15  Venous Thromboembolism & Antithrombotic Drugs

Key Points
  • VTE burden: 300K–600K US cases/yr; elderly ↑ risk; early dx & risk-stratified Rx essential
  • DVT vs PE: DVT in leg, PE in lungs; PE severity → Rx intensity & prognosis
  • Virchow’s triad: ↓ flow + vessel injury + hypercoagulability → thrombosis
  • Dx strategy: Low pretest prob + ↓ D-dimer = safe VTE exclusion (no imaging needed)
  • DOACs 1st-line: Preferred over VKA; rapid onset, no monitoring, ↓ interactions
  • Reversal: Idarucizumab (dabi), andexanet α (apix/riva), 4F-PCC available
  • Heparin: UFH needs aPTT monitoring; LMWH fixed dosing; protamine reverses both

15.1 Epidemiology & Presentation

  • Incidence: 3 per 1000 person-yrs (↑ to 2–7 in age >80)
  • Burden: 300K–600K US cases/yr; 10–15% untreated DVT → PE
  • Morbidity: Post-thrombotic syndrome (edema, pain, skin changes); post-PE (dyspnea, ↓ exercise)
  • Risk factors: Major surgery, hospitalization, estrogen, immobility, malignancy, thrombophilia, prior VTE

15.1.1 DVT Classification & Presentation

  • Proximal (popliteal/femoral/iliac): Requires immediate anticoagulation
  • Distal (calf): Serial imaging required
  • Sx: Leg swelling, pain, cyanosis (asymmetric)
  • Triggers: Surgery, hospitalization, malignancy ↑ hypercoagulability; immobility prolongs risk

15.1.2 PE: Severity Spectrum

  • Massive: RV failure + hemodynamic instability → ICU monitoring
  • Submassive: RV dysfunction (imaging) w/o hypotension → risk assessment needed
  • Low-risk: Normal RV + hemodynamically stable → outpatient anticoagulation OK
  • Dx modalities: CTPA (preferred, >95% sens), V/Q (if renal dz), CXR-U/S (DVT proxy), D-dimer (↓ prob exclude)

15.2 Pathophysiology: Virchow’s Triad

Coagulation: TF → thrombin → fibrin; reversed by Pc, Ps, AT; tPA/plasmin lyses clot

15.2.1 Three Factors (any 1 sufficient)

  1. Stasis (↓ flow)
    • Immobility, venous obstruction, heart failure → ↓ shear stress & anticoagulant dilution
  2. Vessel injury
    • Trauma, surgery, lines, smoking, malignancy, estrogen
  3. Hypercoagulability
    • Congenital: FVL, PT G20210A, ↓ AT/Pc/Ps
    • Acquired: Cancer, APS, pregnancy, inflammation

15.2.2 Risk Model

  • Hereditary baseline: Requires dual-hit (genetic + acquired) for thrombosis
  • Transient acquired: Surgery, hospitalization, estrogen → temp ↑ threshold
  • Chronic acquired: Cancer, thrombophilia → persist ↑ baseline
  • Additive: AT deficiency + surgery = extreme risk

15.3 Diagnosis

15.3.1 Pretest Probability & D-dimer

  • Wells Score (DVT) or Geneva/Hamilton (PE): Predicts imaging need
  • Low prob + ↓ D-dimer = safe VTE exclusion (no imaging)
  • D-dimer: Sens >95% if low prob; non-specific (↑ w/ inflammation, cancer, pregnancy)
  • Troponin/BNP ↑: Worse PE prognosis but don’t guide anticoagulation

15.3.2 Imaging

Modality Use
Compression U/S Proximal DVT (sens/spec >95%); limited in calf, obesity
CTPA PE preferred (>95% sens); rapid, alternative dx, RV size
V/Q PE if renal dz/contrast allergy; high prob = dx, low = may need CTPA
MRI DVT in pregnancy, contrast allergy; not 1st-line

15.3.3 Algorithms

Scenario Approach
Low prob D-dimer → negative = done
Intermediate + ↓ D-dimer No imaging
Intermediate + ↑ D-dimer CTPA or U/S
High prob CTPA or U/S (D-dimer irrelevant)
Renal dz (Cr >2) V/Q preferred
Pregnant Leg U/S (DVT) or PE protocol MRI

15.4 Acute Therapy

15.4.1 Goals

  • Acute: Prevent extension & mortality
  • Long-term: Prevent recurrence & ↓ bleeding
  • IVC filter: ↓ PE if anticoag contraindicated

