Blood Thinners and Hemostasis Quiz

Blood Thinners and Anticoagulants

• Not all blood thinners are anticoagulants.
• Three primary ways of thinning blood:
  • Anti-platelets: Destroy the activity of platelets.
  • Anti-coagulants: Inhibit the coagulation factors involved in clot formation.
  • Thrombolytics: Break down existing clots.

Hemostasis

• The process of stopping bleeding, primarily in response to injury.
• Involves a complex interplay of the vascular system, platelets, and blood proteins/factors.
• Hemostasis prevents and stops bleeding, or hemorrhaging.
• After bleeding stops, the clot is removed through fibrinolysis.
• Crucial for maintaining blood volume and pressure.
• Deficiencies or disorders in hemostasis lead to bleeding disorders or thrombosis (excessive clotting).

Thrombotic Thrombocytopenic Purpura (TTP)

• A disorder characterized by excessive clotting, which consumes platelets.
• Caused by a deficiency in the enzyme ADAMTS13.
• ADAMTS13 controls blood clot formation.
• Without enough ADAMTS13, the body produces too many clots.

Primary Hemostasis: Temporary Clot Formation

• Involves vasoconstriction to reduce blood flow.
• Platelets adhere to exposed subendothelial collagen via glycoprotein Ib (GpIb) binding to von Willebrand factor (vWF).
• Adhered platelets become activated, changing shape and releasing substances (ADP, thromboxane A2, and serotonin) that attract more platelets.
• Platelet aggregation occurs, forming a temporary "plug" at the injury site.

Secondary Hemostasis: Stable Clot Formation

• Involves the coagulation cascade, leading to the formation of a stable fibrin clot.
• Inactive clotting factors, produced in the liver, are activated in a cascade fashion at the injury site.
• The coagulation cascade has two pathways:
  • Intrinsic pathway: Initiated by damage to the blood vessel itself, involving factors XII, XI, IX, and VIII.
  • Extrinsic pathway: Initiated by tissue factor (TF) released from damaged tissue, involving Factor VII and Factor X.
• Both pathways converge into the common pathway, culminating in the conversion of prothrombin (Factor II) to thrombin (Factor IIa).
• Thrombin converts fibrinogen (Factor I) into fibrin (Factor Ia), forming a mesh that strengthens the platelet plug.

Tertiary Hemostasis: Clot Dissolution

• The process of dissolving the fibrin clot as the vessel heals.
• Dependent on plasminogen activation.
• Key components include: plasminogen, plasminogen activators, plasmin, fibrin, fibrin degradation products (FDP), and inhibitors of plasminogen activators & plasmin.

Activators of Fibrinolysis

• Intrinsic activators: Factor XIIa, XIa, kallikrein.
• Extrinsic activators: Tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA).
• Exogenous activators: Streptokinase (derived from beta strep bacteria).

Antiplatelets

• Used both prophylactically and acutely to inhibit platelet activation and aggregation.
• Main classes:
  • Cyclooxygenase (COX-1) inhibitors:
    • Acetylsalicylic acid (aspirin) is the prototype and only COX-1 inhibitor used.
    • MOA: Irreversibly blocks COX-1 activity by acetylating the enzyme.
    • Prevents the conversion of arachidonic acid to TXA2 in platelets, blocking platelet aggregation and vasoconstriction.
    • Platelet-induced TXA2 synthesis is blocked for the lifespan of the platelet (7-10 days).
    • COX-1 inhibition also prevents the formation of PGI2 in vascular endothelium, leading to a net reduction of platelet aggregation.
  • Dipyridamole/ASA combination (Aggrenox):
    • Approved for stroke reduction in patients with TIA or history of thrombotic stroke.
  • Cilostazol (Pletal):
    • Quinolinone derivative used for peripheral artery disease (PAD).
    • MOA: Inhibits phosphodiesterase III, leading to increased cAMP levels, which causes vasodilation and inhibits platelet aggregation.
    • Clinical use: Reduces the symptoms of intermittent claudication.

