P&T News: September/October 2004

Heparin-Induced Thrombocytopenia

Sarah J. Johnson, Pharm.D., Donald E. Macfarlane, M.D., Ph.D.
Peer Review Status: Internally Peer Reviewed

Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune-mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin.  This phenomenon was first recognized as the cause of the “white clot” syndrome, where heparin induces massive intra-arterial thrombosis.  Prospective trials have now established that HIT occurs in 0.5 to 5% of patients treated with heparin.¹ The antibodies cause thrombocytopenia, paradoxically accompanied by an intense hypercoagulable state.

HIT must be distinguished from the transient thrombocytopenia that commonly occurs during the first four days of heparin therapy.  This thrombocytopenia is not immune-mediated; the platelet count rarely drops below 100,000/mm3 and it returns to normal despite continued exposure to heparin.²  Patients with non-immune thrombocytopenia are not at risk of thrombosis. 

Pathogenesis
Platelet factor 4 is a polymeric, heparin-binding protein that is secreted from platelets.  Antibodies responsible for HIT bind to the heparin-PF4 complex on the surface of platelets, and activate the platelets via the Fc portion of the immunoglobulin. This activation results in platelet aggregation, and the release of intensely prothrombotic microparticles consisting of inverted plasma membrane vesicles.³

Clinical Features
The most common clinical feature of HIT, occurring in up to 90% of patients, is thrombocytopenia.⁴  In approximately 70% of patients with thrombocytopenia, the platelet count starts to fall between 5 and 10 days after heparin therapy is initiated and thrombocytopenic levels are reached by 7 to 14 days. Thrombocytopenia can also occur within 12 hours after initiation of heparin therapy if there has been previous exposure to heparin within the past 100 days.^4,5  Unlike other drug-induced thrombocytopenia, HIT is not associated with bleeding, rather it is associated with thrombosis.  Approximately 50% of patients have a deep vein thrombosis, pulmonary embolism, or arterial thrombosis at the time of diagnosis, and a further 25% of patients will have a thromboembolic event after the diagnosis is made.^1,6 The development of heparin-dependent antibodies is not only associated with thrombocytopenia and thrombosis: approximately 25% of patients who have circulating HIT antibodies will develop fever, chills, respiratory distress, hypertension, and even cardiac arrest when a heparin bolus is administered.⁴ Erythematous plaques or skin necrosis may occur at the site of subcutaneous heparin injection.⁴ Prospective dataconfirm that the mortality related to HIT is approximately 10 to 25% and a further 10% of surviving patients require limb amputation.⁴

The development of HIT is most commonly associated with therapeutic doses of intravenous heparin; however, subcutaneous heparin, heparin flushes, and heparin-coated catheters may initiate or sustain HIT.^7-9  Low molecular weight heparin (LMWH) exposure occasionally may result in HIT due to a high cross-reactivity with heparin antibodies.¹⁰ “Rapid-onset HIT” occurs in approximately 30% of patients with HIT and is characterized by an abrupt drop in the platelet count upon administration of heparin; these patients have usually received heparin in the previous 100 days.⁴ HIT may also occurafter heparin therapy has been discontinued; this is referred to as “delayed-onset HIT.”  Delayed-onset HIT may be due to the development of antiPF4 antibodies that are not heparin dependent.  It occurs an average of 9 days after heparin therapy is stopped. Delayed onset HIT should be considered before administering heparin to patients with a recent hospitalization who present with a thromboembolism.¹¹ 

HIT should be suspected when there is a decrease in the platelet count by 30 to 50% from baseline or a platelet nadir of 20 to 100,000/mm³ with a clear onset of between 5 and 10 days after initiation of heparin therapy (within 1 day if heparin exposure within 100 days), and/or new spontaneous arterial or venous thrombus, skin necrosis, or post-bolus acute systemic reaction in a patient who has or is receiving heparin.⁴ It is important to note that thrombotic events have been reported in postoperative patients during a fall in the platelet count that does not necessarily fit the traditional definition of thrombocytopenia; for example, the platelet count does not decrease to less than 150,000/mm.^3,12 Cardiac and orthopedic surgery patients are at the highest risk for development of HIT, followed by medical patients, then obstetrical patients.^1,4 Other causes for thrombocytopenia such as sepsis, disseminated intravascular coagulation, drug-induced thrombocytopenia, hemodialysis, organ failure, and bone marrow depression also need to be considered. 

