L15 Anticoagulant and thrombolytic therapy

• Anticoagulant and thrombolytic therapies involve both medications used to prevent and treat blood clots
• The course will cover mechanisms, uses, effects, and applications of anticoagulants, antiplatelet agents, and thrombolytic agents

Anticoagulants: Key Points

• Anticoagulants are drugs used to treat hemostatic disorders
• They prevent blood clots from forming in various medical conditions
• Anticoagulants interfere with coagulation factors involved in secondary hemostasis
• Common types are unfractionated heparin (UFH) and low molecular weight heparin (LMWH)
• Low molecular weight heparins (LMWHs) are produced from the chemical depolymerization of UFH
• Anticoagulant usage needs to be monitored by healthcare professionals because of side effects

Heparin: Mechanism and Therapeutic Uses

• It potentiates the action of antithrombin III (ATIII), action primarily affects factors IIa (thrombin) and Xa
• This prevents the conversion of fibrinogen to fibrin
• It is indicated for venous thromboembolism (VTE DVT/PE initial treatment)
• It is indicated for acute coronary syndromes (ACS)
• It reduces myocardial infarction (MI) rate and stroke in ACS patients
• Heparin serves as an adjunct to percutaneous coronary intervention (PCI ) and is also used as a primary reperfusion strategy in ST-elevation myocardial infarction (STEMI)

Heparin: Additional Information

• Heparin does not cross the placenta, so it can be used during pregnancy
• The effects of heparin require monitoring of activated partial thromboplastin time (aPTT)
• Protamine sulfate, a positively charged peptide, reverses the action of negatively charged heparin
• Bleeding, Heparin-induced thrombocytopenia (HIT), Osteoporosis (long-term use), and Type 4 renal tubular acidosis can be side effects of Heparin

Heparin-Induced Thrombocytopenia (HIT) Type 2

• HIT type 2 is caused by the binding of heparin to platelet factor 4 (PF4)
• IgG antibodies develop whereafter the antibody-heparin-PF4 complex binds to and activates platelets
• Splenic macrophages remove platelets and thrombosis takes place, lowering platelet count
• It typically occurs 5-10 days after heparin administration
• Unfractionated heparin carries a 5-10% risk, LMWH carries lower risk
• Heparin should be stopped and switched to a different anticoagulant

Heparin Induced Thrombocytopenia (HIT) Type 2 alternative medications

• Direct coagulation factor inhibitors like Bivalirudin, Argatroban, Dabigatran can be used
• Fondaparinux is safe to use, that does not interact with PF4

Heparin-Induced Thrombocytopenia (HIT) Type 1

• HIT Type 1 presents as mild, with platelet counts of > 100,000/mm3
• Platelet counts may drop briefly without immunological causes
• This typically occurs within the first 2 days of heparin administration
• It is often not clinically significant

Warfarin: Mechanism and Therapeutic Uses

• Warfarin inhibits vitamin K epoxide reductase (VKOR)
• This prevents the conversion of vitamin K back to its active form
• It inhibits vitamin K-dependent gamma-carboxylation of clotting factors II, VII, X, and proteins C and S
• Warfarin is used to prevent VTE and stroke in atrial fibrillation

Warfarin: Important Considerations

• Warfarin is contraindicated in pregnant patients, because, unlike heparin, it crosses the placenta
• Warfarin has a narrow therapeutic window
• Prothrombin time (PT) and international normalized ratio (INR), a PT ratio normalized for reagents used, need monitoring
• Vitamin K (slow) +/- fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) are reversal agents

Warfarin: Side Effects

• Bleeding, teratogenic effects, increased risk of hypercoagulation and skin/tissue necrosis are side effects of Warfarin

Pharmacokinetics: Heparin vs Warfarin

• Heparin is administered parenterally (IV, SC) and Warfarin is administered orally
• Heparin’s site of action is blood, while Warfarin’s is the liver
• Heparin's onset of action is rapid in seconds, while Warfarin’s is slow
• Heparin's duration of action is hours, Warfarin's is days
• Heparin is 25-50% unchanged and eliminated by the reticuloendothelial system whilst Warfarin is renal 92% (metabolites)
• Protamine sulfate reverses Heparin and Vitamin K (slow) +/- FFP or PCC (rapid) reverses Warfarin
• Heparin doesn't cross the placenta, and Warfarin does
• Monitoring of PTT for Heparin and PT/INR for Warfarin

