects.
• Protamine only partially reverses the anticoagulant effect of LMWH.
• It is less likely than UFH to trigger heparin-induced thrombocytopenia (HIT) type II.
• It is contraindicated in patients with a history of HIT, active major bleeding, or hypersensitivity to enoxaparin, heparin, or pork products.

Dalteparin

• It increases ATIII-mediated inhibition of the formation and activity of factor Xa (mainly) and factor IIa.
• Anti-factor Xa activity is greater.
• Used for DVT prophylaxis, extended symptomatic VTE treatment, and unstable angina and non-Q-wave myocardial infarction (UA/NSTEMI) treatment, but not for acute VTE treatment.
• Adverse effects are Bleeding and anemia.
• Protamine only partially reverses the anticoagulant effect of LMWH.
• HIT type II is less likely than with UFH.
• Contraindications include HIT history, active major bleed, and hypersensitivity to enoxaparin, heparin, or pork.

Factor IIa Inhibitors (Direct)

• Bivalirudin is given intravenously (IV)
• Argatroban is given intravenously (IV)
• Dabigatran is given orally

Bivalirudin, Argatroban, Dabigatran

• These directly inhibit factor IIa (thrombin) which prevents clot formation.
• Factors V, VII, IX, and XII are not activated without thrombin.
• They reversibly bind thrombin in blood and clots, preventing further conversation of fibrinogen to fibrin.
• Therapeutic uses include HIT when heparin is BAD (Bivalirudin, Argatroban, Dabigatran), VTE prophylaxis and treatment.
• Bivalirudin only is used as an adjunct to percutaneous coronary intervention (PCI).
• Idarucizumab - monoclonal antibody Fab fragments - reverses Dabigatran.
• Bleeding, gastritis, dyspepsia, and nausea are adverse effects, and sudden discontinuation can cause thrombosis and stroke.

Factor Xa Inhibitors

• Apixaban, Edoxaban, and Rivaroxaban are administered orally
• Fondaparinux is administered subcutaneously (SC)

Apixaban, Edoxaban, Rivaroxaban

• These direct-acting oral anticoagulants directly inhibit factor Xa via reversible binding, inhibiting thrombin activation and the coagulation cascade.
• They are used for VTE prophylaxis, VTE treatment, and nonvalvular atrial fibrillation (stroke prophylaxis).
• Andexanet alfa reverses apixaban and rivaroxaban.
• Generally well-tolerated, but may cause bleeding, and thrombosis and stroke can occur if discontinued suddenly.

Fondaparinux: Mechanism, Uses and Effects

• This injectable synthetic pentasaccharide doesn't have direct anticoagulant activity.
• Instead, it relies on enhancing antithrombin (AT) activity, which makes AT a faster inhibitor of Factor Xa.
• Factor Xa is selectively inhibited, disrupting coagulation and preventing thrombin and clot development.
• It is used for HIT, and VTE prophylaxis and treatment.
• Its effects are similar to heparin and protamine will not reverse the activity of fondaparinux.

Antiplatelet Agents: Key Points

• Antiplatelet agents interfere with the first step of hemostasis.
• They halt platelet clumping and blood clot formation by targeting various components.
• Dual antiplatelet therapy (DAPT) is a common treatment for heart attack, stroke patients, and others by involving two antiplatelet agents.

Aspirin

• This irreversibly blocks cyclooxygenase 1 (COX1) enzyme, reducing thromboxane A2 (TXA2) release and platelet aggregation (low dose 81 mg).
• Higher doses (325 mg) inhibits COX-2 and block prostaglandin synthesis for analgesic and antipyretic effects.
• It is used for secondary prevention of cardiovascular events and primary prevention in certain high-risk individuals but should be avoided in patients with bleeding disorders.
• Gastric ulcers, bleeding, tinnitus, allergic reactions, and Reye Syndrome (in children) are potential adverse effects.

ADP P2Y12 Receptor Antagonists

• Ticagrelor
• Cangrelor
• Clopidogrel
• Prasugrel

Clopidogrel

• An effective thienopyridine drug and is a prodrug converted to an active metabolite by CYP2C19 enzyme.
• It blocks ADP P2Y12 receptors on platelets irreversibly, in addition to preventing ADP-mediated activation of the GPIIb/IIIa-receptor complex, reducing platelet activation and aggregation.
• These agents are preferred for coronary artery stenting (reducing stent thrombosis), acute coronary syndromes (reducing MI rate and stroke in ACS), preventing thrombotic stroke, and peripheral arterial disease.
• Bleeding and Thrombotic thrombocytopenic purpura (TTP) can occur. Metabolic issues may occur.

Prasugrel

• It converts rapidly to an active metabolite, is a third generation thienopyridine prodrug that has higher bioavailability.
• Reduces variability with faster action, and decreases the difference in efficacy between individuals.
• It blocks platelet ADP P2Y12 receptors irreversibly and also prevents arterial thrombosis, acute coronary syndromes and stroke.
• Common side effects include bleeding and thrombotic thrombocytopenic purpura (TTP), and is contraindicated in patients with a history of TIA.

Ticagrelor

• It does not require metabolic activation and is a new cyclopentyl triazole pyrimidine with more frequent dosing.
• Significantly better clopidogrel due to a high degree of platelet inhibition that reduces ischemic events of the cardiovascular system.
• It reversibly and non-competitively blocks ADP P2Y12 receptors outside the active site to prevent the receptors affinity for ADP.
• Preferred for CAD stenting, ACS, and to prevent thrombotic stroke.
• Bleeding dyspnea and bradyarrhythmia is to be expected, and is dangerous and fatal.

Cangrelor

• A fast acting intravenous P2Y12 inhibitor.
• It blocks GPIIb and IIa with ADP, as well as prevents ADP-mediated activation of the GPIIb or IIa with no effect on age, sex, renal or cardiac function or presentation.
• For reducing the risk of MI or repeat problems with revascularization it should be used.
• Side effects include bleeding.

Glycoprotein IIb/IIIa Antagonists

• Eptifibatide
• Tirofiban
• Abciximab

Eptifibatide, Tirofiban, Abciximab

• They work by preventing platelet buildup by binding to glycoprotein 2B and 3A.
• Abciximab is non-renal with a longer life, while eptifibatide is renal, and has a shorter half life.
• The same is true for Tirofiban, for both short-life and renal clearing.
• Used via the cardiac PCI by way of unstable angina combined with Heparin
• Causes bleeding often, and Thromocytopenia.

Phosphodiesterase III Inhibitors

• Dipyridamole.
• Cilostazol.

Cilostazol, Dipyridamole

• This is to inhibit blood clots through platelet aggregation and PDE3 enzymes.

• With reduced ADP, cGMP will go up by means of vasodilation as well as improve intermittent issues.

• It is good for stroke and heart attacks or coronary stent malfunctions.

• However some side effects are palpitations, hypotension, nausea or headache.

Thrombolytic Agents: Key points

• They break up blood and help restore it.
• As tPA and protease by way of thrombus will promote plasmin.
• This is to catalyze inactive plasminogen as a proteolytic enzyme as well as boost plasmin and fibrin so no blood clot will form.

Alteplase (tPA), Reteplase (rPA), Tenecteplase (TNK-tPA)

• They converts plasminogen into cleaves thrombin as protein.
• There is no change to platelets, and will go up in PT within 5 minutes.
• It will reduce stemI, or even an early ischemic stroke.
• Fibrin is also good for TPA.