Low molecular weight heparins: how they work ... what they do.
Low molecular weight heparin reproduces all the positive aspects of unfractionated heparin while requiring minimal monitoring from the laboratory. in addition, this type of heparin is easier to regulate, with fewer interfering substances, and exhibits fewer of the negative side effects associated with unfractionated heparin.(1) Many physicians more frequently choose LMWH to treat thrombosis in a variety of clinical situations, such as a major trauma, hip replacement surgery, and proximal deep-vein thrombosis. Because of the increasing popularity of this drug, it is imperative for medical technologists to familiarize themselves with its actions within the coagulation scheme, Laboratory testing and monitoring will undoubtedly change as a result of the difference in how LMWH affects the clotting process.
The coagulation sequence
A review of the coagulation scheme is helpful in comparing how LMWH interferes with the clotting process as compared with unfractionated heparin therapy. Unfractionated heparin is an acidic glycosaminoglycan isolated from bovine lungs or porcine intestines.(2) Its molecular weight ranges from approximately 3,000-30,000 daltons.(3) Heparin interference with the coagulation process is achieved by attaching to thrombin and antithrombin, by attaching to antithrombin alone, or by inhibiting platelets.(4)
Low molecular weight heparins are small fragments of the unfractionated heparin molecule created by chemical or enzymatic depolymerization.(1) These scaled-down versions of the traditional heparin chain have the specific pentasaccharide sequence that is necessary to bind with antithrombin. This binding inactivates the antithrombin, thus interfering with the coagulation process. Preparations of LMWH are fragments of commercially produced unfractionated heparin that yield molecules with mean molecular weights of 4,000-6,000 daltons.(2) Each commercially produced LMWH has a different recommended dose and reacts differently based on molecular weight. Commercially produced LMWH include enoxaparin, dalteparin, and ardeparin.
Either the intrinsic or extrinsic pathway can activate the clotting process. The intrinsic pathway can be activated by internal trauma, which causes blood vessels to constrict and platelets to clump together, attaching to the injured site. Coagulation factors, or procoagulants, are activated sequentially, and a fibrin clot is formed, which slows and ultimately stops blood flow. The extrinsic pathway may be activated when there is external injury to the skin, introducing tissue factors into the bloodstream. These tissue factors activate factor VII (VIIa), and the coagulation process is activated from one factor to another until a fibrin clot is formed.
Unfractionated heparin introduced into the coagulation system is activated by antithrombin. This activation causes a structural change that inhibits the coagulant enzymes, factors IX, X, XI, XII, and thrombin [ILLUSTRATION FOR FIGURE 1 OMITTED]. Antithrombin is the primary coagulation inhibitor as it acts with heparin to prevent the formation of thrombin.(4) In total, unfractionated heparin works through three mechanisms that can interfere with the coagulation system: (1) binding to antithrombin, (2) binding to antithrombin and thrombin, and (3) inhibiting platelets.
One of these mechanisms, binding to antithrombin, may be initiated either by unfractionated heparin or by LMWH, as previously stated. All that is required is the particular pentasaccharide sequence that will bind to antithrombin, causing the inactivation of factor Xa. In contrast, the inactivation of thrombin requires more than just the appropriate pentasaccharide sequence. Heparin must bind both to antithrombin and thrombin. This can only be formed if heparin chains are at least 18 saccharide units in length (see "Comparison of unfractionated heparin versus low molecular weight heparin inhibition of thrombin).(3)
Pros and cons: Unfractionated heparin versus LMWH Several advantages are associated with the use of unfractionated heparin:
* The laboratory-activated partial thromboplastin time (APTT) can be used to monitor the effect of unfractionated heparin. The APTT should be 1.5-2.5 times normal,(5) which should correspond to 0.2-0.4 units of heparin/mL.
* Unfractionated heparin can be neutralized by administering protamine sulfate: 1 mg of protamine sulfate will inactivate about 100 units of heparin.(5)
* Unfractionated heparin is the anticoagulant of choice for therapy for pregnant women because it does not cross the placenta and, therefore, does not affect fetal coagulation.(1)
On the other hand, the negative side effects associated with unfractionated heparin are numerous:
* This type of heparin can bind to plasma proteins and is also inhibited by platelet factor IV, thus neutralizing the anticoagulant effect. This reaction may be responsible for (1) the reduced effectiveness of heparin when used in low concentrations, (2) the difference in response between patients receiving fixed doses, and (3) the laboratory phenomenon called heparin resistance.