Low Molecular Weight Heparin (LMWH) Information

• Enoxaparin and Dalteparin are a class of LMWH medication

Low Molecular Weight Heparin (LMWH) Key Points

• LMWH consists of fragments of standard unfractionated heparin (UFH)
• It contains a pentasaccharide sequence that binds to and activates ATIII
• ATIII binds to and inactivates factor Xa and factor IIa (thrombin)
• Most patients begin warfarin at the time of LMWH initiation
• It should not be given IM, similar to UFH
• It doesn't affect aPTT and routine monitoring is not necessary because of pharmacokinetic predictability
• LMWH is given as a weight-adjusted SC injection with predictable and stable bioavailability
• Unlike UFH, LMWH predominantly inactivates factor Xa rather than thrombin
• The frequency of HIT and thrombosis is lower with LMWH (~0.6%) compared to UFH (3%)

Enoxaparin: Details

• It acts by increasing ATIII-mediated inhibition of the formation and activity of factor Xa (mainly) and factor IIa
• The anti-factor Xa activity is much greater than its anti-factor IIa activity
• It Is used for prophylaxis of DVT, acute DVT treatment (inpatient and outpatient)
• It can be used in treatment for unstable angina and non–Q-wave myocardial infarction (UA/NSTEMI) and treatment of acute ST-segment elevation myocardial infarction (STEMI)
• Bleeding and anemia can be adverse effects
• Enoxaparin is less likely than UFH to trigger heparin-induced thrombocytopenia (HIT) type II
• Protamine will only partially reverse the anticoagulant effect of LMWH
• Do not use on patients with a History of HIT, Active major bleed, and Hypersensitive to enoxaparin, heparin, or pork products

Dalteparin: Details

• It acts by increasing ATIII-mediated inhibition of the formation and activity of factor Xa (mainly) and factor IIa
• The anti-factor Xa activity is much greater than its anti-factor IIa activity
• It Is used for prophylaxis of DVT, extended treatment of symptomatic VTE and can be used in treatment for unstable angina and non–Q-wave myocardial infarction (UA/NSTEMI)
• Limitations of Use - Not indicated for the acute treatment of VTE
• Bleeding and anemia can be adverse effects
• Dalteparin is less likely than UFH to trigger heparin-induced thrombocytopenia (HIT) type II
• Protamine will only partially reverse the anticoagulant effect of LMWH
• Do not use on patients with a History of HIT, Active major bleed, and Hypersensitive to enoxaparin, heparin, or pork products

Direct Factor IIa Inhibitors: Information

• Directly inhibit thrombin, Factor IIa
• Examples: Bivalirudin (IV), Argatroban (IV), and Dabigatran (oral)

Bivalirudin, Argatroban, Dabigatran: Information

• Directly inhibit factor IIa, otherwise known as thrombin to interrupt clot formation
• These medications reversibly bind to thrombin in the circulation and those already attached to a forming clot
• They are able to inhibit any further conversation of fibrinogen to fibrin
• They are used for HIT when heparin is BAD for patients
• Used for Prophylaxis and treatment of VTE and Nonvalvular atrial fibrillation (Stroke prophylaxis)
• Bivalirudin can be used as an adjunct to percutaneous coronary intervention (PCI)
• Idarucizumab - monoclonal antibody Fab fragments. is used for dabigatran reversal
• Bleeding, gastritis, dyspepsia, and nausea can be adverse effects
• Thrombosis and strokes if discontinued suddenly can be a warning

Direct Xa Inhibitors: Information

• Apixaban (oral), Edoxaban (oral), Rivaroxaban (oral), and Fondaparinux (SC) are all Factor Xa (10a) inhibitors

