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A. Overview of DVT Therapy [1,2] navigator

  1. Prevention of DVT in hospitalized patients is effective and safe
    1. Low molecular weight heparin (LMWH) is considered standard
    2. Prevention currently underutilized
  2. Acute DVT Treatment
    1. Immediate antithrombotic effect is desired in patients with new DVT
    2. Initial treatment with high dose anti-coagulation is standard in most cases but
    3. initial thrombolysis can be considered for large clots and high risk pulmonary embolism
    4. Acute treatment is followed by chronic anticoagulation
  3. Acute Treatment of DVT with LMWH Anticoagulation is Recommended [2,11]
    1. Various LMWH are available
    2. LMWH are safer and appear more effective than standard heparin
    3. LMWH are also easier to dose, do not require monitoring APTT
    4. Home treatment with LMWH is possible; both safe and effective [2]
    5. Heparin decreases risk of fatal PE by ~75%
    6. Heparin also decreases risk of recurrent PE from 25% to ~2% in treated patients
    7. Standard heparin administered as fixed-dose, weight adjusted, does not require APTT and is as effective as LMWH in treatment of DVT in outpatients [5]
    8. Underdosing initial heparin may increase risk for delayed recurrence of DVT
    9. Average treatment duration is 5 days prior if converting to warfarin
    10. Compression stockings should be used routinely within 1 month of proximal DVT, to prevent post-thrombotic syndrome (continue for at least 1 year)
  4. Chronic Anticoagulation [2,11]
    1. Chronic anticoagulation for 3-6 months for trasnient risk factors and >12 months for recurrent DVT [1,2]
    2. Chronic anticoagulation recommended due to very high risk for recurrent DVT and extension of existing DVT after initial event
    3. Normalization of D-Dimer levels in patients with DVT treated with at least 3 months of warfarin is associated with 2.4X reduced risk of DVT recurrence [8]
    4. Dalteparin superior to warfarin for 6-month treatment of patients with malignancy associated DVT [4]
    5. Prolonged anticoagulation (>6-12 months) provides 70-85% risk reduction for recurrent DVT compared with short term (3 months) anticoagulation [3]
    6. Prolonged low level warfarin (INR 1.5-2.0) reduces recurrence >60% [11]
    7. Warfarin should not be used in pregnancy, particularly between 6 and 12 weeks' gestation
    8. Continued LMWH (preferred) or standard heparin is recommended in pregnancy
    9. Overall risk for fatal PE after completing anticoagulation course is 0.19-0.49 events per 100 person-years [15]
  5. Contraindications to Anticoagulation [1]
    1. Active bleeding
    2. Severe bleeding diathesis or platelet count <20K/µL
    3. Neurosurgery, ocular surgery, or intracranial bleed within past 10 days
    4. Relative contraindications include:
    5. Mild to moderate bleeding diathesis or platelet counts 20-100K/µL
    6. Brain metastasis
    7. Recent major trauma
    8. Major abdominal surgery within past 2 days
    9. Gastrointestinal or geniturinary bleeding within past 14 days
    10. Endocarditis
    11. Severe hyeprtension: blood pressure systolic >200mm Hg or diastolic >120mm Hg
  6. Thrombolytic Therapy [6]
    1. Consider if no bleeding contraindications (recent surgery is a contraindication)
    2. Strongly consider if limb threatening ischemia is present
    3. Particularly useful in younger persons and in clots that are relatively acute (<7 days)
    4. Consider in patients with severe pain, other severe symptoms
    5. Institute heparin after 24-48 hours of lysis therapy
    6. Local or systemic thrombolytic therapy can be given
    7. Streptokinase or urokinase continuous IV infusion for 24-48 hours typically used
    8. Tissue plasminogen activator (TPA) is likely more specific with less bleeding
    9. Streptokinase clearly reduces risk of post-phlebitic syndrome; see below
    10. Thrombolysis does not decrease risk of pulmonary embolism
  7. Pregnancy
    1. Warfarin is absolutely contraindicated
    2. Heparin in increased doses, is required for treatment or prophylaxis
    3. Long term use may be associated with increased osteopenia
    4. LMWH is at least as effective and safer
  8. Inferior Vena Cava (IVC) Filters [7]
    1. Consider use for prophylaxis in patients at high risk for PE, recurrent PE or DVT
    2. Majority of these patients have large, proximal DVTs
    3. Also used in patients who cannot tolerate anticoagulation
    4. IVC Filters appear to reduce early PEs (at12 days) by 80%
    5. However, in 2 year followup, IVC filters associated with ~2X risk of PE compared with standard anticoagulation
  9. Treatment is highly effective in (nearly) eliminating risk for fatal PE [9]
  10. Duration of treatment varies by individual patient, underlying causes, and future risks

