The prevention and treatment of deep vein thrombosis/pulmonary embolus (DVT/PE) and arterial thrombosis remains a major challenge for physicians, for both hospitalized and home patients. For the past 50 years unfractionated heparin has been the mainstay of antithrombotic therapy. But it has been long recognized that, although unfractionated heparin is very effective, it is not the ideal antithrombotic.

Unfractionated heparin (UH) is a heterogeneous group of glycosaminoglycans ranging in molecular weight from 3000 to 40,000 daltons. The mechanism of action involves heparin's ability to bind to AT III (now just AT) and heparin cofactor II. This heparin AT complex inactivates Factors Xa, IXa, XIa, XIIa. Heparin also binds cofactor II and the combination of the heparin/AT complex and inhibition of cofactor II prevents the cleaving of fibrinogen to fibrin. Factor Xa and thrombin are the most sensitive to heparin's inactivation. In order to bind to both AT and cofactor II, the length of the heparin chain must exceed 18,000 daltons.1

The major side effect of heparin involves the binding to platelet factor 4. This complex is responsible for heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia thrombosis, a severe condition that can result in amputation of an affected limb or patient death. Other problems associated with UH are major hemorrhage and difficulty maintaining a therapeutic aPTT.2

Thanks to Dr. Elaine Hylek and her colleagues, we now have data from the MGH on heparin use. Dr. Hylek and colleagues collected data on 311 patients treated with heparin from July to December 1998. The patients were being treated for venous thromboembolism, a cerebral event, or peripheral arterial thrombosis.

Here are some of the important findings:

· Upon achieving therapeutic dosing (aPTT 55-85), only 29% remained therapeutic on the next two measurements
· 61% of patients received an average of 4 different doses during the first days of therapy
· Only 7% of patients receiving UH for at least 4 days maintained therapeutic aPTT on each of the 4 consecutive days
· 54% of patients treated with heparin had their therapy interrupted, primarily due to either hardware issues or in preparation of an invasive procedure
· Of those transitioned to warfarin therapy, only 20% met national standards for overlap (a minimum of 4-5 days of heparin warfarin overlap with 2 consecutive INR values in range

Side effects were an important issue for our patients as well:

· 4.8% of patients experienced a major bleeding event (defined as fatal intracranial, retroperitoneal or requiring a transfusion of at least 2 units packed red blood cells)
· 2.9% of heparin-treated patients developed HIT Type 23

Based on these findings, the MGH has launched an initiative to improve the anticoagulation process. Over the next weeks you will be seeing more about the recommendations of the multidisciplinary work group. One of the earliest recommendations is the switch to low-molecular-weight-heparin (LMWH) wherever possible. LMWHs are produced by enzymatic depolymerization of UH. The lower chain length, between 4,000 and 6,000 daltons, allows for binding of factor Xa but not cofactor II, which is the factor responsible for most of the bleeding associated with UH.

Here are the advantages of LMWH over unfractionated heparin:

· Easier dosing regimen for both prophylaxis and treatment--simple BID dosing
· Relatively flat dose-response curve-majority of patients in the therapeutic range with weight-based dosing
· Reduced incidence of HIT Type 2--incidence of 0.3% in most studies
· Can be given on an outpatient basis--allows for earlier discharge of patients4

References:

1. Hirsh J, Raschke R, Warkentin TE, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1995; 108 (4 Suppl): 258S-275S.

2. Amiral J. Antigens involved in heparin-induced thrombocytopenia. Semin Hematol 1999; 36 (Suppl 1): 7-11.

3. Hylek EM, Regan S, Henault LE et al. Challenges to the effective use of unfractionated heparin in the hospitalized management of acute thrombosis. Arch Intern Med 2003; 163: 621-627.

4. Turpie AGG. Pharmacology of low-molecular-weight heparins. Am.Heart J. 1998;135: S329-S335.