Low molecular weight heparin

Key Terms: Deep vein thrombosis.

Definition

Low molecular weight heparins (LMWHs) belong to a class of medications known as blood thinners. They are used to stop blood clots from forming and growing.

Purpose

LMWHs are used to prevent and treat blood clots in persons undergoing certain types of surgery, recent heart attack, severe chest pain caused by disease of heart vessels usually from fat deposits (unstable angina), and people who have blood clots in their veins (also known as deep vein thrombosis or DVT) or lungs (also known as pulmonary embolism or PE). As of 2001, there are three drugs that belong to the class of LMWHs: enoxaparin, dalteparin, and tinzaparin. All three have the same mechanism of action, but differ in their doses, structures, and Food and Drug Administration (FDA) indicated uses.

Many cancer patients can become prone to hypercoagulation, or overactive thickening and clotting of the blood. This makes the patient more likely to experience deep vein thrombosis, possibly leading to death.

Description

LMWHs only became available in the mid-1990s, with enoxaparin (Lovenox) being the first and most studied drug in its class. Dalteparin (Fragmin) was the second LMWH to become available and tinzaparin (Innohep) is the latest addition to this class. These medicines work by inhibiting certain clotting factors in the blood (Factor Xa and thrombin) and preventing blood clots from forming and getting bigger.

LMWHs are closely related to heparin, which is one of the oldest blood thinners available. These drugs have an advantage over heparin in that they have longer duration in the body, more predictable effects after a given dose, require less blood tests to check for their effectiveness and side effects, and do not have to be given in the hospital setting only. LMWHs have been found to be safe and effective in blood clot prevention after general surgery, orthopedic surgery, neurosurgery, multiple trauma, hip fracture, certain types of stroke, unstable angina, heart attack and treatment DVT and PE. These drugs are usually given with warfarin (Coumadin) for treatment of blood clots and with aspirin for prevention of complications after heart attack or angina attack. Besides their use for blood clot prevention and treatment, there have been some research studies in animals and humans to suggest that they may prevent cancer by decreasing the blood supply needed for the tumor to grow. The effects of LMWHs on patients with cancer and blood clots are being investigated. In 2004, clinical trails suggested that LMWHs might interfere with tumor growth and cancer spread, but further study was needed.

Recommended Dosage

Administration

These medicines are given by injection beneath the skin (subcutaneous injection) and should not be injected directly into the vein or muscle. Injections can be given around the navel, upper thigh or buttock. The injection site should be changed daily. Massaging of the site before injection with an ice cube can decrease excessive bruising.

Doses and indications differ between three medicines. These drugs can not be used interchangeably for one another.

Adults

Prevention of Blood Clots After Orthopedic Surgery

The usual dose of tinzaparin is 50 units per kg daily starting two hours before surgery and continuing for 7–10 days. Doses of 75 units per kg per day have also been studied.

Prevention of Blood Clots After Hip or Knee Replacement Surgery

Doses vary between different agents. The usual enoxaparin dose is 30 mg every 12 hours starting 12–24 hours after surgery in patients undergoing hip or knee surgery. Alternatively, 40 mg once a day with the first dose given approximately 12 hours before surgery can be used in patients undergoing hip replacement surgery. The average duration of the initial phase of treatment is 7–10 days (up to 14 days). After the initial phase, 40 mg once a day for three weeks is recommended.

For people undergoing hip replacement surgery, 5,000 units of dalteparin are given 10–14 hours before surgery, then 5,000 units 4–8 hours after surgery, followed by 5,000 units daily. The therapy is usually continued for five to ten days (up to 14 days). A physician should be consulted for alternative dosing regimens.

Prevention of Dvt in Patients At High Risk for Blood Clots After Abdominal Surgery

Enoxaparin is usually given at a dose of 40 mg once daily with the first dose given two hours before surgery for seven to ten days, up to 12 days.

In patients who are at moderate to high risk of blood clots, the usual dose of dalteparin is 2,500 units daily generally given for five to ten days. The first dose should be given one to two hours before surgery. In patients who are at high to very high risk of blood clots (those with cancer or history of DVT or PE) 5,000 units are given on the evening before surgery, followed by 5,000 units/day for five to ten days. A physician should be consulted for alternative dosing schedules.