Adverse Effects of Aspirin

• Dose-dependent adverse effects due to PGE2 and TX inhibition.
• GI effects: Abdominal pain, heartburn, nausea, ulcers, and bleeding.
• Bleeding: Potential for excessive bleeding, particularly during surgeries or procedures.
• Renal dysfunction: Progressive dysfunction with chronic use due to vasoconstriction of renal arteries.
• Asthma exacerbation: Increased leukotriene synthesis and risk of bronchospasms.
• Other adverse effects: Tinnitus, headache, dizziness, confusion, vision changes, metabolic acidosis, hypersensitivity reactions, Reye’s syndrome.
• Contraindications: Avoid in children under 16 with viral infections (risk of Reye’s syndrome).
• Interactions: Patients on theophylline require higher doses of dipyridamole during stress testing.

Ticagrelor

• Ticagrelor is a reversible ADP receptor antagonist, meaning it inhibits platelet aggregation.
• Ticagrelor's effect on platelet aggregation takes 24-48 hours to develop, but loading doses can be used to accelerate this process.
• Different dosages and durations of Ticagrelor result in different times to reach maximum platelet inhibition.
  • 75mg PO QD takes 7 days for maximal effect
  • 300mg PO X1 before PCI takes 6-10 hours for maximal effect.
  • 600mg PO X1 before PCI takes 2 hours for maximal effect.
• Ticagrelor's maintenance dose is 75mg PO QD.
• Ticagrelor can cause GI upset, diarrhea, and rash.
• Ticagrelor's effectiveness can be decreased by CYP2C19 inhibitors.
• Ticagrelor is contraindicated in cases of known hypersensitivity and active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Prasugrel

• Prasugrel is an irreversible ADP receptor antagonist.
• The FDA indicates Prasugrel reduces the rate of thrombotic cardiovascular events in patients with unstable angina, non-ST-segment elevation MI, or ST-elevation MI managed with percutaneous coronary intervention (PCI).
• Prasugrel's loading dose is 60mg, and its maintenance dose is 10mg in combination with aspirin.
• Prasugrel's adverse effects are similar to other ADP antagonists, but it carries a higher risk of bleeding in certain patient populations.
• Prasugrel is contraindicated in cases of peptic ulcer disease, intracranial hemorrhage, TIA, or Stroke.

Ticagrelor

• Ticagrelor is a highly effective and preferred medication for patients with ACS, including patients with ST-elevation myocardial infarction (STEMI), patients who are candidates for PCI, and patients who are unstable and not candidates for PCI.
• Ticagrelor's FDA indication is to reduce the risk of CV death, MI, stroke, and stent thrombosis in patients with ACS in combination with aspirin.
• Ticagrelor's loading dose is 180mg, and its maintenance dose is 90mg BID in combination with aspirin 81mg/day.
• Using higher doses of aspirin will reduce Ticagrelor's effectiveness.
• Ticagrelor should be avoided in patients taking strong CYP3A4 inhibitors.
• Ticagrelor's most common adverse effect is bleeding.
• Other adverse effects of Ticagrelor include bradycardia, dyspnea, and gynecomastia in men.
• Ticagrelor is contraindicated in cases of peptic ulcer disease, intracranial hemorrhage, and severe hepatic impairment.

GPIIb/IIIa Receptor inhibitors

• These agents include Tirofiban (Aggrastat) and Eptifibatide (Integrilin); they inhibit platelet aggregation by antagonizing the GPIIb/IIIa receptor.
• These agents have potent antithrombotic effects and have been shown to decrease mortality and reinfarction.
• GPIIb/IIIa receptor inhibitors are indicated for use in acute coronary syndromes, including patients managed medically, those undergoing PCI.
• Integrilin has broader indications compared to Aggrastat, including elective, urgent, or emergency PCI.
• Aggrastat is used in combination with aspirin and heparin.
• Integrilin is used in combination with aspirin and heparin.
• Both Aggrastat and Integrilin have a high incidence of bleeding and thrombocytopenia.

Abciximab (Reopro)

• Abciximab binds to the GPIIb/IIIa receptor, inhibiting platelet aggregation.
• Abciximab is indicated to prevent acute cardiac ischemic complications and abrupt closure of the treated coronary vessel during percutaneous transluminal angioplasty (PCTA).
• Abciximab can be used in patients with UA/NSTEMI not responding to medical therapy when PCI is planned within 24 hours.
• Abciximab use in patients with UA/NSTEMI not undergoing PCI shows no significant benefit.
• Abciximab is a low margin of safety drug due to its long half-life, which affects platelet function for 12-24 hours after infusion.
• Abciximab is used in combination with aspirin and heparin.
• Abciximab’s usual dose is 0.25mg/kg via IV bolus.