Low-Molecular-Weight Heparin (LMWH)

Continuing Education Activity

Low-molecular-weight heparins (LMWHs), for example, dalteparin, enoxaparin, among others, are anticoagulants. These drugs are used in the prophylaxis of venous thromboembolic disease (VTE) on acute or elective admission to the hospital, and they are used in the treatment of deep vein thromboses (DVT) and pulmonary embolism (PE). This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of LMWH, pertinent for members of the interprofessional team in the treatment of patients with conditions where this agent is indicated.

Objectives:

• Identify the mechanism of action of various low molecular weight heparin agents.
• Summarize the indications for using LMWH agents.
• Review the adverse event profiles of various LMWH agents, summarizing the key differences.
• Explain the importance of improving care coordination among the interprofessional team to enhance care delivery for patients when using low molecular weight heparins.

Indications

Low-molecular-weight heparins (LMWHs), for example, dalteparin, enoxaparin, among others, are anticoagulants. These drugs are used in the prophylaxis of venous thromboembolic disease (VTE) on acute or elective admission to the hospital, and they are used in the treatment of deep vein thromboses (DVT) and pulmonary embolism (PE).[1] The British National Formulary (BNF) and National Institute for Health and Care Excellence (NICE) have stated the use of LMWHs have approval for: 

• DVT prophylaxis in medium and high-risk groups (surgical, orthopedic, and medical patients)
• Treatment of venous thromboembolism in pregnancy
• Treatment of DVT and PE in nonpregnant women (those with both high and low risk of recurrence)
• Treatment of STEMI (in both those undergoing percutaneous coronary intervention and those not)
• Unstable angina
• Prevention of clotting in extracorporeal circuits

LMWHs are not the sole medications used for these purposes; therefore, a thorough understanding of the variously available anticoagulants and their pros and cons is necessary for an appropriate prescription.

Mechanism of Action

LMWHs are anticoagulants acting by inhibition of the final common pathway of the coagulation cascade.[2] The coagulation cascade's goal is to fluid blood into a clot, thus preventing bleeding. The final common pathway is the conversion of fibrinogen into fibrin by the activity of thrombin. LMWH inhibits coagulation by activating antithrombin III. Antithrombin III binds to and inhibits factor Xa. In doing so, it prevents activation of the final common path; Xa inactivation means that prothrombin is not activated to thrombin, thereby not converting fibrinogen into fibrin for the formation of a clot. LMHW is a small fragment of a larger mucopolysaccharide, heparin.[2] 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 on Xa inhibition.[2]

Administration

LMWH administration is 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.[3] There are oral options for anticoagulation in the non-pregnant population, which often prefers this option. The oral option poses 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 per day. However, patients with a high body weight will need higher doses and sometimes two doses daily, depending on local administration policy.[2]

Adverse Effects

As an anticoagulant, the main risk of LMWH will be bleeding. 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.[2] Other, less common adverse effects include heparin-induced thrombocytopaenia, osteoporosis, spontaneous fractures, hypoaldosteronism, and hypersensitivity reactions.[4][5][6][7] On assessing the need for anticoagulant medication, there needs to be a risk-benefit analysis of the risks posed by bleeding versus the risks of clotting.

Contraindications

NICE and the BNF suggest that contraindications to all heparins include trauma, epidural half-life, hemorrhagic disorders, peptic ulcer disease, recent cerebral hemorrhage, severe hypertension, and recent surgery to the eye or nervous system. In these cases, the risks of anticoagulation and bleeding outweigh the potential benefit from LMWH acting as a VTE prophylaxis or at treatment doses. As LMWHs are self-administered, it is important to consider dosing in cases of chronic kidney disease, where there is a risk of accumulation and, thus, higher chances of problematic bleeding.

