Low Molecular Weight Heparins (LMWHs)
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30 mg SC every 12 hours or 40 mg SC once daily
5000 International Units daily SC postoperatively; various preoperative doses indicated
30 mg SC every 12 hours
40 mg SC once daily
2500 International Units SC daily
Patients at high risk of thromboembolic complications (e.g., malignancy): 5000 International Units SC once daily or 2500 International Units SC 1—2 hours before surgery followed by 2500 International Units SC 12 hours later then 5000 International Units SC once daily postoperatively
5000 International Units once daily
Inpatient DVT with or without PE: 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily
Outpatient DVT without PE: 1 mg/kg SC every 12 hours
175 International Units/kg SC once daily
200 International Units/kg SC daily for 1st month, then 150 International Units/kg SC daily for months 2—6*
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism
*max daily dose of 18,000 International Units/day
Enoxaparin, as the first approved LWMH, has been included in more comparative studies than the other LMWHs. Key findings from these studies/reviews are:
LMWH Comparative Efficacy Trials
Planes A, et al. Thromb Haemost 1999;81:22-25 
Randomized controlled trial of 440 patients undergoing total hip replacement; compared enoxaparin 40 mg or tinzaparin 4500 anti-factor Xa International Units once daily
Occurrence of DVT:
20.1% for enoxaparin vs.21.7% for tinzaparin.
Proximal DVTs 10.5% for enoxaparin vs.9.5% for tinzaparin.
No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died.
Tinzaparin is as effective and safe as enoxaparin in the prophylaxis of DVT after total hip replacement
Wells PS, et al. Arch Intern Med 2005;165:733-738 
Randomized controlled trial of 505 outpatients comparing tinzaparin 175 international units/kg daily vs. dalteparin 200 international units/kg daily for treatment of acute DVT and PE
3.9% for tinzaparin vs. 3.6% for dalteparin
2% for tinzaparin vs. 0.8% for dalteparin
Tinzaparin and dalteparin are safe and effective for the outpatient treatment of DVT and PE
Michalis LK, et al. Am Heart J. 2003;146:304-310 
Randomized controlled trial of 438 patients with non-ST segment elevation ACS; compared enoxaparin to tinzaparin for up to 7 days
Angina, MI, or death at 7 days:
Enoxaparin 12.3% vs. tinzaparin 21.2% (p=0.015)
Angina, MI, or death at 30 days:
enoxaparin 17.7% vs tinzaparin 28% (p = 0.012)
Of note, at 6 months, superiority of enoxaparin for the same endpoint was maintained (25.5% vs 44%; p<0.001).
Compared to tinzaparin, enoxaparin significantly reduced the rate of recurrent angina, MI, or death at 7 days, 30 days, and 6 months
Bleeding is the most serious adverse reaction associated with the use of LMWHs; this can range from minor bleeding, such as bleeding from the gums, to major bleeding episodes (< 1%—4%) defined as those requiring a transfusion, a decrease in hemoglobin > 2 mg/dL, bleeding leading to interruption of treatment or death, intracranial bleeding, ocular hemorrhage, or retroperitoneal bleeding. Bleeding events may include epistaxis, hematoma, or gastrointestinal bleeding (melena, hematochezia, and/or hematemesis). Of pregnant women who received tinzaparin, approximately 10% experienced significant vaginal bleeding. Several cases of spinal hematoma have been reported with epidural anesthesia or spinal puncture leading to long-term injury or permanent paralysis.
Injection site reactions, including irritation, pain, hematoma, ecchymosis, and erythema, can occur following SC administration of LWMHs. Other adverse skin reactions (nodules, inflammation, oozing, necrosis vesiculobullous rash, purpura, pruritus, urticaria, and vesiculobullous rash), some allergic in nature, have also been reported.
Cases of thrombocytopenia (platelet count < 100,000/mm3) have been reported in patients treated with LMWHs. Cases of thrombocytopenia with disseminated thrombosis have been observed in clinical practice with both heparins and LMWHs. Some of these cases were complicated by organ infarction or limb ischemia. Although it occurs at a lower rate with LMWHs compared to heparin, heparin-induced thrombocytopenia may also occur.