15.4.2 DOACs (Direct Oral Anticoagulants) — 1st-line

Advantages: Rapid onset, no monitoring, ↓ interactions, fixed dosing, no bridging

Agents & Dosing

  • Apixaban: 10 mg BID ×7d → 5 mg BID (↓ if ≥2: age ≥60, wt ≤60, Cr ≥1.5)
  • Rivaroxaban: 15 mg BID ×21d → 20 mg QD w/ food (↓ if CrCl <30)
  • Edoxaban: 60 mg QD (↓ to 30 if CrCl <30 or wt ≤60)
  • Dabigatran: 150 mg BID after 5–10d parenteral lead-in

Monitoring: No labs needed; weight & renal function guide dosing; short half-life (8–17h)

15.4.3 Warfarin (VKA—if DOAC unavailable)

  • Target INR 2–3: Frequent monitoring & diet/drug interactions
  • Onset slow (3–7d); requires bridging w/ heparin until INR ≥2 ×24h

15.4.4 UFH (Unfractionated Heparin)

  • Short half-life (~60–90 min) → rapid reversal w/ protamine
  • Bolus: 80 units/kg IV
  • Infusion: 18 units/kg/hr; titrate aPTT to 1.5–2.5× baseline (60–85 sec)
  • Monitoring: aPTT ≥1.5× control; platelet count (HIT risk 0.5–3%)
  • Use: Renal failure, pregnancy, need for rapid reversal

15.4.5 LMWH (Low-Molecular-Weight Heparin)

  • Dosing: Fixed or weight-based (enoxaparin 1 mg/kg q12h or 1.5 mg/kg QD)
  • Properties: SQ once/twice daily, predictable kinetics, ↓ renal clearance
  • Renal: ↓ if CrCl <30 or switch to UFH
  • Pregnancy: Preferred over warfarin; ↓ transplacental transfer
  • Fondaparinux: Synthetic FXa inhibitor; selective, no monitoring

15.5 Reversal & Bleeding Management

15.5.1 DOAC Reversal

  • Idarucizumab (dabigatran): Monoclonal Ab, 2.5 g IV ×2 (total 5 g), immediate onset, >88% effective
  • Andexanet α (apix/riva): Recombinant FXa decoy, weight & drug-dependent dosing, expensive, limited availability
  • 4F-PCC: 25–50 units/kg if specific agent unavailable; off-label, less predictable

15.5.2 Heparin (UFH/LMWH) Reversal

  • Protamine: 1 mg per 100 units UFH/LMWH (max 50 mg), slow IV (anaphylaxis risk), neutralizes ~60% LMWH
  • FFP: 10–15 mL/kg; ↓ role, volume overload risk; rarely needed w/ protamine

15.5.3 Warfarin Reversal

  • Vit K: 2.5–10 mg IV/PO, onset 12–24h (slow), overdose → refractory hypercoag
  • 4F-PCC + Vit K 10 mg IV: Optimal for major bleeding (superior to FFP)

15.6 Duration of Anticoagulation

VTE Duration Guide
VTE Type Provoked Unprovoked Cancer Recurrent
Duration 3 mo ≥3 mo (extend if benefit >bleed risk) Throughout Rx ±3mo post-remission ≥3 mo (lifetime if ≥2 events)
Yr 1 recurrence <3% 5–10% 15–20% >20%
Extended benefit Minimal 40–50% ↓ recurrence Substantial Clear

15.6.1 Decision Points

  • Provoked (surgery/immobility): 3 mo → low recurrence
  • Unprovoked: ≥3 mo minimum; extend if bleeding risk acceptable
  • Cancer: Until treatment ends ±3 mo post-remission
  • Recurrent: ≥3 mo if 2nd unprovoked; lifetime if ≥2 events or thrombophilia
  • AT/Pc/Ps deficiency: Indefinite after 1st VTE
  • D-dimer guided: ↑ (>500 ng/mL on Rx) predicts ↑ recurrence; may favor extended Rx

15.7 Special Populations

15.7.1 Pregnancy & Postpartum

  • DOACs: Avoid (↓ data on teratogenicity)
  • LMWH: 1st-line (minimal transplacental transfer)
  • UFH: Alt if LMWH unavailable (short half-life → rapid reversal if delivery)
  • Warfarin: Avoid 1st & 3rd trimester (fetal syndrome: nasal hypoplasia, bone abn)
  • Postpartum: Continue ≥6 wk minimum; avoid estrogen-containing contraceptives if prior VTE (unless anticoag planned)

