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Heparin and Low Molecular Weight Heparin

Both heparin and LMWH are classified as indirect thrombin inhibitors because they inhibit the function of thrombin in the coagulation cascade by binding to antithrombin (AT). Unfractionated heparin (UFH) is a heterogeneous mixture of sulfated glycosaminoglycans, of varying molecular weights between 5000 and 30,000 daltons. Heparin complexes with AT, Factor Xa and factor IIa (thrombin) in 1:1 ratio. LMWH is a more homogenous mixture of molecules, with a molecular weight between 4000 and 5000 daltons that preferentially binds to factor Xa in approximately a 3:1 ratio.

Unfractionated heparin works by binding to antithrombin, causing a conformational change that accelerates antithrombin’s inactivation of IIa (thrombin), Xa and IXa. Factor IIa activates the conversion of XI to XIa, VIII to VIIIa, V to Va, and fibrinogen to fibrin. Altogether, UFH decreases the function of factors XIa, IXa, VIIIa in the intrinsic pathway and factors IIa, Va, Xa in the common pathway.

Because heparin decreases the common pathway, it can mildly prolong the INR. The endpoint of a prothrombin time is the conversion of soluble fibrinogen to insoluble fibrin. Fibrin formation can occur when only 5 to 10 nM of thrombin has been produced. This is <5% of the total amount produced in vivo. When a patient is on UFH, factor VIIa initiates a fibrin clot in vitro. Today, many protime assays contain polybrene to neutralize heparin, so that INR is not affected by therapeutic doses of UFH.

Patients receiving full dose intravenous UFH require anticoagulation monitoring. Patients receiving prophylactic doses of UFH and the majority of patients receiving LMWH usually do not require monitoring. Patients with renal dysfunction (CrCl<30 mL/min), due to reduced clearance, and obese patients >150 kg, due to poor absorption, may require monitoring.

Patients receiving intravenous doses of UFH have historically been monitored with the activated partial thromboplastin time (aPTT). PTT is not an ideal test to monitor heparin. Prolongation of aPTT does not necessarily mean that a patient is anticoagulated. Some patients may have a prolonged aPTT at baseline which puts them at risk for under dosing heparin. Increased levels of fibrinogen and factor VIII, which are acute phase reactants, lead to much patient to patient variation in the responsiveness of the aPTT to heparin.

In the past few years, laboratories have replaced the aPTT with anti-Xa levels. Anti-Xa assays tend to have less variation in the presence of acute phase reactants such as fibrinogen and factor VIII compared to the aPTT test. Studies have also shown that patients monitored with anti-Xa assay can achieve therapeutic levels more quickly and require fewer monitoring tests compared to patients monitored with aPTT. The aPTT should not be used to monitor LMWH therapy because it is insensitive. Anti-Xa assays are used to monitor anticoagulation effects of LMWH in special populations.

Patients receiving high dose heparin for catheterization procedures are monitored with an activated clotting time (ACT). ACT tests are used for situations in which the target level of anticoagulation is >200 seconds, above which the aPTT is no longer a reliable measure.

Patients receiving treatment doses of heparin should be monitored 6 hrs after the initiation of treatment and after any dosage change. Once two consecutive heparin levels are within target range, testing can be done once daily. Patients monitored with ACT typically have levels drawn at the physician’s discretion during the procedure in order to stay within a predetermined target range. Patients treated with LMWH should have anti-Xa levels drawn 4 hours post dose.

Target levels must be established by each laboratory. Target anti-Xa level for treating venous thrombosis with with intravenous UFH is 0.3-0.7 u/ml. Anti-Xa target levels for treating arterial thrombosis with UFH is 0.14-0.34 u/ml respectfully. Target levels for LMWH are contingent upon the brand, frequency of administration, and treatment versus prophylactic strategy. The anti-Xa target is 0.6-1 u/ml for treatment of thrombosis with with enoxaparin using twice daily dosing and 1-2 u/ml for once daily dosing. Prophylactic anti-Xa target levels for enoxaparin generally range from 0.2-0.4 u/ml.

If a patient is receiving therapeutic heparin requires an invasive procedure, heparin should be withheld for 2 to 4 hours before the procedure. The half life of UFH is 60 to 90 minutes. Patients who develop significant bleeding complications while receiving UFH therapy should be treated with Protamine, which is a cationic polypeptide. Heparin can be neutralized by administering 1 mg of protamine for every 100 units of UFH. Plasma transfusion has no role in the management of heparin induced bleeding.

If a patient receiving LMWH requires a surgical procedure, an anti-Xa level should be performed to measure LMWH and determine the amount of time that LMWH should be withheld before surgery. The half-lives of LMWH vary by brand, so the length of time required for LMWH clearance will also vary. The half life of is 3-6 hours for enoxaparin and 2.4-4 hours for dalteparin in patients with normal renal function. If bleeding occurs, LMWH can be partially neutralized with protamine. The package insert indicates that 66% inhibition is achievable. Plasma transfusion is not effective in treating the bleeding associated with LMWH.


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