Blood-Thinning Meds: Anti-platelets and Hemostasis NJ

Overview of Blood-Thinning Medications

• Anti-platelets, anticoagulants, and thrombolytics are blood-thinning medications.
• These medications affect different phases of hemostasis.
• Hemostasis involves platelet plug formation, coagulation cascade, and fibrinolytic mechanisms.

Platelet Plug Formation

• Endothelial cells release nitric oxide and prostacyclin to inhibit platelets.
• Damage to endothelial cells reduces nitric oxide and prostacyclin allowing platelets to attach the sub-endothelial layer.
• Collagen exists on the sub-endothelial lining of blood vessels.
• Von Willebrand factor is a protein present in the sub-endothelial layer that platelets bind to.
• Platelets become activated and release molecules like ADP, thromboxane A2, Von Willebrand factor, and fibrinogen.
• Anti-platelet agents are used to prevent pathological clot formation

Platelet Interaction with Sub-Endothelial Layer

• Platelets bind to collagen lining via Von Willebrand factor.
• Von Willebrand factor is made by platelets and injured endothelial cells.
• Platelets bind to Von Willebrand factor using the gp1b protein.
• Activated platelets release cytokines from granules.
• Granules contain Von Willebrand factor, fibrinogen, and calcium.
• ADP released by platelets binds to p2y12 receptors on other platelets.
• Binding of ADP increases intracellular calcium in platelets.

Role of Calcium and Fibrinogen

• Increased intracellular calcium stimulates the expression of gp2b3a receptors on platelets.
• gp2b3a receptors facilitate the connection between platelets.
• Fibrinogen acts as a bridge between platelets, aiding in plug formation.
• Calcium activates granules, releasing more Von Willebrand factor, fibrinogen, calcium, and ADP.

Thromboxane A2 Formation

• Calcium activates phospholipase A2, which breaks down phospholipids into arachidonic acid.
• Arachidonic acid is converted into thromboxane A2 by the cyclooxygenase (Cox) enzyme.
• Thromboxane A2 increases intracellular calcium similarly to ADP.

Cyclic AMP Regulation

• Cyclic AMP inhibits the increase in calcium levels inside platelets.
• Phosphodiesterase 3 enzyme breaks down cyclic AMP.
• Inhibition of phosphodiesterase 3 increases cyclic AMP, reducing calcium levels.

Anti-platelet Drug Mechanisms

• Inhibit p2y12 receptor: Clopidogrel, prasugural, ticagrelor, and taclobodine.
• Inhibit cyclooxygenase (Cox) enzyme: Acetylsalicylic acid (aspirin).
• Inhibit gp2b3a receptor: Abciximab, tirofiban, and eptifibatide.
• Inhibiting the p2y12 receptor and thromboxane A2 formation leads to a decrease in GP 2B 3A production, decreasing thromboxane A2 formation, as well as decreasing ADP formation.
• Inhibit PDE3: dipyridamole and cilostazol

Additional Considerations for Anti-platelet Agents

• Anti-platelet agents inhibit clot formation or propagation, but do not break down existing clots.
• Anti-platelets are more effective in the arterial circulation.
• Anti-platelet medications do not break down a clot, rather the inhibit the formation of the clot, or inhibit the clot from getting bigger.
• Dipyridamole and cilostazol, PDE3 inhibitors, have both anti-platelet and vasodilatory functions, which can be beneficial in conditions like peripheral artery disease (PAD).

Vascular Smooth Muscle and PDE3 Inhibitors

• Adenylate cyclase converts ATP to cyclic AMP, which inhibits smooth muscle contraction.
• PDE3 inhibits cyclic AMP, promoting smooth muscle contraction.
• PDE3 inhibitors increase cyclic AMP, activating protein kinase A and inhibiting smooth muscle contraction, leading to vasodilation.

Anticoagulants

• Anticoagulants inhibit the coagulation cascade.
• Vessels naturally express antithrombin 3, which inhibits thrombin (Factor II) and Factor X.

