Low-Molecular-Weight Heparin (LMWH)

Mechanism of Action

The coagulation cascade aims to convert fluid blood into a clot, thus preventing bleeding. LMWHs are anticoagulants that inhibit the coagulation cascade's final common pathway, which converts fibrinogen into fibrin by the activity of thrombin.[10] LMWH inhibits coagulation by activating antithrombin III, which binds to and inhibits factor Xa. In doing so, it prevents activation of the final common pathway; Xa inactivation means that prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin for clot formation.

LMHW is a small fragment of heparin, a larger mucopolysaccharide.[10] Heparin works similarly by binding antithrombin III and activating it. Heparin also has a binding site for thrombin so that thrombin can interact with antithrombin III and heparin, thus inhibiting coagulation. Heparin has a faster onset of anticoagulant action as it will inhibit Xa and thrombin, while LMWH acts only through Xa inhibition.[10] Enoxaparin and dalteparin are both low-molecular-weight heparins that vary in their molecular size, pharmacodynamics, and potency. Enoxaparin has a lower average molecular weight (approximately 4,500 Da) than dalteparin (approximately 6000 Da), affecting their pharmacodynamic profiles.[11][12][13]

Pharmacokinetics

Absorption: Maximum anti-factor Xa and antithrombin activities occur 3 to 5 hours after subcutaneous administration of LMWH. In healthy subjects, the mean absolute bioavailability of enoxaparin after a 1.5 mg/kg subcutaneous dose is approximately 100%, while dalteparin has an absolute bioavailability of roughly 87%.

Distribution: The volume of distribution for enoxaparin's anti-factor Xa activity is approximately 4.3 L. For dalteparin, the volume of distribution for anti-Xa activity ranges between 40 mL/kg and 60 mL/kg.

Metabolism: LWMH is metabolized in the liver through desulfation and depolymerization to lower molecular weight fragments with reduced biological potency.

Elimination: The total body clearance of enoxaparin is 26 mL/min following intravenous dosing. About 40% of radioactivity and 8% to 20% of anti-factor Xa activity from intravenous dosing are recovered in the urine within 24 hours. The elimination half-life based on anti-factor Xa activity for enoxaparin is approximately 4.5 hours after a single subcutaneous dose and extends to about 7 hours after repeated dosing. The half-life of dalteparin typically ranges between 2 to 2.5 hours after intravenous administration. After subcutaneous administration, longer terminal half-lives (3 to 5 hours) may be observed due to delayed absorption. In patients with chronic kidney disease requiring hemodialysis, the terminal half-life of anti-Xa activity for dalteparin may be prolonged.

Administration

Available Dosage Forms and Strengths

LMWH is administered via subcutaneous injection. This has long-term implications on the choice of anticoagulant for prophylaxis; for example, in orthopedic patients recovering from joint replacement surgery or in the treatment of DVT/PE. Patients often dislike injections, especially self-administered ones, complaining of pain or bleeding with injection and prefer an oral alternative.[14] There are oral options for anticoagulation in the non-pregnant population, whose members often prefer these medications, which are accompanied by fewer needle and sharps-related risks. Outside of pregnancy, these oral options are not suitable because of transport over the placenta and risks to the embryo/fetus. Compared to heparin, LMWHs have a longer half-life, so dosing is more predictable and can be less frequent, most commonly once daily. However, depending on local administration policy, patients with greater body weight may need a higher (and sometimes second) dose daily.[10] Enoxaparin is available as a multidose 100 mg vial and as a prefilled syringe in 30 mg, 40 mg, 60 mg, 100 mg, and 150 mg doses. Additionally, dalteparin is available as an injectable solution in single-dose prefilled syringes with 2,500 IU, 5,000 IU, 7,500 IU, 10,000 IU, 12,500 IU, 15,000 IU, and 18,000 IU. Dalteparin preservative-free subcutaneous injection solution is also available in a dosage of 10,000 IU. Assess all patients for bleeding disorders before starting treatment unless urgently required.

