A. Mechanism of Action

1. Heparin is a highly-sulfated, repeating unit mucopolysaccharide
2. Interacts with antithrombin and activates it
3. Antithrombin (AT; formerly called antithrombin III)
   1. AT is a 58K serine protease inhibitor
   2. Inhibits factors IXa and Xa activity and also blocks XIa and IIa (thrombin)
   3. Active site can block serine protease triad found in all clotting proteases
   4. Platelet bound Xa is highly resistant to proteolysis by AT
   5. Heparin (like substance) is required for efficient function of AT; reverse is also true
   6. Heparin interacts with AT in the AT Lysine rich region
   7. Heparin increases F-X and thrombin inhibitory activity of AT by ~1000 fold
   8. Vascular bed heparin-like substance is possibly heparan sulfate glycosaminoglycan
4. Other Heparin Activities
   1. Heparin MW 2-7K blocks Factor X to Xa conversion in vitro
   2. Heparin MW 8-27K blocks factor II to IIa (thrombin) conversion in vitro
   3. Most heparin fragments act on AT-III as described above
   4. Inhibition of Factor Xa is probably most important for heparin's actions
   5. Heparin does not block the thrombogenic activity of clot-bound thrombin (Factor II)

B. Heparin Preparations

1. Heparin (standard or unfractionated)
   1. These standard heparins consist of a range of molecular weights (MW)
   2. The mixed heparins have mixed and nearly equal Anti-Factor II and X activities
   3. Both Anti-Factor II and X activities are neutralized by platelet factor IV
   4. Thrombocytopenia develops in about 3% of treated patients
2. Low MW (LMW) Heparins
   1. LMW heparin safer and may be more effective for prevention of DVT (versus standard)
   2. More effective in acute coronary syndromes (ACS) versus standard [1,2]
   3. May be preferred for percutaneous coronary interventions (PCI) versus standard [1]
   4. LMWs have a 3-5 fold higher Anti-II than Anti-X activity than standard heparin
   5. Consider LMW Heparin for treatment in patients with history of heparin reaction
   6. LMW heparins can be used safely and effectively in outpatient DVT treatment [8]
   7. LMW heparin dose may need to be increased for prophylaxis in patients on vasopressors [63]
3. Danaparoid (Orgaran®) [23]
   1. Heparanoid, a partially depolymerized mixture of extracellular matrix polysaccharides
   2. Procine intestinal mucosa derivative
   3. Heparan sulfate, dermatan sulfate, and chondroitin sulfate depolymerized
   4. Higher Anti-X to Anti-II activities than LMW heparins
4. Fondaparinux is a non-heparin, pure Factor Xa inhibitor (see below)
5. Side Effects of Heparin
   1. Thrombocytopenia (2-4%) - risk is reduced with LMW heparin
   2. Bleeding - risk may be reduced slightly with LMW heparin
   3. Allergic Skin Reactions
   4. Osteoporosis - particularly with long term heparin; reduced with LMW heparin

C. Utility

1. Cardiovascular Events
   1. Clearly indicated for ACS (MI, unstable angina)
   2. LMW heparin generally preferred over standard heparin in MI with thrombolysis [2,36]
   3. Required for use during angioplasty and stenting
   4. Initial therapy in patients with atrial or ventricular thrombi
   5. Initiated in most patients with atrial fibrillation (AFib)
   6. In patients with ACS and no ST elevation who receive aspirin and heparin (standard or LMW) for 7 days, heparin reduces risk of myocardial infarction or death by 50% [48]
2. Deep Vein Thrombosis (DVT)
   1. Highly recommended for prevention of DVT and pulmonary embolism (PE)
   2. Heparin for DVT prevention in high-risk hospitalized surgical and medical patients is <65% of appropriate target levels [84]
   3. Overall, anticoagulant use in hospital inpatients leads to ~55% reduction in any PE, ~60% reduction in fatal PE, and ~50% reduction in symptomatic DVT [78]
   4. Therefore, it is urgent that heparin use increase for prevention of DVT and PE [84]
   5. Therapy of choice for most patients with new DVT
3. Pulmonary Embolism (PE) [33]
   1. For most patients, treatment of choice for hemodynamically stable PE
   2. Recommended for prevention of PE (see above) [78]
   3. Fondoparinux and unfractionated heparin of equal efficacy in hemodynamically stable PE
4. May be used in patients with adverse reactions to warfarin
5. Perioperative Heparin Therapy
   1. May be given iv prior to surgery to maintain anticoagulation in high risk patients
   2. Heparin should be stopped 6 hours prior to surgery
   3. Heparin should not be restarted until at least 12 hours after major surgery
   4. Longer delays should be considered if surgical bleeding is occurring

