Spotlight Case December 2006

Hidden Heparins: HIT Happens

2

Source and Credits• This presentation is based on the December 2006

AHRQ WebM&M Spotlight Case• See the full article at http://webmm.ahrq.gov • CME credit is available through the Web site

– Commentary by: Patrick F. Fogarty, MD, University of California, San Francisco

– Editor, AHRQ WebM&M: Robert Wachter, MD– Spotlight Editor: Tracy Minichiello, MD– Managing Editor: Erin Hartman, MS

3

Objectives

At the conclusion of this educational activity, participants should be able to:

• Review presentation of heparin-induced thrombocytopenia (HIT)

• Discuss management of HIT• Identify safeguards to avoid future exposure

to heparin in individuals with HIT

4

Case: Hidden HeparinsA patient with a history of end-stage renal disease requiring hemodialysis was admitted for evaluation of non-healing ulcers and leukocytosis. She had been admitted one month prior for evaluation of peripheral artery disease. During that hospitalization, the patient underwent angioplasty of the right femoral artery, complicated by post-operative gangrene of the right foot requiring above-the-knee amputation.

5

Case: Hidden Heparins

She also developed axillary vein thrombosis, and ultimately a diagnosis of heparin-induced thrombocytopenia (HIT) was made. She was treated with argatroban, and it was noted on the chart that the patient should receive no further heparin.

6

Heparin-Induced Thrombocytopenia

• HIT occurs when heparin molecules stimulate formation of a pathogenic IgG antibody or “HIT antibody” which results in: – platelet activation thrombosis– platelet clearance thrombocytopenia

• More frequent with unfractionated heparin than low molecular weight heparin

7

HIT: 4 T’s Diagnosis

• Thrombocytopenia: platelet count drops to <150 x 109/L or by ≥ 50% below baseline

• Timing: within 5-10 days of heparin exposure • Thrombosis: up to half of patients will develop

venous or arterial thrombosis• oTher: no other etiology for thrombocytopenia

Warkentin TE, Kelton JG. N Eng J Med. 2001;344:1286-1292.Warkentin TE, Kelton JG. Am J Med. 1996;101:502-507.

8

HIT: Diagnosis

• Laboratory diagnosis can confirm disease• However, due to slow turnaround time, may

not be helpful in initial diagnosis– HIT antibody ELISA– Serotonin-release assay

9

HIT: Treatment

• Discontinue of all forms of heparin• Initiate an alternative anticoagulant—direct

thrombin inhibitor (DTI)• Continue DTI until platelet count recovery has

occurred and adequate anticoagulation with a coumarin derivative has been achieved

10

Direct Thrombin InhibitorsAGENT DESCRIPTION INDICATION DOSING COMMENT

Argatroban Synthetic direct thrombin inhibitor

Prophylaxis or treatment of HIT, including post-percutaneous coronary intervention

Obtain baseline PTT. Start continuous infusion at 2 µ/kg/min. Titrate to achieve PTT of 1.5 to 3 times the baseline value. Do not allow PTT to exceed 100 seconds, nor the infusion rate to exceed 10 µg/kg/min.

• Patients with hepatic insufficiency: initial infusion rate =0.5 µg/kg/min.• Increases the INR in warfarin-treated patients; interpret INR accordingly

Lepirudin (Refludan)

Recombinant hirudin; direct thrombin inhibitor

Treatment of HIT with associated thrombosis

Obtain baseline PTT. Give slow bolus of 0.4 mg/kg then continuous infusion of 0.15 mg/kg/hr. Titrate to achieve PTT of 1.5 – 2.5 times baseline value. PTTs should be obtained 4 hours after starting the infusion and at least daily during treatment

• Patients with renal insufficiency: initial bolus =0.2mg/kg• Half of patients develop anti-drug antibodies that increase half-life; may necessitate a decrease in dose

Bivalirudin (Angiomax)

Semi-synthetic derivative of hirudin; direct thrombin inhibitor

Unstable angina in patients undergoing percutaneous transluminal coronary angioplasty

1.0 mg/kg IV bolus followed by 2.5 mg/kg/hr infusion for 4 hours; may continue infusion at 0.2 mg/kg/hr for up to 20 hours

• FDA-approved for concomitant use with aspirin• Not approved for use in patients with HIT

11

HIT: Duration of Treatment

• HIT associated with thrombosis—minimum of 3-6 months

• HIT without thrombosis—risk of thrombosis persists for at least 30 days, with up to 50% of patients developing venous or arterial events; continue warfarin for 4 weeks

Warkentin TE, Kelton JG. Am J Med. 1996;101:502-507.Fogarty PF, Dunbar CE. Lippincott, Williams and Wilkins; 2005:256-257.

Alving BM. Blood. 2003;101:31-37. Epub 2002 Aug 15.