Dosage

Enoxaparin 

According to product labeling, the following doses are suggested. However, patients should be evaluated individually regarding renal impairment and obesity, and clinicians should follow institutional protocols.[15] 

• Abdominal surgery: 40 mg subcutaneously once daily, 2 hours before surgery, for 7 to 10 days

• Hip/knee replacement surgery: 30 mg every 12 hours, starting 12 to 24 hours after surgery, for 7 to 10 days. For hip surgery, 40 mg once daily may be considered for up to 3 weeks, starting 12 hours before surgery.

• Medical patients (acute illness): 40 mg once daily for 6 to 11 days due to thromboembolic risk from restricted mobility

• Deep vein thrombosis (DVT):

  • Outpatient: 1 mg/kg every 12 hours
  • Inpatient: 1 mg/kg every 12 hours or 1.5 mg/kg once daily
  • Continue for at least 5 days until the patient's INR is 2 to 3

• Unstable angina/non-Q-wave myocardial infarction: 1 mg/kg every 12 hours, with aspirin (100 to 325 mg daily), for 2 to 8 days

• Acute ST-segment elevation myocardial infarction:

  • Initial: 30 mg IV bolus + 1 mg/kg subcutaneous, then 1 mg/kg every 12 hours
  • Administer aspirin (75 to 325 mg daily)
  • For PCI: No additional dosing if the last dose was administered less than 8 hours before balloon inflation. If more than 8 hours has elapsed, administer 0.3 mg/kg IV bolus.

Dalteparin

• Unstable angina & non-Q-wave myocardial infarction: 120 units/kg (max 10,000 units) subcutaneously every 12 hours with aspirin (75 to 165 mg daily) for 5 to 8 days.

• Prophylaxis of deep vein thrombosis (DVT) after surgery:

  • Hip replacement: 2,500 to 5,000 units subcutaneously, depending on the timing of the dose
  • Abdominal surgery: 2,500 units subcutaneously before surgery, then daily for 5 to 10 days; 5,000 units for high-risk patients
  • Acute illness: 5,000 units subcutaneously once daily for 12 to 14 days

• Symptomatic VTE in cancer patients:

  • First 30 days: 200 units/kg subcutaneously daily, maximum 18,000 units
  • Months 2 to 6: 150 units/kg subcutaneously daily, maximum 18,000 units (weight-based dosing)

• Pediatric VTE treatment:

  • Birth to 2 years: 150 units/kg twice daily subcutaneously
  • 2 to 8 years: 125 units/kg twice daily subcutaneously
  • 8 to 17 years: 100 units/kg twice daily subcutaneously
  • Adjust based on anti-Xa levels

Specific Patient Populations

Hepatic impairment: No dosage adjustments are provided in the product labeling; administer with caution.

Renal impairment: Exposure to enoxaparin is increased in severe renal impairment (CrCl <30 mL/min). A dose adjustment is recommended for both therapeutic and prophylactic dosing. No dose adjustment is necessary for patients with a creatinine clearance between 30 and 80 mL/min. The labeling advises adjusting the dose of dalteparin for patients with a creatinine clearance of less than 30 mL/min.[16]

Pregnancy considerations: The American College of Cardiology and American Heart Association guidelines recommend that pregnant women with mechanical valve prostheses using LMWH transition to unfractionated heparin at least 36 hours before scheduled delivery.[17] The American Society of Hematology (ASH) guideline panel recommends antithrombotic therapy for pregnant women with acute venous thromboembolism (VTE). The ASH also recommends LMWH over unfractionated heparin (UFH) for pregnant women with acute VTE.[18][19] According to ACOG guidelines, LMWH crosses the placenta and is considered safe for pregnant women.[20]