B. Heparin Therapy [1,12] navigator

  1. Mechanism of Action
    1. Heparin is a repeating unit mucopolysaccharide, highly sulfated
    2. Major mechanism of action is binding to antithrombin (AT; formerly antithrombin III)
    3. Heparin activates AT via binding to the lysine rich region of AT
    4. AT has an arginine at its active site which can block clotting factors (serine proteases)
    5. Standard heparins consist of a range of molecular weights (MW) with AT binding
    6. Specific MW heparins have additional anticoagulation properties:
    7. Heparin MW 2-7K blocks Factor X to Xa in vitro
    8. Heparin MW 8-27K blocks factor II to IIa in vitro
    9. Danaparoid, a heparinoid, is also available with similar activity to LMW heparins
    10. Fondaparinux is a specific Factor Xa inhibitor (see below)
  2. Heparin Preparations [2,10,12]
    1. LMWH safer and likely more effective for prevention and treatment of DVT compared with standard MW heparin; it is also more cost effective
    2. Multiple LMWH are available including enoxaparin, dalteparin, ardeparin
    3. LMWH can be used in outpatient setting
    4. Enoxaparin once or twice daily is as effective as standard heparin for DVT treatment [14]
    5. Thrombocytopenia risk is reduced with LMWH or danaparoid
    6. Unfractionated heparin should be reserved for acute uses in the absence of thrombocytopenia where rapid reversal is potentially desirable
  3. LMWH Overview [2,11,16]
    1. Safe and effective for treatment of DVT; generally preferred over standard heparin
    2. Given subcutaneously, may be administered at home
    3. Dose is 1mg/kg enoxaparin sc bid for >4 days; warfarin started on day 2
    4. Should have ~5 days of overlap between LMW Heparin and warfarin
    5. LMWH does not require APTT monitoring and its use reduced hospital stay
    6. LMWH showed greater efficacy, bleeding and mortality reduction versus heparin in all patients (including cancer) with acute venous thromboembolism (VTE), mainly DVT [14]
    7. LMWH reduced death compared with unfractionated heparin in patients with DVT [17]
    8. LMWH and standard heparins had similar bleeding and thrombocytopenia risks [17]
    9. LMWH can safely and effectively be used for treatment of DVT (see above)
    10. Safe and effective in many high risk situations; may be used in outpatients [18]
    11. Safe and effective when initiated preoperatively for DVT prevention (see below) [19]
  4. Specific LWMH in DVT
    1. Most LWMH, including nadroparin, are dosed by Factor Xa inhibitory units
    2. Enoxaparin 40mg qd reduced risk of DVT in elective neurosurgical patients by 50% [21]
    3. Enoxaparin had no increased bleeding risk in these neurosurgical patients [21]
    4. Ardeparin for 2 days in hospital, then for additional 5-15 days, is safe and effective
    5. Extending ardeparin therapy for 6 weeks after hospital discharge is of no overall benefit [20]
    6. Tinzaparin once daily reduced recurrent DVT in patients with PE and proximal DVT [23]
    7. Tinzaparin approved for treatment of acute DVT; less expensive than other agents [24]
    8. Reviparin bid for one week reduced thrombus size and prevented recurrent DVT better than heparin with similar rates of bleeding [25]
    9. Dalteparin superior to warfarin for 6-month treatment of patients with malignancy associated DVT [4]
    10. Dalteparin reduced VTE without increased bleeding in acutely ill medical patients [13]
  5. Standard Heparin: Therapeutic Considerations [1]
    1. Initially, continuous IV heparin maintaining APTT >1.4X-1.8X control (activated PTT)
    2. This APTT level must be achieved within 12 hours (to prevent recurrent DVT)
    3. Weight based IV dosing more effective than standard dosing at achieving APTT target
    4. Weight based is 80U/kg bolus IV, then 18U/kg/hr continuous
    5. Weight based sc heparin dosing is also effective for DVT, and highly efficient, does not require APTT monitoring, and is as effective as LMWH, including for outpatients [5]
    6. Weight-based sc dosing is 333U/kg initially, then 250U/kg q12 hours all sc [5]
    7. The higher dosage prevents platelet / fibrinogen aggregation and reduces recurrent DVTs
    8. Heparin not withdrawn until PT is in therapeutic range of 18-25 seconds for at least 3 days
    9. Side effects: bleeding (7-14%), heparin allergy, hemorrhage, thrombocytopenia
    10. Meta-analysis suggests sc heparin (~30KU/day) equally effective as IV heparin
    11. Warfarin should be started when APTT is >60 seconds on two analyses
  6. Heparin Induced Thrombocytopenia (HIT)
    1. Immune mediated reaction induced by heparin in ~3% of heparin recipients
    2. IgG Antibodies develop and lead to thrombocytopenia with platelet aggregation
    3. Frequently complicated by extension of existing thrombosis
    4. Also is associated with new venous and arterial thrombotic events
    5. Risk of HIT is much reduced with LMWH