In conjunction with clinical diagnosis, laboratory testing may be used to confirm a diagnosis of HIT.  However, when a diagnosis of HIT is strongly suspected, treatment should not be withheld pending the result.  The serotonin-release assay is a functional assay that is technically difficult to perform.  It has high specificity.  The enzyme-linked immunosorbent assay (ELISA) detects antibodies binding to immobilized PF4-polymer-sulphonate complexes.  It has high sensitivity, but false positives are common, especially in patients after bypass surgery.  These assays are not 100% reliable for the diagnosis of HIT.¹³

Initial Management
Once HIT is suspected, all heparin should be discontinued immediately.  Particular care needs to be taken to ensure patients do not continue to receive heparin inadvertently. Heparin line flushes should be switched to saline, and heparin-coated indwelling catheters should be removed.¹⁴  Platelet transfusions should not be given because spontaneous bleeding is uncommon in HIT and transfusion of platelets could (in theory) increase the risk of thrombosis.  The patient should be evaluated for venous and arterial thrombosis.

Continued Anticoagulation
Following cessation of heparin, platelets will generally normalize within 3 to 7 days; however, simple discontinuation of heparin is associated with a 15% risk of thrombosis within 2 days, 40% within 7 days, and a 50% within 1 month.⁶

The intense prothrombotic tendency associated with HIT continues for a few days after heparin is discontinued.  In addition, presence of a thrombus, and the patient’s original indication for anticoagulation warrant the use of an alternate anticoagulant following heparincessation.  The goal of therapy is to maintain anticoagulation and prevent complications of HIT (e.g., amputation, new thrombotic events, and death). 

Low molecular weight heparin agents such as enoxaparin or dalteparin should not be used for treatment of HIT.  Although it has been established that HIT occurs infrequently as a result of exposure to LMWH in heparin-naïve patients, heparin dependent antibodies have been reported in patients receiving LMWH.¹⁰

Direct thrombin inhibitors, such as argatroban and lepirudin, are considered to be the agents of choice for treatment of HIT.⁴  The direct thrombin inhibitors bind irreversibly to both catalytic and substrate recognition sites on the thrombin enzyme.  Direct thrombin inhibitors exhibit no cross-reactivity with HIT antibodies, and they inhibit clot-bound and soluble thrombin.  Argatroban is primarily eliminated by the liver, so it should be used with caution in patients with hepatic impairment.  Lepirudin is renally eliminated; it is best avoided in patients with renal impairment.  Direct thrombin inhibitors should be continued until the platelet count has recovered to at least 100,000/mm³.  The dose of both argatroban and lepirudin should be adjusted to give an aPTT of 1.5 to 2.5 times the baseline value (not to exceed 100 seconds).^15,16 

Other agents may have potential as treatment for HIT.  Bivalirudin is another direct thrombin inhibitor that is FDA-approved for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angiography, but has not been studied in the treatment of HIT.  Although no longer manufactured in the United States, danaparoid is a heparinoid product that has been used for treatment of HIT.   Danaparoid has a long half-life that may make its use less desirable in patients at a high risk for bleeding or potential surgical patients.  In addition, up to a 50% in vitro cross reactivity between danaparoid and HIT antibodies have been reported; however, in vivo cross reactivity is not commonly observed.^17,18  Fondaparinux is an antithrombin-dependent pentasaccharide that is currently FDA-approved for antithrombotic prophylaxis after orthopedic surgery.  Fondaparinux may be useful for the treatment of HIT due to its apparent lack of effect on platelets and platelet factor 4,^19,20 although no clinical trial data have been published. Ximelagatran (Exantra®) is an investigational oral direct thrombin inhibitor that appears to exhibit a predictable dose response and low inter-individual variability.  Ximelagatran may have an advantage for prophylaxis and treatment of venous thromboembolism over other oral anticoagulant agents if monitoring of PT or aPTT is shown to be unnecessary; however, FDA approval has been delayed until concerns about liver toxicity have been addressed.^21,22 

Warfarin should not be used in the acute stage of HIT because it has a slow onset of action and because it increases the risk of distal limb gangrene. It is recommended that warfarin be initiated after platelets have substantially recovered (platelet count of at least 150,000/mm³), when there is absence of a new thrombosis, and once the patient has received a direct thrombin inhibitor for several days.  Argatroban (to a greater extent than lepirudin) prolongs the PT (increasing the INR).  Warfarin therapy should be initiated at a dose expected to be sufficient; do not use a loading dose.  When the INR exceeds 4.0 (when using argatroban) or 2.0 (when using lepirudin) the direct thrombin inhibitor can be discontinued for a few hours.^15,23  Obtain an INR within 4 to 6 hours after discontinuation to determine if the INR is therapeutic.¹⁵

• Limiting courses of heparin to less than 5 days, if possible.
• Using LMWH in place of heparin in at-risk patients (e.g., orthopaedic surgery patients).
• In general, monitoring the platelet count at least every other day between day 4 and 14 of heparin exposure or until heparin is discontinued.  For patients who are starting heparin who have received heparin within the past 100 days, a baseline platelet count and a platelet count within 24 hours of starting heparin should be obtained.¹
• Taking care not to automatically initiate heparin if a patient is re-admitted for a thrombotic event; the medical record must be thoroughly reviewed for use of heparin on a previous admission (within the past 100 days).   Unfortunately, in some cases, the previous heparin exposure may not be recorded in the medical record (e.g., heparin flushes).
• Orders for use of heparin flushes and heparinized normal saline must be written and signed by a physician and use of heparin flushes and heparinized normal saline must be documented in the patient’s medical record.