Breastfeeding considerations: With a molecular weight of 2000 to 9000 daltons, dalteparin has low levels in breast milk, resulting in a small amount ingested by infants. Therefore, no special precautions are necessary. Similarly, enoxaparin, which has a molecular weight of 2000-8000 daltons, is also unlikely to be present in significant amounts in breast milk or absorbed by infants. Limited data indicates that maternal enoxaparin, at doses up to 40 mg daily, does not lead to adverse effects in breastfed infants, so no special precautions are required.[21][22]

Pediatric patients: According to the American Academy of Pediatrics, thrombosis in preterm infants (a growing concern due to improved survival rates) is often treated with low molecular weight heparin (LMWH). A retrospective review of 10 preterm infants with thrombosis showed that higher doses of LMWH are required compared to term neonates to achieve therapeutic anti-factor Xa levels, which took an average of 33 days. Only 2 patients died from complications; the rest achieved clot resolution. No major bleeding events occurred. Continued monitoring and dose adjustments are necessary to maintain therapeutic anticoagulation.[23]

Older patients: LMWH should be cautiously administered in older patients, particularly those with low body weight (<45 kg) or impaired renal function due to potential delayed elimination. Monitoring is recommended, especially when co-administered with antiplatelet agents. A network meta-analysis of 27 RCTs involving older patients showed no significant differences in the efficacy and safety of different low-molecular-weight heparins (LMWHs).[24]

Adverse Effects

As an anticoagulant, the main risk of LMWH is bleeding. Less common adverse effects include heparin-induced thrombocytopenia, osteoporosis, spontaneous fractures, hypoaldosteronism, and hypersensitivity reactions.[25][26][27][28] In assessing the need for anticoagulant medication, clinicians must consider the risks posed by bleeding versus the risks of clotting.

Drug-Drug Interactions

• Drugs that may increase the risk of hemorrhage should be discontinued before LMWH therapy is initiated. These medications include antiplatelet drugs, aspirin, NSAIDs, dipyridamole, and sulfinpyrazone. If co-administration is essential, close clinical and laboratory monitoring is required.

• Administration of LMWH with other anticoagulants, such as direct oral anticoagulants (eg, apixaban and rivaroxaban), is not advisable due to the risk of bleeding.

• The combination of LMWH with thrombolytic drugs should be administered with caution due to the synergistic effect and increased risk of bleeding. If administration is necessary in acute ischemic stroke, a follow-up CT/MRI 24 hours after IV alteplase administration should be obtained before initiating anticoagulants.[29]

Contraindications

Contraindications to all heparins/LMWH include active major bleeding, trauma, epidural hematoma, hemorrhagic disorders, peptic ulcer disease, recent cerebral hemorrhage, severe hypertension, recent surgery on the eye or nervous system, and heparin-induced thrombocytopenia.[30] In these cases, the risks of anticoagulation and bleeding outweigh the potential benefit from LMWH acting as a VTE prophylaxis or at treatment doses.

Box Warnings

The FDA has issued a warning regarding the risk of epidural/spinal hematoma. Epidural or spinal hematomas can occur in patients receiving low molecular weight heparins (LMWH) who are undergoing neuraxial anesthesia or lumbar puncture. These hematomas can lead to permanent paralysis. Several factors may increase the likelihood of developing epidural or spinal hematomas, including indwelling epidural catheters, concurrent administration of drugs that increase the risk of bleeding, such as non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet drugs, or other anticoagulants, traumatic or repeated spinal/epidural punctures, and a history of spinal deformity or previous spinal surgery.

Warnings and Precautions

• Risk of bleeding with concomitant medical conditions: LMWH should be used with caution in patients with a bleeding diathesis, uncontrolled arterial hypertension, recent gastrointestinal bleeding, diabetic retinopathy, renal dysfunction, and hemorrhage.