C. Fondaparinux (Arixtra®) [27]navigator

  1. Synthetic analog of pentasaccharide binding sequence of heparin
  2. Specific Factor Xa inhibitor with no effect on thrombin
  3. Fondaparinux once daily as effective as twice daily enoxparin for DVT treatment [29]
  4. More effective than enoxaparin (Lovenox®) for DVT prevention (day 11 post-operatively)
    1. Hip fracture surgery [34]
    2. Knee replacement surgery [35]
    3. Hip relapcement surgery [27]
  5. Begin fondaparinux 4-8 hours postoperatively, 2.5mg sc qd for 5-9 days
  6. Idraparinux [45,46]
    1. Synthetic pentasaccharide; much longer half-life than fondaparinux
    2. Given once weekly sc
    3. For DVT, similar efficacy at 3-6 months as heparin-warfarin [45]
    4. For PE, efficacy inferior to heparin-warfarin [45]
    5. For DVT with therapy extended 6 months (after initial 6 months), reduced recurrence:
  7. 7% on placebo to 1.0% on idraparinux but with 1.9% major bleeding (0 on placebo) [46]

D. Warfarin (Coumadin®) [26] navigator

  1. Mechanism
    1. Inhibitor of recycling of the Vitamin K dependent carboxylations of clotting factors
    2. Specific factors are II (prothrombin), VII, IX, X; and Protein S, C, and Z
    3. If not carboxylated on Glu residues, these factors cannot bind Ca2+ and won't work
  2. Therapeutic Considerations
    1. May begin coumadin >6 hours after initiation of therapeutic heparin therapy
    2. Loading dose: 10-20mg qd x 3 days; usual daily dose 5-10mg/day; low dose <2.5mg / day
    3. Assess prothrombin time (PT) daily for 1-2 weeks
    4. When stable, assess every 3rd day, then weekly, and chronically every 2 weeks
    5. Maintain heparin for 2-3 days after starting warfarin to prevent thrombosis
    6. Chronic (Lifelong) Therapy for high risk groups is recommended (see below)
    7. Indefinite low level (INR 1.5-2.0X) warfarin provides >60% recurrence reduction [11]
    8. Very low doses (1mg qhs) may lower thromboembolism in breast cancer patients on chemotherapy [26]
    9. Side effects: hemorrhage 5-15%, drug interactions; warfarin induced skin necrosis
  3. Duration of Therapy [28,30]
    1. Warfarin should be maintained indefinitely if underlying condition persists
    2. Warfarin therapy for 4-12 weeks for uncomplicated DVT is too short [31]
    3. In uncomplicated DVT, 3 versus 6 months of warfarin had similar levels of treatment failure, recurrent DVT, or PE [48]
    4. Controversial if 6-12 month warfarin reduces recurrence more than 3 months In idiopathic DVT [3,9,48]
    5. Six months of warfarin for first DVT gives 50% reduction in events in comparison with 6 weeks of warfarin [28]
    6. Nearly all additional events in 6 week occurred within 2-5 months of stopping warfarin
    7. One meta-analysis shows benefit (70-85% reduction) of >6- versus 3-month warfarin [3]
