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Heparin-Induced Thrombocytopenia in Hemodialysis Patients.

Q: We have a PD patient who, in spite of changes in prescription, is not dialyzing adequately. When asked about the possibility of switching her to hemodialysis, our physician said she had a history of heparin-induced thrombocytopenia (HIT). Exactly what is HIT and can it be treated?

A: HIT is an underdiagnosed complication associated with heparin administration. Often it goes undetected or is mistaken for a hypersensitivity reaction related to another treatment variable.

What is HIT?

HIT, also known as "white clot syndrome," is divided into Type I and Type II designations. Type I HIT, the milder version of the disease process, is characterized by a decrease in platelet count shortly after heparin administration. Usually the platelet count does not go below 100,000 [mm.sup.3]. Type I HIT is not associated with thrombosis. The platelet count typically returns to the normal range once the heparin administration is stopped, as long as no other apparent cause of platelet depletion is identified.

In Type I HIT, the administration of unfractionated (standard) heparin results in platelet activation. The type of heparin used does have an effect on the degree of platelet activation. Beef heparin causes more platelet activation than pork heparin. Low molecular weight heparin (LMWH) induces less platelet activation than pork heparin. Type I HIT is thought to be common, occurring in 20% of patients treated with heparin.

Type II HIT, the more serious of the two, appears to be immune-mediated. The decrease in platelet count (thrombocytopenia) occurs later in Type II HIT than in Type I. This decrease may not be present until 6-12 days after the initial heparin administration. Previous exposure to heparin may shorten the time for platelet count decrease to occur. The platelet count will decrease below 50,000/[mm.sup.3].

In Type II HIT, platelet aggregation is enhanced. This leads to arterial and venous thrombi formation (white clot syndrome). HIT patients are at high risk for thromboembolic vascular occlusions, most often affecting the large veins of the extremities and pulmonary arteries, the vessels of the kidneys, mesenteries, skin, and those suppling the brain. Type II HIT has a very high morbidity of 22%-88% and a mortality of 12%-30%. Fortunately, the incidence of Type II HIT is very low. It is estimated that Type II HIT with thrombolytic complications occurs in only 1% of patients treated with unfractionated heparin.

The Therapeutic Role of Heparin

Heparin's role in hemodialysis is to prevent clotting of the hemodialyzer and the extracorporeal circuit. Factor III binds with heparin and then inhibits thrombosis by inactivating Factors II, IX, XI, and XII. Once active thromboses have developed, larger amounts of heparin can inhibit further formation of stable fibrin clot by inhibiting the activation of Factor XIII (fibrin stabilizing factor or FSF). Heparin does not have fibrinolytic activity, that is, it will not lyse existing clots. The effect of heparin is immediate, with systemic anticoagulation occurring within the first 3-5 minutes after IV bolus administration. The half-life of heparin is 30-120 minutes. The effects of heparin can be reversed with the proper administration of protamine sulfate. Heparin is a mucopolysaccharide with a very high sulfuric acid content (up to 40%) that is found in the mast cells of connective tissue around blood vessels as well as in the liver and lungs. Only trace amounts of heparin are found in human plasma and urine. The exact role of endogenous heparin is uncertain, but it may have a role in lipid metabolism. The heparin used for hemodialysis is exogenous heparin that is extracted from hog intestinal mucosa (porcine or pork heparin) or from cow lung tissue (bovine or beef heparin).

Allergic reactions such as urticaria, nasal congestion, wheezing, and anaphylaxis can also be associated with the use of heparin. This allergic response may be confused with a dialyzer membrane reaction. To rule out heparin as the cause, a heparin free dialysis treatment may be tried. The diagnosis of HIT is made when repeated drops in platelet counts after heparin is administered are observed combined with the presence of heparin antibodies.

Treatment of HIT

Heparin administration need not be stopped when the platelet count is maintained above 100,000/[mm.sup.3]. However, patients should be carefully evaluated and the heparin stopped if the platelet count drops below 50,000/[mm.sup.3]. If continued anticoagulation is required, alternative therapies are available such as low molecular weight heparin (LMWH), enoxaparin sodium/Lovenox[R], or the heparinoid, danaparoid sodium/Orgaran[R].

This brings us to the second part of your question. In 1997, Dialysis Clinic Inc., in Monroeville, PA, used Orgaran for a patient with HIT. Organon, Inc. provided the drug free of charge for compassionate use (Akzo Nobel Organon Inc., West Orange, NJ, U.S.A. After FDA approval of Orgaran, we were able to work with the patient's primary care physician and his HMO style heath insurance to get approval and coverage for the Orgaran and anti-factor Xa levels required for chronic dialysis. The patient changed modalities from chronic hemodialysis to home PD, but required incenter hemodialysis as the modality changed and successful PD catheter placement occurred.