• Heparin-induced thrombocytopenia (HIT): LMWH may cause heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITTS), which can lead to organ infarction, limb ischemia, or death.[31] Enoxaparin should not be prescribed to patients with a history of immune-mediated HIT within 100 days or if circulating antibodies are detected. Circulating antibodies may persist for several years. Enoxaparin should only be used in patients with a history of HIT if more than 100 days have passed since the prior HIT episode and no circulating antibodies are present. Using LMWH in these cases should involve a careful benefit-risk assessment and consideration of alternative treatments.

• Thrombocytopenia: Thrombocytopenia may occur with the use of LMWH. Monitor platelet counts.

• Gasping syndrome: Dalteparin should be used with caution in neonates, and pregnant women should be cautious due to the preservative benzyl alcohol, which can cause severe reactions like "gasping syndrome" (CNS depression, gasping, metabolic acidosis). When prescribing, clinicians should consider the total benzyl alcohol exposure from all sources. Preservative-free formulations should be used to minimize the risk of gasping syndrome.

Monitoring

Clinicians must monitor the patient's CBC and look for signs of bleeding/thrombocytopenia.[30] According to the American College of Chest Physicians (ACCP) guidelines, low-molecular-weight heparins (LMWHs) are typically administered in fixed or weight-adjusted doses for thromboprophylaxis and therapeutic purposes, so routine monitoring may not be required. However, coagulation monitoring using anti-factor Xa levels is advisable for patients with obesity, renal insufficiency, or when treatment doses of LMWH are given during pregnancy.[32] According to the American Society of Regional Anesthesia, the anti-factor Xa activity effectively assesses the anticoagulant effect of LMWH. Anti–factor Xa activity may be evaluated before neuraxial blockade.[7] Monitoring serum creatinine and clearance is essential; dosing adjustments may be required for renal impairment.

Toxicity

Signs and Symptoms of Overdose

An overdose of LMWH, like enoxaparin or dalteparin, may cause hemorrhagic complications. Bleeding complications from LMWH overdose can be life-threatening. Clinical presentations may include severe bleeding, disseminated intravascular coagulation and multi-organ failure, traumatic compartment syndrome, hemothorax after cardiac surgery, and spontaneous retroperitoneal hematoma.[33]

Management of Overdose

Clinicians should focus on maintaining hemodynamic stability and provide supportive care. Identifying the source of bleeding is critical.[33] Treatment of bleeding associated with LMWH involves stopping the drug and administering protamine sulfate, a strong half-life protein forming a strong bond with the heparin, producing an inactive complex.[10] Protamine neutralizes the anticoagulant effects of standard heparin in an equimolar dose; however, due to reduced binding to LMWH fractions, only the anti-factor IIa activity of LMWH is entirely reversed. The anti-factor Xa activity is not completely neutralized. Anti-factor IIa and Xa activities may return up to 3 hours following protamine reversal.[7] For enoxaparin, administer 1 mg of protamine per 1 mg of enoxaparin within 8 hours. For dalteparin, use 1 mg of protamine per 100 anti-Xa units. If more than 8 hours have passed or a second dose is needed, administer 0.5 mg of protamine per 1 mg of enoxaparin or 100 anti-Xa units of dalteparin. A second dose may be required if aPTT remains prolonged 2 to 4 hours after the first infusion. If at least 12 hours have passed since the last dose of enoxaparin or dalteparin, protamine may not be needed. However, aPTT may still be prolonged more than after heparin. Anti-factor Xa activity is never fully neutralized, with a maximum of about 60% for enoxaparin and 60% to 75% for dalteparin. Protamine sulfate should be used with caution due to the risk of severe hypotension and anaphylactoid reactions. Fatal reactions, including anaphylaxis, have been reported; protamine sulfate should only be administered when resuscitation and anaphylactic shock treatments are available.[34]

