A case of no response to heparin

A 64 year old gentleman recently present with a large infrarenal AAA.  He was posted to have an endovascular surgical repair.  He was taken to the OR, GETA was induced, an arterial line was placed and then a 16 G PIV was placed in the external jugular vein on the right since no well suited veins were identified elsewhere.  The EJ was verified to be flowing nicely and so it was connected to a fluid warmer and utilized as the primary IV access site.  A few minutes prior to deploying the endovascular graft, the vascular surgeon requested that 100 units / kg of heparin be given.  Aproximately an hour later, the surgeon noticed some clot in the field and asked for an ACT.  The ACT came back at 116 seconds.  The surgeon requested that this be repeated, and the second one (on a different machine at the request of the surgeon) was 134s.  At this time additional heparin was given (5000 units) per request of the surgeon. A stat aPTT was drawn which came back normal.  A hematologist was called to get further insight as to the potential for heparin resistance.  He suggested more heparin be given. 30 minutes later an ACT was rechecked with little change.  Another dose of heparin was given and a dose of rocuronium was given (50 mg) which had no effect.  At this point, I became suspicious of the integrity of the well flowing EJ 16g IV.  A bair hugger was placed over the patient's head at the beginning of the case obscuring the face and neck.  This was removed and it was discovered that the patient had obvious swelling at the IV site.  It was immediately clear that at some point during the case, the EJ had ceased to deliver fluid intravascularly, but into the soft tissues.  This was not apparent initially due to three main reasons: 1)  The fluid continued to flow with no apparent change in resistance from initiation to discovery of infiltration, 2) The patient had a pre existing large neck and large face obscuring subtle amounts of IV fluid, and 3) The face was covered during the case with a warmer so as not to be viewable unless the bair hugger was physical moved away to reveal the face.

Of course, if the strong suspicion for an IV infiltrate had been in place rather than blaming heparin resistance or ACT analysis error, then the issue would have been resolved much more quickly.
Heparin is the most commonly used anticoagulant during operative procedures due to its cost, rapid onset, safety, and short half life as well as its reversibility.  The heparin molecule is a negatively charged sulphated glycosaminoglycan  with alternating uronic and glucoronic acid residues. The chains are extremely variable in size ranging from 3,000 to 30,000 D. It's mode of action is important in understanding its limitations and potential problems that may occur with its use.  Heparin can only function after it binds to a protein that circulates naturally in the blood stream by the name of antithrombin.  Once heparin binds to free circulating antithrombin, this complex is capable of it inhibiting thrombin as well as activated factor X.  Thrombin is the main coagulant protein in the coagulation cascade.   Heparin can bind to other plasma proteins in the circulation as well decreasing its efficacy.

Heparin resistance is defined in terms of the context: A) in treatment of VTE, if more than 35,000 u / 24 hour period is required to prolong the aPTT to the therapeutic range, or B) in cardiac bypass surgery, if after heparinization, there is at least one ACT less than 400 s or if exogenous antithrombin is required.

Heparin has a few important limitations.  First, it has no inhibiting effect on FXa which is already bound to platelets in prothrombinase present at the site of a clot.  Furthermore, thrombin bound to fibrin is also excluded from the effects of the heparin-AT complex.  From a pharmakokinetic standpoint, heparin is limited in cases where large amounts of acute phase reactants are circulating in acutely ill patients as they bind heparin making it unavailable to bind to AT. This is also a problem in patients with malignancy and post partum.

AT (formerly AT III) is a glycoprotein that functions normally as a natural anticoagulant, providing inhibition of coagulation enzymes in a slow progressive manner. In the presence of heparin, AT undergoes a conformational change that results in a 1000 fold increase in inhibitory activity.  AT has anti-inflammatory functions as well related to its effects on on the coagulation cascade.  For example, by inhibiting thrombin and other procoagulant mediators, secondary inhibition of IL-6, IL-8, E-selectin and other pro inflammatory mediators from monocytes are blocked, resulting in protection of the endothelial lining.  AT deficiency is a rare (0.16%) but serious medical condition.  These patients can see an relative risk for VTE of 7 to 8 compared to the normal population underscoring the importance of adequate AT levels.

In general, studies have sited heparin resistance to occur due to a multitude of factors in 22% of patients undergoing major surgery. AT deficiency only accounts for one possible cause among many including increased clearance of heparin from the plasma, elevations of various heparin binding proteins (as mentioned above), elevations in FVIII and fibrinogen levels.  Medications such as aprotinin and nitroglycerin have also been sited as causal of heparin resistance.  In patients previously exposed to heparin or requiring an IABP,  resistance may arise.  In the surgical population it is likely that when resistance to heparin occurs, it is due to decreased AT activity.  Lemmer JH et al.[2]  found 85% of patients to have low AT activity, while another group noted the rate to be 77% [3] of those who were heparin resistant.  Both of these authors reported that  AT concentrate was able to prolong the ACT to the target range in patients found to have below normal AT activity who did not initially achieve the target ACT.

While heparin resistance is real, the question as to how to deal with this is somewhat less straightforward.  Levine et al. looked at 131 patients with so called heparin resistance and found that although the aPTT seemed to indicate resistance to heparin, following anti-Xa heparin activity resulted in far less heparin requirements [1].  The conclusion from this study was that the heparin assay should be used in patients where suspicion for heparin resistance exists. Unfortunately, this has little benefit in the acute surgical setting where resistance is detected for the first time intraoperatively therapeutic anti coagulation is required urgently.

If you are dealing with a situation in which you suspect AT levels to be below normal, then FFP is a therapeutic option as it contains AT.  While FFP is available in almost all blood banks and relatively inexpensive ($70 to $110 / unit), it does carry the risk of transmission of viral infections.  Furthermore, FFP requires time to thaw which may not be a good option in the acute surgical setting where the patient is actively clotting. In the US, AT concentrate is available which although more expensive (around $840), doesn't require thawing and has no risk of viral transmission.  When treating with AT concentrate the goal of therapy is to raise AT activity to 120% of normal baseline levels.  This can often be achieved with 1 vial of 500 IU of thrombate (AT concentrate) reconstituted in 10 mL of sterile water which is approximate to 2 units of FFP.

In conclusion. this case highlights the need to look at all aspects of potential causes when a response to a medication is not achieved.  This includes verification that the delivered medication was delivered intravenously as expected.  Other sources of error must also be determined; but in the case of heparin, it should be noted that heparin resistance is not uncommon, and in those patients who do legitimately have heparin resistance, a majority will have reduced AT activity which is easily treated with AT concentrate, or if not available, FFP.

The above patient did get another IV dose of heparin (5000 units) via another PIV, a recheck of the ACT showed a robust response ruling out the possibility of heparin resistance.  Due to the swelling around the neck combined with the length of the case 8+ hours) I decided to leave the patient intubated post op.  On POD 1, I visited the patient who had been transferrred to the regular floor.  He was in good spirits with little residual swelling in the SQ tissues.


1.   Levine MN, Hirsh J, Gent M. A randomised trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994;154: 49–56
2. Lemmer JH and Despotis GJ.  J Thorac Cardiovasc Surg 2002;123:213-217


3.  Williams MR, D'Ambra AB, Beck JR, et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg.2000;70:873-7.