If HIT is suspected

• Stop all heparin including intravenous, subcutaneous, flushes, and heparin coated catheters.
• Start another anticoagulant agent such as a direct thrombin inhibitor.
• Get an ELISA assay.
• Get imaging studies for thrombosis.

• Physician orders for any administration of heparin are required; this includes all therapeutic heparin, heparin flushes, and heparinized normal saline.
• Use of all forms of heparin must be documented on the Medication Administration Record (MAR). 
• Heparin products, including flushes, must be reviewed by Pharmacy.

Questions regarding the diagnosis or management of HIT may be referred to Dr. Macfarlane or the Hematology/Oncology consult service.

1. Chest. 2004; 126(Supplement 3):311S-337S.
2. Br J Haematol. 1996; 89:431-9.
3. Annu Rev Med. 1999; 50:129-47.
4. Br J Haematol.  2003;121:535-55.
5. N Engl J Med. 2001; 344:1286-92.
6. Am J Med. 1996; 101:502-7.
7. Arch Intern Med. 1989; 149:2285-7.
8. J Intern Med. 1999; 246:325-9.
9. Support Care Cancer. 1999; 7:425-7.
10. N Engl J Med. 1995; 332:1330-5.
11. Ann Intern Med.  2002; 136:210-5.
12. Arch Intern Med. 2003;163:2518-24.
13. Ann Pharmacother. 2002; 36:489-503.
14. Drug Safety. 1997; 17:325-41.
15. Product Information: Argatroban. GlaxoSmithKline Beecham, Research Triangle Park, NC 2003.
16. Product Information: Refludan® (lepirudin). Hoechst Marion Roussel. Kansas City, MO. 1998
17. Transfusion. 1994;34:381-5.
18. Thromb Haemost. 1998; 80:530.
19. Blood Coag Fibrinolysis. 1997;8:114-7.
20. N Eng J Med.  2001;344:619-25.
21. Am Heart J. 2003;145:418-23.
22. J Int Med. 2003;254:322-34.
23. Ann Pharmacother 2001;35:440-51.
    

PHARMACY  AND  THERAPEUTICS  SUBCOMMITTEE  ACTIONS

DRUGS ADDED TO STOCK

ACETYLCYSTEINE

Injection: 6 gram

Acetylcysteine injection (Acetadote® - Cumberland) is indicated to prevent or lessen hepatic injury due to ingestion of a potentially hepatatoxic quantity of acetaminophen.

Note:  Prescribing is restricted to use for acetaminophen overdose in patients unable to take oral acetylcysteine.

AZACITIDINE

Injection: 100 mg

Azacitidine injection (Vidaza® - Pharmion) is an antineoplastic agent indicated for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia.

BALSAM PERU/CASTOR OIL/TRYPSIN

Topical Ointment: 60 gram

This product (Xenaderm® - Healthpoint) is indicated to promote healing of decubitus ulcers, varicose ulcers, and dehiscent wounds.

BUPRENORPHINE

Injection: 0.3 mg/ml

Buprenorphine injection (Buprenex®-Reckitt-Benckiser) is a partial opioid agonist indicated for the relief of moderate to severe pain.

Note:  The prescribing of buprenorphine is restricted to the OR and the Pain Clinic.

ERTAPENEM

Injection: 1 gram

Ertapenem injection (Invaz® - Merck) is a carbopenem antibiotic indicated for the treatment of complicated intrabdominal infections, acute pelvic infections, complicated skin/skin structure infections, community acquired pneumonia, and pyelonephritis caused by susceptible organisms.  Unlike imipenem and meropenem, ertapenem has little or no activity against Pseudomonas and should not be used to treat nosocomial infections.

INFLUENZA VIRUS VACCINE, LIVE

Intranasal: 0.5 ml

Intranasal influenza vaccine (FluMist® - MedImmune) is indicated for the prevention of influenza A and B viruses in healthy children and adults ages

5 - 49 years.

Note: The prescribing and administration of FluMist® is restricted to the Family Care Center Clinics.

LANSOPRAZOLE

Injection: 30 mg

Lansoprazole injection (Prevacid® - TAP) is indicated for the short-term treatment of erosive esophagitis in patients who are unable to take oral formulations.