15.7.2 Cancer-Associated VTE

  • Risk: Pancreatic, lung, ovarian, gastric cancers; central lines, chemo, surgery, tumor stasis
  • Rx: DOACs preferred if no active chemo; continue throughout treatment ±3 mo post-remission
  • Recurrent on Rx: Consider IVC filter, switch anticoagulant
  • Monitoring: Serial D-dimer may guide extended duration

15.7.3 Renal Dysfunction (↓ CrCl)

Agent Adjustment
Apixaban No change if CrCl ≥30; ↓ to 2.5 mg BID if ≥2 criteria
Dabigatran ↓ to 110 mg BID if CrCl <30
Rivaroxaban ↓ to 15 mg QD if CrCl <30
Edoxaban ↓ to 30 mg QD if CrCl <30
LMWH Accumulates if CrCl <30 → UFH preferred
UFH Safe, no renal clearance; needs aPTT monitoring

15.7.4 Thrombophilia

  • FVL/PT G20210A heterozygous: Provoked → 3 mo; unprovoked → extend
  • FVL/PT G20210A homozygous, ↓ AT/Pc/Ps: Indefinite after 1st VTE
  • APS: ↑↑ recurrence (>10%/yr); indefinite after 1st VTE
  • Combined defects: Cumulative risk → extended or indefinite Rx

15.8 Prophylaxis

15.8.1 Hospitalized Patients

  • Major surgery (orthopedic, cancer): LMWH or UFH QD ×7–14d postop
  • Medical admission w/ immobility: Mechanical (SCDs) + LMWH if bleed risk low
  • ICU: LMWH preferred; UFH if renal failure or HIT risk

15.8.2 Ambulatory Cancer

  • High-risk chemo: LMWH ×4–6 wk
  • Central lines: Warfarin 1 mg QD or LMWH reduces line thrombosis

15.8.3 Post-Discharge Extended

  • Hip/knee replacement: 10–35d post-discharge
  • Cancer surgery (abd/pelvis): 7–14d standard; extend 4 wk if high-risk

15.8.4 Mechanical

  • SCDs: 1st-line if anticoag contraindicated
  • Compression stockings: ↓ evidence; adjunct
  • Early mobilization: Reduces VTE risk

15.9 IVC Filters

15.9.1 Indications

  • Absolute: VTE + anticoag contraindicated (active bleed, severe thrombocytopenia, CNS bleed)
  • Relative: Proximal DVT/PE w/ poor cardiopulmonary reserve; recurrent VTE on Rx; cancer-associated high embolic risk

15.9.2 Complications

  • IVC thrombosis: ~25% w/ filter → IVC syndrome
  • Perforation: Rare (<1%); migration into RV reported
  • Recurrent VTE: ~5–10% PE despite filter (collateral vessels); anticoag still essential
  • MAHA: Rare; IVC syndrome w/ edema

15.9.3 Timing

  • Temporary filters: Removable if contraindication temporary
  • Duration: Remove when anticoag safe (typically 2–4 wk)
  • Permanent: Reserve for lifelong anticoag contraindication

15.10 Pearls

Tip

PE Severity → Intensity: Massive (hemodynamically unstable) → ICU, consider thrombolysis, mechanical support. Submassive (RV dys w/o hypotension) → close monitoring; thrombolysis controversial. Low-risk (normal RV) → outpatient anticoag OK.

DOAC Dosing: Weight & renal function (not INR/aPTT) guide dosing. Mismatched dosing (e.g., full-dose apix in 55-kg or edox in CrCl <15) ↑ bleeding w/o benefit. Verify weight & CrCl pre-Rx.

Reversal Available: Idarucizumab (dabi) ~88% effective; andexanet α (apix/riva) effective but $$; 4F-PCC off-label backup; protamine rapidly reverses UFH/LMWH.

15.11 Bibliography

Shatzel JJ, Connelly JM. Pocket Hematology Quick Reference. ASH Self-Assessment Program 9e; 2025.

American Society of Hematology. Introduction to Venous Thromboembolism & Antithrombotic Drugs. Chapter 15 in ASH Self-Assessment Program 9e; 2025. Pages 176-188.