    8. Strongly consider warfarin for 4-6 (or even 6-12) months for complicated DVT
    9. Clinical benefit from extending warfarin to 12 months disappears after cessation of therapy [38]
    10. Indefinite warfarin dosing (INR 1.5-2.0) following 3-12 months of INR 2.0-3.0 warfarin provided 64% reduction in DVT recurrence in one ranomdomized study [11]
    11. In another randomized study, dropping INR to 1.5-1.9 after 3 months at usual INR lead to increased recurrence risk and no reduction in bleeding [28]
    12. High risk of recurrence at 2 and 8 years suggests longer therapy may be desired
    13. D-dimer level <250ng/mL after warfarin withdrawal have very low risk of recurrence [8,36]
    14. If D-dimer levels have not normalized within 1 month of warfarin discontinuation, then strongly consider re-instituting warfarin therapy [8]
  4. Prothrombotic Mutations and Duration of Therapy
    1. Strongly consider testing for Factor V Leiden in all patients started on warfarin
    2. Patients with Factor V Leiden should receive long term warfarin (12 months)
    3. Combination of prothrombin G20210A and Factor V Leiden mutation increases risk of initial DVT by >10X, and for recurrent DVT 2.6-3.7X [37]
    4. Therefore, presence of both of these mutations may be cause for lifelong anticoagulation
  5. Second Episode of VTE [32]
    1. May indicate underlying coagulation disorder
    2. Longer duration of warfarin therapy is indicated
    3. With 6 months' warfarin therapy, recurrence rate was ~20%
    4. Continuous warfarin therapy after second epidose had <3% recurrence
    5. Nearly all patients with recurrent DVT have underlying cause
  6. High Risk DVT Patients should receive very long term (>6 months to lifelong) therapy
    1. Atrial Fibrillation (AFib)
    2. Severe Congestive Heart Failure
    3. Underlying Malignancy
    4. Previous DVT
    5. Factor V Leiden Mutation (Activated Protein C resistance) [44]
    6. Presence of anti-cardiolipin antibody (ACL Ab) after initial DVT predicts recurrence
    7. Other hypercoagulable states
  7. Drug Interactions
    1. Warfarin completely inactivates cyclosporin
    2. Theophylline increases effective levels
    3. Amiodarone and cimetidine increase efficacy of warfarin
    4. Broad spectrum antibiotics will lower bacterial production of vitamin K leading to an increase in efficacy (prothrombin time) in many patients
  8. Risk Factors for Bleeding on Anti-Coagulation
    1. Cardiovascular (Acute MI, Hypotension SBP <90mm)
    2. Liver dysfunction (hyperbilirubinemia or macrocytosis)
    3. Renal Insufficiency (Creatinine >1.5mg/dl)
    4. Cancer
    5. Hematocrit <30%
    6. Use of thrombolytics increases bleeding risk considerably
    7. Age > 60 years
    8. Maximal PT >2.0X control
    9. 2.0-2.9X control (1 point)
    10. Liver Dysfunction - worsening during therapy