Note: Lansoprazole injection has been designated a protocol drug.  The prescribing of lansoprazole injection is restricted to: erosive esophagitis and the medication cannot be administered orally, nasogastrically, or enterally; clinical signs of upper gastrointestinal bleeding prior to planned endoscopy and medication cannot be administered orally, nasogastrically, or enterally; confirmed active or recent upper gastrointestinal bleed at high risk for rebleeding and the medication cannot be administered orally, nasogastrically, or enterally; and Zollinger-Ellison Syndrome andmedication cannot be administered orally, nasogastrically, or enterally.

LEVONORGESTREL WITH ETHINYL ESTRADIOL

Tablets: 0.15 mg/0.03 mg

This extended-cycle oral contraceptive (Seasonale® - Barr/Duramed) is indicated for the prevention of pregnancy.

MEMANTINE

Tablets: 5 mg, 10 mg

Memantine (Namenda® - Forest) is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

Note: Prescribing is restricted to Geriatrics, Neurology, and Psychiatry.

NICARDIPINE

Injection: 2.5 mg/ml

Nicardipine injection (Cardene IV® - ESP Pharma) is an antihypertensive agent.

Note: Restricted to Interventional Radiology.

TELITHROMYCIN

Tablets: 400 mg

Telithromycin (Ketek® - Aventis) is a ketolide antimicrobial agent indicated for the treatment of acute exacerbations of chronic bronchitis, acute bacterial sinusitis, and community acquired pneumonia caused by susceptible organisms.

ADDITIONAL ACTIONS

NITROFURANTOIN (Macrobid®)

A 100 mg capsule which is dosed twice daily was added to stock.

TRIMETHOBENZAMIDE

A 300 mg capsule was added to stock.

DELETED FROM STOCK

IMIPENEM-CILASTATIN (Primaxin®) INJECTION

Replaced with meropenem injection.

INAMRINONE INJECTION

Discontinued due to low use.

PANTOPRAZOLE INJECTION

Replaced with lansoprazole injection.

ROFECOXIB (Vioxx®)

Withdrawn from the market by the manufacturer for safety reasons.

TRIMETHOBENZAMIDE 250 mg CAPSULES

Discontinued by all manufacturers; a 300 mg strength is available.

Reporting Adverse Drug Reactions to the FDA and Maintaining HIPAA Compliance

The Pharmacy and Therapeutics Subcommittee is required by the JCAHO to review suspected adverse drug reactions experienced by UIHC patients.  Adverse drug reactions identified by the Pharmacy and Therapeutics Subcommittee as unusual or serious are recommended for reporting to the Food and Drug Administration’s voluntary adverse drug reaction program. The adverse drug reaction data provided to the FDA are potentially useful for changing package insert information, including contraindications, warnings, precautions, and stated adverse effects.

However, some healthcare practitioners have voiced concern that because of regulations associated with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule such reports can no longer be submitted to the FDA.  This is not the case, and organizations such as the UIHC can continue to submit adverse event reports under the HIPAA regulations. The HIPAA Privacy Rule is not intended to disrupt or discourage adverse event reporting in any way. In fact, the Privacy Rule specifically permits covered entities (such as pharmacists, physicians or hospitals) to report adverse events and other information related to the quality, effectiveness and safety of FDA-regulated products both to the manufacturers and directly to FDA:

“The HIPAA Privacy Rule recognizes the legitimate need for public health authorities and others responsible for ensuring public health and safety to have access to protected health information to carry out their public health mission. The Rule also recognizes that public health reports made by covered entities are an important means of identifying threats to the health and safety of the public at large, as well as individuals. Accordingly, the Rule permits covered entities to disclose protected health information without authorization for specified public health purposes.” ¹ 

In order to keep effective drugs and devices available on the market for use by our patients, FDA relies on the voluntary reporting of serious adverse events or product problems suspected to be associated with a drugs or medical devices. FDA uses these data to maintain the safety surveillance of all FDA-regulated products.  A report from our facility may be the critical action that prompts a modification in use or design of the product, improves the understanding of the safety profile of the drug or device, and leads to increased patient safety.

The Privacy Rule requires that reporters make a reasonable effort to submit the minimum protected health information necessary to achieve the purpose of the report.  Adverse drug reaction reports sent to the FDA via the UIHC’s Adverse Drug Reaction Reporting Program are only identified by institution; these reports remain anonymous with respect to specific patients or particular physicians associated with a patient's care.

¹OCR Guidance Explaining Significant Aspects of the Privacy Rule - DISCLOSURES FOR PUBLIC HEALTH ACTIVITIES, page 28. See also 45 CFR 164.512(b)(1)(i) and (iii)

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