Anti-Thrombotic Mechanisms & Coagulation Cascade Inhibition

• Anti-thrombotic mechanisms aim to prevent pathological clot formation by inhibiting the coagulation cascade.
• Blood vessel injury prevents the release of nitric oxide and prostacyclin, while exposing von Willebrand factor.
• Platelets bind to von Willebrand factor via the GP1b receptor.
• Activated platelets release ADP, which binds to the P2Y12 receptor, increasing intracellular calcium.
• Increased intracellular calcium leads to increased expression of the GP2b3a protein, facilitating platelet aggregation.
• ADP release activates the intrinsic pathway, increasing thromboxane A2, which promotes aggregation.
• PDE3 enzyme inhibits the increase of intracellular calcium, working against platelet activation.
• Anti-platelet drugs inhibit the P2Y12 receptor, COX enzyme, GP2b3a proteins, and PDE3 enzyme to prevent platelet plug formation.
• Activated platelets develop a negatively charged surface, attracting coagulation proteins.
• Coagulation proteins undergo a complex cycle leading to the formation of a fibrin mesh.
• Fibrin mesh stabilizes the clot and increases its size.
• Strategies to inhibit coagulation proteins aim to prevent fibrin formation, thus preventing clot stabilization and growth.

Extrinsic and Intrinsic Pathways

• The coagulation cascade involves two main pathways: extrinsic and intrinsic.
• The intrinsic pathway is initiated by activated platelets, and the extrinsic pathway is triggered by vessel injury.
• Platelets activate Factor 12 in the intrinsic pathway, leading to the activation of Factor 11, then Factor 9, which complexes with Factor 8.
• The Factor 9/Factor 8 complex then converges into the common pathway.
• Vessel injury causes tissues to release tissue factor (Factor 3).
• Tissue factor activates Factor 7, and the Factor 3/Factor 7a complex converges into the common pathway.
• Both pathways converge on Factor 10, activating it and initiating the common pathway.

Common Pathway and Fibrin Mesh Formation

• Both the extrinsic and intrinsic pathways converge to stimulate the activation of Factor 10, thus starting the common pathway.
• Activated Factor 10 converts prothrombin into thrombin (Factor 2).
• Thrombin activates fibrinogen into fibrin and Factor 13.
• Factor 13 combines with fibrin to form the fibrin mesh, which stabilizes the clot by adhering to platelets.
• Factor 10 and thrombin are key proteins to target for inhibiting clot formation.

Liver's Role in Coagulation

• The liver produces coagulation proteins, including Factors 2, 7, 9, 10, Protein C, and Protein S.
• Factors 2, 7, 9, and 10 are pro-coagulants that induce clot formation, while proteins C and S are anticoagulants that help prevent clot formation.
• Gamma-glutamyl transferase activates these proteins into their functional forms.
• Vitamin K, in its reduced form, is a cofactor for gamma-glutamyl transferase, activating it to enable the production of functional proteins.
• Vitamin K epoxide reductase converts vitamin K from its oxidized form back to its reduced form. This sustains the cycle and helps in continuous activation of gamma-glutamyl transferase.

Targeting Factor 10 for Coagulation Inhibition

• Factor 10 can be inhibited to prevent activation of thrombin, subsequent fibrin formation, and the development of a fibrin mesh.
• Factor 10 can be inhibited indirectly or directly.

Indirect Inhibition of Factor 10

• Antithrombin III inhibits both Factor 10 and thrombin.
• Heparin increases antithrombin III activity, leading to indirect inhibition of Factor 10 and thrombin.
• Unfractionated heparin contains a pentasaccharide structure and a long glycosaminoglycan (GAG).
• Unfractionated heparin inhibits Factor 10 and thrombin equally due to the long glycosaminoglycan.
• Low molecular weight heparin contains a pentasaccharide and a smaller glycosaminoglycan.
• Low molecular weight heparin primarily inhibits Factor 10, with minimal inhibition of thrombin, due to its smaller glycosaminoglycan.
• Fondaparinux is a synthetic heparin that only contains a pentasaccharide structure without a glycosaminoglycan.
• Fondaparinux only activates antithrombin III to inhibit Factor 10, with no thrombin inhibition.

