ANTITHROMBOTIC

• Thrombosis


  Pathologic development of blood clots in veins or arteries that obstruct flow and cause tissue ischemia and necrosis
• Antithrombotic drugs


  • Anticoagulants
  • Antiplatelet drugs
  • Fibrinolytics
• Antithrombotic drugs have been employed to prevent and treat thrombosis since intravenous heparin was first described in 1914
• Antithrombotic drugs before 2010

  • Heparin
  • Coumadin
  • Aspirin
  • Heparin derivatives
  • Antiplatelet drugs
• Antithrombotic drugs


  • Original drugs
  • Drugs that entered clinical use in the 1990s
  • Newest drugs (direct-acting oral and intravenous anticoagulants)
• Venous thromboembolic disease (VTE)


  • Superficial vein thrombosis
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
• Anticoagulants used to treat VTE

  • Intravenous standard unfractionated heparin (UFH)
  • Subcutaneous low-molecular-weight heparin (LMWH)
  • Subcutaneous synthetic pentasaccharide (fondaparinux)
  • Oral vitamin K antagonist warfarin sodium (Coumadin)
  • Direct-acting oral anticoagulants (DOACs)
• Anticoagulants used prophylactically


  • To prevent strokes in non-valvular atrial fibrillation
  • To prevent VTE after total hip and total knee replacement surgery, orthopedic repair surgery, immobilization, and in several medical conditions
• Intravenous direct thrombin inhibitors (DTIs)

  • Argatroban
  • Bivalirudin
• Arterial thrombosis


  • Acute myocardial infarction (AMI)
  • Ischemic cerebrovascular accident (CVA, stroke)
  • Transient ischemic attack (TIA)
  • Peripheral arterial occlusion (PAO or peripheral artery disease, PAD)
• Drugs used to manage arterial thrombosis

  • UFH
  • LMWH
  • Fondaparinux
  • Coumadin
  • Antiplatelet drugs (aspirin, clopidogrel, prasugrel, ticagrelor)
  • Intravenous platelet glycoprotein IIb/IIIa inhibitor (GPI) drugs (eptifibatide, abciximab, tirofiban)
• Fibrinolytics or thrombolytic therapy


  • Recombinant forms of tissue plasminogen activator (reteplase, alteplase, tenecteplase)
• Thrombolytic therapy raises the risk of hemorrhage, particularly intracranial hemorrhage
• Antithrombotic therapy is dangerous because their effective dosage ranges are narrow
• Overdose of antithrombotic drugs is critical and leads to emergency department visits for uncontrolled bleeding; inadequate dosages lead to secondary (repeat), often fatal, thrombotic events
• Laboratory monitoring or measurement of anticoagulant therapy is essential
• Coagulation laboratory tests used to measure or monitor anticoagulant therapy

  • Prothrombin time (PT) assays
  • Partial thromboplastin time (PTT, activated partial thromboplastin time, APTT)
  • Chromogenic anti-Xa heparin assays
• Antiplatelet drugs and all antithrombotics require measurement in certain clinical conditions
• Coumadin


  A vitamin K antagonist that suppresses y-carboxylation of glutamic acid by slowing the activity of the enzyme vitamin K epoxide reductase
• Proteins induced by vitamin K antagonists (PIVKA)

  Nonfunctional des-carboxyl proteins that bind few calcium ions, do not assemble on phospholipid surfaces with their substrates, and therefore do not participate in coagulation
• Coumadin therapy


  • Goal is to reduce but not eradicate thrombin generation
  • Prescribed prophylactically to prevent TIAs and strokes in patients with nonvalvular atrial fibrillation, and to prevent VTE after trauma, orthopedic surgery, and general surgery and in a number of chronic medical conditions
  • Prescribed therapeutically to prevent DVT or PE recurrence, after an AMI if the event is complicated by congestive heart failure or coronary insufficiency, and to control clotting in patients with mechanical heart valves
• Coumadin starting dosage


  • 5 mg daily oral dose
  • 2 mg/day for people older than 70, debilitated, malnourished, or with congestive heart failure
  • 2 mg/day for people simultaneously taking drugs that are known to raise Coumadin sensitivity, and for those with inherited Coumadin sensitivity
• Anticoagulant effect of Coumadin at initiation of therapy

  1. Factor VII activity decreases to 50% of normal 6 hours after Coumadin therapy is begun

  2. Factor II (prothrombin), IX, and X activities require at least 3 days to decline by 50%

  3. Patient gains full anticoagulation effects approximately 5 days after the start of Coumadin therapy
• Functional properties of the coagulation factors

  • Fibrinogen (half-life 4 days, plasma level 280 mg/dL, hemostatic level 50 mg/dL)
  • Prothrombin (half-life 60 hr, plasma level 1300 μg/mL, hemostatic level 20%)
  • Factor X (half-life 30 hr, plasma level 1 mg/dL, hemostatic level 25%)
  • Factor IX (half-life 24 hr, plasma level 5 μg/mL, hemostatic level 30%)
  • Factor VII (half-life 6 hr, plasma level 120 μg/mL, hemostatic level 20%)
  • Factor V (half-life 16 hr, plasma level 680 μg/mL, hemostatic level 25%)
  • Factor VIII (half-life 12 hr, plasma level 0.24 μg/mL, hemostatic level 30%)
  • Factor XI (half-life 2-3 days, plasma level 6 μg/mL, hemostatic level 50%)
  • Factor XIII (half-life 7-10 days, plasma level 30 μg/mL, hemostatic level 2%-3%)
  • Von Willebrand factor (half-life 12 hr, plasma level 290 μg/mL)
• For the first 2 or 3 days of Coumadin therapy the patient actually incurs the risk of thrombosis, so Coumadin therapy is "covered" by UFH, LMWH, or fondaparinux
• Coumadin dosage


  2 mg/day for those with inherited Coumadin sensitivity
• There is no loading dose for Coumadin, and subsequent dosing is based on patient response as measured by the PT/INR
• Decline of vitamin K-dependent coagulation factors on Coumadin

  1. Begins immediately but at different rates

  2. Takes about 5 days for all the factors to reach therapeutic levels
• Plasma half-life, plasma concentration, and minimum effective percentage of normal factor activity for the coagulation factors


  • Listed in Table 40.2
• For the first 2 or 3 days of Coumadin therapy


  The patient actually incurs the risk of thrombosis
• Coumadin therapy is "covered" by UFH, LMWH, or fondaparinux therapy for up to 5 days to prevent Coumadin-induced skin necrosis
• Coumadin is contraindicated during pregnancy because it causes birth defects
• When anticoagulation is desired during pregnancy, LMWH or fondaparinux is prescribed
• PT


  Effectively monitors Coumadin therapy because it is sensitive to reductions of factors II, VII, and X
• Monitoring Coumadin therapy with PT/INR

  1. First specimen collected 24 hours after initiation

  2. Subsequent PTs performed daily until at least two consecutive results are within target range

  3. Monitoring continues every 4 to 6 weeks until completion of therapy

  4. More frequent monitoring if there is a dose change, another medication is started/stopped, or the patient's medical condition changes
• INR


  International normalized ratio used to report PT results and accomplish interlaboratory normalization
• The INR has been validated only for use with Coumadin monitoring
• Coumadin INR therapeutic range

  2 to 3, or 2.5 to 3.5 if the patient has a mechanical heart valve
• INRs greater than 5 are associated with increased risk of hemorrhage
• Chromogenic Factor X Assay

  An alternative to the PT/INR system, eliminating the necessity for normalization of test results using the INR