The Heparin Paradox

By Catherine Spader, RN
February 28, 2005

A patient with acute coronary syndrome is admitted to your care with a continuous IV heparin infusion. You’re vigilant about monitoring him for bleeding complications secondary to heparin therapy. On the fifth day after admission, however, you note a sudden drop in his platelet count. Despite this, he begins to complain of calf pain and inflammation. He is eventually diagnosed with a deep vein thrombosis (DVT) secondary to heparin-induced thrombocytopenia (HIT). How could this happen?

“When nurses see a drop in platelets, the first thing they normally look for is bleeding complications,” says Corinne M. Miller, RN, BSN, CCU clinical RN IV, at Duke University Health System, Durham, N.C. “However, HIT is not a bleeding disorder; it is a clotting disorder, and it is frequently missed and untreated.”

HIT is a rare but potentially life-threatening reaction to heparin therapy. Thrombocytopenia is often associated with hemorrhagic conditions. In contrast, the hallmark of HIT is thrombocytopenia possibly coupled with arterial or venous thrombosis.

Benign vs. catastrophic

“The first indication of HIT is usually a drop in the platelet count,” says Miller. But recognition of HIT can be complicated by the fact that heparin can cause a benign thrombocytopenia in many patients.

HIT type I is a nonimmune response to heparin. Its onset is rapid, within hours or up to three days after the initiation of heparin therapy. A mild to moderate thrombocytopenia with a platelet drop of less than 50% from baseline can occur in up to 30% of patients exposed to heparin.¹ Platelet counts often return to normal even with continuation of heparin therapy. Patients are usually asymptomatic, and they do not develop thromboses. No treatment is usually required other than observation and continued monitoring.

On the other hand, HIT type II is an immune-mediated reaction to heparin exposure and represents a true emergency. In predisposed patients, exposure to heparin, even in the small doses used to flush or coat catheters, triggers a complex immune response. This response creates antibodies that intensify platelet clearance, resulting in thrombocytopenia.

Paradoxically, this immune-mediated response stimulates platelet activation and aggregation, possibly triggering a significant life- or limb-threatening venous and/or arterial thromboembolis caused by vessel obstruction when platelet clumps form.

Twelve million patients are exposed annually to heparin in the U.S.² Up to 5% of these patients remain at risk for developing HIT type II.¹ Although this severe reaction to heparin therapy is relatively uncommon, thrombolytic complications are catastrophic and can include DVT, arterial occlusion, ischemic stroke, limb gangrene, acute myocardial infarction, and pulmonary embolism. These sequelae carry a 30% risk of mortality and another 20% risk of limb amputation.³ Consequently, nurses caring for patients receiving heparin therapy need to be as observant in assessing and monitoring for thromboses as they are for bleeding complications.

A high index of suspicion

Nurses should immediately suspect HIT type II if they see clinical or diagnostic evidence of a new thrombosis during exposure to or following heparin therapy, a greater than or equal to 50% decrease in the platelet count from baseline, and/or a decrease in the platelet count to less than 150,000 per microliter.* Nurses should be alert for signs and symptoms such as chest pain, dyspnea, cold or cyanotic limbs, calf pain or inflammation, abdominal pain, or a change in neuro status. Any of these symptoms may indicate thrombus formation that is compromising circulation.

The onset of HIT type II usually occurs four to 14 days following administration of heparin. However, HIT type II can occur sooner if the patient has had a heparin exposure within the last 100 days. A delayed-onset reaction is also possible, occurring nine to 40 days following the discontinuation of all forms of heparin.

All patients receiving heparin therapy need close observation for a possible HIT reaction. Platelet counts should be monitored at least every other day. However, extra surveillance, including daily platelet monitoring, is required when caring for high-risk patients.

High-risk patients include those who have undergone percutaneous coronary intervention, angioplasty, and/or coronary artery bypass grafting. Patients who receive repeated low-level heparin exposure, such as those who undergo dialysis and those who receive heparin flushes of central lines and peripherally inserted central catheters (PICCs), are included among the increased risk groups.