Direct Factor 10a Inhibitors

• Direct oral anticoagulants (DOACs) directly bind to Factor 10 rendering it ineffective.
• Examples of DOACs include apixaban, rivaroxaban, and edoxaban.
• DOACs are oral agents, while heparins are administered via IV or subcutaneous injections.

Direct Thrombin Inhibitors

• Thrombin can be inhibited directly.
• Oral direct thrombin inhibitor is dabigatran.
• IV direct thrombin inhibitors include argatroban and bivalirudin.
• Argatroban and bivalirudin are notably used in cases of heparin-induced thrombocytopenia.

Inhibiting Vitamin K Epoxide Reductase

• Vitamin K antagonists inhibit the Vitamin K epoxide reductase.
• This inhibition prevents the reduction of Vitamin K, which is needed to activate the gamma-glutamyl carboxylase (GGCX).
• When GGCX is inhibited, functional clotting proteins like Factors 7 and 10 cannot be produced.
• The inability to produce functional clotting proteins prevents the activation of Factor 10, thus inhibiting the coagulation cascade.
• Warfarin is the primary drug in the category of Vitamin K antagonists.

Anticoagulants Effect on Clotting

• Anticoagulants inhibit the fibrin mesh formation in the coagulation cascade.
• Anticoagulants do not break down existing clots, instead, they decrease the formation and propagation of clots.
• Anticoagulants work to inhibit both venous and arterial thromboemboli.

Natural Anti-thrombotic Mechanisms

• The body naturally tries to prevent clotting through mechanisms such as nitric oxide, prostacyclin, and antithrombin III.
• Nitric oxide and prostacyclin serve as natural anti-platelet mechanisms by inhibiting platelets.
• Antithrombin III inhibits Factors 10 and thrombin.
• Proteins C and S are additional molecules that inhibit procoagulants.

Clot Formation

• Vessel injury triggers platelets to stick to the von Willebrand factor.
• Platelets release ADP and thromboxane A2, and increase the expression of glycoprotein IIb/IIIa (GP IIb/IIIa) proteins.
• GP IIb/IIIa proteins allow platelets to stick together.

Fibrinolysis

• Fibrinolysis is a natural process that balances clot formation.
• It breaks down fibrin and the connections between platelets, effectively dissolving the clot.
• Plasminogen-converted into plasmin-breaks down fibrinogen into fibrinogen degradation products and fibrin into fibrin degradation products.
• Fibrinolysis decreases fibrin formation and fibrinogen, leading to a decrease in clot size.
• Fibrinogen is the protein that connects platelets and facilitates the platelet plug.
• By breaking down fibrinogen, fibrinolysis reduces the ability of platelets to stick together, which can cause platelet dissolution or separation.
• This process helps to disrupt the platelet plug.

Thrombolytics

• Thrombolytics break down clots, unlike anti-platelets and anticoagulants, which only prevent clot formation and propagation.
• To break down clots, enhance the fibrinolytic pathway.
• Tissue plasminogen activator (TPA) stimulates the conversion of plasminogen into plasmin.
• Drugs that stimulate or act like TPA can be used to increase TPA activity.
• Alteplase acts like true TPA.
• Recombinant TPAs include reteplase and tenecteplase.
• Other synthesized drugs include urokinase and streptokinase.

Inhibiting the Platelet Plug

• P2Y12 receptor inhibitors (such as clopidogrel, prasugrel, ticagrelor, and ticlopidine) work to decrease intracellular calcium, decrease the expression of GP IIb/IIIa proteins, and decrease the release of molecules such as ADP and von Willebrand factor.
• Cyclooxygenase (COX) enzyme inhibitors block the arachidonic acid pathway, thus decreasing thromboxane A2 production and preventing platelet plug stimulation.
• GP IIb/IIIa inhibitors prevent the GP IIb/IIIa connection, thus inhibiting the formation of the platelet plug.
• Phosphodiesterase 3 (PDE3) inhibitors prevent the breakdown of cyclic AMP, which leads to decreased calcium levels and inhibits the ability to express GP IIb/IIIa proteins and release thromboxane A2 and ADP.

