Inpatient Anticoagulation

Direct and indirect anticoagulants utilized in the inpatient setting

  • Indirect anticoagulants  (heparin, LMWHs, & fondaparinux–factor Xa inhibitor):
    • Activity is mediated by plasma cofactors
    • Activate antithrombin (AT–endogenous inhibitor of various clotting factors)
  • Direct anticoagulants (bivalirudin, hirudins, & argatroban)
    • DON’T require plasma cofactors for activity
    • Directly target thrombin

Pharmacodynamic and pharmacokinetic properties of each agent

  • UFH (unfractionated heparin)–derived from either cow lung or pig intestine
    • Heparin causes a conformational change in antithrombin    (UFH binds to both factor Xa & thrombin)
    • Inactivates:  Thrombin (Factor IIa), factors: Xa, IXa, XIa, XIIa
      • Activity at factor-Xa = activity at factor IIa      (Xa:IIa –> 1:1)
    • Administration:
      • Need to monitor activated partial thromboplastin time (aPTT)
        • Initially measured every 6 hours
        • Therapeutic range of aPTT = 0.3-0.7 U/mL of anti-factor Xa  (1.5-2.5x control)
        • Know how to adjust dose for patients with renal dysfunction
      • Adverse effects:
        • Hemorrhagic complication, skin reactions (necrosis), can cause HIT (heparin induced thrombocytopenia–IgG mediated), causes bone metabolism, hypoaldosteronism (HYPERkalemia), elevation of serum transaminases
      • Treatment:  continuous IV
        • Weight-based dosing
          • High doses used for the treatment of DVT/PE
          • Low doses used for the treatment of Ischemic Heart Disease
        • Rapidly achieves anticoagulation, decreases the risk of thromboembolic reoccurrences, improves clinical outcomes
        • Heparin (UFH) dosing:
          • Venous Thromboembolism (VTE)
            • Bolus:  80 units/kg (max:  10,000 units)
            • Infusion:  18 units/kg/hr (max:  2,300 units/hr)
          • Acute Coronary syndrome (ACS)
            • Bolus:  60-70 units/kg (max: 5,000 units)
            • Infusion:  12-15 units/kg/hr (max: 1,000 units/hr)
          • Heparin with fibrinolytic agents
            • Bolus:  60 units/kg (max:  4,000 units)
            • Infusion:  12 units/kg/hr (max:  1,000 units/hr)
      • Prophylaxis:  subcutaneous injection
        • 5,000 units q 8-12 hours
    • Once in the bloodstream heparin binds to a number of plasma proteins, endothelial cells & macrophages thus reducing it’s anticoagulant activity
    • Reversing the anticogulant effects of Heparin:
      • 1 mg of Protamine sulfate neutralizes ~100 units of heparin
        • Must account for the last 2-3 hours worth of heparin when determining how much protamine to administer
      • Watch out for an anaphylactic reaction to protamine in patients who’ve received a protamine-containing insulin, undergone a vasectomy or have an allergy to fish   (if these contraindications are present pretreat the patient with corticosteroids & antihistamines)
  • LMWHs
    • Are derived from depolymerized versions of UFH  (1/3rd the size of UFH)
      • Depending on whether chemical or enzymatic depolymerization was used will determine pharmacokinetic & anticoagulant profile
    • Unlike heparin, LMWH is unable to simultaneously bind to thrombin & AT.
      • LMWH only binds to AT
    • LMWH have greater activity at factor Xa than factor Iia
      • Xa:IIa –>  3-4 : 1    (heparin = 1:1)
    • LMWH’s have reduced binding to proteins & cells w/in vasculature in comparison to UFH (pharmacokinetic advantages)
      • 90% bioavailable after SQ admin, longer plasma half-life (3-5 hours), dosed QD-BID
    • LMWH’s are eliminated through the kidney (bad for people with renal dysfunction, use UFH instead)
    • Also activates platelets, but has a Reduced incidence of HIT in comparison to UFH
      • Adverse SE although less common than with heparin include hemorrhagic complications, skin necrosis, 70-100% cross sensitivity with HIT (don’t use in ppl with a history of HIT) & bone metabolism when used longer than 1 month
    • Lab monitoring not usually warranted (but some places recommend anti-factor Xa levels in obese, renal issues, prego, very skinny)
      • Anti-factor Xa levels are drawn 4-6 hours after admin of LMWHs
    • Enoxaparin (Lovenox)
      • Prevention:
        • Normal kidney function:  40 mg SQ daily     (knee-replacement = 30 mg SQ BID)
        • Renal impairment (CrCl < 30 mL/min) :  30 mg DQ daily
      • Treatment:
        • Normal kidney function:  1 mg/kg SQ q 12h
        • Renal impairment (CrCl < 30 mL/min) :  1 mg/kg SQ q 24h