D. Therapy With Standard Heparin

1. Goal of Anticoagulation
   1. This will depend somewhat on the indication
   2. However, many indications goal has treatment with heparin with APTT 1.5X-2.3X control
   3. APTT is activated partial thromboplastin time, normal range is typically <29 seconds
   4. Goal APTT should be generally be achieved within 12 hours
   5. More intensive anticoagulation regimens lead to highly increased bleeding in MI
2. Weight based IV dosing more effective than standard dosing
   1. Weight based is 60-80U/kg bolus iv, then 12-18U/kg/hr continuous (max 1000U/hr)
   2. For combination with alteplase for MI, bolus 60U/kg (max 4000U), then 12U/kg/hr [55]
   3. Measure APTT every 6 hours or until stable
   4. For APTT <35 seconds, adjust with 80U/kg bolus, then increase 4U/kg/hr
   5. For APTT 35-45 sec, adjust with 40U/kg bolus, then increase 2U/kg/hr
   6. Desired APTT is 50-70 seconds (1.5-2.3X control)
   7. The higher dosage prevents platelet / fibrinogen aggregation and reduces recurrent DVTs
3. Weight Based SC Dosing [38,39]
   1. Safe and effective for treatment of deep vein thrombosis (DVT)
   2. Weight based sc heparin dosing is highly efficient, does not require APTT monitoring
   3. As effective as LMWH for DVT, including for outpatients
   4. Weight-based sc dosing is 333U/kg initially, then 250U/kg q12 hours all sc [39]
4. Heparin and Warfarin
   1. Warfarin often used longer term because it is orally available
   2. Warfarin inhibits vitamin K dependent clotting factors
   3. Warfarin initially blocks Factor VII and Protein C, so can induce transient pro-clotting
   4. Warfarin may be started when APTT is >60 seconds on two analyses
   5. In general, heparin therapy should be continued during initiation of warfarin
   6. Heparin not withdrawn until PT is in therapeutic range of 18-25 seconds for >3days

