- CVT, splanchnic VT, portal VT → atypical VTE sites
- May-Thurner syndrome: LIliac artery compresses L iliac vein → DVT (high autopsy prevalence 26-36%)
- PTS: develops 1-2y post-DVT w/ venous insufficiency; compression stockings provide symptom relief
- CTEPH: <1% acute PE → chronic PH (mPAP >25 mmHg at rest); persistent dyspnea warrants screening
- Superficial thrombophlebitis: lower extremity veins, typically resolves w/o anticoagulation
- Anticoagulation duration: balance recurrence risk, risk factors, individual circumstances
Cerebral Venous Thrombosis (CVT)
- Atypical VTE sites: CVT, retinal VT, splanchnic/mesenteric VT
- IVC filters: retrieve, remove ASAP; resume anticoagulation once bleeding risk permits
- Patho: hypercoagulable state, infection, trauma, thrombophilia
May-Thurner Syndrome & Venous Stenosis
May-Thurner Syndrome
- Def: L common iliac artery compresses L common iliac vein
- Prevalence: 26-36% autopsy (often asymptomatic)
- Risk: L-femoral/iliac DVT w/ anatomic compression
- Mx: Consider balloon angioplasty & stenting post-thrombolysis
- Evidence lacking for ↓ recurrent VTE or PTS
- Venous stents: Also used for CDT, severe PTS (pelvic/arm stenosis)
Postthrombotic Syndrome (PTS)
Clinical Features
- Timing: 1-2y post-DVT
- Sx: Extremity swelling, pain, heaviness
- Skin changes: erythema, pruritus, pigmentation
- Severe: ulceration, varicosities
Risk Factors for Extended Anticoagulation
- Recurrent VTE hx
- Elevated D-dimer at 3-6mo on AC
- Proximal DVT (vs distal)
- Advanced age
- Active cancer, IBD
- Inadequate INR control
Factors for Limited Duration
- Female sex
- Distal/superficial VTE only
- ↓ bleeding risk
- Patient preference
Management
- Compression stockings: If symptomatic relief (IPC not established)
- Anticoagulation: Duration per individual risk-recurrence balance
- Aspirin therapy: Advocate per Kahn-DOTT study (limited evidence)
Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
- Incidence: ~1% acute PE at 6mo
- Def: VTE → ↑ mPAP >25 mmHg
- Sx: Persistent dyspnea post-PE → screen for PH
- Dx: Right-heart cath (mPAP measurement), pulmonary angiography
- Assess for pulmonary endarterectomy candidacy (specialized centers)
- Mx: Long-term AC if surgery not feasible; PH pharmacotherapy @ specialized centers
Primary Prevention of VTE Prophylaxis
- Standard: All hospitalized patients → risk-stratified VTE prophylaxis
- Agents: Fondaparinux once daily (2.5 mg THA), rivaroxaban, LMWH
- Dosing: Once-twice daily per protocol
- Mechan. vs. chem.: THA/TKR/hip fx → mechanical superior to chemical alone
- Duration: Hospitalization ± extended (5 wk post-d/c for hi-risk)
- Hip fx, THA, TKR, major abd surgery → post-d/c proven effective
Superficial Thrombophlebitis
| Location |
Peroneal, posterior tibial, saphenous (legs); antecubital, basilic, cephalic (arms) |
| RF |
Varicose veins, IV catheters, phlebotomy, sepsis |
| AC |
Not routine unless extended thrombosis; monitor DVT progression |
| Prognosis |
Resolves w/o AC; “frozen arm”/migratory thrombophlebitis variant |
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Unusual VTE Sites
CVT, retinal VT, splanchnic VT → covered in this chapter
Antithrombotic Drugs
Heparins
Unfractionated Heparin (UFH)
- MOA: Binds antithrombin III → ↑ AT3 inhibition of IIa, Xa
- Route: IV continuous infusion @ therapeutic doses
- Monitoring: aPTT (lab-dependent range; consult lab)
- Metabolism: Endothelial cells; dose ↓ if GFR <30 (vs LMWH)
- Anti-Xa levels: 1.0-2.0 U/mL (once-daily), 0.6-1.2 U/mL (twice-daily)
- Reversal: Protamine IV (binds/neutralizes UFH)
- Caution: ↓ platelet function, own anticoagulant effect (limit dose)
- Risk: Fish sperm allergy → anaphylaxis, rapid infusion → vasodilation/hypotension
- Fresh frozen plasma: minimal effect
Low-Molecular-Weight Heparin (LMWH)
- MOA: Similar to UFH; ↑ anti-Xa >>anti-IIa ratio
- Dosing: Weight-based SC once-twice daily
- Monitoring: Anti-Xa peak levels if needed (renal impairment, obesity, extremes wt)