Enhancing Healthcare Team Outcomes

Low-molecular-weight heparins are commonly used in clinical practice, especially in VTE (DVT and PE) prophylaxis. Estimates are that over half of the patients admitted to hospital acutely unwell are at risk of thromboembolic disease and that 5% to 10% of hospital deaths are due to VTE, necessitating the need for accurate VTE risk assessment and appropriate prophylaxis.[35][36][37] Approximately one-third of VTE-related deaths occur postoperatively, but research has shown that the use of LMWH postoperatively in general surgery has reduced VTE-related mortality by 70%. At the same time, it also increased the risk of bleeding and wound hematomas.[38][39] 

Risk assessment for VTE prophylaxis considers the reason for hospital admission, potential benefits, and risks of prophylaxis using pharmacologically measured such as LMWH. NICE Guideline NG89 (venous thromboembolism in over 16s) discusses the need for VTE assessment upon admission to the hospital. National Tool for VTE risk assessment was implemented in 2010, and since then, over 90% of patients admitted to hospitals have completed a VTE risk assessment. This guideline describes other VTE prophylaxis measures, including anti-embolism stockings, foot and calf pump devices, LMWH, and other oral anticoagulants such as warfarin and direct Xa inhibitors (direct oral anticoagulants [DOACs], rivaroxaban). Estimates are that prophylaxis, with appropriate risk assessment, has reduced DVT incidence by 70%.[36] Multiple reviews have shown that VTE prophylaxis is appropriate in trauma, medical, and surgical situations and that LMWH is suitable for this purpose.[40][41][42][43][44]  

Interprofessional healthcare team members must understand the risks posed by VTE and engage in appropriate risk assessment and pharmacological or mechanical prophylaxis. When there is an interprofessional approach, it has shown benefits in VTE prophylaxis prescription rates.[45] VTE prophylaxis and the administration of LMWH have been key considerations for patient care in a hospital setting and on discharge for trauma and elective orthopedic surgical patients. The interprofessional approach to minimizing VTE is key; it involves correct and timely assessment and reassessment of pharmacological and mechanical prophylaxis needs, early and appropriate mobilization of patients, education of staff and patients regarding risks, signs, and symptoms of VTE, and understanding the importance of prophylaxis. This interprofessional team includes clinicians, specialists, nurses, and pharmacists, all working collaboratively and engaging in open information sharing to drive optimal patient outcomes while preventing adverse events. Primary care physicians manage patients with chronic conditions requiring low-molecular-weight heparin (LMWH) for thrombosis prevention or treatment. Orthopedic surgeons prescribe LMWH post-surgery to prevent venous thromboembolism (VTE) following joint replacements or orthopedic procedures. Advanced practice providers administer and adjust LMWH dosages while educating patients about anticoagulation therapy and its adverse effects. Emergency medicine physicians rapidly stabilize the patients in overdose. Nurses administer LMWH injections, monitor for adverse effects, and educate patients. Pharmacists review and dispense LMWH prescriptions, ensure correct dosing, check for drug interactions, and provide patient administration guidance.

Clinically, the use of low-molecular-weight heparins is diverse, both in treatment and in prophylaxis. The pros and cons of LMWH, compared with other anticoagulants and mechanical VTE prophylaxis measures, are numerous. However, the key factor is patient assessment, discussing options with them, and ultimately, deciding to promote compliance with their VTE prophylaxis or anticoagulation and understanding their clinical need. The nurse and the pharmacist ensure that the patient is prescribed an LMWH before and after most surgical procedures. Also, before discharge, the patient must be educated on administering the LMWH and the benefits of compliance. The patient should also learn the signs and symptoms of VTE to watch out for and when to return to the primary care provider.[46]

Evidence-Dased Outcomes

There are dozens of randomized studies showing that several LMWHs can lower the risk of VTE and PE in patients with cancer, post-surgery, and after admission to the hospital with a medical illness. Today, the risk of bleeding from LMWH has been minimal. However, the use of LMWH in pregnancy remains debatable because there are not many good, long-term studies that have elucidated the effects of these agents on the fetus.[47][48]