E. Low Molecular Weight (LMW) Heparin [14]

1. Various preparations now available with different Factor Xa inhibition levels
   1. Ardeparin (Normiflo®) - ratio of anti-Xa to anti-IIa activity is 1.9 [23]
   2. Dalteparin (Fragmin®) - ratio is 2.7
   3. Enoxaparin (Lovenox®) - ratio is 3.8
   4. Nadroparin (Fraxiparine®) - ratio is 3.6
   5. Reviparin (Clivarin®) - ratio is 3.5
   6. Tinzaparin (Innohep®) - ratio is 1.9
2. Advantages Over Standard Heparin [44]
   1. More predictable anticoagulant response allows weight-based dosing
   2. Less binding to plasma proteins and proteins released from platelets and endothelium
   3. Better bioavailability at low doses (less binding to endothelium)
   4. Reduced binding to macrophages permits dose-independent clearance
   5. Longer half-life allows twice (or once) daily dosing
   6. Probably safer and at least as effective as standard heparin
   7. Highly cost-effective versus standard heparin for inpatient management of DVT [45]
3. Ease of Use
   1. Drug is given subcutaneously
   2. Does not require APTT monitoring and its use reduces hospital stay
   3. May be administered at home
   4. Dosing depends on indication, prevention or treatment phase, and type of LMW heparin
4. Utility [14]
   1. Prevention and treatment of deep vein thrombosis (DVT)
   2. LMW Heparin showed greater efficacy, bleeding and mortality reduction versus heparin in all patients (including cancer) with acute venous thromboembolism (mainly DVT) [9]
   3. LMW heparin superior to standard heparin on mortality when combined with TPA [76]
   4. LMW heparin superior to standard heparin for preventing reinfarction in heart attack [77]
   5. Much reduced incidence of heparin associated thrombocytopenia [12]
   6. Whether any LMW heparin actually has activity in stroke is questionable [56]
   7. Appear to be as safe as standard heparin in pregnancy
   8. Likely increased bleeding risk in non-dialysis renal failure; consider adjusting doses [75]
   9. Overall cost-effectiveness studies show LMW Heparins are less costly than standard
5. Enoxaparin (Lovenox®)
   1. Dose is 1mg/kg enoxaparin sc bid for >4 days for treatment of DVT [10]
   2. Dose for prevention of DVT by enoxaparin is 30mg sc bid or 40mg sc qd
   3. Ratio of anti-factor Xa to antithrombin acitivty is about 2.7:1
   4. Benefit over standard heparin in ACS: unstable angina (USA), non-Q MI (NSTEMI), and Q wave MI (STEMI) [2,17,36]
   5. Similar efficacy as fondaparinux in reduced recurrent ischemia in ACS, but with increased bleeding and higher 1- and 6-month mortality [4]
   6. Reduced DVT risk in elective neurosurgical patients by 50%; no increased bleeding [37]
   7. Reduced risk of DVT by >60% in high risk (mainly immobilized) medical patients [47]
   8. Highly effective prophylaxis after hip or knee arthroscopy
   9. Safe and effective in a number of high risk situations
   10. Reduced bleeding (0.5mg/kg, trend at 0.75mg/kg) and better target anticoagulation compared with standard heparin in elective PCI [50]
   11. Increased potency and risk of bleeding in non-dialysis renal failure patients; dose should be reduced [75]
   12. Enoxaparin is more effective than standard heparin for DVT prophylaxis in stroke [20]
   13. Enoxaparin has slightly higher extracranial major bleeding but not overall bleeding [20]
6. Dalteparin (Fragmin®)
   1. Ratio of anti-factor Xa to antithrombin activity is about 2.0:1
   2. Dalteparin superior to warfarin for 6-month treatment of malignancy associated DVT [5]
   3. Reduced venous thromboembolic events without increased bleeding in acutely ill medical patients [74]
   4. Showed no statistical benefit over unfractionated heparin in unstable angina [18]
7. Nadroparin (Fraxiparine®) [11]
   1. Dosed by Factor Xa inhibitory units (adjusted for weight)
   2. Significant benefit over unfractionated heparin in reducing cardiovascular endpoints [19]
   3. Nadroparin is more effective than compression stockings
   4. Dose is 3800 anti-Factor Xa IU for 10 days for prevention of DVT after knee arthroscopy; reduced DVT: 3.2% with compression stockings to 0.9% on drug []
8. Reviparin (Clivarin®) [21,53]
   1. Average MW 4.0K with good anti-Xa to anti-IIa ratio of 3.5
   2. In a randomized, blinded study with >1000 patients with DVT including 1/3 with pulmonary embolism, was as safe and effective as standard heparin for treatment [21]
   3. Reviparin bid for one week reduced thrombus size and prevented recurrent DVT better than heparin with similar rates of bleeding [53]
   4. ~50% reduction in DVT following leg injury compared with placebo [6]
   5. Dose is 3500-12,600 anti-Factor Xa units twice daily given sc (weight adjusted)
9. Tinzaparin (Innohep®) [22,52]
   1. Average MW 4.5K, relatively low ratio anti-Xa to anti-IIa of 1.9
   2. In a blinded controlled study of >600 patients with pulmonary embolism, was as effective and safe as standard heparin
   3. Dose was 175 anti-Factor Xa units/kg once per day, making it very easy to administer
   4. Tinzaparin once daily reduced recurrent DVT in patients with PE and proximal DVT [49]
   5. Approved for treatment of acute DVT; less expensive than other agents [52]
   6. No activity in a large, well-designed trial in acute ischemic stroke [56]
10. Ardeparin [42]
    1. Approved for prophylaxis against DVT in setting of elective total knee replacement (TKR)
    2. Given SC for 2 days in-hospital, then 5-15 out of hospital, is safe and effective treatment for patients with low risk DVT
    3. Dose for treatment was 130 Factor Xa units/kg subcutaneously