* Unfractionated heparin may bind to endothelium, adding to the problem of a short plasma half-life.
* This drug inhibits platelet function and increases vascular permeability, which in turn causes hemorrhagic complications.(1)
* With long-term use, unfractionated heparin can cause osteoporosis.
Some experts find LMWH superior to unfractionated heparin for these reasons:
* Low molecular weight heparin binds specifically to antithrombin and has a reduced interference with platelet function and vascular permeability.
* This type of heparin does not bind to endothelium and is not neutralized by plasma proteins, so the dose is more uniform and dependable from patient to patient. This reduced binding to endothelial cells also gives LMWH a longer plasma half-life than unfractionated heparin.
* It can inactivate platelet-bound factor Xa and resist inhibition by platelet factor IV, which is released during clotting.
* The greatest asset is that LMWH can be administered subcutaneously [TABULAR DATA OMITTED] once or twice daily so that patients are not required to remain in the hospital.(3)
* As an effective thrombosis prophylaxis with orthopedic surgical procedures, LMWH is used to treat thrombosis and the hypercoagulable state.
Among the few negative side effects associated with the use of LMWH: Thrombocytopenia can occur, and incidences of bleeding have been noted. This can be monitored in several ways, however. Many physicians order platelet counts periodically, and others test for occult blood in the stool. As previously mentioned, LMWH has one mechanism of action - binding to antithrombin and inhibiting factor Xa - therefore, the only way to test for LMWH is to use a factor Xa inhibition assay. A recommended therapeutic range is 0.6 - 1.1 anti-Xa units per mL.(6)
Currently, the reversal of the anticoagulant effect of all heparins is only achieved with protamine sulfate (a problem for patients who react adversely to protamine). A milligram of protamine sulfate will inactivate 100 units of heparin.(5) (Protamine is a polypeptide derived from salmon sperm.(2)) The basic molecule of protamine interacts with the acidic heparin to form an acid-base complex. Heparin is taken out of the circulation through this binding to protamine. Studies are now being conducted with the enzyme heparinase 1 (Neutralase, Ibex Technologies, Montreal) to reverse the effects of heparin during cardiac bypass surgery. Heparinase I is a heparin-degrading enzyme that cleaves the heparin molecule, rendering it ineffective.(2)
Effect of LMWH on thrombosis
A recent study compared low-dose unfractionated heparin (5,000 units) with LMWH (enoxaparin, 30 units) in preventing thromboembolism after major trauma, using deep-vein thrombosis as an outcome measure. This study also assessed the safety of beginning prophylaxis with anticoagulants after an injury.(7) According to Geerts et al., venous thromboembolism is a common life-threatening complication of major trauma. Pulmonary embolism was observed in 2-22% of patients with trauma, and fatal pulmonary embolism was the third most common cause of death in patients who survived the first 24 hours.(7)
A total of 344 random patients from a trauma center were evaluated. Of that group, 136 who received low-dose unfractionated heparin and 129 who received the LMWH enoxaparin qualified for analysis. Deep-vein thrombosis was found in 44% of patients receiving unfractionated heparin and in 31% of patients receiving enoxaparin. Proximal-vein thrombosis was found in 15% of the unfractionated heparin group and in 6% of the enoxaparin group. There was a 30% risk reduction in the LMWH group for deep-vein thrombosis and a 58% reduction for proximal-vein thrombosis. Six patients had major bleeding, one in the unfractionated heparin group and five in the enoxaparin group (see "Comparison of the rates of thrombosis after major trauma: Low-dose unfractionated heparin versus enoxaparin"').
Although more major bleeding episodes were noted in the enoxaparin group, these occurrences were found to be insignificant because chances of bleeding are low when therapeutic intervention via either type of heparin is initiated early. Considering the noteworthy reduction in deep-vein thrombosis and proximalvein thrombosis, this study concluded that enoxaparin is more effective than low-dose unfractionated heparin in preventing thrombosis.