Orgaran can be used for acute or chronic hemodialysis. The medication is currently FDA approved for prophylaxis of postoperative deep venous thrombosis (DVT) in patients undergoing elective hip surgery. It is not approved for use with hemodialysis but can be used under the supervision of the nephrologist for hemodialysis. Orgaran is very expensive at $97.00 per 0.6 ml ampules containing 750 anti-factor Xa units. A hemodialysis protocol developed in the Netherlands by Chong and Magnani (1992) is presented in Table 1.

Table 1 Hemodialysis Protocol Using Orgaran
Patient's     1st        2nd        3rd      Subsequent
Weight      Dialysis   Dialysis   Dialysis    Dialysis

> 55 kg      3750 U     3750 U     3000 U      3000 U
< 55 kg      2500 U     2500 U     2000 U      2000 U


For hemodialysis every other day or less frequently

Orgaran dose in U given IV bolus prior to the start of the dialysis

Note: From Chong, B.H., & Magnani, H.N. (1992). Orgaran in heparin-induced thrombocytopenia. Haemostasis, 22, 85-91. Used with permission

Plasma anti-Xa levels should be monitored during the use of Orgaran. This test may not be performed by all labs, but may be available at labs with a blood bank or those currently testing anti-Xa levels for other low molecular weight heparins. The plasma anti-Xa level should be drawn prior to the dose administration for the second dialysis treatment and then pretreatment for each subsequent dialysis treatment.

The dose of Orgaran is adjusted for the third hemodialysis treatment and subsequent treatments (see Table 2). Peak plasma levels occur 2 to 5 hours after the IV bolus is administered. The terminal half-life is approximately 24 hours.

Table 2 Orgaran Adjustments Based on Plasma Anti-Xa Level
Patient's    Anti-Xa
Weight        level      Anti-Xa level   Anti-Xa level

Levels      < 0.3 u/ml   0.3-0.35 u/ml   0.35-0.40 u/ml

> 55 kg     3000 U       2500 U          2000 U

< 55 kg     2000 U       1500 U          1500 U

Patient's
Weight           Anti-Xa level

Levels      > 0.40 u/ml

> 55 kg     HOLD
            (if fibrin formation in
            drip chambers give
            1500 U bolus)

< 55 kg     HOLD
            (if fibrin formation in
            drip chambers give
            1500 U bolus)


Note: From Chong, B.H., & Magnani, H.N. (1992). Orgaran in heparin-induced thrombocytopenia. Haemostasis, 22, 85-91. Used with permission.

The Clinical Consult department is designed to provide answers to questions concerning clinical problems and to report innovative clinical practices. Readers are invited to submit questions to be answered by a guest consultant. Questions should provide background information and state specific information requested. Answers will be referenced. Manuscripts that address clinical problems or present innovative ideas are also invited. These should be between 400 and 600 words and contain one to three references. Address correspondence to: Lesley C. Dinwiddie, Clinical Consult Department Editor, through the ANNA National Office; East Holly Avenue/Box 56; Pitman NJ 08071-0056; (856) 256-2320. The opinions and assertions contained herein are the private views of the contributors and do not necessarily reflect the views of the American Nephrology Nurses' Association.

Reference

Chong, B.H., & Magnani, H.N. 1992). Orgaran in heparin-induced thrombocytopenia. Haemostasis, 22, 85-91.

Additional Resources

Magnani, H.N. (1993). Heparin-induced thrombocytopenia (H IT): An overview of 230 patients treated with Orgaran (Org 10172). Thrombosis and Haemostasis, 70(4), 554-561.

Meuleman, D.G. (1992). Orgaran (Org 10172): Its pharmacological profile in experimental models. Haemostasis, 22, 58-65.

Proceedings of a Workshop. (1997). Heparin-induced thrombocytopenia: An under-diagnosed syndrome? Platelets, 8, 65-82.

Web site: www.thrombosite.com

Deborah J. Brouwer, RN, CNN, is a clinical support specialist, In-Line Diagnostics, Farmington, UT

Patt Peterson, RN, CNN, is manager of professional services, Medisystems Services Corp., Seattle, WA.
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Author:Brouwer, Deborah J.; Peterson, Patt
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Apr 1, 2000
Words:1449
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