Chapter 39  ·  Module 2

Heparins and Indirect Thrombin Inhibitors

Mechanism, monitoring, heparin-induced thrombocytopenia, and reversal at a glance

Abbreviations: UFH = unfractionated heparin  ·  LMWH = low-molecular-weight heparin  ·  AT-III = antithrombin III  ·  HIT = heparin-induced thrombocytopenia  ·  aPTT = activated partial thromboplastin time  ·  CrCl = creatinine clearance  ·  DTI = direct thrombin inhibitor

Mechanism & Pharmacokinetics Comparison

Agent Anti-IIa : Anti-Xa Kinetics Monitoring Reversal
UFH 1:1 (equal) Nonlinear; saturable clearance aPTT 60–100 sec Protamine (complete)
LMWH 2:1 to 4:1 (anti-Xa predominant) Linear; renal clearance Anti-Xa if CrCl <30, obesity, pregnancy Protamine partial (~70–80%)
Fondaparinux Anti-Xa only Linear; 100% SC bioavailability Anti-Xa if indicated None (no reversal agent)

HIT — Pathophysiology, Diagnosis, and Management

Mechanism

How HIT Occurs

  • Heparin + platelet factor 4 forms neo-antigen
  • IgG antibodies generated within 5–14 days
  • IgG Fc cross-links platelet Fc receptor → platelet activation + thrombin burst
  • Result: thrombocytopenia WITH thrombosis

4T Score

Pretest Probability

  • Score 0–3: low (<1%); continue heparin
  • Score 4–5: intermediate; stop heparin, send assay
  • Score 6–8: high (>80%); stop all heparin NOW; start alternative anticoagulant empirically
  • ELISA: sensitive; SRA: gold standard functional test

Alternative Anticoagulants

Management

  • Stop ALL heparin (including flushes, coated catheters)
  • LMWH is NOT an alternative (90% cross-reactivity)
  • Argatroban: preferred if renal failure; hepatic metabolism
  • Bivalirudin: preferred if hepatic failure or cardiac surgery
  • Delay warfarin until platelets above 150 × 10&sup9;/L

Reversal Agents

UFH / LMWH Reversal

Protamine Sulfate

  • 1 mg neutralizes 100 units UFH from last 2–4 hours; max 50 mg
  • Give slowly (≥10 min): hypotension, bradycardia if too rapid
  • Partial LMWH reversal (~70–80% anti-Xa); no fondaparinux reversal
  • Anaphylaxis risk: fish allergy, prior protamine, NPH insulin use

Direct Factor Xa Inhibitor Reversal

Andexanet Alfa

  • Recombinant inactive factor Xa decoy; sequesters direct Xa inhibitors
  • Approved: rivaroxaban and apixaban life-threatening bleeding
  • Thrombotic events in ~10–15% post-reversal
  • No activity against fondaparinux (off-label use only)

HIT Management Rule — Act Before Lab Results

4T score 6 to 8 or strong clinical suspicion: stop ALL heparin immediately and start argatroban or bivalirudin empirically. Do not wait for laboratory confirmation. The thrombosis risk of continued heparin exposure outweighs the risk of alternative anticoagulation. Never substitute LMWH for UFH in suspected HIT.