Tinzaparin is usually dosed at 3,500 units daily starting two hours before surgery and continuing for seven to ten days.

Treatment of Dvt With or Without Pe

Enoxaparin doses of 1 mg per kg twice a day are given when people are treated at home. People who are treated in the hospital can be given 1 mg per kg twice a day or 1.5 mg per kg at the same time once a day. Warfarin is usually given to finish treatment and the two drugs over-lap for about 72 hours until good response to warfarin is confirmed by blood tests.

Tinzaparin is usually dosed at 175 units per kg daily for six days or until good response to warfarin is confirmed by blood tests.

Unstable Angina or Heart Attack

In patients who are also getting aspirin the usual dose of enoxaparin is 1 mg per kg every 12 hours for a minimum of two days (usually two to eight days).

The usual dose of dalteparin in people who are also getting aspirin is 120 units per kg (up to a maximum 10,000 units) every 12 hours. Treatment should continue until the patient is stable for five to eight days.

Children

Treatment of Dvt With or Without Pe

Children younger than two months of age should receive enoxaparin 1.5 mg per kg every 12 hours. Children older than two months of age should receive enoxaparin 1 mg per kg every 12 hours. A physician will do a blood test four to six hours after the dose to check for effectiveness.

Prevention of Blood Clots

The usual dose of enoxaparin is 0.75 mg per kg every 12 hours for children younger than two months and 0.5 mg per kg every 12 hours for children older than two months of age. A physician will do a blood test four to six hours after the dose to check for effectiveness.

Precautions

The use of LMWHs should be avoided in persons undergoing any procedure involving spinal puncture or anesthesia. Using these medicines before these procedures has caused severe bruising and bleeding into the spine and can lead to paralysis.

The use of these medicines should be avoided in patients with allergies to LMWHs, heparin, or pork products, allergies to sulfites or benzyl alcohol, people with active major bleeding, and people with a history of heparin-induced low blood platelet count (also known as heparin-induced thrombocytopenia or HIT).

LMWHs should be used with caution in the following persons:

• people with bleeding disorders
• people with a history of recent stomach ulcers
• people who recently had brain, spine, or eye surgery
• people on other blood thinners (such as warfarin, aspirin, ibuprofen, naproxen) because of increased risk of bleeding
• people with kidney or liver disease (the dose of LMWHs may need to be decreased)
• breast-feeding mothers (it is not known if these medicines cross into breast milk)
• women who are pregnant, unless benefits to the mother outweigh the risks to the baby

A doctor should be contacted immediately if any of these symptoms develop:

• tingling, weakness, numbness or pain
• blood in the urine or stool
• itching, swelling, skin rash, trouble breathing
• unusual bleeding or bruising

A physician may perform blood tests during therapy with LMWHs to prevent side effects. Blood tests to check for effectiveness of these medicines are usually not needed, except in children, people with kidney disease, and overweight persons.

Side Effects

The most common side effects of LMWHs include irritation and pain at the injection site, easy bruising and bleeding, fever, increase in liver enzyme tests usually without symptoms, and allergic reactions. Severe painful erection sometimes requiring surgery has been reported with tinzaparin in some patients. LMWHs can lower platelet counts, which may necessitate discontinuation.

Interactions

LMWHs should be used with caution in people on other oral blood thinners (aspirin, non-steroidal anti-inflammatory drugs, warfarin, and ticlopidine) because of increased risk of bleeding. If using both drugs together is necessary, the patients must be closely monitored.

Resources

Periodicals

"Low-molecular Weight Heparins May Interfere With Tumor Growth and Metastasis." Drug Week (July 2, 2004): 269.

—Olga Bessmertny, Pharm.D.; Teresa G. Odle

In medicine, low-molecular-weight heparin (LMWH) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis.^[1]

Heparin is a naturally-occurring polysaccharide that inhibits coagulation, the process whereby thrombosis occurs (see Heparin: Mechanisms of action). Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of molecular weight from 5000 to over 40,000 Daltons, making up polydisperse pharmaceutical-grade heparin.^[2]

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis (see anticoagulation). However, the effects of natural, or unfractionated heparin can be difficult to predict. After a standard dose of unfractionated heparin, coagulation parameters must be monitored very closely to prevent over- or under-anticoagulation.