F. Factor Xa Inhibitors

1. Fondaparinux (Arixtra®) [2,64]
   1. Specific Factor Xa inhibitor with no antithrombin activity
   2. Synthetic pentasaccharide related to antithrombin binding site of heparin
   3. Once daily subcutaneous injection of 2.5mg (being 4-8 hours after surgery)
   4. More effective than enoxaparin for preventing DVT at hip fracture surgery [59] or for TKR or THR [60,66,67]
   5. Fondaparinux once daily as effective as twice daily enoxparin for DVT treatment [73]
   6. As effective and safe as unfractionated heparin for treatment of PE [33]
   7. Does not require monitoring of efficacy
   8. Dose 5.0, 7.5, 10.0mg sc qd for patients <50, 50-75, >100kg weight
   9. In ST segment elevation MI, reduces mortality and reinfarction even when added to heparin without increasing bleeding or stroke [3]
   10. In ACS patients, fondaparinux and enoxaparin had similar reductions in recurrent ischemic events; fondaparinux had reduced bleeding events and mortality at 1 and 6 months [2,4]
   11. Does not cause heparin induced thrombocytopenia
   12. Slightly increased risk of minor (but not major) bleeding versus enoxaparin
2. 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: 2.7% on placebo to 1.0% on idraparinux but with 1.9% major bleeding (0 on placebo) [46]
   6. Idraparinux compared with warfarin (INR 2-3) was superior on preventing thromboembolism in patients with chronic AFib (70% reduction) [85]
   7. Idraparinux caused 1.1 intracranial bleed / 100 patient-years compared with 0.4/100 with warfarin at 10.7 months but similar rates of death [85]
   8. Risk of bleeding increased in elderly and those with renal impairment [85]
3. Rivaroxaban [86,87,88]
   1. Oral factor Xa inhibitor
   2. Dose is 10mg po qd usually given for DVT prophylaxis after surgery
   3. Rivaroxaban 10mg po qd after THR reduced thromboembolic events compared to enoxaparin 40mg sc qd (given peri- and post-surgery) to 1.1% versus 3.7% by day 36 [86]
   4. Rivaroxaban 10mg po qd for 35 days after THR associated with 2% thromboembolism compared to >9% with enoxparin 40mg sc for 10-14 days [87]
   5. Rivaroxaban 10mg po qd after TKR associated with 1.0% thromboemolism compared to 2.0% with enoxaparin 40mg sc (both for 13-17 days) [88]
   6. Major bleeding similar in rivaroxaban and enoxaparin groups

G. Heparin Resistance

1. Mainly occurs in patients with large venous thromboemboli
2. Arbitrarily defined as need for more than 40,000 U per day
3. Mechanisms of Resistance
   1. Increase plasma levels of Factor VIII
   2. Increased plasma levels of heparin binding proteins (HBP)
4. In patients with resistance, monitoring the APTT is not recommended
   1. Instead, monoitoring heparin levels with anti-factor Xa heparin assay can be used
   2. Alternatively, LMW heparins appear to be effective because they have less HBP binding