Select Drugs

• Warfarin inhibits the enzyme Vitamin K epoxide reductase.
• Heparin molecules increase the production of antithrombin III to inhibit Factors 10 and thrombin:
  • Unfractionated heparin inhibits both Factors 10 and thrombin.
  • Low molecular weight heparin primarily inhibits Factor 10 with some inhibition of thrombin.
  • Fondaparinux primarily inhibits Factor 10.

Factor Xa and Thrombin Inhibitors

• Direct Factor Xa inhibitors include apixaban, edoxaban, and rivaroxaban.
• Direct thrombin inhibitors given orally are dabigatran, and those given intravenously are argatroban and bivalirudin.

Fibrinolysis Enhancement

• Enhancing fibrinolysis involves activating an enzyme to increase plasminogen conversion into plasmin.
• Plasmin breaks down fibrinogen and fibrin, preventing stable clot formation and dissolving existing clots.
• Breaking down fibrin prevents platelets from being held together.
• Breaking down fibrinogen prevents platelets from connecting.

Drug Categories and Their Effects

• Anti-platelets and anticoagulants decrease clot formation and propagation.
• Thrombolytics break down and dissolve existing clots.

Indications for Anti-platelets, Anticoagulants, and Thrombolytics

• These drug categories may be used in combination for some diseases.
• Anti-platelets and anticoagulants inhibit clot formation and propagation, but do not dissolve existing clots.
• Anti-platelets work more in the arterial circulation, while anticoagulants work more in the venous circulation, but also in the arterial circulation.
• Thrombolytics break down acute clots.

Neurological Indications: Acute Ischemic Stroke

• Acute ischemic stroke treatment depends on the "last known well" time.
• If between 3 and 4.5 hours, fibrinolysis enhancement with thrombolytics like TPA is the best option if no contraindications exist.
• Thrombolytics are given acutely for stroke, while anti-platelets/anticoagulants are for prevention of atherosclerotic cardiovascular diseases.
• After thrombolytics, chronic anti-platelet therapy, such as aspirin +/- a P2Y12 receptor inhibitor, can prevent further clot formation on plaques.

Neurological Indications: Cerebral Venous Sinus Thrombosis

• Cerebral venous sinus thrombosis is a DVT of the brain.
• Anti-platelets aren't useful for venous thromboembolism.
• Anticoagulants are the best choice for cerebral venous sinus thrombosis.
• Initial therapy usually consists of a heparin infusion (unfractionated or low molecular weight).
• After initial heparin, transition to direct factor Xa inhibitors (DOACs), thrombin inhibitors, or warfarin for long-term management.
• Warfarin may be preferred in anti-phospholipid syndrome due to better outcomes compared to DOACs.

Cardiac Events: Acute Coronary Syndrome (ACS)

• ACS includes unstable angina, NSTEMI, and STEMI.
• Initial treatment includes aspirin and a P2Y12 receptor blocker.
• A GP 2B 3A inhibitor can be added in very high-risk patients prior to PCI, but with caution due to increased bleeding risk.
• An anticoagulant (preferably unfractionated heparin) is added prior to and during PCI.
• Post-PCI, continue aspirin and a P2Y12 receptor blocker for 12 months, then downgrade to aspirin alone.
• If PCI is not available, thrombolytics (e.g., TPA) can be considered for STEMI within 12 hours of onset.