Low-molecular-weight heparins (LMWHs), in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin. They have a potency of greater than 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5.^[3]

Contents 1 Low-molecular-weight heparin products 1.1 Differences between low molecular weight heparin products 2 Differences from unfractionated heparin 3 Clinical uses 3.1 Use in venothromboembolic disease associated with cancer 4 See also 5 References 6 External links

Low-molecular-weight heparin products

The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anhydromannitol

Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin.^[4] These are listed below:

• Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ardeparin (Normiflo)
• Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin (Sandoparin)
• Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the manufacture of enoxaparin (Lovenox and Clexane)
• Oxidative depolymerisation with Cu²⁺ and hydrogen peroxide. Used in the manufacture of parnaparin (Fluxum)
• Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of tinzaparin (Innohep and Logiparin)
• Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (Fragmin), reviparin (Clivarin) and nadroparin (Fraxiparin)

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown to the left.

UA(2S)-GlcNS(6S)

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown to the left.

Differences between low molecular weight heparin products

Comparisons between LMWHs prepared by similar processes vary. For example, a comparison of Dalteparin and Nadroparin suggests they are more similar than products produced by different processes. However, comparison of enoxaparin and tinzaparin shows they are very different from each other with respect to chemical, physical, and biological properties.

As might be expected, products prepared by distinctly-different processes are dissimilar in physical, chemical, and biological properties.

see references.^[5][6][7][8].^[9][10]

Differences from unfractionated heparin

Its differences with unfractioned heparin include:

• Average molecular weight: heparin is about 20000 Da and LMWH is about 3000 Da
• Once-daily dosing, rather than a continuous infusion of unfractionated heparin
• No need for monitoring of the APTT coagulation parameter
• Possibly a smaller risk of bleeding
• Smaller risk of osteoporosis in long-term use
• Smaller risk of heparin-induced thrombocytopenia, a feared side-effect of heparin.
• The anticoagulant effects of heparin are typically reversible with protamine sulfate, while the effect on LMWH is limited
• Has less of an effect on thrombin compared to heparin, but maintains the same effect on Factor Xa.

Clinical uses

Because it can be given subcutaneously and does not require APTT monitoring, LMWH permits outpatient treatment of conditions such as deep vein thrombosis or pulmonary embolism that previously mandated inpatient hospitalization for unfractionated heparin administration.

Because LMWH has more predictable pharmacokinetics and anticoagulant effect, LMWH is recommended over unfractionated heparin for patients with massive pulmonary embolism,^[11] and for initial treatment of deep vein thrombosis.^[12] Prophylactic treatment of hospitalized medical patients with LMWH and similar anticoagulants results in a 53% reduction of risk for symptomatic deep vein thrombosis.^[13]

The use of LMWH needs to be monitored closely in patients at extremes of weight or in-patients with renal dysfunction. An anti-factor Xa activity may be useful for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasible in patients that have end-stage renal disease.

Use in venothromboembolic disease associated with cancer

The CLOT study, published in 2003, showed that, in patients with malignancy and acute venous thromboembolism, dalteparin was more effective than coumarin in reducing the risk of recurrent embolic events.^[14] Use of LMWH in cancer patients for at least the first 3 to 6 months of long-term treatment is recommended in numerous guidelines and is now regarded as a standard of care.^[15]

