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Treatment of HIT

Created: 22/2/2007
Updated: 19/11/2012
 

When the diagnosis of HIT is suspected, heparin should be discontinued immediately. This includes heparin found in pressure-monitoring lines and intravenous flush solutions. There is an extremely high risk of thrombosis, and most patients will develop an associated new or progressive thrombotic event. Immediate substitution with a safe and effective alternative non-heparin anticoagulant at full dosage is recommended. A retrospective cohort study suggested that, in patients with serologically confirmed HIT with isolated thrombocytopaenia alone, managed by either discontinuation of heparin or initiation or continuation of vitamin K antagonist (VKA) therapy, the 30-day thrombotic event rate was approximately 50%.

Alternative anticoagulants to heparin

Danaparoid Sodium

Danaparoid Sodium (Orgaran), a mixture of heparin sulphate (83%), dermatan sulphate (12%) and chondroitin sulphate (5%), is renally metabolised and thus requires modest dose reduction in patients with renal impairment. It has a long half-life, making it ideal for treating venous thromboembolism complicating HIT. Danaparoid Sodium  exerts its major anticoagulant effect by catalysing the inactivation of factor Xa by antithrombin. It also has some anti-thrombin (IIa) effect but the ratio of the anti-Xa to anti-IIa effect is greater than 28:1. Danaparoid Sodium is a non-heparin of proven efficacy in thrombotic disorders and is approved and available for use in the UK for the treatment of HIT complicated by thromboembolism. Danaparoid Sodium  has been recommended as a heparin substitution therapy under the guidelines established by the American College of Chest Physicians (ACCP) for the management of HIT (Recommendation Grade 1B).2

Danaparoid Sodium's anticoagulant activity is dependent on the presence of antithrombin and is mainly related to its ability to inhibit Factor Xa. Monitoring for danaparoid activity is based on anti-Xa activity with specific calibration. The bioavailability following a subcutaneous injection is 100%.

Managing HIT with Danaparoid Sodium 

Once switched from heparin to Danaparoid Sodium, a patient's platelet count may rise rapidly; however, a risk of thrombotic complications remain for approximately 5-6 weeks due to the presence of HIT antibodies, so prolonged parenteral anticoagulation may be required. Danaparoid Sodium  is an anticoagulant, similar in structure to heparin. Danaparoid Sodium  can be used as a substitute to heparin in patients with a previous history of HIT who require treatment for thrombotic disorders.

Danaparoid Sodium should be administered intravenously for the treatment of HIT. Once in use, only individuals over the weight of 90 kg need routine monitoring (amidolytic assay is recommended). Danaparoid Sodium is recommended by the ACCP (grade 1B) as an alternative antithrombotic in isolated HIT.

Undesirable effects: enhanced bleeding or haematoma may occur at the operation site.
Bruising and/or pain may occur at injection sites. Skin rashes and other local or generalised hypersensitivity reactions have occasionally been observed. Antibody induced thrombocytopenia, as can be caused by (low molecular weight) heparin, was observed in rare cases during the use of Danaparoid Sodium, but only in patients who were already sensitised to either heparin or low molecular weight heparin. Liver abnormalities such as changes in transaminase and alkaline phosphatase have been observed, but no clinical significance has been demonstrated.


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Lepirudin

Lepirudin (Refludan) was the first direct thrombin inhibitor (DTI) to be approved by the Food and Drug Administration (in 1998) for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications. Lepirudin is a recombinant hirudin used to treat thrombosis complicating HIT. It forms an irreversible 1:1 complex with thrombin and has a half-life of about 80 minutes, which increases significantly in renal impairment. The dosages are adjusted to achieve a target APTT ratio of 1.5-2.5 times the baseline.

The advantage of Lepirudin lies in the absence of its cross-reactivity with HIT antibodies. But, being a foreign protein derived from leeches, lepirudin frequently causes antihirudin antibodies that lead to drug accumulation in some patients, probably due to impaired renal clearance of anticoagulant-active Lepirudin-IgG complexes. There have been reports of intracranial bleeding with Lepirudin in the absence of concomitant thrombolytic therapy. Serious anaphylactic reactions that have resulted in shock or death have been reported during initial administration or upon second or subsequent re-exposure.

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Argatroban (now licenced in the UK)

This direct thrombin inhibitor is a small molecule of about 527 Da in size. It has a short half-life of about 45 minutes. Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the cofactor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or thrombin-induced reactions, including fibrin formation and activation of coagulation factors V, VIII, and XIII (Figure 1). Argatroban also inhibits the effect of thrombin on protein C activation and platelet aggregation. It undergoes hepatobiliary excretion.

As with all anticoagulants, bleeding is a serious concern. Argatroban is contraindicated in patients with overt major bleeding or those with hypersensitivity to the product or any of its components. Argatroban should be used with extreme caution in disease states or other circumstances in which there is an increased risk of hemorrhage. Overall major bleeding was reported in 5.3% of Argatroban-treated patients with HIT versus 6.7% of the historical controls. Overall major bleeding was reported in 1.8% of Argatroban-treated patients undergoing PCI versus 3.1% of the historical controls. Intracranial bleeding was not observed in the 568 patients treated with Argatroban for HIT (with or without thrombosis) or in the 91 patients who underwent PCI. The most common nonhemorrhagic side effects in HIT patients, regardless of the relationship to treatment, were dyspnea, hypotension, and fever. In patients undergoing PCI, the nonhemorrhagic side effects, regardless of the relationship to treatment, included chest pain, hypotension, and back pain. 

Figure 1 'Classic' Model of Clotting Cascade

References

[1] Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-507

[2] Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311-337

[3] Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94: 132-135

[4] Lubenow N, Warkentin TE, Greinacher A, Wessel A, Sloane DA, Krahn EL, Magnani HN. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod, and/or coumarin explain the rapid shift in clinical practice during the 1990s. Thromb Res 2006; 117: 507-515

[5] Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85: 950-957




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