Dalteparin  (renally eliminated)

Prevention:  5,000 units SQ daily
Treatment:

  • VTE in Cancer Patients:  know that the dose given SQ is greater in the 1st month of treatment vs. months 2-6
  • Normal kidney function:  120 units/kg SQ q 12 hours + ASA
  • Renal impairment (CrCl < 30 mL/min):  check anti-factor Xa levels

Tinzaparin   (don’t need to know doses, just know it’s renally eliminated)

  • Treatment:
    • Normal kidney function:  175 units/kg SQ q 24 hours
    • Renal impairment (CrCl < 30 mL/min):  check anti-factor Xa levels

Reversing LMWH anticoag effects:

  • Protamine sulfate
    • If within 8 hours:
      • 1mg Protamine sulfate per 1 mg enoxaparin (100 anti-Xa units) followed by 0.5 mg per 1 mg LMWH if bleeding continues
    • If LMWH was given more than 8 hours ago give smaller doses of protamine sulfate

Fondaparinux (antifactor Xa inhibitor)

  • Binds to anti-thrombin (AT) & enhances AT’s reactivity with Xa
  • It doesn’t however increase the rate of thombin inhibition by AT
  • Don’t need to routinely monitor the patient’s antifactor Xa levels normally
  • Admin SQ QD  (takes 3-4 doses to reach steady state: half-life = 17-21 hours)
  • NO cross sensitivity for HIT
  • DON’T use in prego (use LMWH)
  • Eliminated through kidneys & has minimal plasma protein binding outside of AT  (rapidly & completely absorbed)
    • Contraindicated in patients w/ CrCl < 30 mL/min   (not contraindicated however in patients < 50 kg)
  • Administration:
    • Prophylaxis:  2.5 mg SQ QD
    • Treatment:
      • 5 mg (BW < 50 kg)
      • 7.5 mg (BW: 50-100 kg)
      • 10 mg (BW > 100 kg)
  • Can NOT use protamine sulfate to reverse excessive coagulation effects

Direct anticoagulants
Hirudins

  • Lepirudin (refludin)
    • Directly binds irreversibly to thrombin   (inhibits both circulating & clot bound thrombin)
    • Can be used for treatment of HIT (doesn’t induce immune-mediated thrombocytopenia)
    • Need to monitor aPTT (should be 1/5 to 3 times control)
    • Short half-life, eliminated through the kidneys (reduce dose if CrCl < 60 mL/min; not recommended if CrCl < 30 mL/min)
    • Adverse effects:
      • Antibodies form in up to 40% of patients using Lepirudin
        • Anaphylactic reactions are common in previously exposed patients
      • Long half life results in drug accumulation
      • Expensive & have a high incidence of bleeding
  • Bivalirudin (angiomax)
    • Directly binds reversibly to thrombin (provides transient antithrombotic activity)
    • Short half-life (renally eliminated, so dose adjustment is needed for patients with CrCl < 30 mL/min
    • Uses:  percutaneous  (PCI & PTCA), only approved agent for patients with HIT undergoing PCI
    • Non-immunogenic effects, less bleeding due to shorter half-life
  • Argatroban
    • Binds reversibly & non-covalently to thrombin
    • Metabolized by CYP 3A4 & CYP 3A5  (Liver—all other meds are metabolized via kidneys)
    • Most commonly used direct anticoagulant
    • Uses: HIT
    • Administration
      • Normal kidney function:  2 mcg/kg/min
      • HF/multi-organ system failure:  0.5-1.2 mcg/kg/min
    • Monitoring:
      • Increases INR
      • Need to dose adjust to maintain aPTT ratio of 1.5-3x baseline
      • Child-pugh score (liver disease) b/c dose adjustment may be needed based on severity of liver disease

Risk factors, presentation, and treatment options for Heparin-Induced-Thrombocytopenia (HIT)
IgG (antibody) mediated prothrombotic condition

  • Heparin binding to PF-4 makes a highly antigenic polysaccharide molecule that activate platelets intravascularly leading to thrombin generation

Usually associated with the use of UFH
Strongly related to venous thrombosis & arterial thrombosis
HIT is typically seen 5-14 days after beginning heparin therapy
Treatment:  discontinue all sources of heparin immediately & initiate an alternative anticoag therapy (argatroban, bivalirudin, or lepirudin)

Heparin-Induced Thrbocytopenia (HIT) Risk Factors

  • Source:  Bovine UFH > Procine (pig) UFH > LMWH
  • Gender:  Female > Male
  • Patient Groups:  Postsurgical > Medical > Pregnancy
  • Dose:  Therapeutic > prophylaxis > flushes (line)
  • Treatment exposure:  14 days > 7 days > 1 day

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