Low molecular weight heparins

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.

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.

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 overlap 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.

Olga Bessmertny, Pharm.D.

KEY TERMS

Deep vein thrombosis

—Also known as DVT, a condition in which a blood clot (thrombus) formed in one part of the circulation, becomes detached and lodges at another point (usually in one of the veins of the legs or arms). People may feel pain, redness, and swelling at the site where the blood clot lodges in. This condition is treated with blood thinning drugs such as LMWHs, heparin, or warfarin.

Pulmonary embolism

—Also known as PE, a condition in which a blood clot usually formed in of the leg veins becomes detached and lodges in the lung artery or one of its branches. Patients may be coughing up blood and experience trouble breathing. This condition is treated with blood thinning drugs such as LMWHs, heparin, or warfarin.