In another study, Siragusa and colleagues analyzed reports from random trials of heparin therapy between 1980 and 1994. This meta-analysis evaluated 1,230 patients who were taking either unfractionated heparin or LMWH for recurrent thromboembolism [ILLUSTRATION FOR FIGURE 2 OMITTED]. A 50% risk reduction in favor of LMWH during a 90-day period was noted. Additionally, major bleeding was evaluated in 1,669 patients. Bleeding was defined as major if there was a [greater than or equal to] 2 g/dL decrease in hemoglobin concentration, if the bleeding was retroperitoneal or intracranial, or if the bleeding resulted in the transfusion of [greater than or equal to] 2 units of blood. Any bleeding found to be less than these criteria was defined as minor. A 66% risk reduction in major bleeding with LMWH and a 48% risk reduction in mortality were noted as well. Minor bleeding was slightly increased with LMWH (8.5% incidence) versus unfractionated heparin (7.6% incidence). This 0.9% difference was determined to be insignificant, however.
Although this group was too small to make a definitive judgment, Siragusa et al. concluded that LMWH is at least as safe and effective (if not more so) as unfractionated heparin and that the former drug is more effective in preventing recurrent venous thromboembolism. As more studies are completed, experts predict physicians will prescribe LMWH more often to prevent thrombosis.
Levine et al. performed a study proving the value of using enoxaparin subcutaneously (1 mg of enoxaparin per kg of body weight twice daily) at home for proximal deep-vein thrombosis. Their findings demonstrated a 5.3% recurrence of thromboembolism using enoxaparin versus a 6.7% recurrence with unfractionated heparin. Currently, LMWH is more expensive than unfractionated heparin but can be administered at home, thus permitting early release from the hospital. Unfractionated heparin, on the other hand, must be administered intravenously, thus requiring patients to remain in the hospital. Home treatment costs for LMWH amounts to significant savings versus the hospital costs associated with the administration of unfractionated heparin.
For many, the drug of choice
The key to inhibiting the coagulation process is a specific pentasaccharide sequence that binds to antithrombin. Low molecular weight heparins contain that sequence, so their binding is specific to antithrombin and they are less susceptible to interfering substances such as endothelium, platelets, platelet factor IV, and plasma proteins. With fewer interfering substances, doses of LMWH are more predictable between patients, and still reduce the incidence of thrombosis. Furthermore, LMWH helps to lower overall treatment costs by allowing for outpatient therapy of a variety of clinical conditions.
Popularity of LMWH among physicians is likely to increase as more studies confirm its usefulness. Indeed, this type of heparin is already the drug of choice among many physicians who contend that commercially produced LMWH is both safer and more effective than unfractionated heparin. Although increased use of this drag will not completely eliminate the need for laboratory monitoring, laboratorians may be required to perform additional types of testing.
1. Hirsh J, Levine MN. Blood. JAm Soc Hematol. 1992;79(1):1-17.
2. Kitura M. Heparin neutralization with methylene blue, hexadimethrine, or vancomycin after cardiopulmonary bypass. Anesth Analg. 1996;83(2):223-227.
3. Schafer AI. Low-molecular-weight heparin - An opportunity for home treatment of venous thrombosis. N Engl J Med. 1996;334(11):724-725.
4. Sirridge M, Reaner S. Laboratory Evaluation of Hemostasis and Thrombosis. 3rd ed. Philadelphia, PA: Lea and Fieber; 1983:8.
5. Williams W J, Beutler E, Erslev AJ, et al. Hematology. 3rd ed. New York, NY: McGraw-Hill Book Company; 1983:1479-1580.
6. Triplett DA. Low molecular weight heparins: Pharmacology and clinical applications. Hemoliance Times. 1997;2(3):1-3.
7. Geerts W, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335(10):701-706.
8. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med. 1996;100(3):269-277.
9. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334(11):677-681.
Objectives of this article:
1. Describe the function of low molecular weight heparin (LMWH).
2. Identify therapeutic use of LMWH.
3. Compare the mechanisms of action of unfractionated heparin and LMWH.
4. Describe clinical outcome differences between unfractionated heparin and LMWH.
CE test published through an educational grant from SB SmithKline Beecham Clinical Laboratories.