Pharmacy & Therapeutics - November 2008 - (Page 650)

Heparin-Induced Thrombocytopenia Fondaparinux (Arixtra) Fondaparinux is a synthetic pentasaccharide that selectively inhibits only factor Xa via highly selective binding (at least 94%) to antithrombin III (ATIII), which subsequently potentiates innate neutralization of factor Xa by ATIII. Fondaparinux does not affect thrombin or platelet activation. It is approved for a broad range of indications: treating and preventing venous thromboembolism (VTE), including VTE prophylaxis after major orthopedic surgery, hip fracture surgery, or abdominal surgery, but is not approved for patients with HIT.36 Although published experience with fondaparinux in HIT is limited, several theoretical advantages make it an attractive alternative for HIT. Fondaparinux does not bind to PF4, in large part because of its structure. Fondaparinux shares a similar structure (namely the same pentasaccharide sequence found on UFH and LMWH), but it contains fewer negatively charged groups and domains necessary for complexation with PF4. These factors contribute to the apparent lack of crossreactivity that is observed with HIT antibodies and result in fewer cases of HIT, compared with UFH and LMWH. In trials of more than 7,500 patients treated with fondaparinux, there have been no case reports of HIT.37 Fondaparinux also has a rapid onset of action, reaching steady state in approximately three hours. It is easy to administer (by subcutaneous injection rather than by continuous infusion), and it can be given once daily. It has a long half-life (17 to 21 hours) and exhibits 100% bioavailability. Routine monitoring is not required. As a result of the comparative insensitivity of routine coagulation tests such as prothrombin time (PT) and aPTT, fondaparinux is best monitored by measuring anti-factor Xa activity and may be especially useful in those patients with deep-vein thrombosis (DVT), pulmonary embolism (PE), or renal insufficiency. This presents challenges for some institutions, because only fondaparinux can be used in the appropriate calibration of the anti-factor Xa assay and the assay might not be readily available. If coagulation parameters change significantly or if major bleeding occurs, fondaparinux should be discontinued. This drug undergoes renal elimination, and patients with renal impairment have reduced prolonged total clearance. For the same reason, fondaparinux is contraindicated in patients with severe renal impairment (CrCl below 30 mL/minute). Elderly patients (those older than 75 years of age) and those weighing less than 50 kg also experience reduced clearance and should be monitored more closely. Adding to the danger of hemorrhage in the setting of excessive dosing or prolonged clearance is the lack of an antidote to reverse anticoagulant effects. In trials, major bleeding occurred in 1.2% to 2.7% of participants, a favorable comparison to the direct thrombin inhibitors. 37 Although fondaparinux increases serum transaminase levels in 0.7% to 2.6% of patients, dosing adjustments are not recommended in patients with hepatic insufficiency because of a lack of available data.36 substantially (usually to 150 × 109/L).13 Paradoxically, if warfarin is not used appropriately, it can predispose patients with acute HIT to microvascular thrombosis such as venous limb gangrene and skin necrosis. Affected patients typically have supratherapeutic INRs (above 4.0) that correspond to severe protein C depletion.38 If warfarin has already been started before a HIT diagnosis, reversal with vitamin K should be implemented to reduce the risk of warfarin necrosis and to reduce the possibility of underdosing of the direct thrombin inhibitor because of warfarin’s ability to prolong aPTT when it is used in monitoring these agents. When platelet counts recover and warfarin can be reinstated, a minimum five-day overlap with alternative anticoagulation is required and initiated with low maintenance doses at a maximum of 5 mg. Alternative anticoagulation must be given in combination until platelet counts stabilize and the INR is within the therapeutic range for at least two days. CONCLUSION Heparin is one of the most widely used and valuable anticoagulants for the treatment and prophylaxis of thrombotic complications. However, its ability to induce severe immunologic reactions upon exposure at any dose (with var ying degrees of risk), and its prothrombotic complications present challenges for patients and clinicians. HIT is more common than most perceive it to be and the diagnosis, therefore, can be easily missed. The diagnosis is made primarily upon clinical presentation, which can vary; HIT can occur early or late, and platelet counts can be within the reference range even after a fall of more than 50%. In patients with multiple medical conditions, the diagnosis can be confounded by medications or disease that can also cause similar manifestations. HIT should be considered in any patient with recent exposure to any type of heparin (UFH or LMWH) and with significant reductions in platelet counts or thrombosis. Without appropriate treatment, 10% to 20% of patients face losing a limb, and 20% to 30% die as a result of the devastating thrombotic complications.8,39 Other complications include DVT, PE, myocardial infarction, cerebrovascular accidents, skin necrosis, and end-organ damage. In light of the rising use of heparin, its complications and potential atypical presentation require a great deal of vigilance; health care providers should learn to expect the unexpected. REFERENCES 1. Warkentin TE. Drug-induced immune-mediated thrombocytopenia: From purpura to thrombosis. N Engl J Med 2007;356(9): 891–893. 2. Bick RL. Heparin and low molecular weight heparins. In: Bick RL, ed. Disorders of Thrombosis and Hemostasis, 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006:359–378. 3. Levy JH, Hursting MJ. Heparin-induced thrombocytopenia, a prothrombotic disease. Hematol Oncol Clin North Am 2007;21(1): 65–88. 4. Newman PM, Chong BH. Heparin-induced thrombocytopenia: New evidence for the dynamic binding of purified anti–PF4heparin antibodies to platelets and the resultant platelet activation. Blood 2000;96(1):182–187. 5. Jang IK, Hursting MJ. When heparins promote thrombosis: Warfarin (Coumadin) Oral anticoagulation with warfarin (Coumadin, BristolMyers Squibb) is not recommended in the acute phase of HIT and should be postponed until platelet counts have recovered 650 P&T® • November 2008 • Vol. 33 No. 11

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - November 2008

Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.