See also

• Deep vein thrombosis — General medical inpatients

References

1. ^ Weitz JI (1997). "Low-molecular-weight heparins". N Engl J Med 337 (10): 688–98. doi:10.1056/NEJM199709043371007. PMID 9278467. 
2. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5–16. 
3. ^ European Pharmacopedia Commission (1991). Pharmeuropa 3: 161–165. 
4. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5–16. 
5. ^ Green, D. Hirsh, J. Heit, J. et al. (1991). "Low molecular weight heparin: A critical analysis of clinical trials". Pharmacol. Rev. 2: 45–50. 
6. ^ Barrowcliffe, T. W. (1995). "Low molecular weight heparin(s)". Br. J. Haematol. 90: 1–7. doi:10.1111/j.1365-2141.1995.tb03373.x. 
7. ^ Donayre C. E. (1996). "Current use of low molecular weight heparins". Semin. Vascul. Surg. 9: 362–371. 
8. ^ Hunt, D. (1998). "Low molecular weight heparins in clinical practice". Southern Medical J. 91: 2–10. 
9. ^ Fareed, J. Jeske, W. Hoppensteadt, D. Clarizio, R. Walenga, J. M. (1998). "Low molecular weight heparins: Pharmacologic profile and product differentiation". Am. J. Cardiol. 82: 3L–10L. doi:10.1016/S0002-9149(98)00105-2. 
10. ^ Ramos-Sánchez MC, Barrio-Arredondo MT, De Andrés Santos AI, Martín-Gil J, Martín-Gil F.J. (1995). "Thermal analysis of aqueous solutions of heparins". Thermochim Acta 262: 109–115. doi:10.1016/0040-6031(95)02375-C. 
11. ^ Hull RD (2008). "Treatment of pulmonary embolism: The use of low-molecular-weight heparin in the inpatient and outpatient settings". THROMBOSIS AND HAEMOSTASIS 99 (3): 502–510. PMID 18327398. 
12. ^ Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, Bass EB, Weiss KB, Green L, Owens DK; American College of Physicians; American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism (2007). "Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians". ANNALS OF INTERNAL MEDICINE 146 (3): 204–210. PMID 17261857. http://www.annals.org/cgi/content/full/146/3/204. 
13. ^ Douketis JD, Moinuddin I (2008). "Prophylaxis against venous thromboembolism in hospitalized medical patients: an evidence-based and practical approach". POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 118 (4): 209–215. PMID 18575420. http://tip.org.pl/pamw/issue/article/164.html. 
14. ^ Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M (2003). "Low-molecular-weight heparin versus a coumadin for the prevention of recurrent venous thromboembolism in patients with cancer". N Engl J Med 349 (2): 146–53. doi:10.1056/NEJMoa025313. PMID 12853587. 
15. ^ Nishioka J, Goodin S (2007). "Low-molecular-weight heparin in cancer-associated thrombosis: treatment, secondary prevention, and survival". JOURNAL OF ONCOLOGY PHARMACY PRACTICE 13 (2): 85–97. PMID 17873108. 

External links

• MeSH Low+Molecular+Weight+Heparin

v • d • e Antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs) (B01) Antiplatelet drugs Glycoprotein IIb/IIIa inhibitors Abciximab • Eptifibatide • Tirofiban ADP receptor/P2Y12 inhibitors (Thienopyridines) Clopidogrel • Ticlopidine • Prasugrel Prostaglandin analogue (PGI2) Beraprost • Prostacyclin • Iloprost • Treprostinil COX inhibitors Acetylsalicylic acid/Aspirin # • Aloxiprin • Carbasalate calcium Other Ditazole • Cloricromen • Dipyridamole • Indobufen • Picotamide • Triflusal Anticoagulants Vitamin K antagonists (inhibit II, VII, IX, X) coumarins: Acenocoumarol • Coumatetralyl • Dicoumarol (Dicumarol) • Ethyl biscoumacetate • Phenprocoumon • Warfarin 1,3-Indandiones: Clorindione • Diphenadione • Phenindione other: Tioclomarol Factor Xa inhibitors (with some II inhibition) Heparin group/ glycosaminoglycans/ (bind antithrombin) low molecular weight heparin (Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, Tinzaparin) oligosaccharides (Fondaparinux, Idraparinux) heparinoid (Danaparoid, Sulodexide, Dermatan sulfate) Direct Xa inhibitors xabans (Apixaban, Otamixaban, Rivaroxaban) Direct thrombin (II) inhibitors bivalent: Hirudin (Bivalirudin, Lepirudin, Desirudin) univalent: Argatroban • Dabigatran • Melagatran‡ • Ximelagatran‡ Other Defibrotide • Ramatroban • Antithrombin III • Protein C (Drotrecogin alfa) Thrombolytic drugs/ fibrinolytics plasminogen activators: TPA (Alteplase, Reteplase, Tenecteplase) • UPA (Urokinase, Saruplase) • Streptokinase # • Anistreplase • Monteplase other serine endopeptidases: Ancrod • Fibrinolysin Brinase Non-medicinal Citrate • EDTA • Oxalate #WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)