Bleeding associated with low molecular weight heparin (LMWH) may be difficult to treat. Protamine sulfate neutralizes about 60% of the anti-factor Xa activity of LMWH, possibly due to reduced protamine binding. The effectiveness of protamine therapy in reversing the antithrombotic effect of LMWH is unclear but may be attempted if there is no alternative.


LMWH after subcutaneous injection:

(1) show a peak anti-Xa activity at 4 hours (3 to 5)

(2) show an elimination half-life of 3 to 6 hours.


Thus at 8 hours after administration about half of the activity should be present (4 hours to peak, then one half-life).


If protamine sulfate is given to neutralize the LMWH the pararmeters to consider are:

(1) number of hours since LMWH given

(2) number of units of anti-Xa activity given (1 mg enoxaparin = 100 units anti-Xa activity, 1 mg dalteparin is 156 units of anti-Xa activity).

Time Since LMWH Admnistration

Dose of Protamine Sulfate

<= 8 hours, first dose protamine

1 mg per 100 units anti-Xa activity

<= 8 hours, second dose protamine for continued bleeding

0.5 mg per 100 units of anti-Xa activity

> 8 hours

“smaller dose”


Synthetic protamine variants may be more effective but have not been approved for clinical use.


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