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.[8][9][10] 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.[11][12] 

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 on admission to hospital that a National Tool for VTE risk assessment was implemented in 2010, and since then, over 90% of patients admitted to hospital have a VTE risk assessment completed. 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%.[9] Multiple reviews have shown that VTE prophylaxis is appropriate in trauma, medical, and surgical situations and that LMWH is suitable for this purpose.[13][14][15][16][17]  

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.[18] VTE prophylaxis and the use of not only LMWH have been a key consideration for patient care in a hospital setting and on discharge for both 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 (MDs, DOs, NPs, PAs), specialists, nurses, and pharmacists, all working collaboratively and engaging in open information sharing to drive optimal patient outcomes while preventing adverse events. [Level 5]

Clinically, the use of low-molecular-weight heparins is diverse, both in treatment and in prophylaxis. The pros and cons of LMWH, as compared with other anticoagulants and mechanical VTE prophylaxis measures, are numerous. However, the key factor is patient assessment, discussing options with them, and ultimately, making a decision that will promote compliance with their VTE prophylaxis or anticoagulation and understand the clinical need for them. The nurse and the pharmacist play a vital role in ensuring that the patient is prescribed an LMWH before and after most surgical procedures. Also, before discharge, the patient needs to be educated on how to administer 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.[19] [Level 2]

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.[20][21] [Level 1]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

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2.

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3.

Seaman S, Nelson A, Noble S. Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study. Patient Prefer Adherence. 2014;8:453-61. [PMC free article: PMC3986276] [PubMed: 24748774]

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Prince M, Wenham T. Heparin-induced thrombocytopaenia. Postgrad Med J. 2018 Aug;94(1114):453-457. [PubMed: 30126928]

5.

Gajic-Veljanoski O, Phua CW, Shah PS, Cheung AM. Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis. J Gen Intern Med. 2016 Aug;31(8):947-57. [PMC free article: PMC4945546] [PubMed: 26895998]

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9.

Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ., American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. [PMC free article: PMC3278060] [PubMed: 22315257]

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11.

Mismetti P, Laporte S, Darmon JY, Buchmüller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg. 2001 Jul;88(7):913-30. [PubMed: 11442521]

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13.

Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH. Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev. 2013 Mar 28;(3):CD008303. [PubMed: 23543562]

14.

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16.

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17.

Salazar CA, Malaga G, Malasquez G. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. Cochrane Database Syst Rev. 2010 Apr 14;2010(4):CD005981. [PMC free article: PMC6486302] [PubMed: 20393944]

18.

Streiff MB, Carolan HT, Hobson DB, Kraus PS, Holzmueller CG, Demski R, Lau BD, Biscup-Horn P, Pronovost PJ, Haut ER. Lessons from the Johns Hopkins Multi-Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative. BMJ. 2012 Jun 19;344:e3935. [PMC free article: PMC4688421] [PubMed: 22718994]

19.

Rohailla S, Malinowski AK, Gandhi S, McLeod A, Nisenbaum R, Shehata N. The Approach to Peripartum Management of Anticoagulation: A Multidisciplinary Survey. J Obstet Gynaecol Can. 2018 Jul;40(7):888-895.e6. [PubMed: 29709455]

20.

Matar CF, Kahale LA, Hakoum MB, Tsolakian IG, Etxeandia-Ikobaltzeta I, Yosuico VE, Terrenato I, Sperati F, Barba M, Schünemann H, Akl EA. Anticoagulation for perioperative thromboprophylaxis in people with cancer. Cochrane Database Syst Rev. 2018 Jul 11;7(7):CD009447. [PMC free article: PMC6389341] [PubMed: 29993117]

21.

Farge D, Cajfinger F, Falvo N, Berremili T, Couturaud F, Bensaoula O, Védrine L, Bensalha H, Bonnet I, Péré-Vergé D, Coudurier M, Li V, Rafii H, Benzidia I, Connors JM, Resche-Rigon M. Quality of life in cancer patients undergoing anticoagulant treatment with LMWH for venous thromboembolism: the QUAVITEC study on behalf of the Groupe Francophone Thrombose et Cancer (GFTC). Oncotarget. 2018 Jun 05;9(43):26990-26999. [PMC free article: PMC6007467] [PubMed: 29930745]

Disclosure: Francesca Solari declares no relevant financial relationships with ineligible companies.

Disclosure: Matthew Varacallo declares no relevant financial relationships with ineligible companies.