12

Case (cont.): Hidden Heparins

On this admission, the patient was found to be tachycardic and hypotensive, with excoriations of the skin over the breast, abdomen, right thigh, and gluteal region. Her labs were significant for leukocytosis of 17.1 x 109/L and hypoalbuminemia of 2.4 gm/dl. The patient was started on antibiotics (amikacin and vancomycin). Blood cultures eventually grew candida, and amphotericin was added to her regimen.

13

Case (cont.): Hidden HeparinsShe appeared to be improving with a decrease in WBC to 10 x 109/L. Over the next few days, however, she developed ischemia in her right hand, which eventually became cold and pulseless. It was also noted at this time that her platelet count had dropped since admission. On hospital day 8 the leukocyte count increased again, her respiratory status worsened, and she died, presumably from overwhelming sepsis.

14

Analysis of the Case

• Patient may have had complications of ongoing HIT when she was admitted – Tachycardia and hypotension: PE– Excoriations on skin: heparin-related skin reaction

vs. warfarin induced skin necrosis– Leukocytosis: due to inflammation from infarction

Warkentin TE. Marcel Dekker; 2004:53-106. Balestra B, et al. Eur J Haematol. 1994;53:61-63.Hartman AR, et al. J Vasc Surg. 1988;7:781-784.

15

Heparin Related Skin Reaction in HIT

• Skin reaction– 10%-20% of patients with HIT will develop skin

lesions at injection site– Painful erythematous plaques that may become

necrotic

Picture reprinted with permission from International Journal of Dermatology. 2005;44:964-966.

16

Case (cont.): Hidden Heparins

Autopsy revealed thrombi in the vessels of skin of breast and abdomen. A thorough review of the chart and hemodialysis records revealed that during this second hospitalization the patient had been repeatedly exposed to heparin during dialysis sessions, despite her recent history of HIT and the chart notes to avoid heparin.

17

Re-exposure to Heparin in Patients with HIT

• When measured by ELISA, the median duration of HIT antibody positivity is 85 days

• If antibodies present at time of re-challenge with heparin, patient can develop rapid-onset HIT with thrombocytopenia and thrombosis as soon as 24 hours after exposure

Warkentin TE, Kelton JG. N Eng J Med. 2001;344:1286-1292.Warkentin TE. Marcel Dekker; 2004:53-106.

Boshkov LK, et al. Br J Haematol. 1993;84:322-328.

18

Re-exposure to Heparin in Patients with HIT

• Not generally recommended but may be considered in certain compelling clinical situations (in need of bypass, vascular surgery) with plan for brief exposure

• Delay until at least 100 days after diagnosis of HIT (to allow antibodies to disappear)

• Document clearance of HIT antibody before re-exposing to heparin

Warkentin TE, Kelton JG. N Eng J Med. 2001;344:1286-1292.Warkentin TE. Marcel Dekker; 2004:53-106.

Boshkov LK, et al. Br J Haematol. 1993;84:322-328.

19

HIT Associated with HeparinExposure from Flushes

• Small quantities of heparin (IV flush) can lead to HIT antibody formation or HIT itself

• Minor exposure via this route in patient with persistently circulating HIT antibodies can promote re-emergence or worsening of thrombocytopenia or thrombosis

• In most institutions, heparin for flushes does not require an order and is available on the floor

See Notes for complete references.

20

Prevention of Re-exposure to Heparin in Patients with HIT

• Add heparin to patient’s allergy list and update hospital electronic profile to provide alerts

• Place “Heparin-Induced Thrombocytopenia: No Heparin” placard above patient’s bed

• Use electronic alerts if heparin ordered in heparin allergic patient

21

Example of Electronic Alert

Example of electronic alert upon attempting to order Heparin in a patient with Heparin allergy: WORx Software.

22

• Consider switch to use of normal saline for flushing IV catheters to prevent inadvertent exposure from heparin not ordered through pharmacy– Meta-analysis shows no benefit of UFH vs. NS for

patency of peripheral or central catheters

• Heparin still used routinely for flushing dialysis circuit– HIT patients at risk not clearly labeled with heparin

allergy

Warkentin TE, et al. Blood. 1998;92(suppl 1):91b. Randolph AG, et al. BMJ. 1998;316:969-975.

Prevention of Re-exposure to Heparin in Patients with HIT

23

Take-Home Points

• HIT can occur in any patient after exposure to any amount of any type of heparin

• Clinical presentation of HIT can include isolated thrombocytopenia, isolated arterial or venous thrombosis or both

• Skin lesions in a thrombocytopenic patient exposed to heparin should raise suspicion for HIT

24

Take-Home Points

• All patients with a prior history of HIT should have the medical and pharmacy record permanently amended to indicate the diagnosis

• Identify in-hospital use of heparin that circumvents a provider’s order

• Consider institutional policies that can lower the risk of heparin exposure by patients who have HIT