Apixaban, Edoxaban, Rivaroxaban

• Direct-acting oral anticoagulants (DOACs)
• They directly inhibit factor Xa (reversible binding), inhibit thrombin activation and the coagulation cascade from progressing
• Used in Prophylaxis and treatment of VTE and Nonvalvular atrial fibrillation (Stroke prophylaxis)
• Andexanet alfa is used to reverse the factor Xa inhibitors Apixaban and Rivaroxaban
• It is Generally well-tolerated unless bleeding occurs
• Thrombosis and strokes if discontinued suddenly is a box warning

Fondaparinux: Information

• It is an injectable synthetic pentasaccharide
• It enhances antithrombin (AT) activity causes conformational change and makes AT a more rapid inhibitor of Factor Xa and disrupt thrombin formation
• Fondaparinux itself doesn’t have anticoagulant activity and the therapeutic activity depends on interaction with AT
• The Uses are HIT and Prophylaxis and treatment of VTE
• Similar side effects to Heparin and Protamine will not reverse the activity of fondaparinux

Antiplatelet Agents: Information

• Antiplatelet agents interfere with the first step of hemostasis
• Antiplatelets stop the platelets from clumping together
• DAPT, Dual antiplatelet therapy (DAPT) is a common treatment for heart attack/stroke patients and for preventive care with the use of two antiplatelet agents

Aspirin: Information

• Aspirin reduces the release of TXA2 and platelet aggregation by irreversibly blocks cyclooxygenase 1 (COX1) enzyme
• At high doses (325 mg), it inhibits COX-2 and block prostaglandin synthesis and analgesic and antipyretic effects
• Indicated for prevention of cardiovascular event, also high-risk individuals
• Side effects are gastric ulcers, bleeding, tinnitus, allergic reactions and Reye Syndrome (in children)

ADP P2Y12 Receptor Antagonists: Information

• Ticagrelor, Cangrelor, Clopidogrel, and Prasugrel are ADP P2Y12 inhibitors

Clopidogrel: Information

• It is an effective thienopyridine prodrug, has to be converted in the body by CYP2C19
• Works by blocking irreversibly to ADP P2Y12 receptor on platelet, and prevents their activation
• Preferred to reduce coronary artery issues, actue coronary syndrom and prevents thrombotic stroke

Prasugrel: Information

• New generation orally effective thienopyridine drug
• Has a higher conversion rate to active thiol metabolite by CYP2BH6 enzyme
• Provides higher bioavailability and effects faster
• It blocks irreversibly to ADP P2Y12 receptor on platelet, and prevents their activation
• Preferred to reduce coronary artery issues
• Has serious and fatal bleeding warnings, contraindicated for stroke patients

Ticagrelor: Information

• It is a new drug with triazole pyrimidine, direct working, requires frequent dosing, but has better inhibition of vessel restriction
• It blocks reversibly and non-competitively to ADP P2Y12 receptor
• Side effects are Bleeding, dyspnea, bradyarrhythmia, with serious bleeding warnings

Cangrelor: Information

• Fast acting intravenus P2Y12 and decreases periprocedural MI for specific patients

Glycoprotein IIb/IIIa Antagonists

• Eptifibatide
• Tirofiban
• Abciximab

Eptifibatide, Tirofiban, Abciximab: Information

• Blocks platelet connectors to stop clots
• Eptifibatide is a synthetic material, cleared in kidneys with fast effect
• Tirofiban is a similar, smaller model, also cleared in kidney has faster action
• Abciximab is a monoclonal, no fast action, not kidney cleaned, longest action
• Can cause bleeding or decrease thrombocytes

Phosphodiesterase III Inhibitors: Information

• Cilostazol and Dipyridamole are examples of phosphodiesterase III inhibitors

Cilostazol, Dipyridamole: Information

• They work by increasing vasodilation and increasing cycle AMP in patients that have pain due to blocked arteries
• Used for Prevention of stroke in patients with transient ischemic attack and cardiac stress testing
• Side effects includes nausea, abdominal pain, and or heart issues

Thrombolytic Agents: Information

• They break up bloodclots to assist blood thru whole cycles
• Tissue Plasmin Assist is a natural helper, to turn Plasmin into the enzyme
• Rapid usage to break clots
• Clears Fibrin to amplify plasmin

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

• Recombinant human IPA, cleans plasmin
• Lowers clots thur decrease death in the system
• Bleeding as the side effect