- Reversal: Protamine (partial only); consider for severe bleeding
Fondaparinux
- MOA: Selective Factor Xa inhibitor (no IIa activity)
- Route: SC; peak 2h, t½ ~17h → once-daily dosing
- Clearance: Renal; ⚠ CrCl <30 mL/min
- Advantage: No HIT risk
- Reversal: No specific antidote; no protamine effect
- Fresh frozen plasma likely ineffective
Vitamin K Antagonists (VKAs)
Mechanism
- Target: Vitamin K-dependent factors (II, VII, IX, X, C, S)
- Sites: Hepatic synthesis w/ post-translational carboxylation
- Timing: 3-5d to full effect (delayed until factors cleared)
- Early: ↓ Protein C (short t½) → transient hypercoagulable state
- Monitoring: INR (International Normalized Ratio)
Available VKAs
- US: Warfarin only (FDA-approved 1957)
- International: Phenprocoumon, acenocoumarol
- Warfarin: t½ 1-2.5d (mean 2.5d)
Dosing
- Loading: 5 mg daily × 2d (in-hospital), then adjust per INR
- Maintenance: Variable (3.1-6.4 mg/d median range); some require 20-30 mg/d
- Populations: Lower doses (liver disease, intestinal resection, women >70y)
- Genetic testing: CYP2C9, VKORC1 polymorphisms (utility uncertain for ↓ bleeding/clot risk)
- Routine DOAC effect monitoring not needed (vs. VKA)
- DOACs: Fixed dosing, no INR monitoring → VKAs reserved for VKA-specific advantages
INR Management for Bleeding
| Supratherapeutic <5.0 |
No |
Any |
Omit next dose(s); ↓ subsequent dose |
| 5.0-9.0 |
No |
Yes |
Omit next dose; vitamin K supplement (assess INR recurrence) |
| ≥9.0 |
No |
Any |
Vitamin K 1-2.5 mg orally |
| Any INR |
Yes (serious) |
— |
Vitamin K 2.5-10 mg IV + PCC (or FFP if PCC unavailable) |
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Direct Oral Anticoagulants (DOACs)
Mechanism & Pharmacology
- Classes: Anti-Xa (apixaban, rivaroxaban, edoxaban, betrixaban) OR anti-IIa (dabigatran)
- Advantages: Rapid onset, minimal monitoring, short t½, fixed dosing
- Caution: Renal clearance → restricted in severe renal disease
- US approvals: 4 anti-Xa, 1 anti-IIa agents
Renal Impairment Management
- Avoid CrCl <30: Dabigatran, edoxaban, betrixaban
- Preferred: Apixaban (adequate AC w/ renal impairment), rivaroxaban
- Strategy: Initial LMWH/DOAC → VKA/DOAC after 5 wk w/ monitoring
Monitoring
- Routine monitoring: Not needed (vs VKA)
- Levels if needed: Specific assays (ecarin-based for DTI; anti-Xa for Xa inhibitors)
- Dose adjustment: Per renal function, weight, drug interactions
Bleeding Management
- Minor bleeding: Discontinue DOAC; supportive care
- Severe/urgent reversal:
- Factor prothrombin complex concentrate (PCC) consider
- Dabigatran: Direct thrombin inhibitor reversal (idarucizumab)
- Factor Xa inhibitor reversal agents emerging
- Caution: Progressive renal failure → ↑ t½, prolonged anticoagulation effect
Management Issues
Obesity & Renal Insufficiency
Obesity
- 1st-line: DOACs (per ISTH)
- Caution: DOAC dosing not weight-based; limited data
- Alternative: LMWH (good efficacy)
Renal Impairment
- ISTH: Against routine peak/trough monitoring for AC adjustment
- Severe (CrCl <30): Avoid dabigatran, edoxaban, betrixaban
- Preferred: Apixaban, rivaroxaban w/ careful absorption monitoring
Bleeding Management
- Assessment: Dose recognition, bleeding severity
- Minor/no urgent reversal: Stop DOAC; supportive care, pressure
- Severe/urgent surgery:
- PCC (consider over FFP)
- Specific antidotes (idarucizumab for dabigatran)
- Factor XI inhibitors: manageable in renal failure
- Dabigatran: Prolonged t½ w/ renal impairment
Thrombolytic Therapy
- Agents: Streptokinase, urokinase, tPA → plasminogen activation, fibrin dissolution
- Limitations: ↑ bleeding risk w/ concurrent AC; restricted VTE use
- Scenarios: Specific indications (e.g., massive PE, acute limb ischemia)
- Risk-benefit: Evaluate carefully vs. AC alone
Perioperative Management
- Rivaroxaban: Hold 48h pre-op → resume once hemostasis achieved
- UFH: Easily reversible (protamine)
- VKA: Reverse if high INR (vitamin K, PCC/FFP)
- DOAC: Shorter t½ → restart sooner post-op vs. VKA