E. Thrombolytic Therapy [1,6,43] navigator

  1. Anticoagulant therapy is standard therapy for DVT
    1. Prevents thrombus extension or embolization
    2. No significant direct clot destruction (ie. no direct thrombolysis)
    3. High incidence of post-phlebitic syndrome (~50%)
    4. Post-phlebitic Syndrome includes pain, recurrent DVT, venous insufficiency
  2. Thrombolytic therapy has been studied in small trials of DVT
    1. Streptokinase, Urokinase, TPA have been used locally or systemically
    2. In general, clot lysis achieved in ~50% of patients receiving lytic agents
    3. Trend towards decreasing post-phlebitic syndrome with use of thrombolytics
    4. Thrombolytic incidence of bleeding (rarely major) is increased in comparison with standard heparin / warfarin treatment
    5. Local therapy with 20mg TPA (Alteplase®) or urokinase (100,000U) directly into dorsal pedal vein over 4 hours
    6. Systemic therapy urokinase (5 million U) over 4 hours or streptokinase (3 million U) over 6 hours
    7. Intraclot therapy using either urokinase or TPA can be very effective [39]
  3. Considerations [43]
    1. Young persons with low bleeding risk likely have most benefit
    2. Main benefits are reduced post-phlebitic syndrome and improved outcome with limb-threatining clots
    3. Probably reduces hospital stay and symptoms compared with heparin
    4. Should consider for large DVTs at permanent limb damage
    5. Patients may not want risk of bleeding even with post-phelebitic syndrome (see below)

F. Miscellaneous Therapynavigator

  1. Intermittent pneumatic compression stockings - of clear benefit
  2. Hirudin
    1. Direct inhibitor of thrombin, derived from leeches
    2. Trials ongoing to assess efficacy in treatment of DVT
  3. Ximelagatran (Exanta®)
    1. Oral direct thrombin inhibitor, does not require coagulation monitoring
    2. Dose 24mg po bid given for 18 months after 6 months of warfarin reduced recurrence of VTE >80% compared with placebo [40]
    3. Ximelagatran 24mg po bid fixed dose was as effectiver as adjusted dose warfarin (with enoxaparin) for the treatment of DVT [41]
    4. Ximelagatran 24mg po bid is associated with 5-10% transaminase elevation [41,42]
    5. Not approved in USA and withdrawn from market in Europe due to liver failure risk
  4. Dabigatran [47]
    1. Orally active, direct thrombin inhibitor
    2. Dabigatran 220mg po qd as effective as a enoxaparin sc in preventing DVT or death after hip replacement surgery
    3. No differences compared with enoxaparin in liver function abnormalities or ischemia
  5. Anti-Platelet Agents [33]
    1. Aspirin originally shown to have marginal benefit on DVTs in small studies
    2. Meta-analysis shows ~60% reduction in DVT, >70% reduction in PE for ASA versus placebo
    3. ASA + dipyridamole (Persantine®) may have mild added benefit to ASA alone
    4. ASA + heparin definitely better than heparin alone
  6. Danaparoid
    1. A heparinoid obtained from pig intestinal mucosa after removal of heparin
    2. Combination of heparan sulfate (84%), dermatan sulfate (12%), chondroitin sulfate (4%)
    3. Major activity is selective inhibition of Factor Xa through antithrombin
    4. High dose (2000U sc bid) more effective than heparin iv in DVT and PE
  7. Inferior Vena Cava (IVC) Filters [44]
    1. Placed from internal jugular vein into IVC (springs open)
    2. Probably useful in patients at risk with anti-coagulation or failed anti-coagulation
    3. Indicence of PE in patients with IVC filters probably <2%
    4. Failure: Filter migration to heart, Improper deployment, clots on or proximal to filter
    5. Complications: migration, perforation, thrombogenic, ineffective, IVC occlusion, edema
  8. Ineffective for Treatment of DVT:
    1. Ambulation
    2. Compression stockings
    3. Questionable efficacy of agents in treating cancer-associated DVT

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