Cardiac Events: Atrial Fibrillation (Afib)

• Afib increases the risk of embolic phenomena due to inadequate atrial contraction and blood stasis, leading to thrombi formation.
• Anticoagulants are the preferred treatment to reduce clot formation in the left atrium and prevent embolization.
• Hospitalized patients are started on heparin initially, then transitioned to an oral anticoagulant.
• For valvular Afib (mitral stenosis or mechanical prosthetic valve), warfarin is the only option.
• For non-valvular Afib, either a DOAC or warfarin can be used.

Cardiac Events: Left Ventricular Thrombus

• Left ventricular thrombi can form after MI or in patients with reduced ejection fraction.
• Mechanical prosthetic valves are highly thrombogenic.
• Heparin is beneficial initially, followed by transition to a DOAC or warfarin.
• For mechanical prosthetic valves, transition to warfarin plus aspirin for thromboembolic complication reduction.

Pulmonary Embolism (PE)

• Thrombolytics are used in hemodynamically unstable patients.
• Anticoagulants are used in hemodynamically stable patients.
• Initial treatment is Heparin then switched to a DOAC or warfarin.

Atherosclerotic Cardiovascular Disease

• Use anti-platelets to prevent adverse events.
• Aspirin is number one choice.
• Add p2y12 if extra anti-platelet needed.
• Add solostazol for intermittent claudication symptoms.

Acute Limb Schemia

• Thrombolytics like catheter directed TPA are best to get ready for a bust.
• Heparin can be used temporarily to prevent further clot formation before interventions.

Deep Vein Thrombosis (DVT)

• Heavy clot -> catheter directed TPA should be considered
• Not heavy clot -> heparize to prevent clotting
• Switch to DOAC or warfarin.

Mesenteric Venous Thrombosis

• Treat venous clot with anticoagulants.
• Heparinize then switch to warfarin.

DVT/PE Risk Reduction

• High risk after an operation
• Give low dose heparin, may be unfractioned or low weight.
• OR anticoagulate for underlying disease.

Low dose treatment against clotting of certain devices

• Use Heparin in heart lung machines like ECMO
• Or with cardiopulmonary bypass.
• prefer unfractionated version
• For central venous cathethers that are clotted infuse a low dose of TPA.

Key Summary

• Antiplatelet and anticoagulants mainly block platelet plug.
• They inhibit clot formation and prevent propagation.
• They don't break down existing clots like thrombolytics do.
• Thrombolytics break fibrin to dissolve clots.

Aspirin Adverse Effects

• Peptic Ulcer Disease:
• Aspirin inhibits cyclooxygenase, reducing PGE2 production.
• Decreased PGE2 leads to reduced mucus production in the stomach lining.
• Without the protective mucus barrier, gastric acid can erode the stomach, leading to ulcers.
• Reye's Syndrome:
• Occurs in children under 19 with viral infections taking aspirin.
• Combination causes liver damage, impairing ammonia metabolism.
• Ammonia buildup damages the central nervous system, causing cerebral edema and seizures.
• Impaired lactic acid clearance leads to anion gap metabolic acidosis.
• Aspirin-Exacerbated Respiratory Disease (AERD):
• Aspirin shifts arachidonic acid metabolism towards leukotriene production.
• Increased leukotrienes cause inflammation, bronchospasm, and worsen nasal polyps/asthma.
• Aspirin Toxicity:
• Mild: Nausea, vomiting, tinnitus (ringing in the ears).
• Moderate to Severe:
• Anion gap metabolic acidosis due to increased lactic acid and ketone bodies.
• Respiratory alkalosis from stimulated respiratory drive.
• Non-cardiogenic pulmonary edema (damage to lung parenchyma).
• Altered mental status, confusion, and seizures.

P2Y12 Receptor Blockers adverse effects.

• High risk of thromotic thrombocytopenic purpura

Explore blood-thinning medications like anti-platelets, anticoagulants, and thrombolytics, which impact hemostasis, including platelet plug formation, coagulation cascade, and fibrinolytic mechanisms. Understand how endothelial cells, nitric oxide, and prostacyclin inhibit platelets, while damage leads to platelet activation and clot formation.