Asymptomatic elevated hepatic enzymes > 3 times the upper limit of normal have been reported in patients treated with LMWHs. These elevations are reversible.
Although less common than heparin, osteoporosis may occur in patients receiving long-term treatment with LMWHs. Most cases relate to long-term use in pregnant patients
Bleeding is the biggest risk with the LMWHs. The risk of bleeding is increased when used with other drugs that affect the coagulation system, although in some clinical situations, the additive effects are desirable. LMWHs should be used with caution in combination with other anticoagulants (eg, heparin and warfarin), thrombolytics, and antiplatelets. Fish oil (omega-3 fatty acids), Gingko biloba, nonsteroidal anti-inflammatory drugs, aspirin, dipyridamole, sulfinpyrazone, dehydroepiandrosterone, and garlic may increase the risk of bleeding due to their antiplatelet effects. Large doses of salicylates and certain cephalosporin antibiotics may cause hypoprothrombinemia and also increase the risk of bleeding.
Bleeding is the major risk associated with use of LMWHs. LMWHs should not be used in patients with severe bleeding disorders, and coagulopathy should be ruled out prior to initiating therapy. The use of LMWH is contraindicated in patients with active major bleeding, and caution is advised when used in patients with any disease state with an increased risk of hemorrhage.
Spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with use of epidural or spinal anesthesia or after lumbar puncture. Additionally, the concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants may also increase the risk. The LMWHs carry a black box warning cautioning users of this risk. Patients should be monitored frequently for symptoms of neurological impairment if epidural anesthesia, lumbar puncture, or spinal anesthesia are employed.
Platelet counts should be monitored in patients receiving LMWHs. If thrombocytopenia occurs, LMWH treatment should be discontinued. LMWHs are contraindicated in patients with HIT or a history of HIT, due to the risk of HIT-associated thrombosis.
LMWHs are excreted via the kidney; therefore, delayed elimination and subsequent accumulation may occur in patients with renal impairment. Patients with renal impairment should be observed for signs and symptoms of bleeding during LMWH therapy. Anti-factor Xa monitoring may be considered in patients with severe renal impairment to avoid toxicity and ensure therapeutic concentrations. In patients with a CrCl < 30ml/min, tinzaparin and dalteparin use is not recommended; however, enoxaparin has been studied in this population and dose adjustment recommendations are available. In a study comparing enoxaparin and tinzaparin for 8 days in 55 elderly patients with CrCl between 20 and 50 ml/min, enoxaparin was found to accumulate, but tinzaparin did not.
Use LMWHs cautiously in geriatric patients, especially those with renal impairment. Tinzaparin should not be used in patients >= 70 years of age with renal impairment and is contraindicated in patients >= 90 years of age with CrCl <= 60 ml/min.
Planes A, Samama MM, Lensing AWA, et al. Prevention of deep vein thrombosis after hip replacement: comparison between two low-molecular weight heparins, tinzaparin and enoxaparin. Thromb Haemost 1999;81:22-25.
Wells PS, Anderson DR, Rodger MA, et al. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2005;165(7):733-8
Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). CHEST 2008;133:340S-380S.
Fareed J, Walenga JM, Hoppensteadt D, et al. Biochemical and pharmacologic inequivalence of low-molecular-weight heparins. Ann N Y Acad Sci. 1989;556:333-353.
Boneu B, Caranobe C, Cadroy Y, et al. Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit. Semin Thromb Hemost. 1988;14(1):18-27.
Palm M, Mattsson C. Pharmacokinetics of heparin and low molecular weight heparin fragment (Fragmin) in rabbits with impaired renal or metabolic clearance. Thromb Res. 1985;40:129-133.
Fareed J, Adiguzel C, Thethi I. Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism. Thromb J. 2011;9(1):5.
Michalis LK, Katsouras CS, Papamichael N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am Heart J. 2003;146:304-310.
Katsouras C, Michalis LK, Papamichael N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months. Am Heart J. 2005;150:385-391.
Mahe I, Aghassarian M, Drouet L, et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97(4):581-586.
Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New York, NY: Informa Healthcare USA; 2007.
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