Other high-risk patients include those receiving bovine heparin, patients with disseminated intravascular coagulation, and those who have an acute systemic reaction immediately after beginning heparin therapy. HIT type II can also occur in patients receiving the commonly used anticoagulant enoxaparin sodium injection (Lovenox). In addition, patients with a documented history of HIT type II should be treated with an alternative to heparin.

Patients receiving subcutaneous injections of heparin also need careful monitoring. They can develop localized reactions at injection sites that lead to skin necrosis.

“If these patients do develop HIT, they are much more likely to have thrombolic complications,” says Miller. “You have to remain vigilant to pick up on these necrotic areas. It can be a marker that HIT is coming down the pipeline.”

Go with your clinical gut

Once suspected, HIT type II can be confirmed with laboratory studies, including the functional assays, such as the heparin-induced platelet aggregation test (HIPA) and the serotonin release assay (SRA). Other forms of testing include the antibody assays, such as the enzyme-linked immunosorbent assay (ELISA). However, neither type of assay is 100% reliable, and both types of tests should be performed.

Occasionally, a patient with HIT may test negative for both tests but develop recurrent thrombocytopenia and thromboembolism when reexposed to heparin. This clinical picture is considered positive evidence of HIT type II. In short, do not wait for, or rely on, laboratory results before acting on suspicion of HIT type II.

As soon as HIT type II is suspected, it is essential to discontinue all forms of heparin therapy, including routine flushes, subcutaneous injections, as well as heparin-coated catheters, such as pulmonary-artery catheters. Platelet counts usually start to rise toward normal within a couple of days of discontinuing heparin.

The clot does not stop here

“Even with the discontinuation of heparin, the process of thrombosis formation continues,” says Miller. The return of the platelet count to normal or baseline may be delayed for weeks in some patients. Without immediate alternative anticoagulation therapy, there remains a high risk of developing thromboembolic disease in the period following cessation of heparin.

Drugs used as alternatives to heparin include lepirudin (Refludan) and Argatroban (see table, next page). Both drugs are direct thrombin inhibitors and reduce the risk of serious complications of HIT type II.

Warfarin (Coumadin) is contraindicated for initial treatment in these patients due to its association with further complications, including tissue ischemia, necrosis, and gangrene. However, once platelet levels return to normal and treatment is started with a direct thrombin inhibitor, warfarin may be an option for long-term anticoagulation.

“For nurses, it’s counterintuitive and unnerving to treat low platelet counts with anticoagulants,” says Miller, “but with HIT, you have to change your mindset.”

With the paradoxical nature of HIT type II, nurses must embrace that change in mindset and monitor heparin-exposed patients for both bleeding and clotting complications. Do not let a clot slip through the cracks because HIT and its potentially lethal consequences are the last things you might expect.

*Normal ranges for platelet counts may vary between individual laboratories.

Catherine Spader, RN, is a freelance writer.

References

1. Heparin-induced thrombocytopenia. Berlex Laboratories/Refludan wesite. Available at: www.refludan.com/hit/index.htm. Accessed January 17, 2005.

2. Rationale for the development of Argatroban. Glaxosmithkline/Argatroban website. Available at: www.argatroban.com/clinic_08.htm. Accessed January 18, 2005.

3. Heparin-Induced Thrombocytopenia. Clinicians Publishing Group and Gale Group on Findarticles website. Available at: www.findarticles.com/p/ articles/mi_m0BUY/ is_2_11/ai_71710879. Accessed January 13, 2005.

Bibliography

Brandt, J. Diagnosing heparin-induced thrombocytopenia. College of American Pathologists website. Available at www.cap.org/apps/docs/cap_today/case_study/coag6.html. Asscessed January 11, 2005.

The FDA Medical Products Reporting Program. FDA website. Available at www.fda.gov/medwatch/safety/1998/jun98.htm. Accessed January 18, 2005.

Heparin-induced thrombocytopenia.Warfarin Institute of America website. Available at: http://warfarinfo.com/hit.htm. Accessed January 4, 2005.

Updated prescribing information for Lovenox. FDA website. Available at http://www.fda.gov/medwatch/SAFETY/2004/Lovenox_HCP.pdf. Accessed January 18, 2005.