H. Heparin Induced Thrombocytopenia (HIT) [41,54]

1. Occurs in 1-5% of patients exposed to heparin, usually for >4 days [24,41,51]
   1. Highest risk in patients undergoing orthopedic surgery on standard heparin: 3-5%
   2. Intermediate risk (~2%) in adults/children undergoing cardiac surgery
   3. Interediate risk in general medical practice, neurologic dysfunction
   4. Risk >2X less with LMWH than with standard heparin
2. Timing of Thrombocytopenia [24,51,54]
   1. Occurs after 4 days' treatment with heparin in ~70% of affected patients
   2. Occurs within 1-2 days (median 10.5 hours) in 30% of affected patients
   3. Patients with rapidly induced HIT had previously received heparin within 100 days of presenting HIT
   4. Delayed HIT can occur up to 5 weeks (median 9-13 days) after starting heparin [57,62]
   5. Delayed HIT can be exacerbated by LMW heparin
3. HIT is an IgG antibody (Ab) Mediated Disease [65]
   1. Heparin bound to platelet factor 4 (PF4) acts as an immunogen
   2. Patients affected develop primarily IgG Abs against PF4-heparin complex
   3. These IgG Abs have a half-life of 50-85 days [54]
   4. IgM and/or IgA Abs are also found in some patients
   5. Effects include thrombocytopenia and paradoxical platelet activation
   6. Also develop Abs against endothelial cells which stimulate tissue factor (F III)
   7. Result is increased risk of thrombotic events in setting of thrombocytopenia
   8. Minimal to massive thromboembolism may occur
   9. Rapid test for antif-heparin/PF4 antibodies
   10. Note very high incidence of antiheparin/PF4 Abs in cardiac surgery even without HIT (HIT occurs in 1-2% versus 25-50% with Abs) [41]
4. Frequently complicated by extension of existing thrombosis
   1. Also is associated with new thrombotic events [12,16]
   2. IgG Abs complexed to Heparin-PF4 activate platelets
   3. Venous thromboembolic events are 2 to 4 times more common than arterial events
5. Historically, death ocurs in ~17% of persons with HIT within 35 days of onset [40,65]
6. Treatment
   1. All heparins should be stopped and direct antithrombins instituted
   2. Unclear whether stopping heparin early changes course of disease [46]
   3. Plasmapheresis to remove autoantibodies may be considered
   4. Antithrombins are approved in HIT
   5. Surgical thromboembolectomy may be required
7. Direct Thrombin Inhibitors in HIT [40,41]
   1. Direct thrombin inhibitors are effective and safe in HIT patients [40]
   2. Argatroban and lepirudin are approved for HIT (see below)
   3. Danaparoid is also effective in HIT
   4. Recombinant hirudin (direct thrombin inhibitor) is effective and safe in HIT
8. Anticoagulation in Patients with History of HIT
   1. LMW heparin is not recommended in patients with HIT [40,41]
   2. Fondaparinux is highly recommended for DVT prevention in patients with history of HIT
   3. Warfarin treatment of HIT can precipitate limb gangrane [25]
   4. This is likely due to warfarin's reduction of Protein C levels
   5. Warfarin can be used safely; begin at low doses after platelets recover to >150K/µL
   6. However, newer agents approved specifically for HIT are preferred

I. Danaparoid (Orgaran®) [13,23]

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 AT III
4. High dose (2000U sc bid) more effective than standard heparin IV in DVT and PE [13]

