Low Molecular Weight Heparins (LMWHs)

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.[50262][49182]

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.[50260]

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.