J. Direct Thrombin Inhibitors [26,27]

1. Natural antithrombin (formerly antithrombin III) is a circulating protein
2. Non-human antithrombins mainly derived from the medicinal leach (Hirudo medicinalis)
   1. Hirudin - 65-66 amino acid molecule, binds very strongly to thrombin with Ki <1 pM
   2. Various derivatives of hirudin have been evaluated for activity
   3. Hirudin and its derivatives do not induce HIT
   4. All of these non-human thrombin inhibitors can block thrombin bound to fibrin
3. Efficacy in Coronary Syndromes [27]
   1. Large meta-analysis of all direct thrombin inhibitors in acute coronary syndromes
   2. Clear reduction in incidence of acute MI compared with heparin
   3. No significant reduction in overall death rate compared with heparin
   4. Hirudin and bivalirudin also effective in percutaneous coronary interventions
   5. Bivalirudin had reduction in bleeding versus heparin
4. Hirudin (Revasc®)
   1. FDA approved for treatment of HIT
   2. TIMI 9B study showed heparin and hirudin had equal efficacy in acute MI [28]
   3. No benefit over heparin in prevention of restenosis after angioplasty [29]
   4. Reduced risk of bleeding compared with standard heparing after angioplasty
   5. Some benefit over heparin for preventing MI in patients with unstable angina [43]
   6. Prevents deep vein thrombosis better than standard [30] or LMW [31] heparins
5. Lepirudin (Refludan®) [40]
   1. Direct inhibitor of thrombin derived from hirudin
   2. Blocks thrombin activity, including clot-bound thrombin
   3. Half-life is 1.3 hours
   4. Effective for patients with HIT, achieving target anticoagulation in ~75%
   5. Dose initial bolus 0.4mg/kg (max 44mg) IV, then 0.15mg/kg/hr for 2-10 days
   6. Goal is aPTT ratio of 1.5-2.5
   7. Also prolongs the prothrombin time, so initiation of warfarin may be difficult
6. Bivalirudin (Angiomax®, formerly Hirulog®)
   1. Reduced risk of immediate complications in high risk angioplasty patients [32]
   2. Similar rates of complications but with reduced bleeding rates in high risk PCI with use of GP2b3a inhibitors [7,71]
   3. Improved early angiographic reperfusion versus heparin in MI patients receiving streptokinase (HERO-1 Trial)
   4. Reduced reinfarction rate in combination with streptokinase in MI patients versus heparin with slightly higher bleeding risk (HERO-2 Trial) [61]
   5. Bivalirudin alone or with GP2b/3a inhibition is as effective with less bleeding than heparin or enoxaparin [79]
   6. Bivalirudin alone is safer and as effective as GP2b/3a inhibitor + heparin or enoxaparin [79,83]
   7. Moderate and hig-risk ACS can be given bivalirudin alone, deferring gp2b3a antagonists for only those patients undergoing PCI [83]
   8. Approved for high risk angioplasty patients but may be cost effective more broadly
7. Argatroban (Novastan®) [51]
   1. Small molecule synthetic derivative of L-arginine
   2. Direct thrombin inhibitor
   3. Also blocks platelet aggregation
   4. FDA-approved for HIT
   5. Increased risk of hematuria (12% versus 1% placebo)
   6. Allergic reactions, including dyspnea, cough, or rash, in 10-15% of recipients
8. Ximelagatran [26]
   1. Orally active, direct thrombin inhibitor
   2. Converted to melagatran, a direct inhibitor of free and clot-bound thrombin
   3. Melagatran in subcutaneous formulation, is also being studied for DVT prophylaxis
   4. Oral 24mg bid ximelagatran is as effective as enoxaparin for DVT prevention after TKR [58]
   5. Oral ximelagratran after sc melagatran is more effective than dalteparin for DVT prevention after THR or TKR [69]
   6. Oral 24mg bid ximelagatran was more effective than warfarin at preventing DVT after TKR [68]
   7. Oral 36mg bid ximelagatran aubstantially more effective than 24mg ximelagatran or warfarin at preventing DVT after TKR [34]
   8. Reduces risk of recurrent DVT when given at 6 months after initial warfarin therapy [35]
   9. At least as effective as warfarin for prevention of stroke in high risk AFib [70]
   10. Major bleeding rates with ximelagatran 24-36mg po bid similar to warfarin
   11. Ximelagatran 24-60mg po bid added to ASA 160mg/d for 6 months post-MI [72]
   12. Combination reduced risk of death or major CV event 24% compared with ASA alone
   13. Minimal increase in major bleeding events (1.8% versus 0.9%) in post-MI study [72]
   14. Causes minor elevation in transaminases in some patients; liver failure reported
   15. Not approved in USA and withdrawn from marketing in Europe due to liver failure
9. Dabigatran [82]
   1. Orally active, direct thrombin inhibitor
   2. Dabigatran 220mg po qd as effective as a enoxaparin sc in preventing DVT or death after THR
   3. No differences compared with enoxaparin in liver function abnormalities or ischemia

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